Functional polymorphisms in the BRCA1 promoter influence transcription and are associated with decreased risk for breast cancer in Chinese women

Background: The BRCA1 gene is an important breast-cancer susceptibility gene. Promoter polymorphisms can alter the binding affinity of transcription factors, changing transcriptional activity and may affect susceptibility to disease. Methods and Results: Using direct sequencing of the BRCA1 promoter region, we identified four polymorphisms c.-2804T→C (rs799908:T→C), c.-2265C→T (rs11655505:C→T), c.-2004A→G (rs799906:A→G) and c.-1896(ACA) 1→(ACA) 2 (rs8176071:(ACA) 1→(ACA) 2) present in Hong Kong Chinese. Each polymorphism was studied independently and in combination by functional assays. Although all four variants significantly altered promoter activity, the c.-2265T allele had stronger binding than the C allele, and the most common mutant haplotype, which contains the c.-2265T allele, increased promoter activity by 70%. Risk association first tested in Hong Kong Chinese women with breast cancer and age-matched controls and replicated in a large population-based study of Shanghai Chinese, together totalling >3000 participants, showed that carriers of the c.-2265T allele had a reduced risk for breast cancer (combined odd ratio (OR) = 0.80, 95% Cl 0.69 to 0.93; p = 0.003) which was more evident among women aged ≥45 years at first diagnosis of breast cancer and without a family history of breast cancer (combined OR = 0.75, 95% Cl 0.61 to 0.91; p = 0.004). The most common haplotype containing the c.-2265T allele also showed significant risk association for women aged ≥45 years without a family history of breast cancer (OR = 0.64, 95% Cl 0.46 to 0.89; p = 0.008). Conclusion: This comprehensive study of BRCA1 promoter polymorphisms found four variants that altered promoter activity and with the most significant contribution from c.-2265C→T, which could affect susceptibility to breast cancer in the Chinese population. Its significance in other populations remains to be investigated.published_or_final_versio

Association of ICAM3 genetic variant with severe acute respiratory syndrome

Genetic polymorphisms have been demonstrated to be associated with vulnerability to human infection. ICAM3, an intercellular adhesion molecule important for T cell activation, and FCER2 (CD23), an immune response gene, both located on chromosome 19p13.3, were investigated for host genetic susceptibility and association with clinical outcome. A case-control study based on 817 patients with confirmed severe acute respiratory syndrome (SARS), 307 health care worker control subjects, 290 outpatient control subjects, and 309 household control subjects unaffected by SARS from Hong Kong was conducted to test for genetic association. No significant association to susceptibility to SARS infection caused by the novel coronavirus (SARS-CoV) was found for the FCER2 and the ICAM3 single nucleotide polymorphisms. However, patients with SARS homozygous for ICAM3 Gly143 showed significant association with higher lactate dehydrogenase levels (P = .0067; odds ratio [OR], 4.31 [95% confidence interval {CI}, 1.37-13.56]) and lower total white blood cell counts (P = .022; OR, 0.30 [95% CI, 0.10-0.89]) on admission. These findings support the role of ICAM3 in the immunopathogenesis of SARS. © 2007 by the Infectious Diseases Society of America. All rights reserved.published_or_final_versio

Development and Validation of Risk Prediction Models for COVID-19 Positivity in a Hospital Setting

Objectives: To develop: (1) two validated risk prediction models for coronavirus disease-2019 (COVID-19) positivity using readily available parameters in a general hospital setting; (2) nomograms and probabilities to allow clinical utilisation. Methods: Patients with and without COVID-19 were included from 4 Hong Kong hospitals. The database was randomly split into 2:1: for model development database (n = 895) and validation database (n = 435). Multivariable logistic regression was utilised for model creation and validated with the Hosmer–Lemeshow (H–L) test and calibration plot. Nomograms and probabilities set at 0.1, 0.2, 0.4 and 0.6 were calculated to determine sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Results: A total of 1330 patients (mean age 58.2 ± 24.5 years; 50.7% males; 296 COVID-19 positive) were recruited. The first prediction model developed had age, total white blood cell count, chest x-ray appearances and contact history as significant predictors (AUC = 0.911 [CI = 0.880−0.941]). The second model developed has the same variables except contact history (AUC = 0.880 [CI = 0.844−0.916]). Both were externally validated on the H–L test (p = 0.781 and 0.155, respectively) and calibration plot. Models were converted to nomograms. Lower probabilities give higher sensitivity and NPV; higher probabilities give higher specificity and PPV. Conclusion: Two simple-to-use validated nomograms were developed with excellent AUCs based on readily available parameters and can be considered for clinical utilisation.published_or_final_versio

Painless Asymptomatic Ascending Aortic Dissection with Four-Dimensional Flow Magnetic Resonance Imaging: a Case Report

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Empirical treatment based on "typical" reflux symptoms is inappropriate in a population with a high prevalence of Helicobacter pylori infection

Background: Empirical therapy or early endoscopy have been recommended as acceptable management options for GERD. The objective of this study was to determine whether diagnosis and empirical treatment based on reflux symptoms alone are appropriate as initial management for patients with gastroesophageal reflux. Method: Consecutive patients presenting with weekly reflux symptoms were evaluated with a structured questionnaire followed by endoscopy. Patients with dyspepsia as the predominant symptom, "alarm" symptoms (weight loss, dysphagia, or bleeding), history of peptic ulcer or gastric surgery, or recent nonsteroidal anti-inflammatory drugs intake were excluded. Results: Four hundred sixty patients were studied: 82 (18%) were found to have peptic ulcer disease and 78 (95%) were infected with Helicobacter pylori. Concomitant erosive esophagitis was found in 26 (32%) of these patients with peptic ulcer disease. In the remaining 378 patients, 218 (58%) had erosive esophagitis and 1 had esophageal cancer. Among the 159 patients with no endoscopic lesion, 148 (93%) had relief of symptoms when treated with a proton pump inhibitor. Multivariate analysis showed that male gender (OR: 1.8, p = 0.03), age greater than 60 years (OR: 2.2, p = 0.01) and H pylori infection (OR: 3.6, p = 0.008) were significantly associated with a diagnosis of peptic ulcer disease. Coexisting dyspeptic symptom was not a predictor (p = 0.13) for peptic ulcer disease. Conclusions: In populations with a high prevalence of H pylori infection, a significant proportion of patients with GERD have concomitant peptic ulcer disease. Empirical treatment based on "typical" GERD symptoms alone may not be appropriate. Copyright © 2002 by the American Society for Gastrointestinal Endoscopy.link_to_subscribed_fulltex

An ensemble approach for record matching in data linkage

© 2016 The authors and IOS Press. Objectives: To develop and test an optimal ensemble configuration of two complementary probabilistic data matching techniques namely Fellegi-Sunter (FS) and Jaro-Wrinkler (JW) with the goal of improving record matching accuracy. Methods: Experiments and comparative analyses were carried out to compare matching performance amongst the ensemble configurations combining FS and JW against the two techniques independently. Results: Our results show that an improvement can be achieved when FS technique is applied to the remaining unsure and unmatched records after the JW technique has been applied. Discussion: Whilst all data matching techniques rely on the quality of a diverse set of demographic data, FS technique focuses on the aggregating matching accuracy from a number of useful variables and JW looks closer into matching the data content (spelling in this case) of each field. Hence, these two techniques are shown to be complementary. In addition, the sequence of applying these two techniques is critical. Conclusion: We have demonstrated a useful ensemble approach that has potential to improve data matching accuracy, particularly when the number of demographic variables is limited. This ensemble technique is particularly useful when there are multiple acceptable spellings in the fields, such as names and addresses

Low-dose imipramine for refractory functional dyspepsia: a randomised, double-blind, placebo-controlled trial

Background: Guidelines recommend the use of neuromodulators in patients with functional dyspepsia not responding to proton pump inhibitors (PPIs) and prokinetics; however, there is a lack of data from randomised controlled trials supporting their use. We aimed to assess the safety and efficacy of imipramine, a tricyclic antidepressant (TCA), in treatment-refractory functional dyspepsia. Methods: In this single-centre, double-blind, randomised controlled trial, we enrolled consecutive patients with Rome II functional dyspepsia aged 18–80 years. Eligible patients were Helicobacter pylori-negative, had a normal upper gastrointestinal endoscopy and abdominal ultrasound, and remained symptomatic after open-label treatment with 8 weeks of esomeprazole and 4 weeks of domperidone. Patients completed questionnaires assessing dyspepsia symptoms, mood, and insomnia, and were then randomly assigned (1:1) via a computer-generated list of random numbers to receive imipramine (at a dose of 25 mg once nightly for the first 2 weeks, and then 50 mg thereafter) or placebo for 12 weeks. The primary endpoint was overall satisfactory relief of global dyspepsia symptoms at 12 weeks, via patient-reported assessment in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00164775, and is completed. Findings: Between Sept 11, 2005, and Aug 20, 2010, 107 patients with treatment-refractory functional dyspepsia were randomly assigned to receive imipramine (n=55) or placebo (n=52). Relief of global dyspepsia symptoms at 12 weeks occurred in 35 (63·6%, 95% CI 50·4–75·1) of 55 patients on imipramine compared with 19 (36·5%, 95% CI 24·8–50·1) of 52 on placebo (p=0·0051). Ten (18%) patients on imipramine discontinued the study due to adverse events (three dry mouth, two constipation, two drowsiness, and one each insomnia, palpitations, and blurred vision), compared with four (8%) on placebo (one dry mouth and constipation, and one each palpitations, worsening of gastro-oesophageal reflux, and limb paraesthesia). There were no serious adverse events. Interpretation: Low-dose imipramine should be considered as a possible therapy for patients with functional dyspepsia refractory to both PPIs and prokinetics, although patients should be cautioned about the adverse event profile. Funding: None