Tumour infiltrating lymphocytes and survival after adjuvant chemotherapy in patients with gastric cancer: post-hoc analysis of the CLASSIC trial.

BACKGROUND: Only a subset of gastric cancer (GC) patients with stage II-III benefits from chemotherapy after surgery. Tumour infiltrating lymphocytes per area (TIL density) has been suggested as a potential predictive biomarker of chemotherapy benefit. METHODS: We quantified TIL density in digital images of haematoxylin-eosin (HE) stained tissue using deep learning in 307 GC patients of the Yonsei Cancer Center (YCC) (193 surgery+adjuvant chemotherapy [S + C], 114 surgery alone [S]) and 629 CLASSIC trial GC patients (325 S + C and 304 S). The relationship between TIL density, disease-free survival (DFS) and clinicopathological variables was analysed. RESULTS: YCC S patients and CLASSIC S patients with high TIL density had longer DFS than S patients with low TIL density (P = 0.007 and P = 0.013, respectively). Furthermore, CLASSIC patients with low TIL density had longer DFS if treated with S + C compared to S (P = 0.003). No significant relationship of TIL density with other clinicopathological variables was found. CONCLUSION: This is the first study to suggest TIL density automatically quantified in routine HE stained tissue sections as a novel, clinically useful biomarker to identify stage II-III GC patients deriving benefit from adjuvant chemotherapy. Validation of our results in a prospective study is warranted.

Immunotherapies for hepatocellular carcinoma.

Cases of hepatocellular carcinoma (HCC) are rapidly rising. This is particularly the case in the Western world, as a result of increasing rates of chronic liver disease, secondary to lifestyle-associated risk factors and the lack of an established screening programme for the general population. Traditionally, radical/curative treatment options for HCC, including liver transplantation and surgical resection are reserved for the minority of patients, presenting with an early stage cancer. For patients with advanced disease, Sorafenib and Lenvatinib were, until recently, the only licensed systemic treatments, and provided only limited survival benefits at the cost of a multitude of potential side effects. Recent scientific advances in the field of cancer immunotherapy have renewed significant interest in advanced HCC, in order to fulfil this apparent area of unmet clinical need. This has led to the success and recent regulatory approval of an Atezolizumab/Bevacizumab combination for the first-line treatment of advanced HCC following results from the IMbrave150 clinical trial in 2019, with further immune checkpoint inhibitors currently undergoing testing in advanced clinical trials. Furthermore, other cancer immunotherapies, including chimeric antigen receptor T-cells, dendritic cell vaccines and oncolytic viruses are also in early stage clinical trials, for the treatment of advanced HCC. This review will summarise the major approaches that have been and are currently in development for the systemic treatment of advanced HCC, their advantages, drawbacks, and predictions of where this revolutionary treatment field will continue to travel for the foreseeable future.

Development and validation of deep learning classifiers to detect Epstein-Barr virus and microsatellite instability status in gastric cancer: a retrospective multicentre cohort study.

BACKGROUND: Response to immunotherapy in gastric cancer is associated with microsatellite instability (or mismatch repair deficiency) and Epstein-Barr virus (EBV) positivity. We therefore aimed to develop and validate deep learning-based classifiers to detect microsatellite instability and EBV status from routine histology slides. METHODS: In this retrospective, multicentre study, we collected tissue samples from ten cohorts of patients with gastric cancer from seven countries (South Korea, Switzerland, Japan, Italy, Germany, the UK and the USA). We trained a deep learning-based classifier to detect microsatellite instability and EBV positivity from digitised, haematoxylin and eosin stained resection slides without annotating tumour containing regions. The performance of the classifier was assessed by within-cohort cross-validation in all ten cohorts and by external validation, for which we split the cohorts into a five-cohort training dataset and a five-cohort test dataset. We measured the area under the receiver operating curve (AUROC) for detection of microsatellite instability and EBV status. Microsatellite instability and EBV status were determined to be detectable if the lower bound of the 95% CI for the AUROC was above 0·5. FINDINGS: Across the ten cohorts, our analysis included 2823 patients with known microsatellite instability status and 2685 patients with known EBV status. In the within-cohort cross-validation, the deep learning-based classifier could detect microsatellite instability status in nine of ten cohorts, with AUROCs ranging from 0·597 (95% CI 0·522-0·737) to 0·836 (0·795-0·880) and EBV status in five of eight cohorts, with AUROCs ranging from 0·819 (0·752-0·841) to 0·897 (0·513-0·966). Training a classifier on the pooled training dataset and testing it on the five remaining cohorts resulted in high classification performance with AUROCs ranging from 0·723 (95% CI 0·676-0·794) to 0·863 (0·747-0·969) for detection of microsatellite instability and from 0·672 (0·403-0·989) to 0·859 (0·823-0·919) for detection of EBV status. INTERPRETATION: Classifiers became increasingly robust when trained on pooled cohorts. After prospective validation, this deep learning-based tissue classification system could be used as an inexpensive predictive biomarker for immunotherapy in gastric cancer. FUNDING: German Cancer Aid and German Federal Ministry of Health.

Characterising cancer-associated fibroblast heterogeneity in non-small cell lung cancer: a systematic review and meta-analysis.

Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with evidence suggesting they represent a heterogeneous population. This study summarises the prognostic role of all proteins characterised in CAFs with immunohistochemistry in non-small cell lung cancer thus far. The functions of these proteins in cellular processes crucial to CAFs are also analysed. Five databases were searched to extract survival outcomes from published studies and statistical techniques, including a novel method, used to capture missing values from the literature. A total of 26 proteins were identified, 21 of which were combined into 7 common cellular processes key to CAFs. Quality assessments for sensitivity analyses were carried out for each study using the REMARK criteria whilst publication bias was assessed using funnel plots. Random effects models consistently identified the expression of podoplanin (Overall Survival (OS)/Disease-specific Survival (DSS), univariate analysis HR 2.25, 95% CIs 1.80-2.82) and α-SMA (OS/DSS, univariate analysis HR 2.11, 95% CIs 1.18-3.77) in CAFs as highly prognostic regardless of outcome measure or analysis method. Moreover, proteins involved in maintaining and generating the CAF phenotype (α-SMA, TGF-ß and p-Smad2) proved highly significant after sensitivity analysis (HR 2.74, 95% CIs 1.74-4.33) supporting attempts at targeting this pathway for therapeutic benefit.

A non-linear optimisation method to extract summary statistics from Kaplan-Meier survival plots using the published P value.

BACKGROUND: Meta-analyses of studies evaluating survival (time-to-event) outcomes are a powerful technique to assess the strength of evidence for a given disease or treatment. However, these studies rely on the adequate reporting of summary statistics in the source articles to facilitate further analysis. Unfortunately, many studies, especially within the field of prognostic research do not report such statistics, making secondary analyses challenging. Consequently, methods have been developed to infer missing statistics from the commonly published Kaplan-Meier (KM) plots but are liable to error especially when the published number at risk is not included. METHODS: We therefore developed a method using non-linear optimisation (nlopt) that only requires the KM plot and the commonly published P value to better estimate the underlying censoring pattern. We use this information to then calculate the natural logarithm of the hazard ratio (ln (HR)) and its variance (var) ln (HR), statistics important for meta-analyses. RESULTS: We compared this method to the Parmar method which also does not require the number at risk to be published. In a validation set consisting of 13 KM studies, a statistically significant improvement in calculating ln (HR) when using an exact P value was obtained (mean absolute error 0.014 vs 0.077, P = 0.003). Thus, when the true HR has a value of 1.5, inference of the HR using the proposed method would set limits between 1.49/1.52, an improvement of the 1.39/1.62 limits obtained using the Parmar method. We also used Monte Carlo simulations to establish recommendations for the number and positioning of points required for the method. CONCLUSION: The proposed non-linear optimisation method is an improvement on the existing method when only a KM plot and P value are included and as such will enhance the accuracy of meta-analyses performed for studies analysing time-to-event outcomes. The nlopt source code is available, as is a simple-to-use web implementation of the method.

Using immersive virtual reality to modify body image.

We tested the efficacy of a training programme, delivered in virtual reality (VR), to modify the perceptual boundary between what participants classify as a fat versus a thin body. Three cohorts of 20 female volunteers with high body image concerns were recruited to two intervention groups and one control group. All participants completed a 4-day training programme in VR where they categorised a series of 3D models as either thin or fat; one intervention group was presented with the stimuli briefly, while the other group had no time limits imposed. Both intervention groups were given inflationary feedback to shift their categorisations of the stimulus models towards higher BMIs. Our results show that, compared to controls, both intervention groups shifted their categorical boundaries between Day 1 and follow-up on Day 14. Unlimited stimulus presentation times were associated with a larger training effect. Furthermore, both intervention groups experienced statistically significant reductions in their concerns about their own body shape, weight and eating habits. However, only in the group with longer stimulus presentation times were these reductions consistent with a clinically meaningful effect. These findings suggest that manipulating categorical perception in VR might provide a complementary addition to existing treatments for eating disorders.

ZEB1 and IL-6/11-STAT3 signalling cooperate to define invasive potential of pancreatic cancer cells via differential regulation of the expression of S100 proteins.

BACKGROUND: S100 proteins have been implicated in various aspects of cancer, including epithelial-mesenchymal transitions (EMT), invasion and metastasis, and also in inflammatory disorders. Here we examined the impact of individual members of this family on the invasion of pancreatic ductal adenocarcinoma (PDAC) cells, and their regulation by EMT and inflammation. METHODS: Invasion of PDAC cells was analysed in zebrafish embryo xenografts and in transwell invasion assays. Expression and regulation of S100 proteins was studied in vitro by immunoblotting, quantitative PCR and immunofluorescence, and in pancreatic lesions by immunohistochemistry. RESULTS: Whereas the expression of most S100 proteins is characteristic for epithelial PDAC cell lines, S100A4 and S100A6 are strongly expressed in mesenchymal cells and upregulated by ZEB1. S100A4/A6 and epithelial protein S100A14 respectively promote and represses cell invasion. IL-6/11-STAT3 pathway stimulates expression of most S100 proteins. ZEB1 synergises with IL-6/11-STAT3 to upregulate S100A4/A6, but nullifies the effect of inflammation on S100A14 expression. CONCLUSION: EMT/ZEB1 and IL-6/11-STAT3 signalling act independently and congregate to establish the expression pattern of S100 proteins, which drives invasion. Although ZEB1 regulates expression of S100 family members, these effects are masked by IL-6/11-STAT3 signalling, and S100 proteins cannot be considered as bona fide EMT markers in PDAC.

Fatigue and its associated factors in microscopic colitis.

BACKGROUND: Fatigue is a well-recognized symptom in patients with inflammatory bowel disease and irritable bowel syndrome (IBS), and has been associated with psychological comorbidity and impaired quality of life in both. However, features associated with fatigue in patients with microscopic colitis (MC) are less clear. MATERIALS AND METHODS: We conducted a cross-sectional survey of patients with a new diagnosis of MC including levels of anxiety, depression, somatization, quality of life, and IBS-type symptoms. Levels and impact of fatigue were assessed using the Inflammatory Bowel Disease Fatigue self-assessment scale. Mean scores were compared against various patient characteristics, and were also correlated with anxiety, depression, somatization, and quality-of-life scores. RESULTS: In total, 129 patients with MC diagnosed between 2010 and 2015 returned completed postal questionnaires. Common histological subtypes were collagenous colitis (53.5%, n = 69) and lymphocytic colitis (38.8%, n = 50). Higher mean fatigue severity and impact scores were associated with the presence of irritable-bowel-syndrome-type symptoms, abnormal levels of anxiety and depression, and high levels of somatization (p < 0.0001 for all), but those reporting ongoing symptoms attributable to MC did not report significantly higher scores. There were significant positive correlations between total anxiety, depression, or somatization scores and fatigue severity and impact scores, and significant negative correlations with quality-of-life measures (p < 0.001 for all). CONCLUSIONS: Fatigue in MC appears to be associated with reporting IBS-type symptoms, psychological comorbidity and impaired quality of life. It may therefore represent an important target for treatment.

Targeting the Platelet-Derived Growth Factor-beta Stimulatory Circuitry to Control Retinoblastoma Seeds.

Purpose: Vitreous seeding remains the primary reason for treatment failure in eyes with retinoblastoma (Rb). Systemic and intra-arterial chemotherapy, each with its own inherent set of complications, have improved salvage rates for eyes with advanced disease, but the location and biology of vitreous seeds present a fundamental challenge in developing treatments with minimal toxicity and risk. The aim of this study was to target the platelet-derived growth factor (PDGF)- PDGF-receptor ß (PDGFRß) signaling pathway and investigate its role in the growth of Rb seeds, apoptotic activity, and invasive potential. Methods: We performed ex vivo analyses on vitreous samples from Rb patients that underwent enucleation and from patient-derived xenografts. These samples were evaluated by quantitative PCR, immunohistochemistry, and ELISA. The effects of disruption of the PDGF-PDGFRß signaling pathway, both by pharmacologic and genomic knockdown approaches, were evaluated in vitro by cell proliferation and apoptotic assays, quantitative PCR analyses, Western blotting, flow cytometry, and imaging flow cytometry. A three-dimensional cell culture system was generated for in-depth study of Rb seeds. Results: Our results demonstrated that PDGFRß signaling is active in the vitreous of Rb patients and patient-derived xenografts, sustaining growth and survival in an AKT-, MDM2-, and NF-κB-dependent manner. The novel three-dimensional cell culture system mimics Rb seeds, as the in vitro generated spheroids have similar morphologic features to Rb seeds and mimicked their natural physiology. Conclusions: Targeting the PDGFRß pathway in vitro reduces Rb cell growth, survival, and invasiveness and could augment current therapies. This represents a novel signaling pathway for potential targeted therapy to further improve ocular survival in advanced Rb.

High prevalence of irritable bowel syndrome-type symptoms in microscopic colitis: implications for treatment.

BACKGROUND: Patients with microscopic colitis (MC) often present with abdominal pain and diarrhoea, and previous data suggest that there may be overlap between MC and irritable bowel syndrome (IBS). We evaluated the prevalence of IBS-type symptoms in patients with MC, and assess the impact of these symptoms on psychological health and quality of life. METHODS: We conducted a cross-sectional survey of individuals with a histological diagnosis of MC, collecting demographic data, Rome III IBS-type symptoms, and mood, somatization, and quality of life data. RESULTS: In total, 151 (31.6%) of 478 individuals with a new diagnosis of MC completed questionnaires, 52 (34.4%) of whom reported IBS-type symptoms. The commonest histological subtype was collagenous colitis (51.7%, n = 78), followed by lymphocytic colitis (39.1%, n = 59). Individuals with IBS-type symptoms had significantly higher levels of anxiety [Hospital Anxiety and Depression Scale (HADS) anxiety score 8.6 versus 5.1, p < 0.001], depression (HADS depression score 6.2 versus 3.6, p = 0.001), and somatoform-type behaviour (Patient Health Questionnaire 15 score 12.7 versus 8.0, p < 0.001) compared with individuals who did not. Those with IBS-type symptoms scored significantly worse across all domains of the 36-item Short Form questionnaire, except for physical functioning. CONCLUSIONS: More than one third of individuals with MC reported IBS-type symptoms, although whether this is due to ongoing inflammation is unclear. These individuals had higher levels of anxiety, depression, and somatization, and impaired quality of life. Identifying concomitant IBS in individuals with MC may have important implications for management decisions.

Return to learn after concussion in children.

Question Despite recent interest in the pathophysiology and management of concussion in children, as well as the ongoing concern about return to activity, advice regarding the type and length of cognitive rest has been inconsistent. What should I recommend to the children and adolescents in my clinic regarding cognitive rest following mild concussion? Answer Strict cognitive rest is not needed in those with mild concussion. Evidence suggests a decrease in usual activity to a level that allows children to remain asymptomatic, followed by a gradual return to learning, is appropriate. It is clear that either too little or too much activity is disadvantageous to recovery and can worsen outcomes.

Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in in vitro models of retinoblastoma.

BACKGROUND: Retinoblastoma (Rb) is the most common primary intraocular tumor in children. Local treatment of the intraocular disease is usually effective if diagnosed early; however advanced Rb can metastasize through routes that involve invasion of the choroid, sclera and optic nerve or more broadly via the ocular vasculature. Metastatic Rb patients have very high mortality rates. While current therapy for Rb is directed toward blocking tumor cell division and tumor growth, there are no specific treatments targeted to block Rb metastasis. Two such targets are matrix metalloproteinases-2 and -9 (MMP-2, -9), which degrade extracellular matrix as a prerequisite for cellular invasion and have been shown to be involved in other types of cancer metastasis. Cancer Clinical Trials with an anti-MMP-9 therapeutic antibody were recently initiated, prompting us to investigate the role of MMP-2, -9 in Rb metastasis. METHODS: We compare MMP-2, -9 activity in two well-studied Rb cell lines: Y79, which exhibits high metastatic potential and Weri-1, which has low metastatic potential. The effects of inhibitors of MMP-2 (ARP100) and MMP-9 (AG-L-66085) on migration, angiogenesis, and production of immunomodulatory cytokines were determined in both cell lines using qPCR, and ELISA. Cellular migration and potential for invasion were evaluated by the classic wound-healing assay and a Boyden Chamber assay. RESULTS: Our results showed that both inhibitors had differential effects on the two cell lines, significantly reducing migration in the metastatic Y79 cell line and greatly affecting the viability of Weri-1 cells. The MMP-9 inhibitor (MMP9I) AG-L-66085, diminished the Y79 angiogenic response. In Weri-1 cells, VEGF was significantly reduced and cell viability was decreased by both MMP-2 and MMP-9 inhibitors. Furthermore, inhibition of MMP-2 significantly reduced secretion of TGF-ß1 in both Rb models. CONCLUSIONS: Collectively, our data indicates MMP-2 and MMP-9 drive metastatic pathways, including migration, viability and secretion of angiogenic factors in Rb cells. These two subtypes of matrix metalloproteinases represent new potential candidates for targeted anti-metastatic therapy for Rb.

Effect of psychological therapy on disease activity, psychological comorbidity, and quality of life in inflammatory bowel disease: a systematic review and meta-analysis.

BACKGROUND: Inflammatory bowel disease is associated with psychological comorbidity and impaired quality of life. Psychological comorbidity could affect the natural history of inflammatory bowel disease. Psychological therapies might therefore have beneficial effects on disease activity, mood, and quality of life in patients with inflammatory bowel disease. We did a systematic review and meta-analysis examining these issues. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, Embase, Embase Classic, PsychINFO, and the Cochrane Central Register of Controlled Trials for articles published between 1947 and Sept 22, 2016. Randomised controlled trials (RCTs) recruiting patients with inflammatory bowel disease aged at least 16 years that compared psychological therapy with a control intervention or usual treatment were eligible. We pooled dichotomous data to obtain relative risks of induction of remission in active disease or prevention of relapse of quiescent disease, with 95% CIs. We pooled continuous data to estimate standardised mean differences in disease activity indices, anxiety, depression, perceived stress, and quality-of-life scores in patients dichotomised into those with clinically active or quiescent disease, with 95% CIs. We extracted data from published reports and contacted the original investigators of studies for which the required data were not available. We pooled all data using a random-effects model. FINDINGS: The search identified 1824 studies, with 14 RCTs of 1196 patients eligible for inclusion. The relative risk of relapse of quiescent inflammatory bowel disease with psychological therapy versus control was 0·98 (95% CI 0·77-1·24; p=0·87; I2=50%; six trials; 518 patients). We observed a significant difference in depression scores (standardised mean difference -0·17 [-0·33 to -0·01]; p=0·04; I2=0%; seven trials; 605 patients) and quality of life (0·30 [0·07-0·52]; p=0·01; I2=42%; nine trials; 578 patients) with psychological therapy versus control at the end of therapy for patients with quiescent disease. However, these beneficial effects were lost at final point of follow-up (depression scores -0·11 [-0·27 to 0·05], p=0·17, I2=0%, eight trials, 593 patients; quality of life 0·15 [-0·05 to 0·34], p=0·14, I2=22%, ten trials, 577 patients). When we assessed the effect of individual physiological therapies on quality of life, only cognitive behavioural therapy had any significant beneficial effect (0·37 [0·02-0·72]). We noted no effect on disease activity indices or other psychological wellbeing scores when compared with control in patients with quiescent disease. Dichotomous data for induction of remission and continuous data for change in clinical disease activity indices, depression, anxiety, and perceived stress scores were only reported in one RCT of patients with active disease. Quality of life was assessed in two RCTs of patients with active disease, but was not significantly different between intervention and control groups (0·27 [-0·05 to 0·59]). INTERPRETATION: Psychological therapies, and cognitive behavioural therapy in particular, might have small short-term beneficial effects on depression scores and quality of life in patients with inflammatory bowel disease. Further RCTs of these interventions in patients with coexistent psychological distress are required. FUNDING: None.

Endoscopic ultrasound sedation in the United Kingdom: Is life without propofol tolerable?

There is compelling evidence to support the quality, cost effectiveness and safety profile of non-anesthesiologist-administered propofol for endoscopic ultrasound (EUS). However in the United Kingdom, it is recommended that the administration and monitoring of propofol sedation for endoscopic procedures should be the responsibility of a dedicated and appropriately trained anaesthetist only. The majority of United Kingdom EUS procedures are performed with opiate and benzodiazepine sedation rather than anaesthetist led propofol lists due to anaesthetist resource availability. We sought to prospectively determine the tolerability and safety of EUS with benzodiazepine and opiate sedation in single United Kingdom centre. Two hundred consecutive patients undergoing either EUS or oesophago-gastroduodenoscopy (OGD) with conscious sedation were prospectively recruited with a 1:1 enrolment ratio. Patients completed questionnaires pre and post procedure detailing anticipated and actual pain experienced on a 1-10 visual analogue scale. Demographics, procedure duration, sedation doses and willingness to repeat the procedure were also recorded. EUS procedures lasted significantly longer than OGDs (15 min vs 6 min, P < 0.0001), however, there was no difference in anticipated pain scores between the groups (EUS 3.37/10 vs OGD 3.47/10, P = 0.46). Pain scores indicated EUS was better tolerated than OGD (1.16/10 vs 1.88/10, P = 0.03) although higher doses of sedation were used for EUS procedures. There were no complications identified in either group. We feel our study demonstrates that the tolerability of EUS with opiate and benzodiazepine sedation is acceptable.

Minimal differences in prevalence and spectrum of organic disease at upper gastrointestinal endoscopy between selected secondary care patients with symptoms of gastro-oesophageal reflux or dyspepsia.

OBJECTIVES: Gastro-oesophageal reflux and dyspepsia are felt to be separate upper gastrointestinal (GI) conditions. We aimed to measure the degree of overlap between them, and assess whether endoscopic findings differed. MATERIAL AND METHODS: Demographic, symptom, upper GI endoscopy and histology data were collected from consecutive adults in secondary care. Patients were categorised according to whether they reported gastro-oesophageal reflux alone, dyspepsia alone or both, and patient demographics and endoscopic findings were compared. RESULTS: Of 1167 patients, 97 (8.3%) had gastro-oesophageal reflux alone, 571 (48.9%) dyspepsia alone, and 499 (42.8%) overlap. Patients with overlap symptoms were more likely to smoke, compared with those with gastro-oesophageal reflux alone, or dyspepsia alone (p = .009), but there were no other differences. Patients with gastro-oesophageal reflux alone or overlap had a higher prevalence of erosive oesophagitis (18.6% and 15.4% respectively, p < .001), but this was still the commonest diagnosis among those with dyspepsia alone (7.2%). No significant differences were seen in prevalence of other endoscopic findings. CONCLUSIONS: Gastro-oesophageal reflux and dyspepsia symptoms commonly overlap. There were minimal differences in demographics or spectrum of underlying organic disease between various symptom groups, suggesting that restrictive classifications according to predominant symptom may not be clinically useful.

Screening for Celiac Disease in Irritable Bowel Syndrome: An Updated Systematic Review and Meta-analysis.

OBJECTIVES: Celiac disease (CD) and irritable bowel syndrome (IBS) share similar symptoms, leading to confusion between the two and diagnostic delay. International guidelines recommend screening individuals with IBS for CD, via serological testing. However, studies published recently have cast doubt on the utility of this. We updated a previous meta-analysis examining this issue. METHODS: MEDLINE, EMBASE, and EMBASE Classic were searched through to May 2016. Eligible studies recruited adults with IBS according to symptom-based criteria, physician's opinion, or questionnaire data. Tests for CD included IgA-class antigliadin antibodies (AGA), endomysial antibodies (EMA), tissue transglutaminase antibodies (tTG), or duodenal biopsies following positive serology. The proportion of individuals meeting criteria for IBS testing positive for CD was combined to give a pooled prevalence for all studies, and compared between cases with IBS and, healthy controls without (where reported), using an odds ratio (OR) with a 95% confidence interval (CI). RESULTS: There were 36 eligible studies, recruiting 15,256 individuals, of whom 9,275 (60.8%) met criteria for IBS. Pooled ORs for positive IgA AGAs, EMA and/or tTG, and biopsy-proven CD in IBS subjects vs. controls were 3.21 (95% CI 1.55-6.65), 2.75 (95% CI 1.35-5.61), and 4.48 (95% CI 2.33-8.60), respectively. There was no increase in ORs for any test for CD among cases with IBS in North American studies, and results were inconsistent in population-based studies. The prevalence of biopsy-proven CD was significantly higher across all subtypes of IBS. Limitations included heterogeneity in some analyses, and few North American studies. CONCLUSIONS: Overall, prevalence of positive celiac serology and biopsy-proven CD was significantly higher in subjects with symptoms suggestive of IBS vs. healthy controls. However, the utility of screening for CD in individuals with suspected IBS in North America or in the community is less clear.

How does tolerability of double balloon enteroscopy compare to other forms of endoscopy?

BACKGROUND AND AIMS: Gastrointestinal endoscopy can be difficult for patients to tolerate. Studies on endoscopic tolerability mainly focus on gastroscopy or colonoscopy with a paucity of data on double balloon enteroscopy (DBE). We aimed to prospectively evaluate tolerability in patients undergoing several forms of endoscopy including DBE. METHODS: Consecutive patients undergoing colonoscopy, flexible sigmoidoscopy, gastroscopy, endoscopic retrograde pancreatography (ERCP), capsule endoscopy (CE) and DBE were prospectively recruited. A questionnaire recorded demographics, procedural data, patient tolerability (pain, discomfort and distress recorded on numerical rating scales) and the Hospital Anxiety and Depression Scale (HADS). RESULTS: 956 patients were recruited (512 women; median age 57 years). The median pain score for DBE was poor with a score of 5 compared with 1 and 0 for oesophagogastroduodenoscopy and ERCP, respectively (p<0.001). Colonoscopy and retrograde DBE scores were not dissimilar. CE was well tolerated with a median pain score of 0. Patients with DBE required significantly higher doses of sedation and analgesia than other patients. The HADS Anxiety Score was also associated with poorer tolerability. CONCLUSIONS: DBE is poorly tolerated when compared with other forms of endoscopy despite higher doses of sedation. Increasing demand to improve tolerability of DBE in the UK may be addressed with the use of propofol.

Reconfigurable Boolean logic using magnetic single-electron transistors.

We propose a novel hybrid single-electron device for reprogrammable low-power logic operations, the magnetic single-electron transistor (MSET). The device consists of an aluminium single-electron transistor with a GaMnAs magnetic back-gate. Changing between different logic gate functions is realized by reorienting the magnetic moments of the magnetic layer, which induces a voltage shift on the Coulomb blockade oscillations of the MSET. We show that we can arbitrarily reprogram the function of the device from an n-type SET for in-plane magnetization of the GaMnAs layer to p-type SET for out-of-plane magnetization orientation. Moreover, we demonstrate a set of reprogrammable Boolean gates and its logical complement at the single device level. Finally, we propose two sets of reconfigurable binary gates using combinations of two MSETs in a pull-down network.

Magnonic charge pumping via spin-orbit coupling.

The interplay between spin, charge and orbital degrees of freedom has led to the development of spintronic devices such as spin-torque oscillators and spin-transfer torque magnetic random-access memories. In this development, spin pumping represents a convenient way to electrically detect magnetization dynamics. The effect originates from direct conversion of low-energy quantized spin waves in the magnet, known as magnons, into a flow of spins from the precessing magnet to adjacent leads. In this case, a secondary spin-charge conversion element, such as heavy metals with large spin Hall angle or multilayer layouts, is required to convert the spin current into a charge signal. Here, we report the experimental observation of charge pumping in which a precessing ferromagnet pumps a charge current, demonstrating direct conversion of magnons into high-frequency currents via the relativistic spin-orbit interaction. The generated electric current, unlike spin currents generated by spin-pumping, can be directly detected without the need of any additional spin-charge conversion mechanism. The charge-pumping phenomenon is generic and gives a deeper understanding of its reciprocal effect, the spin orbit torque, which is currently attracting interest for their potential in manipulating magnetic information.

Point-of-care testing for celiac disease has a low sensitivity in endoscopy.

BACKGROUND: Celiac disease (CD) is a common but underdiagnosed condition. A rapid point-of-care test (POCT) could reduce lead times and missed diagnoses. OBJECTIVE: To assess the utility of an immunoglobulin (Ig) A tissue transglutaminase (TTG) antibody POCT in an endoscopic setting. DESIGN: Prospective observational study. SETTING: A single UK university hospital. PATIENTS: Patients presenting with suspected CD, known CD, and routine endoscopy for upper GI symptoms. INTERVENTIONS: All patients were tested with POCT, serum TTG, endomysial antibody (EMA), and upper GI endoscopy with duodenal biopsies at the same visit. MAIN OUTCOME MEASUREMENTS: Comparison was made with histology in all cases, with villous atrophy regarded as diagnostic of CD. RESULTS: A total of 576 patients (63.5% female, mean [± standard deviation] age 49.7 years [± 17.6 years]) were recruited. A total of 523 patients had no prior diagnosis of CD, and 53 patients had known CD coming for reassessment. A total of 117 patients were newly diagnosed with CD, and 82 were positively identified by the POCT. Sensitivity, specificity, positive predictive value, and negative predictive value were 70.1%, 96.6%, 85.4%, and 91.8%, respectively. In comparison, TTG and EMA both performed significantly better than the POCT. Sensitivity and specificity of TTG were 91.0% and 83.5%, respectively, and EMA were 83.8% and 97.5%, respectively. Of patients with known CD coming for reassessment, 26 had villous atrophy, and POCT results were positive in 16 (61.5%). There was poor agreement between POCT and standard serology. LIMITATIONS: High pre-test probability of CD. CONCLUSION: The performance of this POCT was disappointing compared with standard serology and cannot at present be recommended within the context of an endoscopy unit.