Associations between patient factors and successful colon capsule endoscopy - A prospective cohort study.

AIM: To establish patient factors associated with a successful colon capsule endoscopy (CCE) test. METHOD: This prospective cohort study used data collected from patients who underwent CCE as part of the ScotCap evaluation prior to April 2020. A CCE was defined as successful if the capsule visualized the whole colon and rectum (complete test) with sufficient bowel cleansing to permit assessment of the colonic mucosa (adequate bowel preparation). Factors from patients in symptomatic and surveillance groups were analysed for associations with a successful test, complete test, adequate bowel preparation and requirement for further procedure using univariate, multivariate logistic, least absolute shrinkage and selection operator regression. RESULTS: Data from 263 symptomatic and 137 surveillance patients were analysed. There was an association between a symptomatic patient's age and a successful test (OR = 0.97, 95% CI: 0.95-0.99), adequate bowel preparation (OR = 0.97, 95% CI: 0.94-1.00) and further procedure requirement (OR = 1.04, 95% CI: 1.02-1.06). An association was found, for symptomatic patients, between a faecal immunochemical test result in the range 10-399 µg/g and a further procedure (OR = 2.32, 95% CI: 1.23-4.48). In patients undergoing surveillance for previous colorectal cancer (OR = 0.42, 95% CI: 0.18-0.97), had previous bowel resection surgery (OR = 0.43, 95% CI: 0.19-0.98) or took a beta blocker medication (OR = 0.32, 95% CI: 0.11-0.88), an association was found with further procedure requirement. CONCLUSIONS: Among symptomatic patients, younger age was associated with obtaining a successful CCE test. Clinicians could consider patient selection based on these results to improve the rate of successful testing in clinical practice.

An evaluation of a novel bowel preparation regimen and its effect on the utility of colon capsule endoscopy: a prospective cohort study with historical controls.

BACKGROUND: The aim of this study was to evaluate the efficacy of a novel bowel preparation and booster regimen for colon capsule endoscopy (CCE) using macrogol, phospho-soda and gastrografin, compared with a control regimen consisting of polyethylene glycol and sodium picosulfate. METHODS: This was a prospective cohort study using historical controls. Symptomatic patients undergoing CCE between 11/07/2021 and 21/12/2021 using the novel regimen were included. Symptomatic patients who underwent CCE in the ScotCap evaluation using the control regimen were used as historical controls. We measured the rate of complete test (visualisation of the whole colon and rectum), adequate bowel preparation, successful test (complete and adequate bowel preparation) and need for further test following CCE. The rate of adverse events was also collected. RESULTS: Patients undergoing CCE using the new and control regimen were 200 and 316, respectively. The median age, age range and proportion of female patients in the new and control regimen cohorts was 61 vs 60 years, 16-86 vs 20-83 years, and 60.5% vs 56.6%. The rate of complete test, adequate bowel reparation and successful test for the new and control regimen was 69% vs 72.2%, 86.6% vs 80.7% and 60.5% vs 65.8%. Comparing the new and control regimen, 39.5% vs 37.3% of patients required no test following CCE, 26% vs 32.6% required a colonoscopy, 31.5% vs 21.5% required a flexible sigmoidoscopy and 3% vs 2.9% required a computed tomography colonogram. No adverse events were reported using the new regimen compared to 2 (0.6%) in the control group. CONCLUSIONS: The rate of adequate bowel preparation has improved following the introduction of a new regimen. However, further work is needed to increase the complete test rate. A significant proportion of patients continue to avoid colonoscopy following CCE.

A colorectal cancer missed by colon capsule endoscopy: a case report.

BACKGROUND: Colon capsule endoscopy (CCE) is a non-invasive alternative to colonoscopy. The reported sensitivity and specificity of CCE for the detection of clinically significant colonic neoplasia is high. To date, there have been no reported cases of colorectal cancer (CRC) missed by CCE which were located in segments adequately visualised by the capsule. CASE PRESENTATION: We present the case of a 71-year-old female, who underwent CCE for new lower gastrointestinal symptoms. The CCE reported 17 polyps (largest size 10 mm) and angiodysplasia. A 40 mm caecal pole tumour, not detected by the CCE, was identified at follow up colonoscopy. Surgical resection was performed, and the pathology sample was reported as moderately differentiated adenocarcinoma, pT2 pN0 (0/19) M0, with no evidence of EMVI. The patient made an uneventful recovery. The caecal pole tumour was not definitively identified on retrospective review of the CCE images. CONCLUSION: To date, this is the first published case of a CRC missed entirely by CCE. Further research is required to allow calculation of the post CCE interval CRC rate to allow comparison with colonoscopy and CT colonogram.

Colon capsule endoscopy: an innovative method for detecting colorectal pathology during the COVID-19 pandemic?

AIM: The coronavirus pandemic has led to significant challenges for healthcare delivery across the globe. Non-emergency endoscopic activity in the UK has been postponed, raising concerns of increased delays in the diagnosis of colorectal cancer and a surge in demand once services resume. Measures to mitigate this risk must be considered. METHOD: This paper reviews various investigative modalities for colorectal disease which could be deployed during cessation of colonoscopy services. We focus on colon capsule endoscopy (CCE) due to its relevance during the COVID-19 pandemic and its ability to triage patients effectively to further endoscopic investigations. RESULTS: CT of the abdomen and pelvis has been suggested as a triage tool while access to colonoscopy is limited. However, CT may lead to the spread of COVID-19 as patients attend the hospital, and it exposes them to the risks of radiation. Faecal immunochemistry tests have been demonstrated as a good predictor of colonic pathology and could be safely used to risk stratify patients when prioritizing colonoscopy. CCE is a safe and innovative technology for investigating the colon. Procedures can be carried out in the community and can be conducted safely during the coronavirus pandemic. It has been shown to be an accurate detector of colonic neoplasia and can reduce demand for colonoscopy. CONCLUSION: As colonoscopy services resume, they will probably experience high demand leading to further delays for patients. CCE could be used to reduce the number of patients requiring colonoscopy and triage those requiring further endoscopic investigations appropriately.

Colon capsule endoscopy.

There are multiple indications for luminal imaging of the colon. From assessment of known disease, to diagnosing new pathology; intra-luminal visualisation is the mainstay of gastrointestinal diagnosis. Colonoscopy and radiological imaging are currently the most frequently deployed diagnostic methods. However, both have an associated risk profile, have significant resource pressures and are not universally tolerated. Colon capsule endoscopy (CCE) offers an adjunct to these diagnostic options. In this narrative review the utility of CCE is described. Its current uses, potential benefits and future developments are also discussed.

Antibody-mediated protection against MERS-CoV in the murine model.

Murine antisera with neutralising activity for the coronavirus causative of Middle East respiratory syndrome (MERS) were induced by immunisation of Balb/c mice with the receptor binding domain (RBD) of the viral Spike protein. The murine antisera induced were fully-neutralising in vitro for two separate clinical strains of the MERS coronavirus (MERS-CoV). To test the neutralising capacity of these antisera in vivo, susceptibility to MERS-CoV was induced in naive recipient Balb/c mice by the administration of an adenovirus vector expressing the human DPP4 receptor (Ad5-hDPP4) for MERS-CoV, prior to the passive transfer of the RBD-specific murine antisera to the transduced mice. Subsequent challenge of the recipient transduced mice by the intra-nasal route with a clinical isolate of the MERS-CoV resulted in a significantly reduced viral load in their lungs, compared with transduced mice receiving a negative control antibody. The murine antisera used were derived from mice which had been primed sub-cutaneously with a recombinant fusion of RBD with a human IgG Fc tag (RBD-Fc), adsorbed to calcium phosphate microcrystals and then boosted by the oral route with the same fusion protein in reverse micelles. The data gained indicate that this dual-route vaccination with novel formulations of the RBD-Fc, induced systemic and mucosal anti-viral immunity with demonstrated in vitro and in vivo neutralisation capacity for clinical strains of MERS-CoV.

Intensity-modulated Radiotherapy for Anal Cancer: Dose-Volume Relationship of Acute Gastrointestinal Toxicity and Disease Outcomes.

AIMS: Intensity-modulated radiotherapy (IMRT) is increasingly used in the treatment delivery of chemoradiotherapy in anal cancer with the ability to reduce toxicity. We report on 4 year outcomes since the introduction of IMRT and identify the most predictive bowel organ at risk that correlates with acute diarrhoea. MATERIALS AND METHODS: Fifty-eight patients receiving definitive chemoradiotherapy for squamous or basaloid cell anal carcinoma (T1-4NanyM0) were reviewed. Fifty-four per cent of patients had stage III disease and most (79%) were treated with a dose of 54 Gy in 30 fractions. Patient acute gastrointestinal toxicity was recorded using Common Terminology Criteria of Adverse Events (CTCAE) diarrhoea grading. Four different methods of bowel were re-contoured for each patient and correlated with acute diarrhoea. Locoregional control and overall survival were analysed. RESULTS: CTCAE grade 3 or more diarrhoea occurred in 11/58 patients (19%). Seven patients did not complete treatment; 10 patients (17%) required a treatment break of 3 or more days. 'Bowel cavity' was the best predictor of acute grade 3 toxicity using volume (P = 0.002) or volume to bowel cavity in 5 Gy bins (V5-V50Gy); P < 0.05. Bowel cavity V30Gy ≤ 300 cm3 predicts a 6% grade 3 diarrhoea risk versus > 300 cm3 predicts a 42% risk. Four year progression-free survival was 84% (95% confidence interval 73-92%) and overall survival was 88% (95% confidence interval 75-95%). CONCLUSION: Chemoradiation using IMRT provides excellent local control and acceptable acute gastrointestinal toxicity. Bowel cavity is the most sensitive predictor for grade 3 versus grade 0-2 diarrhoea, with any volume receiving 5-50 Gy discriminatory.

Complications after laparoscopic and open subtotal colectomy for inflammatory colitis: a case-matched comparison.

AIM: The aim of this study was to compare the early postoperative outcome of patients undergoing laparoscopic subtotal colectomy with those undergoing open subtotal colectomy for colitis refractory to medical treatment. METHOD: A retrospective observational study was carried out of patients who underwent subtotal colectomy for refractory colitis, at a single centre, between 2006 and 2012. Patients were matched for age, gender, American Society of Anesthesiology (ASA) grade, urgency of operation and immunosuppressant/modulator treatment. The primary outcome measure was the number of postoperative complications, classified using the Clavien-Dindo scale. Secondary end-points included procedure duration, laparoscopic conversion rates, blood loss, 30-day readmission rates and length of hospital stay. RESULTS: Ninety-six patients were included, 39 of whom had laparoscopic surgery. Thirty-two of these were matched to similar patients who underwent an open procedure. The overall duration of the procedure was longer for laparoscopic surgery than for open surgery (median: 240 vs 150 min, P < 0.005) but estimated blood loss was less (median: 75 vs 400 ml, P < 0.005). In the laparoscopic group, 23 patients experienced 27 complications, and in the open surgery group, 23 patients experienced 30 complications. Most complications were minor (Grade I/II), and the distribution of complications, by grade, was similar between the two groups. There was no statistically significant difference in 30-day readmission rates between the laparoscopic and open groups (five readmissions vs eight readmissions, P = 0.536). Length of hospital stay was 4 days shorter for laparoscopic surgery, but this difference was not statistically significant (median: 7 vs 11 days, P = 0.159). CONCLUSION: In patients requiring colectomy for acute severe colitis, laparoscopic surgery reduced blood loss but increased operating time and was not associated with a reduction in early postoperative complications, length of hospital stay or readmission rates.

A case of HIV-1 slow seroconversion: diagnostic implications.

We report the case of a 30-year-old woman who failed to achieve diagnostic Western blot criteria for HIV-1 infection until 21 months after her initial presentation. This case highlights the importance of suspecting delayed HIV seroconversion in cases with persistently indeterminant Western blots.

Pharmacokinetics and unexpected safety issues of LBM415, a novel oral peptide deformylase inhibitor.

Peptide deformylase (PDF) inhibitors represent a potential new class of antibiotics targeting a large number of bacterial species. We studied the pharmacokinetics and safety of LBM415, a novel PDF inhibitor, administered as a single oral dose at 100-3,000 mg in the fasted state and at 1,000 mg in the fed state in healthy volunteers. LBM415 was then administered at dosages ranging from 100 mg q.d. to 1,000 mg t.i.d. for 11 days. Dose-proportional pharmacokinetics was observed, with a peak plasma concentration (C(max)) of 17.85 ± 5.96 µg/ml at 1,000 mg b.i.d. (the projected therapeutic dose) and an area under the concentration-time curve (AUC)(0-24h) of 36.83 ± 10.36 µg/ml·h. The half-life, as determined after a 1,000-mg single dose, was 2.18 ± 0.61 h. The compound was well tolerated at low doses, but at the highest dose, 1,000 mg t.i.d., reversible cyanosis and low oxygen saturation, attributable to methemoglobinemia, were detected on day 11. Oxygen saturation was as low as 88% in one subject on day 11.

Adult living liver donors have excellent long-term medical outcomes: the University of Toronto liver transplant experience.

Right lobe living donor liver transplantation is an effective treatment for selected individuals with end-stage liver disease. Although 1 year donor morbidity and mortality have been reported, little is known about outcomes beyond 1 year. Our objective was to analyze the outcomes of the first 202 consecutive donors performed at our center with a minimum follow-up of 12 months (range 12-96 months). All physical complications were prospectively recorded and categorized according to the modified Clavien classification system. Donors were seen by a dedicated family physician at 2 weeks, 1, 3 and 12 months postoperatively and yearly thereafter. The cohort included 108 males and 94 females (mean age 37.3 +/- 11.5 years). Donor survival was 100%. A total of 39.6% of donors experienced a medical complication during the first year after surgery (21 Grade 1, 27 Grade 2, 32 Grade 3). After 1 year, three donors experienced a medical complication (1 Grade 1, 1 Grade 2, 1 Grade 3). All donors returned to predonation employment or studies although four donors (2%) experienced a psychiatric complication. This prospective study suggests that living liver donation can be performed safely without any serious late medical complications and suggests that long-term follow-up may contribute to favorable donor outcomes.

Optimal scheduling to reduce morbidity of involved field radiotherapy with transplantation for lymphomas: a prospective Australasian Leukaemia and Lymphoma Group Study.

This study evaluated delivery of involved field radiotherapy (IFRT) with transplantation for lymphomas timed to minimise toxicity. Patients transplanted for lymphoma had infradiaphragmatic disease irradiated pre-transplant and supradiaphragmatic disease post transplant. A total of 31 patients were studied, with a median follow-up duration of 4 years. Transplant conditioning was according to clinician preference. In all, 14 patients had pre-transplant abdominopelvic IFRT and 19 had post transplant IFRT (including three who had pre-transplant IFRT). Grade III-IV haematological toxicity from pre-transplant IFRT occurred in three patients and from post transplant IFRT in 10 patients. Pre-transplant IFRT had no effect on haematological recovery post transplant, but was associated with a trend towards increased gastrointestinal toxicity (P = 0.094). Pneumonitis due to post transplant thoracic IFRT occurred in one patient. Two patients failed in involved sites after completion of protocol radiotherapy. One case of myelodysplasia has been reported. As sequenced in this study, IFRT was feasible and produced a low incidence of severe pulmonary and haematological toxicities. Patient selection, field size and radiotherapy dose warrant further study.

Solidification of stainless steel slag by accelerated carbonation.

On exposure to carbon dioxide (CO2) at a pressure of 3 bars, compacts formed from pressed ground slag, and 12.5 weight percent water, were found to react with approximately 18% of their own weight of CO2. The reaction product formed was calcium carbonate causing the slag to self-cement. Unconfined compressive strengths of 9MPa were recorded in carbonated compacts whereas strengths of < 1 MPa were recorded in non-carbonated slag compacts. As molten stainless steel slag containing dicalcium silicate (C2S) cools it can undergo several phase transitions. The final transformation from the beta-polymorph to gamma-C2S is accompanied by a volume change that causes the slag to self-pulverise or 'dust'. As a consequence of this the fine grained portion of the slag contains more of this phase whilst the coarser particles of the slag contain more of the calcium magnesium silicates that contribute the bulk of the waste. The fine fraction (< 125 microm) of the slag when ground is found to react to the same extent as the ground bulk slag and produces compacts with equivalent strength. A coarser fraction (4-8 mm) when ground to a similar grading does not react as extensively and produces a weaker product. Additions of ordinary Portland cement (OPC) at 5 and 10 percent by weight did not alter the degree of reaction during carbonation of the bulk slag or ground fine fraction, however the strength of the 4-8 mm fraction was increased by this change.

Acid neutralisation capacity of accelerated carbonated stainless steel slag.

The acid neutralisation capacity test is widely used to assess the long-term performance of waste materials prior to disposal. Samples of fixed mass are exposed to increasing additions of nitric add in sealed containers and the resultant pH is plotted as a titration curve. In this work, the add neutralisation capacity test was used in the assessment of an accelerated carbonated stainless steel slag. Difficulties arose in applying the test procedure to this material. This was largely because of the raised pressure from significant volumes of released carbon dioxide trapped in the sealed sample containers, causing an alteration to leachate pH values. Consequently, the add neutralisation capacity test was modified to enable testing of samples in equilibrium with the atmosphere. No adverse effects on the results from testing of a carbonate free material were recorded.

Transgenic Polyoma middle-T mice model premalignant mammary disease.

Mice transgenic for the Polyomavirus middle T (PyV-mT) gene have been widely used to study mammary tumorigenesis and metastasis. Although numerous molecular insights were gained from the analysis of these transgenic malignant tumors, the early events leading to malignant transformation have not been systematically investigated nor has the biological potential of hyperplastic lesions been documented. This paper presents the first comprehensive histopathological characterization of transgenic PyV-mT hyperplasias together with classical transplantation experiments designed to test the growth potential of these lesions. Moreover, stable hyperplastic outgrowth lines were established as a tool to study premalignant PyV-mT-induced hyperplasias in detail. Each line has a different tumor latency, indicating that PyV-mT-induced hyperplasias, like early proliferative lesions seen in the human breast, are heterogeneous with respect to their malignant potential. Our results settle a controversy; they establish that PyV-mT gene expression alone is insufficient to induce tumors and that additional events are required for tumorigenesis and metastasis. These results support the use of PyV-mT transgenic mice as a model for investigating the multistep progression of malignant mammary tumorigenesis and metastasis.

Anti-inflammatory activity of clarithromycin in adults with chronically inflamed sinus mucosa.

In a phase IV, open-label study, 25 patients with clinically stable chronic sinusitis and persistent maxillary sinus inflammation were treated for 14 days with clarithromycin 500 mg twice daily. Biopsy specimens of the maxillary sinus mucosa were obtained pretreatment and evaluated for macrophages (CD68), eosinophils (MBP), elastase, interleukin-6 (IL-6), IL-8, tumor necrosis factor-alpha (TNF-alpha), and activity of eosinophils (EG2), as well as edema score. Clinical signs and symptoms were assessed pretreatment, at the end of treatment, and 1 and 2 weeks later. Statistically significant reductions (P < or = .05) from pretreatment were observed for all markers of sinus mucosal inflammation, including CD68, EG2, elastase, IL-6, IL-8, TNF-alpha, and edema score, with a trend to decreased total eosinophil count. Improvement was observed for all clinical signs and symptoms of chronic sinusitis--sinus pain, sinus headache, nasal congestion, nasal discharge, and mucopurulent discharge--up to 14 days after the end of treatment. Cultures to evaluate persistent infection with Chlamydia pneumoniae showed negative results. Significant reductions in various markers of sinus mucosal inflammation support the role of clarithromycin in modulating immunologic responses. Improvement of clinical signs and symptoms in patients with chronic inflammatory sinusitis not meeting criteria for known or presumed bacterial infection was also noted up to 2 weeks after completion of a 14-day course of clarithromycin.

Lipopolysaccharide-induced apoptosis of macrophages determines the up-regulation of concentrative nucleoside transporters Cnt1 and Cnt2 through tumor necrosis factor-alpha-dependent and -independent mechanisms.

In murine bone marrow macrophages, lipopolysaccharide (LPS) induces apoptosis through the autocrine production of tumor necrosis factor-alpha (TNF-alpha), as demonstrated by the fact that macrophages from TNF-alpha receptor I knock-out mice did not undergo early apoptosis. In these conditions LPS up-regulated the two concentrative high affinity nucleoside transporters here shown to be expressed in murine bone marrow macrophages, concentrative nucleoside transporter (CNT) 1 and 2, in a rapid manner that is nevertheless consistent with the de novo synthesis of carrier proteins. This effect was not dependent on the presence of macrophage colony-stimulating factor, although LPS blocked the macrophage colony-stimulating factor-mediated up-regulation of the equilibrative nucleoside transport system es. TNF-alpha mimicked the regulatory response of nucleoside transporters triggered by LPS, but macrophages isolated from TNF-alpha receptor I knock-out mice similarly up-regulated nucleoside transport after LPS treatment. Although NO is produced by macrophages after LPS treatment, NO is not involved in these regulatory responses because LPS up-regulated CNT1 and CNT2 transport activity and expression in macrophages from inducible nitric oxide synthase and cationic amino acid transporter (CAT) 2 knock-out mice, both of which lack inducible nitric oxide synthesis. These data indicate that the early proapoptotic responses of macrophages, involving the up-regulation of CNT transporters, follow redundant regulatory pathways in which TNF-alpha-dependent- and -independent mechanisms are involved. These observations also support a role for CNT transporters in determining extracellular nucleoside availability and modulating macrophage apoptosis.

Sustained nitric oxide production in macrophages requires the arginine transporter CAT2.

The aberrant production of nitric oxide (NO) contributes to the pathogenesis of diseases as diverse as cancer and arthritis. Sustained NO production via the inducible enzyme, nitric-oxide synthase 2 (NOS2), requires extracellular arginine uptake. Three closely related cationic amino acid transporter genes (Cat1-3) encode the transporters that mediate most arginine uptake in mammalian cells. Because CAT2 is induced coordinately with NOS2 in numerous cell types, we investigated a possible role for CAT2-mediated arginine transport in regulating NO production. The complexity of arginine transport systems and their biochemically similar transport properties called for a genetic approach to determine the role of CAT2. CAT2-deficient mice were generated and found to be healthy and fertile in contrast to Cat1(-/-) animals. Analysis of cytokine-activated macrophages from Cat2(-/-) mice revealed a 92% reduction in NO production and a 95% reduction in l-Arg uptake. The reduction in NO production was not due to differences in NOS2 protein expression, NOS2 activity, or intracellular l-arginine content. In conclusion, our results show that sustained abundant NO synthesis by macrophages requires arginine transport via the CAT2 transporter.