St Richard's Hospital

From family medical practices 15775 men and women aged 65-80 years were identified and randomized into two groups: one group was invited for ultrasonographic screening for abdominal aortic aneurysm (AAA), and the other acted as age- and sex-matched controls. Of the 7887 invited for screening 5394 (68.4 per cent) accepted. AAA was detected in 218 (4.0 per cent overall and 7.6 per cent of men). Aortic surgery was offered to the screened group if certain criteria were met and no patient died from rupture who was fit for operation and accepted elective treatment. The incidence of rupture was reduced by 55 per cent in men in the group invited for screening, compared with controls. The incidence of rupture in women was low in both groups.

BACKGROUND: The outcome of local excision of early rectal cancer using transanal endoscopic microsurgery (TEM) lacks consensus. Screening has substantially increased the early diagnosis of tumours. Patients need local treatments that are oncologically equivalent to radical surgery but safer and functionally superior. METHODS: A national database, collated prospectively from 21 regional centres, detailed TEM treatment in 487 subjects with rectal cancer. Data were used to construct a predictive model of local recurrence after TEM using semiparametric survival analyses. The model was internally validated using measures of calibration and discrimination. RESULTS: Postoperative morbidity and mortality were 14.9 and 1.4 per cent respectively. The Cox regression model predicted local recurrence with a concordance index of 0.76 using age, depth of tumour invasion, tumour diameter, presence of lymphovascular invasion, poor differentiation and conversion to radical surgery after histopathological examination of the TEM specimen. CONCLUSION: Patient selection for TEM is frequently governed by fitness for radical surgery rather than suitable tumour biology. TEM can produce long-term outcomes similar to those published for radical total mesorectal excision surgery if applied to a select group of biologically favourable tumours. Conversion to radical surgery based on adverse TEM histopathology appears safe for p T1 and p T2 lesions.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

BACKGROUND: Screening for abdominal aortic aneurysm (AAA) is commonly restricted to men. Recent studies have indicated a possible increase in deaths due to ruptured AAA in women, and a higher rate of rupture in women than in men. The present report details results from a randomized controlled trial that assessed the effects of screening women for AAA. METHODS: Some 9342 women aged 65-80 years were entered into the trial and randomized to age-matched screen and control groups. A single ultrasonographic scan was offered to women in the screening arm of the study. Women with an AAA received follow-up scans, and were considered for elective surgery if certain criteria were met. RESULTS: The prevalence of AAA was six times lower in women (1.3 per cent) than in men (7.6 per cent). Over 5- and 10-year follow-up intervals, the incidence of rupture was the same in the screened and control groups of women. CONCLUSION: Screening women for AAA is neither clinically indicated nor economically viable.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

BACKGROUND: The prevalence of abdominal aortic aneurysm (AAA) in a community-based sample of men and women aged 65-79 years was correlated with known risk factors. In addition, the effect of high blood pressure and the use of antihypertensive medication on growth of AAAs were studied. METHODS: Aortic diameter was assessed by ultrasonography and data on risk factors were collected by self-administered questionnaire for 5356 men and women as part of a randomized controlled trial. RESULTS: Current hypertension increased the risk of having an aortic aneurysm by 30-40 per cent while use of antihypertensive medication increased the risk by 70-80 per cent, adjusting for current blood pressure. There was no clear relationship between hypertension and growth rates of existing aneurysms in this study, although these results were largely from data on small aneurysms. Men were nearly six times more likely to develop an AAA than women; the risk increased by 40 per cent every 5 years after the age of 65 years. Smoking was an independent risk factor for AAA, with level of exposure being more significant than duration. CONCLUSION: Male sex, smoking and hypertension are strong risk factors for the development of AAA. In this study hypertension did not significantly increase the growth rate of existing aneurysms. Smoking remains the most important avoidable risk factor for AAA. The analyses presented here suggest that selection for screening, other than by age and sex, is not worthwhile.

OBJECTIVES: To assess whether the mortality benefit from screening men aged 65-74 for abdominal aortic aneurysm decreases over time, and to estimate the long term cost effectiveness of screening. DESIGN: Randomised trial with 10 years of follow-up. SETTING: Four centres in the UK. Screening and surveillance was delivered mainly in primary care settings, with follow-up and surgery offered in hospitals. PARTICIPANTS: Population based sample of 67 770 men aged 65-74. INTERVENTIONS: Participants were individually allocated to invitation to ultrasound screening (invited group) or to a control group not offered screening. Patients with an abdominal aortic aneurysm detected at screening underwent surveillance and were offered surgery if they met predefined criteria. MAIN OUTCOME MEASURES: Mortality and costs related to abdominal aortic aneurysm, and cost per life year gained. RESULTS: Over 10 years 155 deaths related to abdominal aortic aneurysm (absolute risk 0.46%) occurred in the invited group and 296 (0.87%) in the control group (relative risk reduction 48%, 95% confidence interval 37% to 57%). The degree of benefit seen in earlier years of follow-up was maintained in later years. Based on the 10 year trial data, the incremental cost per man invited to screening was pound100 (95% confidence interval pound82 to pound118), leading to an incremental cost effectiveness ratio of pound7600 ( pound5100 to pound13,000) per life year gained. However, the incidence of ruptured abdominal aortic aneurysms in those originally screened as normal increased noticeably after eight years. CONCLUSIONS: The mortality benefit of screening men aged 65-74 for abdominal aortic aneurysm is maintained up to 10 years and cost effectiveness becomes more favourable over time. To maximise the benefit from a screening programme, emphasis should be placed on achieving a high initial rate of attendance and good adherence to clinical follow-up, preventing delays in undertaking surgery, and maintaining a low operative mortality after elective surgery. On the basis of current evidence, rescreening of those originally screened as normal is not justified. Trial registration Current Controlled Trials ISRCTN37381646.

BACKGROUND: The long-term effects of abdominal aortic aneurysm (AAA) screening were investigated in extended follow-up from the UK Multicentre Aneurysm Screening Study (MASS) randomized trial. METHODS: A population-based sample of men aged 65-74 years were randomized individually to invitation to ultrasound screening (invited group) or to a control group not offered screening. Patients with an AAA (3·0 cm or larger) detected at screening underwent surveillance and were offered surgery after predefined criteria had been met. Cause-specific mortality data were analysed using Cox regression. RESULTS: Some 67 770 men were enrolled in the study. Over 13 years, there were 224 AAA-related deaths in the invited group and 381 in the control group, a 42 (95 per cent confidence interval 31 to 51) per cent reduction. There was no evidence of effect on other causes of death, but there was an overall reduction in all-cause mortality of 3 (1 to 5) per cent. The degree of benefit seen in earlier years of follow-up was slightly diminished by the occurrence of AAA ruptures in those with an aorta originally screened normal. About half of these ruptures had a baseline aortic diameter in the range 2·5-2·9 cm. It was estimated that 216 men need to be invited to screening to save one death over the next 13 years. CONCLUSION: Screening resulted in a reduction in all-cause mortality, and the benefit in AAA-related mortality continued to accumulate throughout follow-up. REGISTRATION NUMBER: ISRCTN37381646 (http://www.controlled-trials.com).

An ultrasonography screening programme for detecting abdominal aortic aneurysm (AAA) in the community is described in which 7200 men and women aged between 65 and 80 years were contacted by letter. Of these, 4237 were screened; the aorta was visualized in 4122 and 179 AAAs of 3 cm or more in diameter were detected (4.3 per cent). Criteria for surgery are suggested and the results of their application prospectively over 6 years are discussed. Using these criteria, under 10 per cent of patients with ultrasonographically-detected AAA should require surgery for this condition provided ultrasonography follow-up is used.

BACKGROUND: The prevalence of chronic daily headache in association with regular use of analgesics is about 2%. Whether regular use of analgesics has a causal or consequential relationship to daily headache has not been established. A causal relationship has been suggested consequent to the observation of improvement or resolution of headache following analgesic withdrawal in patients attending headache clinics, but this observation has not been validated by controlled trials. PURPOSE: The aim of our investigation was to determine whether regular use of analgesics is associated with the development of chronic daily headache de novo and to characterize the clinical phenotype of those headaches by carefully studying chronic daily headache in patients with regular use of analgesics for a nonheadache indication. METHODS: Patients attending a rheumatology-monitoring clinic of second-line agents were interviewed by a training neurologist with regard to their analgesic and headache history. Headache classification was according to the criteria of the International Headache Society. Daily headache characteristics were surveyed via a standardized questionnaire, and headache features were further explored by a trained medical interviewer. RESULTS: Of 110 patients presenting to a rheumatology-monitoring clinic, 73% had a diagnosis of rheumatoid arthritis, 23% had seronegative arthritis, and 4% comprised a miscellaneous group. One hundred three were using one or more analgesics regularly for their arthritis. Of this group, 8 (7.6%) reported a history of chronic daily headache, each of whom reported a history of migraine. The onset of migraine occurred before the onset of chronic daily headache in 7 patients and at about the same time as the chronic daily headache in 1 patient. In those with onset of migraine prior to chronic daily headache, the mean interval before the onset of headache was 30 years (range, 10 to 50 years). Regular use of analgesics preceded the onset of daily headache in 5 patients by a mean of 5.4 years (range, 2 to 10 years). In 1 patient, analgesic use and the development of daily headache occurred at about the same time. In 1 patient, the onset of daily headache preceded regular use of analgesics by almost 30 years. Five of those with regular use of analgesics had been taking an opiate-based preparation in combination with a nonsteroidal anti-inflammatory agent in 4. Two had been on a combination of acetaminophen (paracetamol) and a nonsteroidal anti-inflammatory drug. The minimum number of tablets per week was 7, and the mean was 48 (range, 7 to 87). Of those patients who did not have daily headache, 41% had a history of migraine and 27% reported a history of tension-type headache. CONCLUSION: These findings suggest that individuals with primary headache, specifically migraine, are predisposed to developing chronic daily headache in association with regular use of analgesics.

What's known on the subject? And what does the study add? There is a wealth of evidence on the development, indications, outcomes and complications of augmentation cystoplasty (AC). Over the last decade, new evidence has been emerging to influence our clinical practice and application of this technique. AC is indicated as part of the treatment pathway for both neurogenic and idiopathic detrusor overactivity, usually where other interventions have failed or are inappropriate. The most commonly used technique remains augmentation with a detubularised patch of ileum (ileocystoplasty). Controversy persists over the role of routine surveillance following ileocystoplasty for the detection of subsequent bladder carcinoma; however the indication for surveillance after gastrocystoplasty is clearer due to a rising incidence of malignancy in this group. Despite a reduction in the overall numbers of AC operations being performed, it clearly still has a role to play, which we re-examine with contemporary studies from the last decade.

PURPOSE: Surgery for recurrent rectal cancer is the only therapy with curative potential. This study was designed to assess factors that affect survival after surgery for locally recurrent rectal cancer. METHODS: Prospective databases of patients undergoing surgical resection for recurrent rectal cancer at three tertiary centers between 1990 and 2006 were combined and analyzed. Cox regression and Kaplan-Meier survival analysis were used to assess factors associated with survival. RESULTS: A total of 160 patients (96 males) underwent surgery (median age, 63 (range, 27-93) years). Ninety-five patients (59 percent) received neoadjuvant radiotherapy. Sixty-three patients (39 percent) underwent radical resection and 90 (56 percent) underwent extended radical resection. Seven patients (5 percent) were irresectable. There was one death and 27 percent had major postoperative complications, independent of extent of resection. Negative resection margins were obtained in 98 patients (R0 61 percent). Median cancer-specific and overall survival was 48 months (41.5 percent 5-year survival) and 43 months (36.6 percent 5-year survival), respectively. Margin involvement was a significant predictor of cancer-specific (P<0.001) and overall survival (P<0.02). CONCLUSIONS: Resection for recurrent rectal cancer results in good survival with acceptable morbidity, unaffected by the extent of resection. Extended radical resection to obtain clear resection margins is the appropriate management of locally recurrent rectal cancer.

The objective of the study is to provide evidence-based guidance on nutritional management and optimal care for pregnancy after bariatric surgery. A consensus meeting of international and multidisciplinary experts was held to identify relevant research questions in relation to pregnancy after bariatric surgery. A systematic search of available literature was performed, and the ADAPTE protocol for guideline development followed. All available evidence was graded and further discussed during group meetings to formulate recommendations. Where evidence of sufficient quality was lacking, the group made consensus recommendations based on expert clinical experience. The main outcome measures are timing of pregnancy, contraceptive choice, nutritional advice and supplementation, clinical follow-up of pregnancy, and breastfeeding. We provide recommendations for periconception, antenatal, and postnatal care for women following surgery. These recommendations are summarized in a table and print-friendly format. Women of reproductive age with a history of bariatric surgery should receive specialized care regarding their reproductive health. Many recommendations are not supported by high-quality evidence and warrant further research. These areas are highlighted in the paper.

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.

BACKGROUND: Long-term benefits of screening for abdominal aortic aneurysm (AAA) are uncertain. These are the final results of a randomized controlled screening trial for AAA in men, updating those reported previously. Benefit and compliance over a median 15-year interval were examined. METHODS: One group of men were invited for ultrasonographic AAA screening, and another group, who received standard care, acted as controls. A total of 6040 men aged 65-80 years were randomized to one of the two groups. Outcome was monitored in terms of AAA-related events (surgery or death). RESULTS: In the group invited for screening, AAA-related mortality was reduced by 11 per cent (from 1.8 to 1.6 per cent, hazard ratio 0.89) over the follow-up interval. Screening detected an AAA in 170 patients; 17 of these died from an AAA-related cause, seven of which might have been preventable. The incidence of AAA rupture after an initially normal scan increased after 10 years of follow-up, but was still low overall (0.56 per 1000 person-years). CONCLUSION: Screening with a single ultrasonography scan still conferred a benefit at 15 years, although the results were not significant for this population size. Fewer than half of the AAA-related deaths in those screened positive could be prevented. REGISTRATION NUMBER: ISRCTN 00079388 (http://www.controlled-trials.com).

Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).

BACKGROUND: Lowering serum homocysteine levels with folic acid is expected to reduce mortality from ischemic heart disease. Homocysteine reduction is known to be maximal at a folic acid dosage of 1 mg/d, but the effect of lower doses (relevant to food fortification) is unclear. METHODS: We randomized 151 patients with ischemic heart disease to 1 of 5 dosages of folic acid (0.2, 0.4, 0.6, 0.8, and 1.0 mg/d) or placebo. Fasting blood samples for serum homocysteine and serum folate analysis were taken initially, after 3 months of supplementation, and 3 months after folic acid use was discontinued. RESULTS: Median serum homocysteine level decreased with increasing folic acid dosage, to a maximum at 0.8 mg of folic acid per day, when the homocysteine reduction (placebo adjusted) was 2.7 micromol/L (23%), similar to the known effect of folic acid dosages of 1 mg/d and above. The higher a person's initial serum homocysteine level, the greater was the response to folic acid, but there were statistically significant reductions regardless of the initial level. Serum folate level increased approximately linearly (5.5 nmol/L for every 0.1 mg of folic acid). Within-person fluctuations over time in serum homocysteine levels, measured in the placebo group, were large compared with the effect of folic acid, indicating that monitoring of the reduction in an individual is impractical. CONCLUSIONS: A dosage of folic acid of 0.8 mg/d appears necessary to achieve the maximum reduction in serum homocysteine level across the range of homocysteine levels in the population. Current US food fortification levels will achieve only a small proportion of the achievable homocysteine reduction.

BACKGROUND: Early identification of abdominal aortic aneurysms (AAAs) may reduce the risk of death from rupture by providing the opportunity for elective repair. Before a screening policy for AAA is implemented, the growth rates of AAAs and the accompanying risk of rupture without intervention should be established. METHODS: The growth rates of AAAs were calculated using longitudinal aneurysmal growth data from screening studies in Chichester and Huntingdon. Estimates of the growth rates of AAAs and the risks of rupture over time were made taking measurement error and individual variability into account. RESULTS: Growth rate estimates were found to vary by initial aortic diameter, with a more rapid growth seen in large aneurysms (50 mm or more). The rate of aneurysm growth did not differ with age or sex. The estimated risk of rupture of an AAA with an initial diameter of 45 mm did not exceed 20-5 per cent over 5 years. An AAA with an initial diameter of 30 mm has a 4.0 per cent or less chance of rupture over 5 years. CONCLUSION: The study provides a more accurate assessment of the risk of aneurysm rupture without surgery and helps to define rescreening intervals for those with an enlarged aortic diameter.

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case–control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10−12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a ‘helper virus’ to support AAV2 replication) and disease susceptibility related to HLA class II status. A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

OBJECTIVES: The aim of the present study was to develop, implement and evaluate a brief intervention to improve adherence to the recommended lifestyle changes for patients with Type 2 diabetes, in particular to help patients to reduce the total amount of fat consumed and to increase lifestyle physical activity levels. DESIGN AND METHOD: A brief, tailored lifestyle self-management intervention for patients with Type 2 diabetes was evaluated in a randomized controlled trial. One hundred participants (aged 40 - 70 yrs) completed assessments at three time points- baseline, three months and one year. Participants were allocated to either an intervention group who received the brief tailored intervention including follow-up telephone calls, or a usual care control group. RESULTS: Results indicate that the intervention was successful in helping patients to reduce fat intake and, to a lesser extent, increase lifestyle physical activity levels. These self-reported changes in behaviour were reflected in the objective data with weight maintenance in the intervention group compared to the control group, together with a significant reduction (2 cm) in waist circumference. CONCLUSIONS: These results provide further evidence of the effectiveness of tailored interventions for lifestyle change.