Hospitals Bristol NHS Foundation Trust Research Articles

Association between 6-thioguanine nucleotide levels and preventing production of antibodies to infliximab in patients with inflammatory bowel disease

ObjectiveCombination therapy with infliximab and a thiopurine has been shown to be more effective than monotherapy in patients with inflammatory bowel disease (IBD). The therapeutic efficacy of thiopurines is correlated...

Linked Cardiology records of the children in the Avon Longitudinal Study of Parents and Children (ALSPAC) From The University Hospitals Bristol and Weston NHS Foundation Trust (UHBW) Heart-Suite (HS) dataset

This data note describes the linked records of the index children of the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort study found within the cardiology records of the University Hospitals Bristol and Weston NHS Foundation Trust (UHBW) Heart-Suite (HS) dataset. It is important to note that ALSPAC only provided details of participants alive after one year of age, and who had allowed their data to be used for linking, which may have excluded a non-trivial, unknown, quantity from linking to the Bristol tertiary cardiac clinic database. These records were extracted from the computerised record system ‘Heart-Suite’ which is maintained by the Bristol Heart Institute (BHI) in UHBW based at Bristol Royal Infirmary (BRI). The Heart-Suite database is the case management system used by the BHI. A data extract was provided by the BHI data team to ALSPAC. The cleaned Heart-Suite records provide a dataset of specialist, clinical records of a subset of the ALSPAC cohort who were referred to the tertiary cardiac team at UHBW. These data can be linked to the wider ALSPAC dataset and made available to approved research users.

The Bristol Self Harm Register (BSHR) dataset: Linked self-harm register records of the children in the Avon Longitudinal Study of Parents and Children (ALSPAC)

This data note describes the linking of records of the Bristol Self Harm Register with the cohort of the index children of the Avon Longitudinal Study of Parents and Children (ALSPAC – also known as ‘Children of the 90s’). These records were obtained from the computerised data base maintained by the Bristol Self Harm Register (BSHR). The BSHR is operated out of the two largest NHS trusts in the ALSPAC study catchment area, North Bristol NHS Trust (NBT) based at Southmead Hospital (SMH) in Bristol and the University Hospitals Bristol and Weston NHS Foundation Trust (UHBWT) based at Bristol Royal Infirmary (BRI), also in Bristol. The BSHR database was designed to be populated by staff after an encounter with a patient attending with an indication of self-harm. Some of the information in the BSHR database was self-reported by the patient and was unable to be independently verified. Software syntax was written using STATA (StataCorp LLC, version 17) to convert the original files into a single consistent format in a data base which was reviewed for its potential use in future research. The cleaned BSHR records provide a contemporaneous record of a subset of the ALSPAC cohort over a period of the ALSPAC study in an easily accessible format, which is valuable when other sources of data may be missing.

Avon Community-Acquired Pneumonia (AvonCAP) Surveillance Study: A Pan-pandemic Acute Lower Respiratory Tract Disease Surveillance Study, and the linked records of the participants in the Avon Longitudinal Study of Parents and Children (ALSPAC)

This data note describes the linking of records of the Avon Community-Acquired Pneumonia (AvonCAP) Surveillance Study – A Pan-pandemic Acute Lower Respiratory Tract Disease Surveillance Study (ISRCTN: 17354061), with the participants of the Avon Longitudinal Study of Parents and Children (ALSPAC – also known as ‘Children of the 90s’). These records were obtained from a database created specifically by AvonCAP operating within the two acute care NHS Trusts in Bristol, which is the centre of the ALSPAC study catchment area. These two trusts are the (a) North Bristol NHS Trust (NBT) based at Southmead Hospital (SMH) and (b) the University Hospitals Bristol and Weston NHS Foundation Trust (UHBWT) based at Bristol Royal Infirmary (BRI). The AvonCAP database was updated by staff using a combination of clinical records and self-reporting by the participant, which was unable to be independently verified. Data was collected using the REDCap (Research Electronic Data Capture) software program. Software code was created to transform the original files into a single data base which was reviewed for data-completeness and for its potential value as a research resource. The AvonCAP records provide a contemporaneous record of a subset of the ALSPAC cohort who experienced Lower Respiratory Tract Disease. It is available for research and may be used in conjunction with other ALSPAC data.

The Bristol Self Harm Register (BSHR) dataset: Linked self-harm register records of the children in the Avon Longitudinal Study of Parents and Children (ALSPAC)

This data note describes the linking of records of the Bristol Self Harm Register with the cohort of the index children of the Avon Longitudinal Study of Parents and Children (ALSPAC – also known as ‘Children of the 90s’). These records were obtained from the computerised data base maintained by the Bristol Self Harm Register (BSHR). The BSHR is operated out of the two largest NHS trusts in the ALSPAC study catchment area, North Bristol NHS Trust (NBT) based at Southmead Hospital (SMH) in Bristol and the University Hospitals Bristol and Weston NHS Foundation Trust (UHBWT) based at Bristol Royal Infirmary (BRI), also in Bristol. The BSHR database was designed to be populated by staff after an encounter with a patient attending with an indication of self-harm. Some of the information in the BSHR database was self-reported by the patient and was unable to be independently verified. Software syntax was written using STATA (StataCorp LLC, version 17) to convert the original files into a single consistent format in a data base which was reviewed for its potential use in future research. The cleaned BSHR records provide a contemporaneous record of a subset of the ALSPAC cohort over a period of the ALSPAC study in an easily accessible format, which is valuable when other sources of data may be missing.

How long do revised and multiply revised hip replacements last? A retrospective observational study of the National Joint Registry.

Hip replacements are common and effective operations but patients that undergo this intervention are at risk of the replacements failing, requiring costly and often complex revision surgery with poorer outcomes than primary surgery. There is paucity of reliable data examining the treatment pathway for hip replacements over the life of the patient in terms of risk of revision and re-revisions. We aim to provide detailed information on the longevity of hip revision surgery. We did a retrospective observational registry-based study of the National Joint Registry, using data on hip replacements from all participating hospitals in England and Wales, UK. We included data on all first revisions, with an identifiable primary procedure, with osteoarthritis as the sole indication for the original primary procedure. Kaplan-Meier estimates were used to determine the cumulative probability of revision and subsequent re-revision after primary hip replacement. Analyses were stratified by age and gender, and the influence of time from first to second revision on the risk of further revision was explored. Between April 1, 2003, and Dec 31, 2019, there were 29 010 revision hip replacements with a linked primary episode. Revision rates of revision hip replacements were higher in patients younger than 55 years than in older age groups. After revision of primary total hip replacement, 21·3% (95% CI 18·6-24·4) of first revisions were revised again within 15 years, 22·3% (20·3-24·4) of second revisions were revised again within 7 years, and 22·3% (18·3-27·0) of third revisions were revised again within 3 years. After revision of hip resurfacing, 23·7% (95% CI 19·6-28·5) of these revisions were revised again within 15 years, 21·0% (17·0-25·8) of second revisions were revised again within 7 years, and 19·3% (11·9-30·4) of third revisions were revised again within 3 years. A shorter time between revision episodes was associated with earlier subsequent revision. Younger patients are at an increased risk of multiple revisions. Patients who undergo a revision have a steadily increasing risk of further revision the more procedures they undergo, and each subsequent revision lasts for approximately half the time of the previous one. Although hip replacements are effective for improving pain and function and usually last a remarkably long time, if they are revised, successive revisions are progressively and markedly less successful. NIHR Biomedical Research Centre at the University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Healthcare Quality Improvement Partnership; and the National Joint Registry.

Assessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study.

Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker. We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671-13,879; N controls = 173,493-372,016), FinnGen (N cases = 719-8401; N controls = 74,685-174,006) and several international cancer genetic consortia (N cases = 11,348-122,977; N controls = 15,861-105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach. Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04-1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09-1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97-1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers. GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results. FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic's Operational Programme 'Competitiveness, Entrepreneurship & Innovation' (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer's Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor's Research Fellow at the University of Bristol.

Associations between plasma fatty acid concentrations and schizophrenia: a two-sample Mendelian randomisation study

Although studies suggest that concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence for beneficial effects of fatty acid supplementation is scarce. Therefore, in this study, we aimed to determine whether omega-3 and omega-6 fatty acid concentrations are causally related to schizophrenia. We did a two-sample Mendelian randomisation study, using deidentified summary-level data that were publicly available. Exposure-outcome relationships were evaluated using the inverse variance weighted two-sample Mendelian randomisation method using results from genome-wide association studies (GWASs) of fatty acid concentrations and schizophrenia. GWAS results were available for European (fatty acids) and European and Asian (schizophrenia) ancestry samples. Overall age and gender information were not calculable from the summary-level GWAS results. Weighted median, weighted mode, and Mendelian randomisation Egger regression methods were used as sensitivity analyses. To address underlying mechanisms, further analyses were done using single instruments within the FADS gene cluster and ELOVL2 gene locus. FADS gene cluster and ELOVL2 gene causal effects on schizophrenia were calculated by dividing the single nucleotide polymorphism (SNP)-schizophrenia effect estimate by the SNP-fatty acid effect estimate with standard errors derived using the first term from a delta method expansion for the ratio estimate. Multivariable Mendelian randomisation was used to estimate direct effects of omega-3 fatty acids on schizophrenia, independent of omega-6 fatty acids, lipoproteins (ie, HDL and LDL), and triglycerides. Mendelian randomisation analyses indicated that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with a lower risk of schizophrenia (eg, inverse variance weighted odds ratio [OR] 0·83 [95% CI 0·75-0·92] for docosahexaenoic acid). By contrast, there was weak evidence that short-chain omega-3 and short-chain omega-6 fatty acids were associated with an increased risk of schizophrenia (eg, inverse variance weighted OR 1·07 [95% CI 0·98-1·18] for α-linolenic acid). Effects were consistent across the sensitivity analyses and the FADS single-SNP analyses, suggesting that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with lower risk of schizophrenia (eg, OR 0·74 [95% CI 0·58-0·96] for docosahexaenoic acid) whereas short-chain omega-3 and short-chain omega-6 fatty acid concentrations were associated with an increased risk of schizophrenia (eg, OR 1·08 [95% CI 1·02-1·15] for α-linolenic acid). By contrast, estimates from the ELOVL2 single-SNP analyses were more imprecise and compatible with both risk-increasing and protective effects for each of the fatty acid measures. Multivariable Mendelian randomisation indicated that the protective effect of docosahexaenoic acid on schizophrenia persisted after conditioning on other lipids, although evidence was slightly weaker (multivariable inverse variance weighted OR 0·84 [95% CI 0·71-1·01]). Our results are compatible with the protective effects of long-chain omega-3 and long-chain omega-6 fatty acids on schizophrenia, suggesting that people with schizophrenia might have difficulty converting short-chain polyunsaturated fatty acids to long-chain polyunsaturated fatty acids. Further studies are required to determine whether long-chain polyunsaturated fatty acid supplementation or diet enrichment might help prevent onset of schizophrenia. National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol.

Association of medically assisted reproduction with offspring cord blood DNA methylation across cohorts.

STUDY QUESTIONIs cord blood DNA methylation associated with having been conceived by medically assisted reproduction?SUMMARY ANSWERThis study does not provide strong evidence of an association of conception by medically assisted reproduction with variation in infant blood cell DNA methylation.WHAT IS KNOWN ALREADYMedically assisted reproduction consists of procedures used to help infertile/subfertile couples conceive, including ART. Due to its importance in gene regulation during early development programming, DNA methylation and its perturbations associated with medically assisted reproduction could reveal new insights into the biological effects of assisted reproductive technologies and potential adverse offspring outcomes.STUDY DESIGN, SIZE, DURATIONWe investigated the association of DNA methylation and medically assisted reproduction using a case–control study design (N = 205 medically assisted reproduction cases and N = 2439 naturally conceived controls in discovery cohorts; N = 149 ART cases and N = 58 non-ART controls in replication cohort).PARTICIPANTS/MATERIALS, SETTINGS, METHODSWe assessed the association between medically assisted reproduction and DNA methylation at birth in cord blood (205 medically assisted conceptions and 2439 naturally conceived controls) at >450 000 CpG sites across the genome in two sub-samples of the UK Avon Longitudinal Study of Parents and Children (ALSPAC) and two sub-samples of the Norwegian Mother, Father and Child Cohort Study (MoBa) by meta-analysis. We explored replication of findings in the Australian Clinical review of the Health of adults conceived following Assisted Reproductive Technologies (CHART) study (N = 149 ART conceptions and N = 58 controls).MAIN RESULTS AND THE ROLE OF CHANCEThe ALSPAC and MoBa meta-analysis revealed evidence of association between conception by medically assisted reproduction and DNA methylation (false-discovery-rate-corrected P-value < 0.05) at five CpG sites which are annotated to two genes (percentage difference in methylation per CpG, cg24051276: Beta = 0.23 (95% CI 0.15,0.31); cg00012522: Beta = 0.47 (95% CI 0.31, 0.63); cg17855264: Beta = 0.31 (95% CI 0.20, 0.43); cg17132421: Beta = 0.30 (95% CI 0.18, 0.42); cg18529845: Beta = 0.41 (95% CI 0.25, 0.57)). Methylation at three of these sites has been previously linked to cancer, aging, HIV infection and neurological diseases. None of these associations replicated in the CHART cohort. There was evidence of a functional role of medically assisted reproduction-induced hypermethylation at CpG sites located within regulatory regions as shown by putative transcription factor binding and chromatin remodelling.LIMITATIONS, REASONS FOR CAUTIONSWhile insufficient power is likely, heterogeneity in types of medically assisted reproduction procedures and between populations may also contribute. Larger studies might identify replicable variation in DNA methylation at birth due to medically assisted reproduction.WIDER IMPLICATIONS OF THE FINDINGSNewborns conceived with medically assisted procedures present with divergent DNA methylation in cord blood white cells. If these associations are true and causal, they might have long-term consequences for offspring health.STUDY FUNDING/COMPETING INTERESTS(S)This study has been supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 669545, European Union’s Horizon 2020 research and innovation programme under Grant agreement no. 733206 (LifeCycle) and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Methylation data in the ALSPAC cohort were generated as part of the UK BBSRC funded (BB/I025751/1 and BB/I025263/1) Accessible Resource for Integrated Epigenomic Studies (ARIES, http://www.ariesepigenomics.org.uk). D.C., J.J., C.L.R. D.A.L and H.R.E. work in a Unit that is supported by the University of Bristol and the UK Medical Research Council (Grant nos. MC_UU_00011/1, MC_UU_00011/5 and MC_UU_00011/6). B.N. is supported by an NHMRC (Australia) Investigator Grant (1173314). ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (Contract no. N01-ES-75558), NIH/NINDS (Grant nos. (i) UO1 NS 047537-01 and (ii) UO1 NS 047537-06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (Grant no. 221097). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, Project no. 262700.D.A.L. has received support from national and international government and charity funders, as well as from Roche Diagnostics and Medtronic for research unrelated to this study. The other authors declare no conflicts of interest.TRIAL REGISTRATION NUMBERN/A.

Decade-long trends in surgery for acute Type A aortic dissection in England: A retrospective cohort study.

BackgroundLittle is known about variations in care and outcomes of patients undergoing surgical repair for type A aortic dissection(TAAD). We aim to investigate decade-long trends in TAAD surgical repair in England.MethodsRetrospective review of the National Adult Cardiac Surgery Audit, which prospectively collects demographic and peri‑operative information for all major adult cardiac surgery procedures performed in the UK. We identified patients undergoing surgery for TAAD from January 2009-December 2018, reviewed trends in operative frequency, patient demographics, and mortality.FindingsOver the 10-year period,3,680 TAAD patients underwent surgical repair in England. A doubling in the overall number of operations conducted in England was observed (235 cases in 2009 to 510 in 2018). Number of procedures per hospital per year also doubled(9 in 2009 to 23 in 2018). Overall, in-hospital mortality was 17.4% with a trend toward lower mortality in recent years(23% in 2009 to 14.7% in 2018). There was a significant variation in operative mortality between hospitals and surgeons. We also found that most patients presented towards the middle of the week and during winter.InterpretationSurgery is the only treatment for acute TAAD but is associated with high mortality. Prompt diagnosis and referral to a specialist center is paramount. The number of operations conducted in England has doubled in 10 years and the associated survival has improved. Variations exist in service provision with a trend towards better survival in high volume centers.FundingBritish Heart Foundation and NIHR Biomedical Research center(University Hospitals Bristol and Weston NHS Foundation Trust and University of Bristol).

Surgical reconstruction of the right ventricular outflow tract-The clock is still ticking.

Surgical reconstruction of the right ventricular outflow tract-The clock is still ticking.

What change in BMI is required to improve cardiovascular outcomes in childhood and adolescent obesity lifestyle interventions: a meta-regression

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): This study was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol Background There is minimal evidence regarding the change of body mass index (BMI) needed to improve cardiovascular health in obese children. This paper aims to establish the minimum change in body mass index standard deviation score (BMI-SDS) needed to improve lipid profile and blood pressure (BP) of obese children and adolescents, to aid future trials and guidelines. Methods Studies with participants involved in lifestyle interventions, aged 4–19 years, with a diagnosis of obesity according to defined BMI thresholds, were considered for inclusion in a large systematic review. Interventions had to report pre- and post-intervention (or mean change in) BMI-SDS, plus either systolic blood pressure (SBP), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and/or triglycerides (TG). Random effects meta-regression quantified the relationship between mean change in BMI-SDS and mean change in cardiovascular outcomes. Results Seventy-one papers reported various cardiovascular measurements and mean change in BMI-SDS. Fifty-four, 59, 46, and 54 studies were analysed; reporting change in SBP, HDL, LDL, and TG respectively. Reduction in mean BMI-SDS was significantly related to improvements in SBP, LDL, TG, and HDL (p &amp;lt; 0.05); BMI-SDS reductions of 1, 1.2, and 0.7 ensured a mean reduction of SBP, LDL, and TG respectively although an equivalent value for HDL improvement was indeterminate. Conclusions Reductions in mean BMI-SDS of &amp;gt;1, &amp;gt;1.2, or &amp;gt;0.7 are likely to reduce SBP, LDL, and TG respectively. Further studies are needed to clarify the optimal duration, intensity, and setting for interventions. Consistency is required regarding derived BMI values to facilitate future systematic reviews and meta-analyses.

Daytime and Outcomes After Cardiac Surgery: Systematic Review and Meta-Analysis, Insights From a Large UK Database Review and Post-Hoc Trial Analysis

Background: Several studies have suggested a variation of myocardial tolerance to ischaemia depending on the daytime of surgery. To test this hypothesis, we conducted a three-level analysis: meta-analysis, national patient-level dataset analysis and a post-hoc trial analysis. Methods: We first performed a systematic review and meta-analysis of available studies comparing clinical outcomes following cardiac surgery performed in the morning (am) versus afternoon (pm). Then, we interrogated the UK national adult cardiac surgery audit database (NACSA) and analysed the am or pm outcomes of patients undergoing non-emergency aortic valve replacement (AVR) or coronary artery bypass grafting (CABG). In a post-hoc analysis, we further investigated the effect of time of surgery on serum troponin release and ventricular myocardial biopsy adenine nucleotide metabolism. Results: A total of 18377 patients undergoing uncomplicated isolated CABG or isolated AVR on the same day am or pm were included in the meta-analysis. Meta-analytic estimates showed no difference in the risk of MI between patients operated in pm vs am (OR 1.02, 95% CI:0.79–1.32) and in the risk of mortality (OR 1.1, 95% CI:0.85-1.42). Outcomes of 91248 patients from the NACSA dataset were analysed according to the daytime of the procedure. Patient-level analysis showed no significant effect of daytime for both isolated AVR (p=0.094) and isolated CABG (p=0.425). Finally, we performed a post-hoc trial database analysis in 124 patients undergoing isolated AVR or CABG of serial cardiac troponin and nucleotides metabolism on ventricular myocardial biopsies. We found no significant diurnal changes in the perioperative cardiac troponin release or nucleotide metabolism in the AVR (p=0.30) or the CABG cohort (p=0.97). Conclusion: The present three-level analysis found no evidence that daytime influences clinical outcomes and myocardial injury in patients undergoing cardiac surgery. Funding: This study was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust, and the University of Bristol. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Declaration of Interest: None to declare.

Cerebral visual impairment‐related vision problems in primary school children: a cross‐sectional survey

To estimate how many children in mainstream primary schools have cerebral visual impairment (CVI)-related vision problems and to investigate whether some indicators might be useful as red flags, if they were associated with increased risk for these problems. We conducted a survey of primary school children aged 5 to 11years, using whether they were getting extra educational help and/or teacher- and parent-reported behaviour questionnaires to identify children at risk for CVI. These and a random 5% sample were assessed for CVI-related vision problems. We compared the usefulness of potential red flags using likelihood ratios. We received questionnaires on 2298 mainstream-educated children and examined 248 children (152 [61%] males, 96 females [39%]; mean age 8y 1mo, SD 20mo, range 5y 6mo-11y 8mo). We identified 78 out of 248 children (31.5% of those examined, 3.4% of the total sample), who had at least one CVI-related vision problem. The majority (88%) were identified by one or more red flag but none were strongly predictive. Fewer than one in five children with any CVI-related vision problem had reduced visual acuity. Children with CVI-related vision problems were more prevalent than has been appreciated. Assessment of at-risk children may be useful so that opportunities to improve outcomes for children with CVI-related vision problems are not missed.

Decade-Long Trends in Surgery for Acute Type A Aortic Dissection

Background: Little is known about unwarranted variations in care, with regional differences and outcomes of patients who undergo surgical repair for type A acute aortic dissection (TAAD) in England. We aim to investigate decade-long trends in TAAD surgical repair in England using national-level data. Method: Retrospective review of the National Institute for Cardiovascular Outcomes Research (NICOR) National Adult Cardiac Surgery Audit (NACSA) registry, which prospectively collects demographic, as well as pre-, peri- and post-operative clinical information, including mortality, for all major adult cardiac surgery procedures performed in the UK. We identified patients undergoing surgery for TAAD from January 2009 to December 2018 and reviewed trends in operative frequency and mortality. Findings: Over the 10-year period,3,686 TAAD patients underwent surgical repair in England. A steady doubling in the overall number of operations conducted in England was observed from 237 cases recorded in 2009 to 510 in 2018. Number of procedures per hospital per year also doubled, from 10 in 2009 to 21 in 2018. The risk profile of the operated patients remained unchanged. Overall, in-hospital mortality was 17.4% with a trend toward lower mortality in the most recent years (from 22.8% in 2009 to 14.7% in 2018). There was a significant variation in operative mortality across regions with a trend towards lower mortality in regions with a high-volume hospital. Interpretation: Surgery is the only treatment for acute TAAD but is associated with high mortality. Prompt diagnosis and referral to a specialist center is paramount. The number of operations conducted in England has doubled in 10 years and the associated survival following surgery has improved. Regional variations exist in service provision with a trend towards better survival in high volume centers. Funding Statement: British Heart Foundation and NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and University of Bristol. Declaration of Interests: Authors have no conflict of interests to declare. Ethics Approval Statement: This study is part of research approved by the Health Research Authority (HRA) and Health and Care Research Wales (HCRW) (IRAS ID: 278171).

Trans-Ethnic Mendelian Randomization Study Reveals Causal Relationships Between Cardiometabolic Factors and Chronic Kidney Disease

Background: The chronic kidney disease (CKD) public health burden has not declined as expected with current interventions on treatments focusing only on the disease. This study aims to systematically estimate the causal roles of cardiometabolic risk factors on CKD in Europeans and East Asians using Mendelian randomization (MR). Methods: A total of 45 risk factors with genetic data in Europeans and 17 risk factors in East Asians were identified as exposures from PubMed. A total of 51,672 CKD cases and 958,102 controls in Europeans and 13,093 CKD cases and 238,118 controls of East Asian ancestry were used as outcome for this study. We defined the CKD case by clinical diagnosis or by estimated glomerular filtration rate (eGFR)<60 ml/min/1·73m2. Findings: Eight risk factors showed causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asian ancestry, BMI, T2D and nephrolithiasis showed causal effects. Comprehensive follow-up analyses suggested that: (1) increased hypertension is a risk factor for CKD in Europeans but not in East Asians, suggesting the possibility of ancestry-specific disease aetiology; (2) T2D may have glucose-independent mechanisms to influence CKD; (3) non-linear MR indicated BMI above 25 kg/m2 as a threshold for increasing CKD risk. Conclusion: This study built up a strong causal link between cardiometabolic risk factors and CKD in two ancestries. This evidence could inform the design of future interventions to reduce the burden of CKD and its cardiometabolic co-morbidities. Funding: J.Z. is funded by a Vice-Chancellor Fellowship from the University of Bristol. This research was also funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/1, MC_UU_00011/4 and MC_UU_00011/7). Jie Zheng is supported by the Academy of Medical Sciences (AMS) Springboard Award, the Wellcome Trust, the Government Department of Business, Energy and Industrial Strategy (BEIS), the British Heart Foundation and Diabetes UK (SBF006\1117). JZ is funded by the Vice-Chancellor Fellowship from the University of Bristol. This study was funded/supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol (GDS, TRG and REW). This study received funding from the UK Medical Research Council (MR/R013942/1). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. J.Z., Y.M.Z. and T.R.G are funded by a BBSRC Innovation fellowship. Y.M.Z. is supported by the National Natural Science Foundation of China (81800636). H.Z. is supported by the Training Program of the Major Research Plan of the National Natural Science Foundation of China (91642120), the Grant from the Science and Technology Project of Beijing, China (D18110700010000) and the University of Michigan Health System–Peking University Health Science Center Joint Institute for Translational and Clinical Research (BMU2017JI007). N.F. is supported by the National Institutes of Health awards R01-MD012765, R01- DK117445 and R21-HL140385. R.C. is funded by a Wellcome Trust GW4 Clinical Academic Training Fellowship (WT 212557/Z/18/Z). The Trondelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trondelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. M.C.B. is supported by the UK Medical Research Council (MRC) Skills Development Fellowship (MR/P014054/1). S.F. is supported by a Wellcome Trust PhD studentship (WT108902/Z/15/Z). Q.Y. is funded by a China Scholarship Council PhD scholarship (CSC201808060273). Y.C. was supported by the National Key R&D Program of China (2016YFC0900500, 2016YFC0900501, 2016YFC0900504). The China Kadoorie Biobank baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (202922/Z/16/Z, 088158/Z/09/Z, 104085/Z/14/Z). Japan-Kidney-Biobank was supported by AMED under Grant Number 20km0405210. P.C.H. is supported by Cancer Research UK [grant number: C18281/A19169]. A.K. was supported by DFG KO 3598/5-1. N.F. is supported by NIH awards R01-DK117445, R01-MD012765, R21- HL140385. Declaration of Interest: T.R.G. and J.Z. receive funding from GlaxoSmithKline and Biogen for unrelated research. All other authors have nothing to declare. Ethical Approval: All participants included in the CKDGen, UK Biobank, HUNT, Biobank Japan, China Kadoorie Biobank and Japan Kidney Biobank/ToMMo provided written informed consent and studies were approved by their local research ethics committees and institutional review boards as applicable.

Vascular emergencies-The new COVID-19 crisis?

Vascular emergencies-The new COVID-19 crisis?

Liver steatosis is a risk factor for hepatotoxicity in inflammatory bowel disease patients treated with azathioprine.

The literature demonstrates that hepatic steatosis reduces the tolerance of immunosuppression in people with inflammatory bowel disease. It also shows that elevated methylmercaptopurine may be responsible for thiopurine-induced hepatitis. This exploratory study investigates the relationship between hepatic steatosis, methylmercaptopurine and alanine transaminase. We performed a retrospective review of patients started on azathioprine treatment at University Hospitals Bristol NHS Foundation Trust between 2014 and 2017. There were 600 patients in total. Ninety-one patients met our inclusion criteria which were at least one ultrasound scan commenting on the appearance of the liver, liver function tests at commencement of azathioprine and liver function tests and a methylmercaptopurine level between 6 and 8 weeks after starting treatment. Of 91 patients included in our study, 32 patients (32%) were identified as having radiological hepatic steatosis on ultrasound imaging and 59 patients had no evidence of steatosis. We found a positive association between methylmercaptopurine levels and change in alanine transaminase in patients with hepatic steatosis (P < 0.001) but not in those with a normal liver on ultrasound imaging. We conclude that the higher levels of methylmercaptopurine may be a risk factor for hepatitis in patients with hepatic steatosis but not in those with a normal liver.

Guided self-help for depression in autistic adults: the ADEPT feasibility RCT.

Co-occurring depression frequently occurs in autism. Evidence-based psychological interventions have been successfully adapted to treat co-occurring anxiety, but there is little evidence about the usefulness of adapted cognitive-behavioural therapy for depression. To the authors' knowledge, to date there have been no randomised trials investigating the usefulness of low-intensity cognitive-behavioural therapy for depression in autism. The objectives of the study were to (1) develop a low-intensity psychological intervention for depression adapted for autism, (2) assess the feasibility and patient and therapist acceptability of the intervention, (3) estimate the rates of recruitment and retention for a full-scale randomised controlled trial and (4) identify an appropriate measure of depression to be used in a full-scale randomised controlled trial. The study comprised a randomised controlled trial (n = 70) with a nested qualitative evaluation (n = 21). Seventy eligible and consenting participants were randomly allocated to guided self-help or to treatment as usual. Adult autism services in two NHS regions. Adults with a diagnosis of autism spectrum disorder with depression, that is, a Patient Health Questionnaire-9 items score of ≥ 10. People who had attended more than six sessions of cognitive-behavioural therapy in the previous 6 months were excluded. The low-intensity intervention (guided self-help) comprised materials for nine individual sessions, based on behavioural activation adapted for autism, facilitated by therapist guides (coaches) who were graduate-level psychologists who attended training and regular supervision. Treatment as usual was standard NHS care for depression. Outcomes were measured 10, 16 and 24 weeks post randomisation using self-report and interview measures of depression, anxiety, obsessive-compulsive symptoms, social function and quality of life, and a health-care and service use questionnaire. As this was a feasibility study also designed to identify the most appropriate measure of depression, it was not possible to specify the primary outcome measure or outcome point a priori. The aims of the study were met in full. The guided self-help intervention was feasible and well received by participants and coaches. The majority of allocated participants attended the intervention in full. The most practical outcome point was determined to be 16 weeks. There were differential rates of attrition across the treatment groups: 86% of the guided self-help group remained in the study at 24 weeks, compared with 54% of treatment as usual group. The qualitative study suggested that guided self-help had enhanced credibility with participants at the point of randomisation. Inter-rater reliability of the interview measure of depression was less than adequate, limiting the conclusions that can be drawn from the prespecified sensitivity to change analyses. The intervention was feasible and well received. Although this feasibility study was not a fully powered trial, it provided some evidence that the guided self-help intervention was effective in reducing depressive symptoms. A full-scale clinical effectiveness and cost-effectiveness trial of the intervention is warranted. Improvements to the intervention materials as a result of qualitative interviews. Stakeholder consultation to consider future trial design, consider strategies to improve retention in a treatment as usual arm and select a self-report measure of depression to serve as the primary outcome measure. Current Controlled Trials ISRCTN54650760. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 68. See the NIHR Journals Library website for further project information. This study was also supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol.

Is social support associated with patient-reported outcomes after joint replacement? A systematic review and meta-analysis.

Identifying prognostic factors for outcomes after joint replacement could improve the provision of stratified care. This systematic review evaluated whether social support is a prognostic factor for better patient-reported outcomes after total hip replacement (THR) and total knee replacement (TKR). MEDLINE, Embase and PsycINFO were searched from inception to April 2019. Cohort studies evaluating the association between social support and patient-reported outcomes at three months or longer after THR or TKR were included. Data were extracted from study reports. Study quality was assessed using the QUIPS tool. Data were synthesized using meta-analysis and narrative synthesis. The review was registered on PROSPERO (CRD42016041485). Searches identified 5,810 articles and 56 studies with data from 119,165 patients were included. In meta-analysis, the presence of social support had a beneficial effect on long-term post-operative WOMAC (mean difference 2.88; 95% CIs 1.30; 4.46) and Oxford Knee Score (0.29; 0.12, 0.45). Social support measured using a validated questionnaire was found to be associated with WOMAC pain (0.04; 0.00, 0.08) but not WOMAC function (-0.01; -0.12, 0.11). The presence of social support had a positive association with some SF-36 subscales but not others. For all outcomes, results of narrative synthesis were inconsistent. There is evidence that social support is a prognostic factor for some outcomes after joint replacement. Development and evaluation of complex interventions to improve social support and social integration is warranted. This study was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol.