Dual-colour HER2/chromosome 17 chromogenic in situ hybridisation assay enables accurate assessment of HER2 genomic status in gastric cancer and has potential utility in HER2 testing of biopsy samples

Determination of HER2 protein expression by immunohistochemistry (IHC) and genomic status by fluorescent in situ hybridisation (FISH) are important in identifying a subset of high HER2-expressing gastric cancers that might respond to trastuzumab. Although FISH is considered the standard for determination of HER2 genomic status, brightfield ISH is being increasingly recognised as a viable alternative. Also, the impact of HER2 protein expression/genomic heterogeneity on the accuracy of HER2 testing has not been well studied in the context of gastric biopsy samples.

Identification of MET genomic amplification, protein expression and alternative splice isoforms in neuroblastomas

Crizotinib, a dual anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition (MET) tyrosine kinase inhibitor, is currently being evaluated for the treatment of neuroblastoma. Its effects are thought to be mediated mainly via its activity against ALK. Although MET genomic/protein expression status might conceivably affect crizotinib efficacy, this issue has hitherto not received attention in neuroblastomas.

Exercise training improves activity in adolescents with congenital heart disease

To ascertain if motivational techniques and a structured exercise programme can increase activity in adolescents afflicted with congenital heart disease (CHD).

Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: Implications for respiratory virus-induced cough reflex sensitivity

ABSTRACT (250 words)
BACKGROUND: The mechanism underlying respiratory virus-induced cough hypersensitivity is unknown. Up-regulation of airway neuronal receptors responsible for sensing physical and chemical stimuli is one possibility and the transient receptor potential (TRP) channel family are potential candidates. We have used an in vitro model of sensory neurones and human rhinovirus (HRV-16) to study the effect of virus infection on TRP expression.
METHODS: IMR32 neuroblastoma cells were differentiated in culture to express three TRP channels, TRPV1, TRPA1 and TRPM8. Flow cytometry and qRT-PCR were used to measure TRP channel protein and mRNA levels following inoculation with live virus, inactivated virus, virus- induced soluble factors or pelleted virus particles. Multiplex bioassay was used to determine nerve growth factor (NGF), interleukin (IL)-1ß, IL-6 and IL-8 levels in response to infection.
RESULTS: Early up-regulation of TRPA1 and TRPV1 expression occurred 2 to4 hours post infection. This was independent of replicating virus as virus induced soluble factors alone were sufficient to increase channel expression 50 and 15 fold, respectively. NGF, IL-6 and IL-8 levels, increased in infected cell supernatants, represent possible candidates. In contrast, TRPM8 expression was maximal at 48 hours (9.6 fold) and required virus replication rather than soluble factors
CONCLUSIONS We show for the first time that rhinovirus can infect neuronal cells. Furthermore, infection causes up-regulation of TRP channels by channel specific mechanisms. Increase in TRPA1 and TRPV1 levels can be mediated by soluble factors induced by infection whereas TRPM8 requires replicating virus. TRP channels may be novel therapeutic targets for controlling virus-induced cough.

Intra-operative decision making by ophthalmic surgeons

Research on surgical decision making and risk management usually focuses on peri-operative care, despite the magnitude and frequency of intra-operative risks. The aim of this study was to examine ophthalmic surgeons' intra-operative decisions and risk management strategies in order to explore differences in cognitive processes.

Development of a genotyping microarray for Usher syndrome

Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein-coding exons.

Why do people present late with advanced glaucoma?:A qualitative interview study

To explore the presentation behaviours and pathways to detection of adults who first presented to UK hospital eye services with severe glaucoma.

A prospective cohort study of obesity and risk of oesophageal and gastric adenocarcinoma in the NIH-AARP Diet and Health Study

Objective: The incidence of oesophageal adenocarcinoma (EAC) has increased rapidly over the past 40 years and accumulating evidence suggests that obesity, as measured by body mass index (BMI), is a major risk factor. It remains unclear whether abdominal obesity is associated with EAC and gastric adenocarcinoma.

Design: Cox proportional hazards regression was used to examine associations between overall and abdominal obesity with EAC and gastric adenocarcinoma among 218 854 participants in the prospective NIHeAARP cohort.

Results: 253 incident EAC, 191 gastric cardia adenocarcinomas and 125 gastric non-cardia adenocarcinomas accrued to the cohort. Overall obesity (BMI) was positively associated with EAC and gastric
cardia adenocarcinoma risk (highest ($35 kg/m2) vs referent (18.5e<25 kg/m2); HR 2.11, 95% CI 1.09 to 4.09 and HR 3.67, 95% CI 2.00 to 6.71, respectively). Waist circumference was also positively associated with EAC and gastric cardia adenocarcinoma risk (highest vs referent; HR 2.01, 95% CI 1.35 to 3.00 and HR 2.22, 95% CI 1.43 to 3.47, respectively), whereas waist-to-hip ratio (WHR) was positively associated with EAC risk only (highest vs referent; HR 1.81, 95% CI 1.24 to 2.64) and persisted in patients with normal BMI (18.5e<25 kg/m2). Mutual adjustment of WHR and BMI attenuated
both, but did not eliminate the positive associations for either with risk of EAC. In contrast, the majority of the anthropometric variables were not associated with adenocarcinomas of the gastric non-cardia.

Conclusion Overall obesity was associated with a higher risk of EAC and gastric cardia adenocarcinoma, whereas abdominal obesity was found to be associated with increased EAC risk; even in people with normal BMI

Lung cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK:A population-based study, 2004-2007

Background: The authors consider whether differences in stage at diagnosis could explain the variation in lung cancer survival between six developed countries in 2004-2007. Methods: Routinely collected population-based data were obtained on all adults (15-99 years) diagnosed with lung cancer in 2004-2007 and registered in regional and national cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK. Stage data for 57 352 patients were consolidated from various classification systems. Flexible parametric hazard models on the log cumulative scale were used to estimate net survival at 1 year and the excess hazard up to 18 months after diagnosis. Results: Age-standardised 1-year net survival from non-small cell lung cancer ranged from 30% (UK) to 46% (Sweden). Patients in the UK and Denmark had lower survival than elsewhere, partly because of a more adverse stage distribution. However, there were also wide international differences in stage-specific survival. Net survival from TNM stage I non-small cell lung cancer was 16% lower in the UK than in Sweden, and for TNM stage IV disease survival was 10% lower. Similar patterns were found for small cell lung cancer. Conclusions: There are comparability issues when using population-based data but, even given these constraints, this study shows that, while differences in stage at diagnosis explain some of the international variation in overall lung cancer survival, wide disparities in stage-specific survival exist, suggesting that other factors are also important such as differences in treatment. Stage should be included in international cancer survival studies and the comparability of population-based data should be improved.

Prescribing for weight loss in primary care: evidence from a population based study

Background Taking antiobesity medication can be a cost effective way to lose weight. Uptake is determined in part by a General Practitioner's decision to prescribe weight loss medication and, in part, by patient preference. It is probable that the latter may indicate a patient's readiness to lose weight.


Methods Analysis of cross-sectional data (from February 2003 to March 2011) from a population based prescribing database (~1.75 million people) using an adjusted Poisson regression.


Results The number of antiobesity medications increased from 23.4 per 1000 population in 2004 to 30.7 per 1000 population in 2010 and was three times higher in female than in male subjects. Against this background, a marked seasonal variation in the number of antiobesity medications dispensed was evident (p<0.001), peaking in June/July with a trough in December/January (±8.0% peak to trough). The seasonal component was stronger in female subjects, ±11.2% peak to trough, compared with ±3.5% for male subjects.


Conclusions Obese patients, particularly women, increase their uptake of weight loss medication in the months leading up to the summer holiday period. The period prior to the summer may represent a time that health professionals could promote increased participation of obese patients in weight loss programmes.

The relationship between informal caregiving and mortality: an analysis using the ONS Longitudinal Study of England and Wales.

BACKGROUND:

Many studies have suggested that caregiving has a detrimental impact on health. However, these conclusions are challenged by research which finds evidence of a comparative survivorship advantage, as well as work which controls for group differences in the demand for care.

METHODS:

We use a large record linkage study of England and Wales to investigate the mortality risks of carers identified in the 2001 Census. The analysis focuses on individuals aged 35-74 living with others in private households and a distinction is made between those providing 1-19 and 20 or more hours of care per week. Logit models identify differences in carers' health at baseline and postcensal survival is analysed using Cox proportional hazards models.

RESULTS:

12.2% of study members reported providing 1-19 h of care and 5.4% reported providing 20 or more hours. While carers were significantly more likely to report poorer health at baseline, survival analyses suggested that they were at a significantly lower risk of dying. This comparative advantage also held when the analyses were restricted to individuals living with at least one person with poor health.

CONCLUSIONS:

The comparative mortality advantage revealed in this analysis challenges common characterisations of carers' health and draws attention to important differences in the way carers are defined in existing analyses. The survival results are consistent with work using similar data for Northern Ireland. However, the study also affords more uniform conclusions about carers' baseline health and this provides grounds for questioning existing hypotheses about the reasons for this advantage.

Variation of clinical outcomes used in glaucoma randomised controlled trials:a systematic review

Purpose: In randomised clinical trials (RCTs) the selection of appropriate outcomes is crucial to the assessment of whether one intervention is better than another. The purpose of this review is to identify different clinical outcomes reported in glaucoma trials.

Methods We conducted a systematic review of glaucoma RCTs. A sample or selection of glaucoma trials were included bounded by a time frame (between 2006 and March 2012). Only studies in English language were considered. All clinical measured and reported outcomes were included. The possible variations of clinical outcomes were defined prior to data analysis. Information on reported clinical outcomes was tabulated and analysed using descriptive statistics. Other data recorded included type of intervention and glaucoma, duration of the study, defined primary outcomes, and outcomes used for sample size calculation, if nominated.

Results The search strategy identified 4323 potentially relevant abstracts. There were 315 publications retrieved, of which 233 RCTs were included. A total of 967 clinical measures were reported. There were large variations in the definitions used to describe different outcomes and their measures. Intraocular pressure was the most commonly reported outcome (used in 201 RCTs, 86%) with a total of 422 measures (44%). Safety outcomes were commonly reported in 145 RCTs (62%) whereas visual field outcomes were used in 38 RCTs (16%).

Conclusions There is a large variation in the reporting of clinical outcomes in glaucoma RCTs. This lack of standardisation may impair the ability to evaluate the evidence of glaucoma interventions.