Adam, Eve and the reflux enigma: age and sex differences across the gastro-oesophageal reflux spectrum.

INTRODUCTION: We present demographic differences across the gastro-oesophageal reflux disease (GORD) spectrum in a UK District General Hospital. PATIENTS AND METHODS: Data were prospectively collected over 37 years. At endoscopy patients were categorized as: erosive oesophagitis (EO), Barrett's oesophagus (BO) or nonerosive reflux disease (NER). Analysis 1: comparison of EO, BO and NER 1977-2001 when the database for GORD without BO closed. Analysis 2: demographic differences in oesophageal adenocarcinoma (OAC) in total BO population diagnosed 1977-2011. RESULTS: GORD 1977-2001 (n=11 944): sex, male predominance in EO and BO but not NER; male : female ratios, 1.81, 1.65, 0.87, respectively (P<0.0001); mean age at presentation, EO 54 years, BO 62 years, NER 50 years; women were older than men by 10, 7 and 6 years, respectively.BO 1977-2011: prevalent OAC, 87/1468 (6%); male : female ratio, 4.1 (P<0.0001); incident OAC, 54/1381 (3.9%); male : female ratio, 3.5 (P<0.0001). Among all BO, more men developed OAC (3 vs. 0.9%). Within each sex, proportion of OAC higher among men (4.9 vs. 2.3%); at OAC diagnosis women were slightly but not significantly older (69.9 vs. 72.3 years, P=0.322). CONCLUSION: Two views may explain our findings. First, women have either milder reflux, or reduced mucosal sensitivity hence reflux remains silent for longer. Alternatively, women genuinely develop reflux later, that is, are more protected and for longer from developing GORD and its complications. Early evidence is emerging that female sex hormones may indeed have a protective role in GORD during the reproductive period. We suggest reflux and its consequences may be an example of 'protection' conferred on Eve.

Variation in Gas and Volatile Compound Emissions from Human Urine as It Ages, Measured by an Electronic Nose.

The medical profession is becoming ever more interested in the use of gas-phase biomarkers for disease identification and monitoring. This is due in part to its rapid analysis time and low test cost, which makes it attractive for many different clinical arenas. One technology that is showing promise for analyzing these gas-phase biomarkers is the electronic nose--an instrument designed to replicate the biological olfactory system. Of the possible biological media available to "sniff", urine is becoming ever more important as it is easy to collect and to store for batch testing. However, this raises the question of sample storage shelf-life, even at -80 °C. Here we investigated the effect of storage time (years) on stability and reproducibility of total gas/vapour emissions from urine samples. Urine samples from 87 patients with Type 2 Diabetes Mellitus were collected over a four-year period and stored at -80 °C. These samples were then analyzed using FAIMS (field-asymmetric ion mobility spectrometry--a type of electronic nose). It was discovered that gas emissions (concentration and diversity) reduced over time. However, there was less variation in the initial nine months of storage with greater uniformity and stability of concentrations together with tighter clustering of the total number of chemicals released. This suggests that nine months could be considered a general guide to a sample shelf-life.

The socioeconomic profile of a Barrett's oesophagus cohort assessed by the 2010 Index of Multiple Deprivation.

BACKGROUND: Several reports have described the relationship between socioeconomic status and oesophageal adenocarcinoma but only one with its precursor condition, Barrett's oesophagus. We therefore investigated such an association. PATIENTS: The majority (88%) of patients diagnosed with Barrett's at Rotherham District General Hospital between 28 April 1978 and 31 August 2012 consented to inclusion in the UK Barrett's Oesophagus Registry. Those residing within Rotherham form the basis of this study. METHODS: We assessed socioeconomic status using the Index of Multiple Deprivation 2010 scores which can be assigned to every English postcode. The scores for the whole of England were divided into five equal groups; those of the 6257 postcodes within Rotherham (including those of Barrett's patients) were compared against the national quintile relevant to their score. We examined the ratio of observed against expected numbers of Barrett's in each quintile before and since 2001, the median year of diagnosis. RESULTS: The study group comprised 1076 patients with Barrett's oesophagus. Before 2001 their distribution across the deprivation quintiles was similar to that expected. Since then it has changed significantly, with 37% more Barrett's patients than expected among the two least deprived quintiles, but 11% fewer than expected in the larger population comprising the two most deprived quintiles (P=0.0001). There was no significant difference in the distribution of sex (P=0.27), nor the mean age at diagnosis between the two time periods (P=0.92). CONCLUSION: Since 2001, there has been a major change in the distribution of Barrett's in relation to socioeconomic status, measured by the Index of Multiple Deprivation.

Differentiating coeliac disease from irritable bowel syndrome by urinary volatile organic compound analysis--a pilot study.

Coeliac disease (CD), a T-cell-mediated gluten sensitive enteropathy, affects ∼ 1% of the UK population and can present with wide ranging clinical features, often being mistaken for Irritable Bowel Syndrome (IBS). Heightened clinical awareness and serological screening identifies those with potential coeliac disease; the diagnosis is confirmed with duodenal biopsies, and symptom improvement with a gluten-free diet. Limitations to diagnosis are false negative serology and reluctance to undergo biopsy. The gut microbiome is altered in several gastrointestinal disorders, causing altered gut fermentation patterns recognisable by volatile organic compounds (VOC) analysis in urine, breath and faeces. We aimed to determine if CD alters the urinary VOC pattern, distinguishing it from IBS. 47 patients were recruited, 27 with established CD, on gluten free diets, and 20 with diarrhoea-predominant IBS (D-IBS). Collected urine was stored frozen in 10 ml aliquots. For assay, the specimens were heated to 40 ± 0.1°C and the headspace analysed by Field Asymmetric Ion Mobility Spectrometry (FAIMS). Machine learning algorithms were used for statistical evaluation. Samples were also analysed using Gas chromatography and mass spectroscopy (GC-MS). Sparse logistic regression showed that FAIMS distinguishes VOCs in CD vs D-IBS with ROC curve AUC of 0.91 (0.83-0.99), sensitivity and specificity of 85% respectively. GCMS showed a unique peak at 4'67 found only in CD, not D-IBS, which correlated with the compound 1,3,5,7 cyclooctatetraene. This study suggests that FAIMS offers a novel, non-invasive approach to identify those with possible CD, and distinguishes from D-IBS. It offers the potential for monitoring compliance with a gluten-free diet at home. The presence of cyclooctatetraene in CD specimens will need further validation.

Detection of colorectal cancer (CRC) by urinary volatile organic compound analysis.

Colorectal cancer (CRC) is a leading cause of cancer related death in Europe and the USA. There is no universally accepted effective non-invasive screening test for CRC. Guaiac based faecal occult blood (gFOB) testing has largely been superseded by Faecal Immunochemical testing (FIT), but sensitivity still remains poor. The uptake of population based FOBt testing in the UK is also low at around 50%. The detection of volatile organic compounds (VOCs) signature(s) for many cancer subtypes is receiving increasing interest using a variety of gas phase analytical instruments. One such example is FAIMS (Field Asymmetric Ion Mobility Spectrometer). FAIMS is able to identify Inflammatory Bowel disease (IBD) patients by analysing shifts in VOCs patterns in both urine and faeces. This study extends this concept to determine whether CRC patients can be identified through non-invasive analysis of urine, using FAIMS. 133 patients were recruited; 83 CRC patients and 50 healthy controls. Urine was collected at the time of CRC diagnosis and headspace analysis undertaken using a FAIMS instrument (Owlstone, Lonestar, UK). Data was processed using Fisher Discriminant Analysis (FDA) after feature extraction from the raw data. FAIMS analyses demonstrated that the VOC profiles of CRC patients were tightly clustered and could be distinguished from healthy controls. Sensitivity and specificity for CRC detection with FAIMS were 88% and 60% respectively. This study suggests that VOC signatures emanating from urine can be detected in patients with CRC using ion mobility spectroscopy technology (FAIMS) with potential as a novel screening tool.

A novel tool for noninvasive diagnosis and tracking of patients with inflammatory bowel disease.

BACKGROUND: The pathogenesis of inflammatory bowel disease (IBD) involves the role of bacteria. These bacteria ferment nonstarch polysaccharides in the colon producing a fermentation profile that through altered gut permeability can be traced in urine. We proposed to track the resultant volatile organic compounds or gases that emanate from urine using noninvasive real-time tools, specifically by electronic nose and Field Asymmetric Ion Mobility Spectrometer (FAIMS) instruments. The aim of this study was to determine the utility of electronic nose and FAIMS instruments to detect and track the fermentation profile of patients with IBD. METHODS: Sixty-two individuals were recruited, 48 individuals with IBD (24 with Crohn's disease and ulcerative colitis, respectively) and 14 controls. The disease activity was recorded, and urine samples were collected. The headspace (the air above the sample) was analyzed using the electronic nose and FAIMS instruments. RESULTS: Electronic nose data analysis was conducted through (1) Principal Component Analysis (data were analyzed together without previous categorization); and (2) Discriminant Function Analysis (samples were precategorized [clinical groups]). The FAIMS data were processed by Fisher's Discriminant Analysis (precategorized [clinical groups]). Both technologies consistently showed the ability to separate those with IBD and controls with a >75% accuracy; P < 0.001. In a smaller subgroup (n = 24), we also demonstrated that the electronic nose and FAIMS instruments can distinguish between active disease and those in remission. CONCLUSIONS: The fermentation profile or fermentome is disparate in those with IBD compared with controls--a reflection of the bacterial diversity in health and disease. This profile also changes (and was tracked) as the disease is induced into remission. Thus, the electronic nose and FAIMS instruments offer the potential of a noninvasive real-time diagnostic tool for point of care clinical use.

The detection of patients at risk of gastrointestinal toxicity during pelvic radiotherapy by electronic nose and FAIMS: a pilot study.

It is well known that the electronic nose can be used to identify differences between human health and disease for a range of disorders. We present a pilot study to investigate if the electronic nose and a newer technology, FAIMS (Field Asymmetric Ion Mobility Spectrometry), can be used to identify and help inform the treatment pathway for patients receiving pelvic radiotherapy, which frequently causes gastrointestinal side-effects, severe in some. From a larger group, 23 radiotherapy patients were selected where half had the highest levels of toxicity and the others the lowest. Stool samples were obtained before and four weeks after radiotherapy and the volatiles and gases emitted analysed by both methods; these chemicals are products of fermentation caused by gut microflora. Principal component analysis of the electronic nose data and wavelet transform followed by Fisher discriminant analysis of FAIMS data indicated that it was possible to separate patients after treatment by their toxicity levels. More interestingly, differences were also identified in their pre-treatment samples. We believe these patterns arise from differences in gut microflora where some combinations of bacteria result to give this olfactory signature. In the future our approach may result in a technique that will help identify patients at "high risk" even before radiation treatment is started.

Initial observations using a novel "cine" magnetic resonance imaging technique to detect changes in abdominal motion caused by encapsulating peritoneal sclerosis.

Encapsulating peritoneal sclerosis (EPS) is an uncommon complication of peritoneal dialysis (PD), with high mortality and morbidity. The peritoneum thickens, dysfunctions, and forms a cocoon that progressively "strangulates" the small intestine, causing malnutrition, ischemia, and infarction. There is as yet no reliable noninvasive means of diagnosis, but recent developments in image analysis of cine magnetic resonance imaging for the recognition of adhesions offers a way forward. We used this protocol before surgery in 3 patients with suspected EPS. Image analysis revealed patterns of abdominal movement that were markedly different from the patterns in healthy volunteers. The volunteers showed marked movement throughout the abdomen; in contrast, movement in EPS patients was restricted to just below the diaphragm. This clear difference provides early "proof of principle" of the approach that we have developed.

Look--but also listen! ReQuest: an essay on a new validated scale to assess the outcome of GERD treatment.

UNLABELLED: The ReQuest (Reflux Questionnaire) is a new instrument: a diary developed specifically to allow patients to measure the totality of their gastroesophageal reflux disease (GERD) symptoms and to track changes each day during treatment, an increasingly important need in clinical trials. This paper reviews the background, development, testing, and validation of the instrument and shows how its flexibility allows it to be used in new ways to assess different aspects of GERD. DEVELOPMENT: There were four key steps. (1) A full symptom spectrum was gathered from experts, literature and, crucially, from GERD patients, and comprised 67 symptom descriptions. (2) By expert consensus, these symptom descriptions were empirically condensed into six easier-to-handle 'dimensions' (acid complaints, upper abdominal/stomach complaints, lower abdominal/digestive complaints, nausea, sleep disturbances, other complaints), to which the seventh, general well-being, was added, a key feature of the instrument. The symptom burden of each dimension is measured as frequency x intensity (general well-being: intensity only). (3) This prototype instrument was tested in PPI clinical trials involving patients with erosive and non-erosive GERD, while the data generated were used to validate the prototype. (4) Finally, the scale was refined by factor analysis, a statistical process. OUTCOME: Detailed statistical testing validating the scale and factor analysis confirmed that empirically condensing the symptom descriptions into dimensions did not affect the measurement properties of the instrument. FURTHER APPLICATION: The structure of ReQuest and its product, which is numerical, makes the instrument highly flexible and allows for its use in other GERD areas. (1) Its subscales, ReQuest-GI and ReQuest-WSO, measure symptoms traditionally associated with reflux and with general well-being, respectively, and permit these to be quantified and tracked independently. (2) Minor degrees of reflux symptoms are common amongst the healthy. The level was determined in a large population without evidence of disease, and a 'GERD symptom threshold' calculated. Reduction below this threshold to 'background levels' is a more realistic end point in clinical trials than the rarely achieved 'complete absence'. (3) ReQuest-GI was re-scaled and integrated with the modified Los Angeles scale used to grade esophageal appearances at endoscopy. The new instrument is a matrix, the ReQuest/LA-classification, which allows both symptoms and endoscopy appearances to be expressed by a single set of numbers in individual patients and in populations. (4) This in turn allows identification of patients who on treatment achieve 'complete remission', i.e. healing and symptom relief. PPI clinical trials confirm that it takes a longer period of treatment to reach this endpoint than healing or symptom relief alone. Thus the conventional 4-8 weeks of PPI therapy may unwittingly result in under-treatment. (5) Studies are in progress to determine the 'minimum clinically important difference' (MCID). This is the minimum change measured on treatment, which is judged as being of clinical benefit, an increasingly important subject. (6) Finally, the ReQuest used in clinical trials has been simplified for application in day-to-day clinical practice. The results obtained with 'ReQuest in Practice', the simplified version, are similar to those observed with the full version, as confirmed in a large-scale study in general practice. The clinical practice version has also been validated. CONCLUSION: (1) The characteristics of ReQuest make it suitable for use as the primary endpoint in clinical trials assessing the outcome of GERD. (2) The subscales allows for closer examination on the nature of GERD and response to treatment. (3) A simplified version has proven suitable for use in daily practice.

Esomeprazole 40 mg and 20 mg is efficacious in the long-term management of patients with endoscopy-negative gastro-oesophageal reflux disease: a placebo-controlled trial of on-demand therapy for 6 months.

BACKGROUND: On-demand therapy may offer an effective approach to the long-term management of gastro-oesophageal reflux disease (GORD) without oesophagitis. AIM: To examine the efficacy of the novel proton pump inhibitor esomeprazole as on-demand therapy in endoscopy-negative GORD. PATIENTS AND METHODS: Endoscopy-negative GORD patients who achieved complete resolution of heartburn after short-term esomeprazole or omeprazole treatment (n = 721) were randomized to esomeprazole 20 mg (n = 282), 40 mg (n = 293) or placebo (n = 146) on demand (maximum one dose/day) for 6 months. The primary and secondary efficacy endpoints were time to study discontinuation due to (i) unwillingness to continue and (ii) inadequate control of heartburn, respectively. RESULTS: Both doses of esomeprazole were more effective than placebo. During the 6-month period, 42% of placebo recipients discontinued treatment due to unwillingness to continue, compared with 8% and 11% of esomeprazole 20 mg and 40 mg recipients, respectively. Overall, more patients treated with esomeprazole were free from gastrointestinal symptoms after 6 months of on-demand therapy. CONCLUSIONS: Esomeprazole 20 mg was superior to placebo for on-demand treatment of GORD; a higher dose did not confer additional clinical benefit. Over 90% of patients were willing to continue on-demand treatment with esomeprazole 20 mg over a 6-month period.