Scottish Cohort Research Articles

Genome-wide analysis identifies gallstone-susceptibility loci including genes regulating gastrointestinal motility.

Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely that many genetic determinants are undiscovered. The aim of this study was to identify genetic variants that represent new targets for gallstone research and treatment. We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1089 cases, 5228 controls), and conducted a GWA meta-analysis (43,639 cases, 506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (p<5 ×10-8 ), of which 46 were new. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism, and gastrointestinal motility. Anoctamin 1 (ANO1) and transmembrane Protein 147 (TMEM147), both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression, suggesting that the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6-fold increased odds of gallstones compared with the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes, and C-reactive protein concentrations, and decreased lipoprotein cholesterol concentrations. This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. We implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.

Like mother, like child? Sex differences in the maternal transmission of offending among a Scottish cohort of pre-adolescent children

That parental offending acts as a strong risk factor for offending in children is well-established within criminology. Yet, research on maternal offending is relatively limited, even though many women take on a significantly higher share of childcare responsibilities, and as such, might reasonably be expected to exert an especially strong influence on their children. In part, this lacuna might be attributed to a male-centric lens within criminology, which has tended to overlook female offending. Aimed in part at redressing this imbalance, this article investigates the maternal transmission of offending among a cohort of 12-year-olds, using self-report data from the longitudinal Growing Up in Scotland study. The analysis shows that intragenerational maternal offending acts as a significant predictor of offending among daughters, but that intergenerational offending does not. We found no significant relationship between mothers’ offending and sons’, who appear more vulnerable to a range of wider risk factors.

Growth pattern evaluation of the Edinburgh and Gothenburg cohorts by QEPS height model.

The QEPS-growth-model, developed and validated in GrowUp-Gothenburg cohorts, used for developing growth references and investigating healthy/pathological growth, lacks external validation from other longitudinal cohorts of healthy individuals. To investigate if the QEPS-model can fit the longitudinal Edinburgh growth study of another design than GrowUp-Gothenburg cohorts, and to compare growth patterns in the individuals born in mid-1970s in North-Western Europe. Longitudinal growth data were obtained from the Edinburgh and the GrowUp1974Gothenburg cohorts. The QEPS-model was used to describe length/height from birth to adult height with confidence interval, and the multivariable regression model for estimating the contribution of the different QEPS-functions to adult height. The QEPS-model fitted the Edinburgh cohort well, with high accuracy, and low confidence intervals indicating high precision. Despite 3 cm shorter stature (less QE-function growth) in Scottish children, the growth patterns of the cohorts were similar, especially for specific pubertal growth. The contribution to adult height from different QEPS functions was similar. The QEPS-model is validated for the first time in a longitudinal study of healthy individuals of another design and found to fit with high accuracy and precision. The Scottish and Western-Swedish cohorts born in mid-1970s showed similar growth patterns for both sexes, especially pubertal growth. For the first time, the QEPS height model was used and found to fit another longitudinal cohort of healthy individuals other than the Swedish longitudinal cohorts. With large numbers of individual measurements in each growth phase, the QEPS model calculates growth estimates with narrow confidence intervals (high precision) and high accuracy. The two different cohorts born in the mid-1970s from Scotland and Western Sweden have similar growth patterns, despite a 3 cm difference in adult height.

Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection

Emerging reports of rare neurological complications associated with COVID-19 infection and vaccinations are leading to regulatory, clinical and public health concerns. We undertook a self-controlled case series study to investigate hospital admissions from neurological complications in the 28 days after a first dose of ChAdOx1nCoV-19 (n = 20,417,752) or BNT162b2 (n = 12,134,782), and after a SARS-CoV-2-positive test (n = 2,005,280). There was an increased risk of Guillain–Barré syndrome (incidence rate ratio (IRR), 2.90; 95% confidence interval (CI): 2.15–3.92 at 15–21 days after vaccination) and Bell’s palsy (IRR, 1.29; 95% CI: 1.08–1.56 at 15–21 days) with ChAdOx1nCoV-19. There was an increased risk of hemorrhagic stroke (IRR, 1.38; 95% CI: 1.12–1.71 at 15–21 days) with BNT162b2. An independent Scottish cohort provided further support for the association between ChAdOx1nCoV and Guillain–Barré syndrome (IRR, 2.32; 95% CI: 1.08–5.02 at 1–28 days). There was a substantially higher risk of all neurological outcomes in the 28 days after a positive SARS-CoV-2 test including Guillain–Barré syndrome (IRR, 5.25; 95% CI: 3.00–9.18). Overall, we estimated 38 excess cases of Guillain–Barré syndrome per 10 million people receiving ChAdOx1nCoV-19 and 145 excess cases per 10 million people after a positive SARS-CoV-2 test. In summary, although we find an increased risk of neurological complications in those who received COVID-19 vaccines, the risk of these complications is greater following a positive SARS-CoV-2 test.

Performance of models to predict hepatocellular carcinoma risk among UK patients with cirrhosis and cured HCV infection

Background & AimsHepatocellular carcinoma (HCC) prediction models can inform clinical decisions about HCC screening provided their predictions are robust. We conducted an external validation of 6 HCC prediction models for UK patients with cirrhosis and a HCV virological cure.MethodsPatients with cirrhosis and cured HCV were identified from the Scotland HCV clinical database (N = 2,139) and the STratified medicine to Optimise Treatment of Hepatitis C Virus (STOP-HCV) study (N = 606). We calculated patient values for 4 competing non-genetic HCC prediction models, plus 2 genetic models (for the STOP-HCV cohort only). Follow-up began at the date of sustained virological response (SVR) achievement. HCC diagnoses were identified through linkage to nation-wide cancer, hospitalisation, and mortality registries. We compared discrimination and calibration measures between prediction models.ResultsMean follow-up was 3.4–3.9 years, with 118 (Scotland) and 40 (STOP-HCV) incident HCCs observed. The age-male sex-ALBI-platelet count score (aMAP) model showed the best discrimination; for example, the Concordance index (C-index) in the Scottish cohort was 0.77 (95% CI 0.73–0.81). However, for all models, discrimination varied by cohort (being better for the Scottish cohort) and by age (being better for younger patients). In addition, genetic models performed better in patients with HCV genotype 3. The observed 3-year HCC risk was 3.3% (95% CI 2.6–4.2) and 5.1% (3.5–7.0%) in the Scottish and STOP-HCV cohorts, respectively. These were most closely matched by aMAP, in which the mean predicted 3-year risk was 3.6% and 5.0% in the Scottish and STOP-HCV cohorts, respectively.ConclusionsaMAP was the best-performing model in terms of both discrimination and calibration and, therefore, should be used as a benchmark for rival models to surpass. This study underlines the opportunity for ‘real-world’ risk stratification in patients with cirrhosis and cured HCV. However, auxiliary research is needed to help translate an HCC risk prediction into an HCC-screening decision.Lay summaryPatients with cirrhosis and cured HCV are at high risk of developing liver cancer, although the risk varies substantially from one patient to the next. Risk calculator tools can alert clinicians to patients at high risk and thereby influence decision-making. In this study, we tested the performance of 6 risk calculators in more than 2,500 patients with cirrhosis and cured HCV. We show that some risk calculators are considerably better than others. Overall, we found that the ‘aMAP’ calculator worked the best, but more work is needed to convert predictions into clinical decisions.

ACEs, Places and Inequality: Understanding the Effects of Adverse Childhood Experiences and Poverty on Offending in Childhood

Abstract Over the last three decades, an extensive body of research evidence has emerged on the relationship between adverse childhood experiences (ACEs) and a range of negative outcomes, including offending. Using data from a Scottish child cohort study, this article seeks to better understand how both ACEs and material deprivation influence childhood offending. We show that while the number of ACEs is a strong predictor of childhood offending, certain types of childhood adversity are of greater importance than others. We also find that living in persistent poverty at the neighbourhood level remains a key predictor of childhood offending, but there are complex interactions between poverty and ACEs that should be considered in developing policy responses.

Utilizing Large Electronic Medical Record Data Sets to Identify Novel Drug-Gene Interactions for Commonly Used Drugs.

Real-world prescribing of drugs differs from the experimental systems, physiological-pharmacokinetic models, and clinical trials used in drug development and licensing, with drugs often used in patients with multiple comorbidities with resultant polypharmacy. The increasing availability of large biobanks linked to electronic healthcare records enables the potential to identify novel drug-gene interactions in large populations of patients. In this study we used three Scottish cohorts and UK Biobank to identify drug-gene interactions for the 50 most commonly used drugs and 162 variants in genes involved in drug pharmacokinetics. We defined two phenotypes based upon prescribing behavior-drug-stop or dose-decrease. Using this approach, we replicate 11 known drug-gene interactions including, for example, CYP2C9/CYP2C8 variants and sulfonylurea/thiazolidinedione prescribing and ABCB1/ABCG2 variants and statin prescribing. We identify eight novel associations after Bonferroni correction, three of which are replicated or validated in the UK Biobank or have other supporting results: The C-allele at rs4918758 in CYP2C9 was associated with a 25% (15-44%) lower odds of dose reduction of quinine, P=1.6×10-5 ; the A-allele at rs9895420 in ABCC3 was associated with a 46% (24-62%) reduction in odds of dose reduction with doxazosin, P=1.2×10-4 , and altered blood pressure response in the UK Biobank; the CYP2D6*2 variant was associated with a 30% (18-40%) reduction in odds of stopping ramipril treatment, P=1.01×10-5 , with similar results seen for enalapril and lisinopril and with other CYP2D6 variants. This study highlights the scope of using large population bioresources linked to medical record data to explore drug-gene interactions at scale.

Eye Movement Patterns Can Distinguish Schizophrenia from the Major Affective Disorders and Healthy Control Subjects

Background: At present there are no objective tests or biomarkers in routine use that can help with the diagnosis of major mental disorders. This study aimed to determine the potential value of eye movement behaviour patterns for distinguishing individuals with schizophrenia compared to those with major affective disorders and control groups. Methods: Using a boosted decision tree multiclass classifier in a machine learning framework, we compared eye movement viewing patterns in a training set of UK subjects with Schizophrenia (SCZ) n=120, Bipolar affective disorder (BPAD) n=141, Major depressive disorder (MDD) n=136 and control (CON) n=142 group. A total of 133 individuals with group ratios similar to the training set acted as a hold-out test set for internal validation and a German cohort of SCZ (n=60) and a Scottish cohort of CON subjects (n=184) were used as a semi-independent test set for external validation. Findings: Based on internal validation, estimates of the area under the curve (AUC) for the one-versus-all comparisons for SCZ (0.85), BPAD (0.78), MDD (0.76) and CON (0.85) (with an overall estimate of 0.81) suggested high levels of discriminability between groups. The estimates of AUCs for the one-versus-one comparisons were also reasonably high; SCZ v CON 0.84, SCZ v BPAD 0.82, SCZ v MDD 0.76. The classifier showed good discrimination of BPAD and MDD from CON with AUCs 0.85 and 0.82, respectively; however, the performance was relatively lower between BPAD versus MDD with AUC 0.69. The estimates of AUC based on external validation were comparable: 0.89 for German SCZ and 0.65 for Scottish CON. The best individual discriminators included free viewing, fixation duration and smooth pursuit tasks. Our findings appear robust in the presence of potential confounders such as age, sex, medication or mental state at the time of testing. Interpretation: Eye movement behaviour patterns have good power to discriminate schizophrenia from both the major mood disorders and control subjects. The performance characteristics are within the range required of diagnostic biomarkers. Our findings are consistent with the Kraepelinian dichotomy of the functional psychoses. Funding: Royal Society of London, Chief Scientist Office Scotland (CZB/4/734), NHS Grampian,Tenovus Scotland (G12/31), Miller MacKenzie Trust, EU-FP6 (SGENE) and Health Innovation Challenge Fund, Wellcome Trust and Department of Health (WT-103911/Z/14/Z Declaration of Interest: Philip Benson and David St Clair are co-founders of SACCADE Diagnostics Ltd a spin out company tasked to develop eye movement technology to assist diagnosis of major mental health disorders. The University of Aberdeen has patents pending in Europe (PCT/GB2013/050016) and USA (14/370,611). The data reported in this paper arose solely from the acknowledged UK research bodies and charities none of whom have vested interests in the company. There are otherwise no competing interests. Ethical Approval: The Scottish and German studies obtained full multiregional ethics committee (MREC) and institutional review board (IRB) approvals respectively and were conducted in accordance with the Declaration of Helsinki.

Higher Sun Exposure in the First Trimester Is Associated With Reduced Preterm Birth; A Scottish Population Cohort Study Using Linked Maternity and Meteorological Records.

Background: Preterm birth (birth at <37 weeks gestation) is the leading cause of death in children under 5-years-old, and prevention is a global public health issue. Seasonal patterns of preterm birth have been reported, but factors underlying this have been poorly described. Sun exposure is an important environmental variable that has risks and benefits for human health, but the effects of sun exposure on pregnancy duration and preterm birth are unknown.Objectives: To determine the association between available sun exposure and preterm birth.Methods: We performed a population-based data-linkage study of 556,376 singleton births (in 397,370 mothers) at or after 24 weeks gestation, in Scotland between 2000 and 2010. Maternity records were linked to available sun exposure from meteorological records, by postcode. Logistic regression analysis was used to explore the relationship between available sunshine and preterm birth at <37 weeks gestation. Exploratory analyses included a subgroup analysis of spontaneous and indicated preterm births and a sibling analysis in sib pairs discordant for preterm birth.Results: The rate of preterm birth was 6% (32,958/553,791 live births). Increased available sun exposure in the first trimester of pregnancy was associated with a reduced risk of preterm birth, with evidence of a dose-response. Compared with the lowest quartile of sun exposure, the highest quartile of sun exposure was associated with a reduced odds ratio (OR) of preterm birth of 0.90 (95% Confidence Interval (CI) 0.88–0.94 p < 0.01) on univariable analysis and OR of 0.91 (95% CI 0.87, 0.93 p < 0.01) after adjustment for second trimester sunlight exposure, parity, maternal age, smoking status, and deprivation category. No association was seen between preterm birth and second trimester available sun exposure or combined first and second trimester exposure. Similar patterns were seen on sibling analysis and within both the indicated and spontaneous preterm subgroups.Discussion: Available sun exposure in the first trimester of pregnancy is associated with a protective effect on preterm birth <37 weeks gestation. This opens up new mechanisms, and potential therapeutic pathways, for preterm birth prevention.

Risk of anticholinergic burden in adults with intellectual disabilities: a Scottish retrospective cohort study of n=17220.

Several drugs have anticholinergic side effects that are associated with adverse health outcomes. Anticholinergic burden studies in adults with intellectual disabilities (ID) have focused exclusively on older adults. This study investigates anticholinergic burden and its associations in adults with ID of all ages (17-94years). Adults with ID (n=4 305), each with three general population age-sex-neighbourhood-matched controls (n=12915), were linked to their prescribed medications with anticholinergic effects between 2009 and 2017. Analyses were undertaken using logistic regression models. Adults with ID were more likely to be prescribed any anticholinergic medicines, odds ratio (OR)=1.49 (1.38-1.59), especially 'very strong' risk medicines, OR=2.59 (2.39-2.81); 48.5% had very high total anticholinergic burden (3+) compared with 35.4% of the general population, OR=1.77 (1.64-1.90). This group difference was greater for males, OR=2.02 (1.84-2.22), than females, OR=1.48 (1.33-1.65). Adults with ID had significantly higher odds of having very high total anticholinergic burden up to 75years old, with the greatest group effect occurring in younger ages, 17-24-year-olds, OR=3.05 (2.39-3.89), and the extent of the difference decreased as age increased. The main effect of neighbourhood deprivation showed greater group differences with increasing affluence of neighbourhood. Results examining only the ID group showed that very high total anticholinergic burden was greatest for females, OR=1.21 (1.07-1.37), and those over age 55, and extent of neighbourhood deprivation was not significant. Adults with ID are at higher risk of anticholinergic burden than the general population, especially young adults. Overall anticholinergic burden increased with age, but burden was high across all ages in the ID group. Very high total anticholinergic burden is prevalent across all types of neighbourhoods for the adults with ID, in contrast to the steeper gradient seen in the general population. Adults with ID have increased likelihood of unintended adverse effects, regardless of potential confounds, so clinicians undertaking medication reviews need to consider anticholinergic side effects and cumulative burden across concomitant medications, including in young adults with ID, not just older adults, and particularly women.

The phenotypic and genotypic features of a Scottish cohort with McArdle disease

This retrospective study evaluated the phenotypic and genotypic features of 14 patients with McArdle disease attending the West of Scotland adult muscle clinic. Although all patients experienced exercise-induced cramps, exercise intolerance and hyperCKaemia, only 71% (n = 10) experienced the second wind phenomenon, rhabdomyolysis and/or myoglobinuria. We observed a high rate of fixed muscle weakness (50%; n = 7), coronary artery disease (36%; n = 5), and psychological comorbidity (50%; n = 7). Although 79% had symptom onset in the first decade of life, the mean age at presentation and at genetic diagnosis was 43.8 years and 47.7 years, respectively. 93% had at least one copy of the common PYGM pathogenic variant, c.148C > T, p.(Arg50*), with 50% (n = 7) of the cohort being homozygous. Our cohort highlights the phenotypic variability seen in McArdle disease and underscores the potential for late-onset presentations. It emphasises the need for improved awareness and recognition of this condition amongst neurologists, rheumatologists and general physicians. A history of exercise intolerance and second wind phenomenon may not always be volunteered by the patient, underscoring the need to ask specific questions in clinic to extrapolate the relevant symptoms in this patient cohort.

Cohort profile: DOLORisk Dundee: a longitudinal study of chronic neuropathic pain

PurposeNeuropathic pain is a common disorder of the somatosensory system that affects 7%–10% of the general population. The disorder places a large social and economic burden on patients as well...

Epidemiology and outcome of status epilepticus in children: a Scottish population cohort study.

To describe the epidemiology and outcomes of convulsive status epilepticus (CSE) since the introduction of buccal midazolam and the change in International League Against Epilepsy definition of CSE to include seizures of at least 5minutes. All children presenting to paediatric emergency departments with CSE (2011-2017) in Lothian, Scotland, were identified. Data, collated from electronic health records, included patient demographics, clinical characteristics, acute seizure management, and adverse outcomes (for example admission to intensive care). Six hundred and sixty-five children were admitted with CSE who had 1228 seizure episodes (381 males, 284 females; median age 3y 8mo; age range 0-20y 11mo). CSE accounted for 0.38% (95% confidence interval 0.34-0.42) of annual attendances at emergency departments. Annual prevalence was 0.8 per 1000 children aged 0 to 14 years. Thirty-four per cent of children had recurrent CSE. Sixty-nine per cent of seizures lasted 5 to 29minutes (median duration 10min). Buccal midazolam was given to 30% of children with CSE and had no effect on need for ventilatory support. Seventy per cent of children with CSE required hospital admission. Four per cent resulted in adverse outcome and there were only two deaths. Recurrent seizures, longer duration, and unprovoked seizures increased the odds of adverse outcome. Adverse outcomes have decreased and the use of buccal midazolam is promising. Identifying high-risk groups provides an opportunity for early intervention. These data form the basis for an extensive evaluation of acute seizure management and monitoring long-term outcomes. What this paper adds The annual prevalence of convulsive status epilepticus in Lothian, Scotland, was 0.8 per 1000 children. There was a decrease in case-fatality proportion from 3-9% to 0.2%. Use of buccal midazolam has increased, with no increase in adverse outcomes.

Intensity Matters for Musculoskeletal Health: A Cross-Sectional Study on Movement Behaviors of Older Adults from High-Income Scottish and Low-Income South African Communities.

This study aimed to investigate differences in physical activity (PA) patterns and the associations between objectively measured 24-h movement behaviors and musculoskeletal measures (muscle strength, muscle mass, physical performance, and bone mineral density) in a high-income and a low-income community. This cross-sectional study recruited independent living older adults aged 60–85 years from high-income Scottish (n = 150) and low-income South African (n = 138) settings. Participants completed demographic and health questionnaires, and testing included body composition and bone mineral density (dual energy X-ray absorptiometry), physical performance (grip strength, gait speed), and PA (accelerometry). Participants accumulated similar amounts of weekly total PA, however, the Scottish cohort engaged in more moderate-to-vigorous intensity PA (MVPA) and sedentary behavior (SB), while the South African cohort spent more time sleeping and in light intensity PA (LPA). From compositional data analysis, more time spent in MVPA relative to the other movement behaviors was positively associated with higher muscle mass (p < 0.001) and strength (p = 0.001) in the Scottish cohort. Conversely, more time spent in MVPA was associated with faster gait speed (p < 0.001) and greater hip bone mineral density (p = 0.011) in the South African cohort. Our findings confirm the beneficial role of MVPA in both high- and low-income cohorts, however, the relationship MVPA had with components of musculoskeletal health in older adults differed between settings.

Outcomes of adults with repaired tetralogy of Fallot from the national Scottish Cohort - CORRIGENDUM.

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Real-world effectiveness and safety of ustekinumab for the treatment of Crohn's disease: the Scottish ustekinumab cohort.

Ustekinumab is a monoclonal antibody that targets interleukin-12/23. In Scotland, it was approved for the treatment of moderate to severe Crohn's disease in 2017. The objective of this study was to establish the real-world effectiveness and safety of ustekinumab in the treatment of Crohn's disease. We conducted a retrospective study of patients receiving ustekinumab across eight Scottish National Health Service health boards between 2017 and 2019. Inclusion criteria included a diagnosis of Crohn's disease with symptoms attributed to active disease plus objective signs of inflammation at baseline (C-reactive protein≥5mg/L or fecal calprotectin≥250μg/g or inflammation on endoscopy/magnetic resonance imaging) and completion of induction plus at least one clinical follow-up at 8weeks. Kaplan-Meier survival analysis was used to establish 12-month cumulative rates of clinical remission, mucosal healing, deep remission, and perianal fistula response. Rates of serious adverse events were described quantitatively. Our cohort consisted of 216 patients (female sex, 37.9%; median age, 39.0years, interquartile range [IQR] 28.8-51.8years; disease duration, 9.9years, IQR 6.0-16.5years; prior biologic, 98.6%) with a median follow-up of 35.0weeks (IQR 17.4-52.0weeks). Twelve-month cumulative rates of clinical remission, mucosal healing, and deep remission (clinical remission plus mucosal healing) were 32.0%, 32.7%, and 19.3%, respectively. In patients with active perianal disease (n=37), the 12-month cumulative perianal response rate was 53.1%. The serious adverse event rate was 13.6 per 100 patient-years of follow-up. Ustekinumab is a safe and effective treatment for the treatment of complex Crohn's disease.

Outcomes of adults with repaired tetralogy of Fallot from the national Scottish Cohort.

The adult population of repaired tetralogy of Fallot is increasing and at risk of pre-mature death and arrhythmia. This study evaluates risk factors for adverse outcome and the effect of pulmonary valve replacement within a national cohort. A retrospective cohort study of 341 adult repaired tetralogy of Fallot (16-72 years) managed through a single national service was undertaken incorporating over 1200 patient-years of follow-up. Demographics, cardiopulmonary exercise testing, cardiac magnetic resonance, reintervention (including pulmonary valve replacement), and clinical events were analysed. The influence of these parameters on a primary outcome (death or arrhythmia) was evaluated. Compared with an age-/gender-matched population, patients experienced a reduced survival, particularly males over 55 years (standardised mortality ratio : 6.12, 95% CI: 1.64-15.66, p = 0.004). Cox proportional hazards modelling identified increased indexed right ventricle (RV) end-diastolic volume (hazard ratio (HR): 2.86, 95% CI: 1.4-5.85, p = 0.004) and female gender (HR (male): 0.37, 95% CI: 0.14-0.98, p = 0.045) to be predictors significantly associated with the primary outcome. Pulmonary valve replacement undertaken at indexed RV end-diastolic volume = 145ml/m2 reduced RV volumes and QRS duration but did not improve cardiopulmonary exercise testing nor NYHA class. Pulmonary valve replacement during cohort period was associated with increased risk of primary outcome (HR: 2.82, 95% CI: 1.36-5.86, p = 0.005). Although the majority of adult tetralogy of Fallot were asymptomatic in NYHA 1, cardiopulmonary exercise testing revealed important deficits. Tetralogy of Fallot survival was reduced compared to the general population. Female gender and increasing RV end-diastolic volume predicted adverse events. Pulmonary valve replacement reduced RV volumes and QRS duration but did not improve primary outcome.

Colorectal cancer risk variants rs10161980 and rs7495132 are associated with cancer survival outcome by a recessive mode of inheritance.

Previous studies using additive genetic models failed to identify robust evidence of associations between colorectal cancer (CRC) risk variants and survival outcomes. However, additive models can be prone to false negative detection if the underlying inheritance mode is recessive. Here, we tested all currently known CRC‐risk variants (n = 129) in a discovery analysis of 5675 patients from a Scottish cohort. Significant associations were then validated in 2474 CRC cases from UK Biobank. We found that the TT genotype of the intron variant rs7495132 in the CRTC3 gene was associated with clinically relevant poorer CRC‐specific survival in both the discovery (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.41‐2.74, P = 6.1 × 10−5) and validation analysis (HR = 1.69, 95% CI = 1.03‐2.79, P = .038). In addition, the GG genotype of rs10161980 (intronic variant of AL139383.1 lncRNA) was associated with worse overall survival in the discovery cohort (HR = 1.24, 95% CI = 1.10‐1.39, P = 3.4 × 10−4) and CRC‐specific survival in the validation cohort (HR = 1.26, 95% CI = 1.01‐1.56, P = .040). Our findings show that common genetic risk factors can also influence CRC survival outcome.

Epidemiology of bloodstream infections in a Scottish haemodialysis population with focus on vascular access method

Infection is the second highest cause of mortality in end-stage renal disease, with a significant proportion relating to haemodialysis (HD) vascular access-related infection (VARI). To report the rate and antimicrobial resistance (AMR) of all-source bloodstream infections (BSIs) by vascular access type in a Scottish HD cohort. Retrospective analysis was undertaken of data on adult patients attending seven HD units during 2017. Total HD days for each vascular access type were calculated. BSIs were analysed with rates expressed per 1000 HD days. AMR was verified using health board microbiology databases. Excluding contaminant organisms, there was an overall BSI rate of 0.57 per 1000 HD days. The highest all-source and vascular access-related infection (VARI) BSI rates per 1000 HD days were in the non-tunnelled central venous catheter (CVC) group (3.11 and 2.07 respectively), followed by tunnelled CVC (1.10 and 0.67), arteriovenous graft (0.51 and 0.31), and finally arteriovenous fistula (0.29 and 0.02). The non-VARI BSI rates were lowest in the arteriovenous graft group. Staphylococci comprised the majority of events, with Staphylococcus aureus implicated in 29%. Gram-negative BSIs were prevalent, particularly in CVC groups, and associated with higher mortality. Multidrug-resistant (MDR) S.aureus and carbapenem resistance were relatively low. MDR Gram-negatives were high compared with the Scottish population. Arteriovenous fistula access is confirmed as having lowest all-source and VARI BSI rates, and arteriovenous graft access the lowest non-VARI BSI rates. Staphylococci remain the prevailing genus; however, the contributions of Gram-negative BSIs, the higher mortality, and proportion of MDR organisms in this group are notable.

Risk of melanoma in women with endometriosis: A Scottish national cohort study

ObjectiveTo explore the risk of melanoma in women with endometriosis. Study DesignA retrospective cohort study using Scottish national population-based data was conducted. The study comprised 281,937 women with nearly 5 million person years (4,923,628) of follow up from 1981 to 2010. 17,834 women with a new surgical diagnosis of endometriosis were compared with 83,303 women with no evidence of endometriosis at laparoscopy, 162,966 women who underwent laparoscopic sterilisation and 17,834 age-matched women from the general population to determine the risk of melanoma. Cox proportional hazards regression was used to calculate crude and adjusted Hazards ratios with 95 % Confidence Intervals. ResultsWomen with endometriosis had a significantly higher risk of melanoma when compared to women with no evidence of endometriosis at laparoscopy (HR 1.59, 95 % CI 1.19–2.13), women who had undergone laparoscopic sterilisation (HR 1.82, 95 % CI 1.39–2.40) and age-matched women from the general population (HR 1.63, 95 % CI 1.08–2.45). ConclusionA diagnosis of endometriosis was associated with an increased risk of developing melanoma compared to those without endometriosis. These findings highlight the need for further research to explore shared pathways in the pathogenesis of the two conditions. It is important to acknowledge that the absolute increase in the risk of melanoma in women with endometriosis remains low, which should be considered when counselling women.