Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's Esophagus

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (P combined = 4.09 × 10-9; odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (P combined = 2.74 × 10-10; OR = 1.14, 95% CI = 1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus. © 2012 Nature America, Inc. All rights reserved.

Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants

Background: The vast majority of BRCA1 missense sequence variants remain uncharacterised for their possible effect on protein expression and function, and therefore are unclassified in terms of their pathogenicity. BRCA1 plays diverse cellular roles and it is unlikely that any single functional assay will accurately reflect the total cellular implications of missense mutations in this gene. Objective: To elucidate the effect of two BRCA1 variants, 5236G>C (G1706A) and 5242C>A (A1708E) on BRCA1 function, and to survey the relative usefulness of several assays to direct the characterisation of other unclassified variants in BRCA genes. Methods and Results: Data from a range of bioinformatic, genetic, and histopathological analyses, and in vitro functional assays indicated that the 1708E variant was associated with the disruption of different cellular functions of BRCA1. In transient transfection experiments in T47D and 293T cells, the 1708E product was mislocalised to the cytoplasm and induced centrosome amplification in 293T cells. The 1708E variant also failed to transactivate transcription of reporter constructs in mammalian transcriptional transactivation assays. In contrast, the 1706A variant displayed a phenotype comparable to wildtype BRCA1 in these assays. Consistent with functional data, tumours from 1708E carriers showed typical BRCA1 pathology, while tumour material from 1706A carriers displayed few histopathological features associated with BRCA1 related tumours. Conclusions: A comprehensive range of genetic, bioinformatic, and functional analyses have been combined for the characterisation of BRCA1 unclassified sequence variants. Consistent with the functional analyses, the combined odds of causality calculated for the 1706A variant after multifactorial likelihood analysis (1:142) indicates a definitive classification of this variant as "benign". In contrast, functional assays of the 1708E variant indicate that it is pathogenic, possibly through subcellular mislocalisation. However, the combined odds of 262:1 in favour of causality of this variant does not meet the minimal ratio of 1000:1 for classification as pathogenic, and A1708E remains formally designated as unclassified. Our findings highlight the importance of comprehensive genetic information, together with detailed functional analysis for the definitive categorisation of unclassified sequence variants. This combination of analyses may have direct application to the characterisation of other unclassified variants in BRCA1 and BRCA2.

Nutritional impact of antipseudomonas intravenous antibiotic courses in cystic fibrosis

Editor,—In their study of cystic fibrosis patients who were nutritionally assessed at the start and end of a 14 day period of home intravenous antibiotic treatment for chest disease, Vicet al concluded that increased weight was a result of increased fat storage.1 While this may in part be true, their methodology dictates caution in drawing conclusions....

Communicating consequences with costs: A commentary on Corso et al's cost of injury

Estimating the economic burden of injuries is important for setting priorities, allocating scarce health resources and planning cost-effective prevention activities. As a metric of burden, costs account for multiple injury consequences—death, severity, disability, body region, nature of injury—in a single unit of measurement. In a 1989 landmark report to the US Congress, Rice et al1 estimated the lifetime costs of injuries in the USA in 1985. By 2000, the epidemiology and burden of injuries had changed enough that the US Congress mandated an update, resulting in a book on the incidence and economic burden of injury in the USA.2 To make these findings more accessible to the larger realm of scientists and practitioners and to provide a template for conducting the same economic burden analyses in other countries and settings, a summary3 was published in Injury Prevention. Corso et al reported that, between 1985 and 2000, injury rates declined roughly 15%. The estimated lifetime cost of these injuries declined 20%, totalling US$406 billion, including US$80 billion in medical costs and US$326 billion in lost productivity. While incidence reflects problem size, the relative burden of injury is better expressed using costs.

Finite element analysis of vulnerable atherosclerotic plaques: A comparison of mechanical stresses within carotid plaques of acute and recently symptomatic patients with carotid artery disease

Objectives: There is considerable evidence that patients with carotid artery stenosis treated immediately after the ischaemic cerebrovascular event have a better clinical outcome than those who have delayed treatment. Biomechanical assessment of carotid plaques using high-resolution MRI can help examine the relationship between the timing of carotid plaque symptomology and maximum simulated plaque stress concentration. Methods: Fifty patients underwent high-resolution multisequence in vivo MRI of their carotid arteries. Patients with acute symptoms (n=25) underwent MRI within 72 h of the onset of ischaemic cerebrovascular symptoms, whereas recently symptomatic patients (n=25) underwent MRI from 2 to 6 weeks after the onset of symptoms. Stress analysis was performed based on the geometry derived from in vivo MRI of the symptomatic carotid artery at the point of maximum stenosis. The peak stresses within the plaques of the two groups were compared. Results: Patient demographics were comparable for both groups. All the patients in the recently symptomatic group had severe carotid stenosis in contrast to patients with acute symptoms who had predominantly mild to moderate carotid stenosis. The simulated maximum stresses in patients with acute symptoms was significantly higher than in recently symptomatic patients (median (IQR): 313310 4 dynes/cm 2 (295 to 382) vs 2523104 dynes/cm 2 (236 to 311), p=0.02). Conclusions: Patients have extremely unstable, high-risk plaques, with high stresses, immediately after an acute cerebrovascular event, even at lower degrees of carotid stenoses. Biomechanical stress analysis may help us refine our risk-stratification criteria for the management of patients with carotid artery disease in future.

Characterisation of carotid atheroma in symptomatic and asymptomatic patients using high resolution MRI

Background and purpose: To prospectively evaluate differences in carotid plaque characteristics in symptomatic and asymptomatic patients using high resolution MRI. Methods: 20 symptomatic and 20 asymptomatic patients, with at least 50% carotid stenosis as determined by Doppler ultrasound, underwent preoperative in vivo multispectral MRI of the carotid arteries. Studies were analysed both qualitatively and quantitatively in a randomised manner by two experienced readers in consensus, blinded to clinical status, and plaques were classified according to the modified American Heart Association (AHA) criteria. Results: After exclusion of poor quality images, 109 MRI sections in 18 symptomatic and 19 asymptomatic patients were available for analysis. There were no significant differences in mean luminal stenosis severity (72.9% vs 67.6%; p = 0.09) or plaque burden (median plaque areas 50 mm2 vs 50 mm 2; p = 0.858) between the symptomatic and asymptomatic groups. However, symptomatic lesions had a higher incidence of ruptured fibrous caps (36.5% vs 8.7%; p = 0.004), haemorrhage or thrombus (46.5% vs 14.0%; p<0.001), large necrotic lipid cores (63.8% vs 28.0%; p = 0.002) and complicated type VI AHA lesions (61.5% vs 28.1%; p = 0.001) compared with asymptomatic lesions. The MRI findings of plaque haemorrhage or thrombus had an odds ratio of 5.25 (95% CI 2.08 to 13.24) while thin or ruptured fibrous cap (as opposed to a thick fibrous cap) had an odds ratio of 7.94 (95% CI 2.93 to 21.51) for prediction of symptomatic clinical status. Conclusions: There are significant differences in plaque characteristics between symptomatic and asymptomatic carotid atheroma and these can be detected in vivo by high resolution MRI.

Analysis of human immunodeficiency virus type 1 drug resistance in children receiving nucleoside analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir (Pediatric AIDS Clinical Trials Group 377)

In Pediatric AIDS Clinical Trials Group 377, antiretroviral therapy-experienced children were randomized to 4 treatment arms that included different combinations of stavudine, lamivudine (3TC), nevirapine (Nvp), nelfinavir (Nfv), and ritonavir (Rtv). Previous treatment with zidovudine (Zdv), didanosine (ddI), or zalcitabine (ddC) was acceptable. Drug resistance ((R)) mutations were assessed before study treatment (baseline) and at virologic failure. Zdv(R), ddI(R), and ddC(R) mutations were detected frequently at baseline but were not associated with virologic failure. Children with drug resistance mutations at baseline had greater reductions in virus load over time than did children who did not. Nvp(R) and 3TC(R) mutations were detected frequently at virologic failure, and Nvp(R) mutations were more common among children receiving 3-drug versus 4-drug Nvp-containing regimens. Children who were maintained on their study regimen after virologic failure accumulated additional Nvp(R) and 3TC(R) mutations plus Rtv(R) and Nfv(R) mutations. However, Rtv(R) and Nfv(R) mutations were detected at unexpectedly low rates.

Neonatal screening for cystic fibrosis

Two groups of patients with cystic fibrosis were compared. The screened group, detected with an improved neonatal screening assay for immunoreactive trypsin, developed fewer chest infections requiring treatment and gained more weight than the unscreened group. Early diagnosis by screening seems to affect early morbidity.

Long-term ambient air pollution exposure and self-reported morbidity in the Australian Longitudinal Study on Women's Health: A cross-sectional study

- Objective We sought to assess the effect of long-term exposure to ambient air pollution on the prevalence of self-reported health outcomes in Australian women. - Design Cross-sectional study - Setting and participants The geocoded residential addresses of 26 991 women across 3 age cohorts in the Australian Longitudinal Study on Women's Health between 2006 and 2011 were linked to nitrogen dioxide (NO2) exposure estimates from a land-use regression model. Annual average NO2 concentrations and residential proximity to roads were used as proxies of exposure to ambient air pollution. - Outcome measures Self-reported disease presence for diabetes mellitus, heart disease, hypertension, stroke, asthma, chronic obstructive pulmonary disease and self-reported symptoms of allergies, breathing difficulties, chest pain and palpitations. - Methods Disease prevalence was modelled by population-averaged Poisson regression models estimated by generalised estimating equations. Associations between symptoms and ambient air pollution were modelled by multilevel mixed logistic regression. Spatial clustering was accounted for at the postcode level. - Results No associations were observed between any of the outcome and exposure variables considered at the 1% significance level after adjusting for known risk factors and confounders. - Conclusions Long-term exposure to ambient air pollution was not associated with self-reported disease prevalence in Australian women. The observed results may have been due to exposure and outcome misclassification, lack of power to detect weak associations or an actual absence of associations with self-reported outcomes at the relatively low annual average air pollution exposure levels across Australia.

Effect of an interactive therapeutic robotic animal on engagement, mood states, agitation and psychotropic drug use in people with dementia: A cluster-randomised controlled trial protocol

Introduction: Apathy, agitated behaviours, loneliness and depression are common consequences of dementia. This trial aims to evaluate the effect of a robotic animal on behavioural and psychological symptoms of dementia in people with dementia living in long-term aged care. Methods and analysis: A cluster-randomised controlled trial with three treatment groups: PARO (robotic animal), Plush-Toy (non-robotic PARO) or Usual Care (Control). The nursing home sites are Australian Government approved and accredited facilities of 60 or more beds. The sites are located in South-East Queensland, Australia. A sample of 380 adults with a diagnosis of dementia, aged 60 years or older living in one of the participating facilities will be recruited. The intervention consists of three individual 15 min non-facilitated sessions with PARO or Plush- Toy per week, for a period of 10 weeks. The primary outcomes of interest are improvement in agitation, mood states and engagement. Secondary outcomes include sleep duration, step count, change in psychotropic medication use, change in treatment costs, and staff and family perceptions of PARO or Plush-Toy. Video data will be analysed using Noldus XT Pocket Observer; descriptive statistics will be used for participants’ demographics and outcome measures; cluster and individual level analyses to test all hypotheses and Generalised Linear Models for cluster level and Generalised Estimation Equations and/or Multi-level Modeling for individual level data. Ethics and dissemination: The study participants or their proxy will provide written informed consent. The Griffith University Human Research Ethics Committee has approved the study (NRS/03/14/HREC). The results of the study will provide evidence of the efficacy of a robotic animal as a psychosocial treatment for the behavioural and psychological symptoms of dementia. Findings will be presented at local and international conference meetings and published in peer-reviewed journals.

Fostering interpersonal trust on social media: Physicians' perspectives and experiences

Background The problem of developing and sustaining mutual trust is one of the main barriers to knowledge sharing on social media platforms such as blogs, wikis, micro-blogs and social networking websites. While many studies argue that mutual trust is necessary for online communication and knowledge sharing, few have actually explored and demonstrated how physicians can establish and sustain trusted relationships on social media. Objectives To identify approaches through which physicians establish interpersonal trust on social media. Methods Twenty-four physicians, who were active users of social media, were interviewed using a semi-structured approach between 2013 and 2014. Snowball sampling was employed for participant recruitment. The data were analysed using a thematic analysis approach. Results Physicians trust their peers on social media in a slightly different way than in face-to-face communication. The study found that the majority of participants established trust on social media mainly through previous personal interaction, authenticity and relevancy of voice, professional standing, consistency of communication, peer recommendation, and non-anonymous and moderated sites. Conclusions Healthcare professionals need to approach social media carefully when using it for knowledge sharing, networking and developing trusted relations with like-minded peers.

A dosimetric retrospective planning study comparing volumetric arc therapy (VMAT) and stereotactic body radiotherapy (SBRT) treatment plans for non-small cell lung cancer (NSCLC)

Purpose A retrospective planning study comparing volumetric arc therapy (VMAT) and stereotactic body radiotherapy (SBRT) treatment plans for non-small cell lung cancer (NSCLC). Methods and materials Five randomly selected early stage lung cancer patients were included in the study. For each patient, four plans were created: the SBRT plan and three VMAT plans using different optimisation methodologies. A total of 20 different plans were evaluated. The dose parameters of dose conformity results and the target dose constraints results were compared for these plans. Results The mean planning target volume (PTV) for all the plans (SBRT and VMAT) was 18·3 cm3, with a range from 15·6 to 20·1 cm3. The maximum dose tolerance to 1 cc of all the plans was within 140% (84 Gy) of the prescribed dose, and 95% of the PTV of all the plans received 100% of the prescribed dose (60 Gy). In all the plans, 99% of the PTV received a dose >90% of the prescribed dose, and the mean dose in all the plans ranged from 67 to 72 Gy. The planning target dose conformity for the SBRT and the VMAT (0°, 15° collimator single arc plans and dual arc) plans showed the tightness of the prescription isodose conformity to the target. Conclusions SBRT and VMAT are radiotherapy approaches that increase doses to small tumour targets without increasing doses to the organs at risk. Although VMAT offers an alternative to SBRT for NSCLC and the potential advantage of VMAT is the reduced treatment times over SBRT, the statistical results show that there was no significant difference between the SBRT and VMAT optimised plans in terms of dose conformity and organ-at-risk sparing.

Prospective decrease in progesterone concentrations in female lightweight rowers during the competition season compared with the off-season: A controlled study examining weight loss and intensive exercise

The purpose of this study was to monitor ovarian hormone function response to intense exercise and body weight changes in female athletes. Ovarian hormone function was evaluated in 12 female lightweight rowers and 10 age-height-weight matched sedentary controls. Ovarian hormone function was assessed during consecutive competition season and off season, by measurement of peak and average alternative day overnight urinary oestrone glucuronide (E1G) and pregnanediol glucuronide (PdG) excretion. Competition season was associated with a 5.8 kg (9.3%) body weight loss in the lightweight rowers. Significantly lower competition season peak and average urinary excretion of PdG were found in the lightweight rowers compared with the controls. Lower competition season peak and average urinary excretion of E1G were also found in the lightweight rowers compared with the controls, but the difference did not reach significance. The number of rowing training hours was a significant determinant of peak PdG excretion in the rowers (R2 = 0.40; p<0.02). The seasonal suppression of PdG excretion was associated with degree of weight loss (R2 = 0.46; p<0.01). The competition related decrease in E1G and PdG excretion for the lightweight rowers was predominantly restored during the off season when exercise intensity and duration were decreased and body weight increased. These results showed a significant (p<0.05) reduction in progesterone metabolite excretion and a non-significant decrease in oestrone metabolite excretion associated with intensive competition season training loads and body weight reduction in female lightweight rowers.

Seasonal variations in the body composition of lightweight rowers

OBJECTIVE To monitor the seasonal body composition alterations in 18 lightweight rowers (six females, 12 males) across a rowing season incorporating preseason, early competition, competition, and postseason. METHODS Subject age was 23.1 (SD 4.5) years, height 170.8 (5.6) cm (female, 23.5 (3.5) years, 180.5 (2.7) cm (male). Body weight, fat mass, and fat-free mass (FFM) were assessed using dual energy x ray absorptiometry (DXA-L Lunar) and skinfold techniques. Weight control techniques were documented before major regattas by a questionnaire. RESULTS Female body weight was reduced from 61.3 (2.9) to 57.0 (1.1) kg (5.9%), while male body weight was reduced from 75.6 (3.1) to 69.8 (1.6) kg (7.8%) preseason to competition season respectively. These body weight reductions were mirrored by a significant reduction in fat mass as indicated by the sum of skinfolds [female seven sites: 80.9 (8.1) to 68.2 (11.8) mm; male eight sites: 54.2 (8.7) to 41.8 (4.8) mm], percentage body fat [female 22.1 (1.0) to 19.7 (2.4)%; male 10.0 (0.9) to 7.8 (0.8)%], and total fat [female 12.5 (5.2) to 10.9 (1.4) kg; male 7.3 (1.9) to 5.6 (1.8) kg] (DXA). In contrast, no changes were observed in FFM despite a season of intensive rowing training. Seasonal body weight control was achieved through reduced total energy and dietary fat intakes. Acute body weight reductions were achieved by exercise in 73.3% of participants, food restriction in 71.4%, and fluid restrictions in 62.9%. CONCLUSIONS Seasonal body weight alterations in lightweight rowers are in response to a significant reduction in fat mass. However, the weight restrictions appear to be limiting an increase in FFM which could be beneficial to rowing performance.