Training pathway for small bowel capsule endoscopy in the UK.

The demand for small bowel (SB) capsule endoscopy (CE) is increasing in the UK. However, there remains a wide variation in the number of CE procedures performed in different centres. Across the UK there is a lack of a clear training pathway or certification process. A standardised national Joint Advisory Group (JAG) on Gastrointestinal Endoscopy approved a 1-year training and accreditation programme accessible to all professional groups that may wish to train in SB CE. Structured training is delivered using JAG-accredited CE courses and an electronic learning module. Prior to setting a knowledge-based assessment, a minimum of 50 SB CE cases are recommended to be read in tandem with a trainer at a local centre, with proficiency documented using Direct Observation of Procedural Skill (DOPS) assessments.

Panenteric capsule endoscopy identifies proximal small bowel disease guiding upstaging and treatment intensification in Crohn's disease: A European multicentre observational cohort study.

BACKGROUND: Endoscopically defined mucosal healing in Crohn's disease is associated with improved outcomes. Panenteric capsule endoscopy enables a single non-invasive assessment of small and large bowel mucosal inflammation. AIMS AND METHODS: This multicentre observational study of patients with suspected and established Crohn's disease examined the feasibility, safety and impact on patient outcomes of panenteric capsule endoscopy in routine clinical practice. The potential role in assessment of disease severity and extent by a comparison with existing clinical and biochemical markers is examined. RESULTS: Panenteric capsule endoscopy was performed on 93 patients (71 with established and 22 with suspected Crohn's disease). A complete examination occurred in 85% (79/93). Two cases (2.8%) of capsule retention occurred in patients with established Crohn's disease. Panenteric capsule resulted in management change in 38.7% (36/93) patients, including 64.6% (32/48) of those with an established diagnosis whose disease was active, and all three patients with newly diagnosed Crohn's disease. Montreal classification was upstaged in 33.8% of patients with established Crohn's disease and mucosal healing was demonstrated in 15.5%. Proximal small bowel disease upstaged disease in 12.7% and predicted escalation of therapy (odds ratio 40.3, 95% confidence interval 3.6-450.2). Raised C-reactive protein and faecal calprotectin were poorly sensitive in detecting active disease (0.48 and 0.59 respectively). CONCLUSIONS: Panenteric capsule endoscopy was feasible in routine practice and the ability to detect proximal small bowel disease may allow better estimation of prognosis and guide treatment intensification. Panenteric capsule endoscopy may be a suitable non-invasive endoscopic investigation in determining disease activity and supporting management decisions.

Targeting the ion channel TRPM7 promotes the thymic development of regulatory T cells by promoting IL-2 signaling.

The thymic development of regulatory T (Treg) cells, crucial suppressors of the responses of effector T (Teff) cells, is governed by the transcription factor FOXP3. Despite the clinical importance of Treg cells, there is a dearth of druggable molecular targets capable of increasing their numbers in vivo. We found that inhibiting the function of the TRPM7 chanzyme (ion channel and enzyme) potentiated the thymic development of Treg cells in mice and led to a substantially higher frequency of functional Treg cells in the periphery. In addition, TRPM7-deficient mice were resistant to T cell-driven hepatitis. Deletion of Trpm7 and inhibition of TRPM7 channel activity by the FDA-approved drug FTY720 increased the sensitivity of T cells to the cytokine interleukin-2 (IL-2) through a positive feed-forward loop involving increased expression of the IL-2 receptor α-subunit and activation of the transcriptional regulator STAT5. Enhanced IL-2 signaling increased the expression of Foxp3 in thymocytes and promoted thymic Treg (tTreg) cell development. Thus, these data indicate that inhibiting TRPM7 activity increases Treg cell numbers, suggesting that it may be a therapeutic target to promote immune tolerance.

CART-WHEEL.org: An Ethically Approved Online Database for Patient-Entered Data to Facilitate Rare Cancer Research.

PURPOSE: Rare cancers are challenging for researchers, as clinicians and scientists have difficulty recruiting sufficient patient cases to power studies appropriately. Likewise, patients often are frustrated by a lack of specific information or evidence base for their cancer and, although eager to participate in research, have limited opportunities. We established CART-WHEEL.org, an online patient-entered database, to directly engage patients in the research process, collect rare cancer data, and facilitate their entry into additional research. PATIENTS AND METHODS: Patients access CART-WHEEL.org directly online. Clinical information is collected from users via a streamlined questionnaire developed collaboratively with consumer groups to ensure accessibility and relevance. Data collected include the following: patient demographics, comorbidities, and risk factors and tumor diagnostic, biomarker, and treatment history. Patients can download a medical summary for personal use; consent for research use of data; and indicate willingness to be contacted about other research or clinical trials. We describe data collected to date and its validation, and we provide examples of how CART-WHEEL.org can facilitate rare cancer research. RESULTS: From January 2010 to March 2018, 558 patients provided consent and entered their rare cancer data. One hundred distinct rare tumor types and patients from 22 countries were included. Validation of data entered by 21 patients with sarcoma against a hospital database demonstrated accuracy sufficient to facilitate future research in key fields, such as tumor site (95%) and histopathologic diagnosis (90%). Examples of CART-WHEEL-based disease-specific projects, subsequent recruitment to other rare cancer projects, and rare cancer patient cases of interest are described. CONCLUSIONS: Online platforms like CART-WHEEL.org can engage consumers directly, facilitating collection of patient-entered rare cancer data for hypothesis generation, and connect patients with researchers to enable specific rare cancer research and clinical trials.

Predicting hospital admission at the emergency department triage: A novel prediction model.

BACKGROUND: Emergency department (ED) overcrowding is a growing international patient safety issue. A major contributor to overcrowding is long wait times for inpatient hospital admission. The objective of this study is to create a model that can predict a patient's need for hospital admission at the time of triage. METHODS: Retrospective observational study of electronic clinical records of all ED visits over ten years to a large urban hospital in Singapore. The data was randomly divided into a derivation set and a validation set. We used the derivation set to develop a logistic regression model that predicts probability of hospital admission for patients presenting to the ED. We tested the model on the validation set and evaluated the performance with receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 1,232,016 visits were included for final analysis, of which 38.7% were admitted. Eight variables were included in the final model: age group, race, postal code, day of week, time of day, triage category, mode of arrival, and fever status. The model performed well on the validation set with an area under the curve of 0.825 (95% CI 0.824-0.827). Increasing age, increasing triage acuity, and mode of arrival via private patient transport were most predictive of the need for admission. CONCLUSIONS: We developed a model that accurately predicts admission for patients presenting to the ED using demographic, administrative, and clinical data routinely collected at triage. Implementation of the model into the electronic health record could help reduce the burden of overcrowding.

BASELINE CORTICOSTERONE, HEMATOLOGY, AND BIOCHEMISTRY RESULTS AND CORRELATIONS TO REPRODUCTIVE SUCCESS IN NESTING LOGGERHEAD SEA TURTLES ( CARETTA CARETTA).

Characterizing the health status and reproductive success of wild populations of sea turtles can be difficult; however, obtaining data to do this can provide important insight into the stability and long-term success of a population. This study examined the use of baseline corticosterone to assess reproductive success of a population of nesting loggerhead sea turtles ( Caretta caretta) on Jekyll Island, Georgia and investigated hematological and biochemical trends in this population. A total of 37 nesting loggerhead sea turtles was sampled for this study. Eleven (29.7%) turtles were sampled in 2013 and 26 (70.3%) were sampled in 2014. A majority of the turtles sampled successfully nested (29/37, 78.4%; false crawls: 8/37, 21.6%). There was no significant correlation between baseline corticosterone concentrations and reproductive success (hatch success or emergence success) in this population. There was a significant positive correlation ( r = 0.461, P = 0.02) between corticosterone concentrations and absolute monocyte counts. There was a significant negative correlation between monocyte count and hatch success ( r = -0.464, P = 0.05) and a positive correlation between phosphorus and hatch success ( r = 0.405, P = 0.05). Calcium concentrations were significantly different ( P = 0.01) between animals that false crawled and those that nested, with nesting turtles having lower calcium concentrations than those that false crawled. Turtles that false crawled were significantly ( P = 0.008) more likely to have elevated potassium concentrations than turtles that nested. This study provides the first attempt at characterizing baseline corticosterone, hematology, and biochemistry data and correlations with reproductive success in nesting loggerhead sea turtles. Overall, loggerhead sea turtles capable of nesting were found to be in good health and have good reproductive success while maintaining low levels of corticosterone during reproductive activities.

Are there biological differences between screen-detected and interval colorectal cancers in the English Bowel Cancer Screening Programme?

BACKGROUND: We measured biomarkers of tumour growth and vascularity in interval and screen-detected colorectal cancers (CRCs) in the English Bowel Cancer Screening Programme in order to determine whether rapid tumour growth might contribute to interval CRC (a CRC diagnosed between a negative guaiac stool test and the next scheduled screening episode). METHODS: Formalin-fixed, paraffin-embedded sections from 71 CRCs (screen-detected 43, interval 28) underwent immunohistochemistry for CD31 and Ki-67, in order to measure the microvessel density (MVD) and proliferation index (PI), respectively, as well as microsatellite instability (MSI) testing. RESULTS: Interval CRCs were larger (P=0.02) and were more likely to exhibit venous invasion (P=0.005) than screen-detected tumours. There was no significant difference in MVD or PI between interval and screen-detected CRCs. More interval CRCs displayed MSI-high (14%) compared with screen-detected tumours (5%). A significantly (P=0.005) higher proportion (51%) of screen-detected CRC resection specimens contained at least one polyp compared with interval CRC (18%) resections. CONCLUSIONS: We found no evidence of biological differences between interval and screen-detected CRCs, consistent with the low sensitivity of guaiac stool testing as the main driver of interval CRC. The contribution of synchronous adenomas to occult blood loss for screening requires further investigation.

Transnasal endoscopy: no gagging no panic!

BACKGROUND: Transnasal endoscopy (TNE) is performed with an ultrathin scope via the nasal passages and is increasingly used. This review covers the technical characteristics, tolerability, safety and acceptability of TNE and also diagnostic accuracy, use as a screening tool and therapeutic applications. It includes practical advice from an ear, nose, throat (ENT) specialist to optimise TNE practice, identify ENT pathology and manage complications. METHODS: A Medline search was performed using the terms "transnasal", "ultrathin", "small calibre", "endoscopy", "EGD" to identify relevant literature. RESULTS: There is increasing evidence that TNE is better tolerated than standard endoscopy as measured using visual analogue scales, and the main area of discomfort is nasal during insertion of the TN endoscope, which seems remediable with adequate topical anaesthesia. The diagnostic yield has been found to be similar for detection of Barrett's oesophagus, gastric cancer and GORD-associated diseases. There are some potential issues regarding the accuracy of TNE in detecting small early gastric malignant lesions, especially those in the proximal stomach. TNE is feasible and safe in a primary care population and is ideal for screening for upper gastrointestinal pathology. It has an advantage as a diagnostic tool in the elderly and those with multiple comorbidities due to fewer adverse effects on the cardiovascular system. It has significant advantages for therapeutic procedures, especially negotiating upper oesophageal strictures and insertion of nasoenteric feeding tubes. CONCLUSIONS: TNE is well tolerated and a valuable diagnostic tool. Further evidence is required to establish its accuracy for the diagnosis of early and small gastric malignancies. There is an emerging role for TNE in therapeutic endoscopy, which needs further study.

Capsule endoscopy--not just for the small bowel: a review.

Video capsule endoscopy is being increasingly used to investigate the esophagus and colon as well as the small bowel. With the advancement of technology used in capsule endoscopy there have been marked improvements in diagnostic rates for colon capsule endoscopy in the detection of colonic polyps and colorectal cancer. It is also being increasingly used in the field if inflammatory bowel disease to investigate for mucosal inflammation and could potentially be used to assess mucosal healing. It also has role in completing the evaluation of colonic pathology in those in whom colonoscopy is incomplete. Esophageal capsule is preferred by patients over esophagogastroduodenoscopy (EGD) but as yet does not rival EGD in terms of diagnostic accuracy however the advent of magnetically steerable capsules may improve this. This review covers advances in the field of colon and esophageal capsule endoscopy; it covers diagnostic capabilities of these 2 tools as well as technical aspects of both procedures and preparation.

Baseline plasma corticosterone, haematological and biochemical results in nesting and rehabilitating loggerhead sea turtles (Caretta caretta).

The evaluation of hormonal responses to stress in reptiles relies on acquisition of baseline corticosterone concentrations; however, the stress associated with the restraint needed to collect the blood samples can affect the results. The purpose of this study was to determine a time limit for the collection of blood samples to evaluate baseline corticosterone, haematological and biochemical results in nesting (n = 11) and rehabilitating (n = 16) loggerhead sea turtles (Caretta caretta). Blood samples were collected from the dorsal cervical sinus of each turtle immediately after touching the animal (t 0; 0-3 min) and 3 (t 3; 3-6 min), 6 (t 6; 6-9 min; nesting turtles only), 10 (t 10; 10-13 min) and 30 min (t 30; rehabilitating turtles only) after the initial hands-on time. Consistent between the rehabilitating and nesting turtles, there was a subtle yet significant increase in white blood cell counts over time. Despite the fact that white blood cell counts increased during the sampling period, there was no direct correlation between white blood cell count and corticosterone in the sampled turtles. In the nesting turtles, significant elevations in corticosterone were noted between t 0 and t 3 (P = 0.014) and between t 0 and t 6 (P = 0.022). Values at t 10 were not significantly different from those at t 0 (P = 0.102); however, there was a trend for the corticosterone values to continue to increase. These results suggest that sampling of nesting loggerhead sea turtles within 3 min of handling will provide baseline corticosterone concentrations in their natural environment. Significant elevations in corticosterone were also noted in the rehabilitating loggerhead sea turtles between t 0 and t 10 (P = 0.02) and between t 0 and t 30 of sampling (P = 0.0001). These results suggest that sampling of loggerhead sea turtles within 6 min of handling should provide baseline corticosterone concentrations in a rehabilitation setting. The delay in the corticosterone response noted in the rehabilitating turtles may be associated with the daily contact (visual or direct) they have with their human caretakers.

Intraperitoneal IL-6 signaling in incident patients treated with icodextrin and glucose bicarbonate/lactate-based peritoneal dialysis solutions.

OBJECTIVE: In this study, we compared the activity of interleukin-6 (IL-6), a marker of ongoing peritoneal inflammation and biocompatibility, and its other signaling components, the soluble IL-6 receptor (sIL-6R) and soluble Gp130 (sGp130), in peritoneal effluent from patients treated with icodextrin-based (E) peritoneal dialysis (PD) solution and glucose-based bicarbonate/lactate-buffered (P) solution. METHODS: Using baseline peritoneal ultrafiltration capacity, 33 stable incident PD patients were allocated either to P only (n = 20) or to P plus E for the overnight dwell (n = 13). We used ELISA to determine IL-6, sIL-6R, and sGp130 in timed overnight effluent at 1, 6, and 12 months after PD initiation. Flow cytometry was used to measure expression of IL-6R and Gp130 on isolated peritoneal leukocytes at the same time points. Peritonitis was an exclusion criterion. RESULTS: At all time points, levels of IL-6 and sIL-6R, and the appearance rates of IL-6 (90.5 pg/min vs. 481.1 pg/min, p < 0.001; 138.6 pg/min vs. 1187.5 pg/min, p < 0.001; and 56.1 pg/min vs. 1386.0 pg/min, p < 0.001), sIL-6R (2035.3 pg/min vs. 4907.0 pg/min, p < 0.01; 1375.0 pg/min vs. 6348.4 pg/min, p < 0.01; and 1881.3 pg/min vs. 5437.8 pg/min, p < 0.01), and sGp130 (37.6 ng/min vs. 65.4 ng/min, p < 0.01; 39.2 ng/min vs. 80.6 ng/min, p < 0.01; 27.8 ng/min vs. 71.0 ng/min, p < 0.01) were significantly higher in peritoneal effluent from E-treated patients than from P-treated patients. Expression of IL6-R and Gp130 on individual leukocyte types isolated from PD effluent did not differ between E- and P-treated patients. The numbers of white blood cells present in effluent were higher in E-treated than in P-treated patients at all time points, but no significant differences were seen in the differential counts or in the number of exfoliated mesothelial cells. The IL-6 parameters in effluent from E-treated patients correlated with their plasma C-reactive protein. Despite the increased activation of the IL-6 system, no increase in peritoneal permeability as assessed by the dialysate-to-plasma ratio of creatinine in E effluent or by systemic inflammation was observed throughout the study. CONCLUSIONS: Higher levels of IL-6, its soluble receptors, and leukocyte expression were observed in E-treated than in P-treated patients, but this difference was not associated with alterations in peritoneal permeability or systemic inflammation during 1 year of follow-up. Leukocyte counts in effluent from E-treated patients were within the normal range previously reported for glucose solutions. This lack of clinical consequences may be a result of a parallel rise in sIL-6R and sGp130, which are known to control the biologic activity of IL-6. The utility of IL-6 level determinations, in isolation, for assessing the biocompatibility of PD solutions is questionable.

Provision of service and training for small bowel endoscopy in the UK.

OBJECTIVE: To determine the location and use of small bowel endoscopy services in the UK and to analyse training uptake to assess future demand and shape discussions about training and service delivery. DESIGN: Surveys of British Society of Gastroenterology (BSG) members by web-based and personal contact were conducted to ascertain capsule endoscopy practice and numbers of procedures performed. This was compared with expected numbers of procedures calculated using BSG guidelines, hospital episode statistics and published data of capsule endoscopy in routine practice. Analysis of data from two national training courses provided information about training. RESULTS: 45% of UK gastroenterology services offered in-house capsule endoscopy. 91.3% of survey responders referred patients for capsule endoscopy; 67.7% felt that local availability would increase referrals. Suspected small bowel bleeding and Crohn's disease were considered appropriate indications by the majority. Demand is increasing in spite of restricted use in 21.6% of centres. Only two regions performed more than the minimum estimate of need of 45 procedures per 250 000 population. Eight centres perform regular device-assisted enteroscopy; 14 services are in development. 74% of trainees were interested in training and of those training in image interpretation, 67% are doctors and 28% are nurses. CONCLUSIONS: Capsule endoscopy is used by the majority of UK gastroenterologists but appears to be underused. Current demand for device-assisted enteroscopy seems likely to be matched if new services become established. Future demand is likely to increase, however, suggesting the need to formalise training and accreditation for both doctors and nurses.

Loss of CD4+ T cell IL-6R expression during inflammation underlines a role for IL-6 trans signaling in the local maintenance of Th17 cells.

IL-6 responses are classically orchestrated via a membrane-bound IL-6R (CD126) alpha subunit (classical IL-6R signaling) or through a soluble form of this cognate receptor (IL-6 trans signaling). Appraisal of IL-6R expression on human and mouse T cells emphasized that IL-6R expression is closely linked with that of CCR7 and CD62L. In this regard, infiltrating effector T cells from clinical and experimental peritonitis episodes lose IL-6R expression, and anti-CD3/CD28 Ab costimulation of peripheral T cells in vitro leads to a downregulation in IL-6R expression. Consequently, IL-6 signaling through membrane-bound IL-6R seems to be limited to naive or central memory T cell populations. Loss of IL-6R expression by activated T cells further suggests that these effector cells might still retain IL-6 responsiveness via IL-6 trans signaling. Using IL-6R-deficient mice and recombinant tools that modulate the capacity of IL-6 to signal via its soluble receptor, we report that local control of IL-6 trans signaling regulates the effector characteristics of the T cell infiltrate and promotes the maintenance of IL-17A-secreting CD4(+) T cells. Therefore, we concluded that classical IL-6R signaling in naive or central memory CD4(+) T cells is required to steer their effector characteristics, whereas local regulation of soluble IL-6R activity might serve to maintain the cytokine profile of the Th cell infiltrate. Therefore, the activation status of a T cell population is linked with an alteration in IL-6 responsiveness.

Alteration of polymorphonuclear neutrophil surface receptor expression and migratory activity after isolation: comparison of whole blood and isolated PMN preparations from normal and postfracture trauma patients.

BACKGROUND: Post-traumatic MOF results from local tissue injury because of migration and activation of dysfunctional polymorphonuclear leukocytes (PMN). Although fracture surgery exacerbates the postinjury inflammatory response, it is usually beneficial. This study compared changes in PMN receptor expression and migratory activity, in whole blood and following PMN isolation. METHODS: IL-8 mediated PMN migration and expression of CXCR-1, CD11b, and CD18 was studied in isolated and whole blood PMN in normal controls. Migration was studied at admission and day 5 after surgery in trauma patients undergoing fracture surgery. RESULTS: PMN isolation results in increased expression of surface receptors and enhanced migration in normal controls. In trauma patient samples, isolated PMN migration is enhanced after injury, but suppressed when migration from whole blood is studied, both after injury and fracture surgery. CONCLUSION: PMN isolation results in priming for migration, which has a relatively greater impact upon PMN in trauma patients. The observation that PMN activity may decline but priming potential remains enhanced is novel. Further refinements of whole blood and isolated PMN techniques are clearly warranted. This may help to resolve the mismatch in clinical and scientific experience in those patients with major fractures requiring surgical stabilization.

IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation.

Interleukin (IL)-6 signaling through its soluble receptor (IL-6 transsignaling) directs transition between innate and acquired immune responses by orchestrating the chemokine-directed attraction and apoptotic clearance of leukocytes. Through analysis of mononuclear cell infiltration in WT and IL-6-deficient mice during peritoneal inflammation, we now report that IL-6 selectively governs T cell infiltration by regulating chemokine secretion (CXCL10, CCL4, CCL5, CCL11, and CCL17) and chemokine receptor (CCR3, CCR4, CCR5, and CXCR3) expression on the CD3+ infiltrate. Although blockade of IL-6 trans-signaling prevented chemokine release, chemokine receptor expression remained unaltered suggesting that this response is regulated by IL-6 itself. To dissect the signaling events promoting T cell migration, inflammation was established in knock-in mice expressing mutated forms of the universal signal-transducing element for IL-6-related cytokines gp130. In mice (gp130Y757F/Y757F) deficient in SHP2 and SOCS3 binding, but presenting hyperactivation of STAT1/3, T cell recruitment and CCL5 expression was enhanced. Conversely, both of these parameters were suppressed in mice with ablated gp130-mediated STAT1/3 activation (gp130DeltaSTAT/DeltaSTAT). T cell migration was related to STAT3 activity, because monoallelic deletion of Stat3 in gp130(Y757F/Y757F) mice (gp130Y757F/Y757F:Stat3+/-) corrected the exaggerated responses observed in gp130Y757F/Y757F mice. Consequently, STAT3 plays a defining role in IL-6-mediated T cell migration.