Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9)). CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

The Scanning CONfoCal Ophthalmoscopy foR DIAbetic eye screening (CONCORDIA) study paper 1.

OBJECTIVE: This project was to determine the performance of the Zeiss Clarus 700 (Clarus) and the Optos California (Optos) with staged mydriasis in a Diabetic Eye Screening Programme (DESP). METHODS: Trial participants were recruited from people attending appointments in DESP or Virtual Eye clinics for delayed hospital appointments. Non-mydriatic photographs from the Clarus and Optos cameras were compared to 2-field 45 degrees mydriatic digital photography (the reference standard) and mydriatic photographs compared if the non-mydriatic photos were unassessable (staged mydriasis). RESULTS: 1573 patients were recruited. 76 individuals were withdrawn, leaving 1497 individuals (2993 eyes). For the Clarus and the Optos, the sensitivity for any retinopathy were 94.2% (95% CI: 92.9-95.3%) and 91.9% (95% CI: 90.5-93.2%) with specificities of 87.3% (95% CI: 85.4-89.0%) and 78.1% (95% CI: 75.7-80.3%) respectively. For referable DR the sensitivities for the Clarus and Optos were 86.0% (95% CI: 82.9-88.8%) and 77.6% (95% CI: 73.9-80.9%) with specificities of 92.8% (95% CI: 91.7-93.8%) and 95.4% (95% CI: 94.5-96.2%) respectively. The Clarus and Optos without mydriasis produced 100 (3.3%) and 152 (5.1%) unassessable eyes respectively, and after staged mydriasis 51 (1.7%) and 102 (3.4%) respectively with 52 (1.7%) reference standard images unassessable. CONCLUSIONS: This study reports the performance of the Clarus and the Optos using staged mydriasis in DR screening with wider fields detecting more referable retinopathy peripherally with some reduction in sensitivity centrally for macular lesions.

The scanning CONfoCal Ophthalmoscopy foR DIAbetic eye screening (CONCORDIA) study paper 2.

PURPOSE: To determine if the Eidon white light 60-degree field Scanning Confocal Ophthalmoscope (SCO) camera was safe to use with staged mydriasis in a Diabetic Eye Screening Programme (DESP). METHODS: The trial participants were recruited from people with diabetes attending appointments in DESP or Virtual Eye clinics for post-Covid delayed hospital appointments. Using staged mydriasis, the SCO images were taken before the pupils were dilated and compared to two-field 45 degrees mydriatic digital photography (the reference standard). Mydriatic SCO images were only compared to the reference standard if the non-mydriatic SCO images were unassessable. RESULTS: 1050 patients were recruited, 35 individuals were withdrawn, the majority (18) due to an imaging protocol deviation leaving 1015 individuals (2029 eyes). Using staged mydriasis, the sensitivity and specificity for any retinopathy was 97.5% (95% CI: 96.4-98.4%) and 82.3% (95% CI: 79.6-84.7%) respectively. The sensitivity and specificity for referable retinopathy was 92.7% (95% CI: 89.9-94.9%) and 85.4% (95% CI: 83.6-87.2%) respectively. The total number of eyes that were unassessable with the Eidon without mydriasis was 85/2029 (4.2%), and after mydriasis was 34/2029 (1.7%) and, with the reference standard, 34/2029 (1.7% - not always the same images) were unassessable. CONCLUSIONS: This study provides promising early results of the performance of the Eidon camera using staged mydriasis in a DESP which needs further evidence from a non-Caucasian population and from cost-effectiveness analyses.

'Look after your legs': patients' experience of an assessment clinic.

Venous leg ulcers are a chronic, recurring condition and a major cause of morbidity, especially in older people. Two inner city district nursing teams initiated a weekly, nurse-led, leg ulcer assessment clinic, and a monthly support group for patients with healed or almost healed leg ulcers. The group supports and empowers patients with self-care 'look after your legs' health promotion messages. The support group uses a similar model to the expert patient programme (Department for Health, 2001). Patients in the group coined the unique name 'patient ambassador'. Patient ambassadors, with nursing support, are used to promote self care and lifestyle changes to members of the group to prevent recurrence of leg ulceration. The aim of the research reported here was to evaluate teh 'Look after Your Legs'(LAYL) service and the benefit to others of the patient ambassador role.

Barrett's Oesophagus Surveillance versus endoscopy at need Study (BOSS): protocol and analysis plan for a multicentre randomized controlled trial.

OBJECTIVES: The absolute annual risk of patients with Barrett's oesophagus (BO) developing oesophageal adenocarcinoma (OAC) is ≤ 0.5%. Screening BO patients for malignant progression using endoscopic surveillance is widely practised. To assess the efficacy and cost-effectiveness of this, we developed a protocol for a randomized controlled trial of surveillance versus 'at need' endoscopy. METHODS: In a multicentre trial, 3400 BO patients randomized to either 2-yearly endoscopic surveillance or 'at need' endoscopy will be followed up for 10 years. Urgent endoscopy will be offered to all patients who develop symptoms of dysphagia, unexplained weight loss > 7lb (3.2 kg), iron deficiency anaemia, recurrent vomiting, or worsening upper gastrointestinal symptoms. Participants must have endoscopically and histologically confirmed BO, with circumferential BO ≥ 1 cm or maximal tongue/island length ≥ 2 cm. Candidates with existing oesophageal high-grade dysplasia or cancer, or previous upper gastrointestinal cancer will be excluded. Primary outcome will be overall survival. Secondary outcomes will be cost effectiveness (cost per life year saved and quality adjusted life years); cancer-specific survival; time to OAC diagnosis and stage at diagnosis; morbidity and mortality related to any interventions; and frequency of endoscopy. CONCLUSIONS: This randomized trial will provide data to evaluate the efficacy and cost-effectiveness of screening BO patients for OAC.

The age of ovarian failure following premenopausal hysterectomy with ovarian conservation.

OBJECTIVE: To test the hypothesis that premenopausal hysterectomy compromises ovarian function and accelerates ovarian failure. DESIGN: Longitudinal prospective cohort study. Annual follow-up with serum follicle-stimulating hormone levels with all women being 46 years of age or less at the time of hysterectomy for benign disease. SETTING: Gloucestershire Royal Hospital, Gloucester, UK. PARTICIPANTS: Five hundred and thirty-one women recruited over a four-year period from 1994 to 1997. RESULTS: The median age of women in the study was 37 (range 22-46). Women had earlier ovarian failure after unilateral oophorectomy (hazard ratio 2.41, 95% confidence interval (CI) 1.44-4.04) and after vaginal hysterectomy (hazard ratio 2.04, 95% CI 1.33-3.14) compared with abdominal hysterectomy. The mean age of ovarian failure across all groups was 45.87 (+/-3.58), and 59 (11%) women remained in the study at the end of 10 years who had not yet entered the menopause. CONCLUSION: This is the largest number of cases collected prospectively looking at ovarian failure after hysterectomy. Earlier ovarian failure occurred in those women having unilateral oophorectomy or vaginal hysterectomy. Early ovarian failure was not confirmed across the study group with only 2% of women having confirmed ovarian failure by Kaplan-Meier estimate one year after surgery and 14% at five years.

Compliance with estrogen hormone replacement therapy after oophorectomy: a prospective study.

OBJECTIVE: To quantify compliance with using estrogen-only hormone replacement therapy (HRT) up until the time of mean age of natural menopause in women undergoing either bilateral oophorectomy or removal of one remaining ovary at the time of hysterectomy for benign disease. DESIGN: Prospective study. Annual questionnaire follow-up for ten years of women undergoing hysterectomy and bilateral oophorectomy for benign disease aged 46 or less at the time of surgery. SETTING: Gloucestershire Royal Hospital. PARTICIPANTS: Five hundred and twenty-one women recruited over a four-year period from 1994 to 1997. MAIN OUTCOME MEASURES: Compliance with HRT use, changes in HRT preparations and reasons for discontinuation. RESULTS: The median age of women at the time of hysterectomy was 42 (range 22-46) years; 4.9% (n = 24) stopped HRT within the first two years and 16.5% (n = 86) by the end of the study. The majority of women were prescribed HRT tablets (253, 48%) and the next most common being patches. In total, there were 1271 episodes of changing HRT, with the range between 0 and 18 changes per woman over the ten-year period. In all, 32% of changes were to a different route of HRT, 19% were to a different preparation of the same route, 18% were to an increased dose of the same preparation and 7% were to a decreased dose of the same preparation. CONCLUSIONS: Compliance with HRT use was high throughout the study, although responses decreased after five years. Change to HRT preparations was consistently high across all preparations. Women requiring HRT after surgical menopause need to be supported in finding the right preparation for them.