Random duodenal biopsy to exclude coeliac disease as a cause of anaemia is not cost‑efective and should be replaced with universally performed pre‑endoscopy serology in patients on a suspected cancer pathway

Background: Random duodenal biopsy to exclude coeliac disease during upper gastrointestinal endoscopy for the investigation of iron defciency anaemia remains a common procedure, but is expensive and time-consuming. Serological investigation for coeliac disease is also recommended, having excellent accuracy with the added beneft of lower cost. This study sought to examine the utility of duodenal biopsy and coeliac serology in the diagnosis of coeliac disease. Methods: A prospectively maintained database was interrogated to identify all patients having upper gastrointestinal endoscopy for the investigation of anaemia between January 01, 2016, and December 31, 2016. Results Of the 1131 patients having an endoscopy, coeliac serology was measured in only 412 (36%) and was positive in 9 cases (2%), leading to 6 histological diagnoses of coeliac disease and 3 false positives. Two-hundred and seventy-four patients with negative serology had biopsies taken which were all negative. Only 2/451 (0.4%) patients who had biopsies performed in the absence of a serology test were histologically positive for coeliac disease. The cost per diagnosis of a case of coeliac disease in those with either negative or absent coeliac serology was £18,839 (US$25,244, €21,196). Conclusions: Random duodenal biopsy is not a cost-efective method of diagnosing coeliac disease and should be replaced with pre-endoscopy coeliac serology

A systematic review and meta-regression analysis of prophylactic gabapentin for postoperative pain

We searched MEDLINE, Embase, CINAHL, AMED and CENTRAL databases until December 2014 and included 133 randomised controlled trials of peri-operative gabapentin vs placebo. Gabapentin reduced mean (95% CI) 24-h morphine-equivalent consumption by 8.44 (7.26–9.62) mg, p < 0.001, whereas more specific reductions in morphine equivalents were predicted (R2 = 90%, p < 0.001) by the meta-regression equation: 3.73 + (−0.378 × control morphine consumption (mg)) + (−0.0023 × gabapentin dose (mg)) + (−1.917 × anaesthetic type), where ‘anaesthetic type’ is ‘1’ for general anaesthesia and ‘0’ for spinal anaesthesia. The type of surgery was not independently associated with gabapentin effect. Gabapentin reduced postoperative pain scores on a 10-point scale at 1 h, 2 h, 6 h, 12 h and 24 h by a mean (95% CI) of: 1.68 (1.35–2.01); 1.21 (0.88–1.55); 1.28 (0.98–1.57); 1.12 (0.91–1.33); and 0.71 (0.56–0.87), respectively, p < 0.001 for all. The risk ratios (95% CI) for postoperative nausea, vomiting, pruritus and sedation with gabapentin were: 0.78 (0.69–0.87), 0.67 (0.59–0.76), 0.64 (0.51–0.80) and 1.18 (1.09–1.28), respectively, p < 0.001 for all. Gabapentin reduced pre-operative anxiety and increased patient satisfaction on a 10-point scale by a mean (95% CI) of 1.52 (0.78–2.26) points and 0.89 (0.22–1.57) points, p < 0.001 and p = 0.01, respectively. All the effects of gabapentin may have been overestimated by statistically significant small study effects

Baseline morphine consumption may explain between-study heterogeneity in meta-analyses of adjuvant analgesics and improve precision and accuracy of effect estimates

BACKGROUND: Statistical heterogeneity can increase the uncertainty of results and reduce the quality of evidence derived from systematic reviews. At present, it is uncertain what the major factors are that account for heterogeneity in meta-analyses of analgesic adjuncts. Therefore, the aim of this review was to identify whether various covariates could explain statistical heterogeneity and use this to improve accuracy when reporting the efficacy of analgesics. METHODS: We searched for reviews using MEDLINE, EMBASE, CINAHL, AMED, and the Cochrane Database of Systematic Reviews. First, we identified the existence of considerable statistical heterogeneity (I2 > 75%). Second, we conducted meta-regression analysis for the outcome of 24-hour morphine consumption using baseline risk (control group morphine consumption) and other clinical and methodological covariates. Finally, we constructed a league table of adjuvant analgesics using a novel method of reporting effect estimates assuming a fixed consumption of 50 mg postoperative morphine. RESULTS: We included 344 randomized controlled trials with 28,130 participants. Ninety-one percent of analyses showed considerable statistical heterogeneity. Baseline risk was a significant cause of between-study heterogeneity for acetaminophen, nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors, tramadol, ketamine, [alpha]2-agonists, gabapentin, pregabalin, lidocaine, magnesium, and dexamethasone (R2 = 21%-100%; P 10 mg). We could not exclude a moderate clinically significant effect with ketamine. Dexamethasone demonstrated a small clinical benefit (>5 mg). CONCLUSIONS: We empirically identified baseline morphine consumption as the major source of heterogeneity in meta-analyses of adjuvant analgesics across all surgical interventions. Controlling for baseline morphine consumption, clinicians can use audit data to estimate the morphine-reducing effect of adding any adjuvant for their local population, regardless which surgery they undergo. Moreover, we have utilized these findings to present a novel method of reporting and an amended method of graphically displaying effect estimates, which both reduces confounding from variable baseline risk in included trials and is able to adjust for other clinical and methodological confounding variables. We recommend use of these methods in clinical practice and future reviews of analgesics for postoperative pain

Palmitoylethanolamide and Cannabidiol Prevent Inflammation-induced Hyperpermeability of the Human Gut In Vitro and In Vivo—A Randomized, Placebo-controlled, Double-blind Controlled Trial

Background and aimsWe aimed to examine, for the first time, the effect of cannabidiol (CBD) and palmitoylethanolamide (PEA) on the permeability of the human gastrointestinal tract in vitro, ex vivo, and in vivo.MethodsFlux measurements of fluorescein-labeled dextrans 10 (FD10) and fluorescein-labeled dextrans 4 (FD4) dextran across Caco-2 cultures treated for 24 hours with interferon gamma (IFNγ) and tumour necrosis factor alpha (TNFα) (10 ng·mL−1) were measured, with or without the presence of CBD and PEA. Mechanisms were investigated using cannabinoid receptor 1 (CB1), cannabinoid receptor 2 (CB2), transient receptor potential vanilloid 1 (TRPV1), and proliferator activated receptors (PPAR) antagonists and protein kinase A (PKA), nitric oxide synthase, phosphoinositide 3-kinases, extracellular signal–regulated kinases (MEK/ERK), adenylyl cyclase, and protein kinase C (PKC) inhibitors. Human colonic mucosal samples collected from bowel resections were treated as previously stated. The receptors TRPV1, PPARα, PPARδ, PPARγ, CB1, CB2, G-coupled protein receptor 55 (GPR55), G-coupled protein receptor 119 (GPR119), and claudins-1, -2, -3, -4, -5, -7, and -8 mRNA were measured using multiplex. Aquaporin 3 and 4 were measured using enzyme-linked immunosorbent assay (ELISA). A randomized, double-blind, controlled-trial assessed the effect of PEA or CBD on the absorption of lactulose and mannitol in humans taking 600 mg of aspirin. Urinary concentrations of these sugars were measured using liquid chromatography mass spectrometry.ResultsIn vitro, PEA, and CBD decreased the inflammation-induced flux of dextrans (P < 0.0001), sensitive to PPARα and CB1 antagonism, respectively. Both PEA and CBD were prevented by PKA, MEK/ERK, and adenylyl cyclase inhibition (P < 0.001). In human mucosa, inflammation decreased claudin-5 mRNA, which was prevented by CBD (P < 0.05). Palmitoylethanolamide and cannabidiol prevented an inflammation-induced fall in TRPV1 and increase in PPARα transcription (P < 0.0001). In vivo, aspirin caused an increase in the absorption of lactulose and mannitol, which were reduced by PEA or CBD (P < 0.001).ConclusionCannabidiol and palmitoylethanolamide reduce permeability in the human colon. These findings have implications in disorders associated with increased gut permeability, such as inflammatory bowel disease

Expression of a large LINE-1-driven antisense RNA is linked to epigenetic silencing of the metastasis suppressor gene TFPI-2 in cancer

LINE-1 retrotransposons are abundant repetitive elements of viral origin, which in normal cells are kept quiescent through epigenetic mechanisms. Activation of LINE-1 occurs frequently in cancer and can enable LINE-1 mobilization but also has retrotransposition-independent consequences. We previously reported that in cancer, aberrantly active LINE-1 promoters can drive transcription of flanking unique sequences giving rise to LINE-1 chimeric transcripts (LCTs). Here, we show that one such LCT, LCT13, is a large transcript (>300 kb) running antisense to the metastasis-suppressor gene TFPI- 2. We have modelled antisense RNA expression at TFPI-2 in transgenic mouse embryonic stem (ES) cells and demonstrate that antisense RNA induces silencing and deposition of repressive histone modifications implying a causal link. Consistent with this, LCT13 expression in breast and colon cancer cell lines is associated with silencing and repressive chromatin at TFPI-2. Furthermore, we detected LCT13 transcripts in 56% of colorectal tumours exhibiting reduced TFPI-2 expression. Our findings implicate activation of LINE-1 elements in subsequent epigenetic remodelling of surrounding genes, thus hinting a novel retrotransposition-independent role for LINE-1 elements in malignancy

Development of a new SonovueTM contrast-enhanced ultrasound approach reveals temporal and age-related features of muscle microvascular responses to feeding

Compromised limb blood flow in aging may contribute to the development of sarcopenia, frailty, and the metabolic syndrome. We developed a novel contrast-enhanced ultrasound technique using Sonovue™ to characterize muscle microvasculature responses to an oral feeding stimulus (15 g essential amino acids) in young (~20 years) and older (~70 years) men. Intensity-time replenishment curves were made via an ultrasound probe “fixed” over the quadriceps, with intermittent high mechanical index destruction of microbubbles within muscle vasculature. This permitted real-time measures of microvascular blood volume (MBV), microvascular flow velocity (MFV) and their product, microvascular blood flow (MBF). Leg blood flow (LBF) was measured by Doppler and insulin by enzyme-linked immunosorbent assay. Steady-state contrast concentrations needed for comparison between different physiological states were achieved <150 sec from commencing Sonovue™ infusion, and MFV and MBV measurements were completed <120 sec thereafter. Interindividual coefficients of variation in MBV and MFV were 35–40%, (N = 36). Younger men (N = 6) exhibited biphasic vascular responses to feeding with early increases in MBV (+36%, P < 0.008 45 min post feed) reflecting capillary recruitment, and late increases in MFV (+77%, P < 0.008) and MBF (+130%, P < 0.007 195 min post feed) reflecting more proximal vessel dilatation. Early MBV responses were synchronized with peak insulin but not increased LBF, while later changes in MFV and MBF occurred with insulin at post absorptive values but alongside increased LBF. All circulatory responses were absent in old men (N = 7). Thus, impaired postprandial circulation could impact age-related declines in muscle glucose disposal, protein anabolism, and muscle mass

Creatinine and myoglobin are poor predictors of anaerobic threshold in colorectal cancer and health

Aims Myoglobin is a haem protein produced in skeletal muscles. Serum concentrations of myoglobin have been proposed as a surrogate marker of muscle mass and function in both cachectic cancer patients and healthy non-cancer individuals. Creatinine, a metabolite of creatine phosphate, an energy store found in skeletal muscle, is produced at a constant rate from skeletal muscle. Urinary and plasma creatinine have been used in clinical practice as indicators of skeletal muscle mass in health and disease. Our study aimed to test the hypothesis that plasma myoglobin and creatinine concentration could accurately predict skeletal muscle mass and aerobic capacity in colorectal cancer (CRC) patients and matched healthy controls and thereby an indicative of aerobic performance. Methods We recruited 47 patients with CRC and matching number of healthy volunteers for this study. All participants had their body composition measured by dual-energy X-ray absorptiometry scan, aerobic capacity measured to anaerobic threshold (AT) by cardiopulmonary exercise testing and filled in objective questionnaires to assess the qualitative functions. This study was carried out in accordance with the Declaration of Helsinki, after approval by the local National Health Service (NHS) Research Ethics Committee. Results Age-matched groups had similar serum myoglobin and creatinine concentrations in spite of differences in their aerobic capacity. AT was significantly lower in the CRC group compared with matched controls (1.18 ± 0.44 vs. 1.41 ± 0.71 L/min; P < 0.01). AT had significant correlation with lean muscle mass (LMM) among these groups, but myoglobin and creatinine had poor correlation with LMM and AT. Conclusions Serum myoglobin is a poor predictor of muscle mass, and serum myoglobin and creatinine concentrations do not predict aerobic performance in CRC patients or healthy matched controls

The use of cannabinoids in colitis: a systematic review and meta-analysis

Background: Clinical trials investigating the use of cannabinoid drugs for the treatment of intestinal inflammation are anticipated secondary to preclinical literature demonstrating efficacy in reducing inflammation. Methods: We systematically reviewed publications on the benefit of drugs targeting the endocannabinoid system in intestinal inflammation. We collated studies examining outcomes for metaanalysis from EMBASE, MEDLINE and Pubmed until March 2017. Quality was assessed according to mSTAIR and SRYCLE score. Results: From 2008 papers, 51 publications examining the effect of cannabinoid compounds on murine colitis, and two clinical studies were identified. 24 compounds were assessed across 71 endpoints. Cannabidiol, a phytocannabinoid, was the most investigated drug. Macroscopic colitis severity (disease activity index - DAI) and myeloperoxidase activity (MPO) were assessed throughout publications and were meta-analysed using random effects models. Cannabinoids reduced DAI in comparison with vehicle; SMD -1.36, 95% CI -1.62 to-1.09, I²=61%). FAAH inhibitor URB597 had the largest effect size (SMD-4.43, 95% CI-6.32,-2.55), followed by the synthetic drug AM1241 (SMD–3.11, 95% CI -5.01, -1.22) and the endocannabinoid anandamide (SMD-3.03, 95% CI -4.89,-1.17, I² not assessed). Cannabinoids reduced MPO in rodents compared to vehicle; SMD -1.26, 95% CI-1.54 to -0.97, I²=48.1%. Cannabigerol had the largest effect size (SMD -6.20, 95%CI-9.90, -2.50), followed by the synthetic CB₁ agonist ACEA(SMD -3.15, 95%CI-4.75, -1.55) and synthetic CB₁/₂ agonist WIN55,212-2(SMD-1.74, 95%CI-2.81, -0.67, I²=57%). We found no evidence of reporting bias. No significant difference was found between the prophylactic and therapeutic use of cannabinoid drugs. Conclusions: There is abundant pre-clinical literature demonstrating the anti-inflammatory effects of cannabinoid drugs in inflammation of the gut. Larger randomised controlled-trials are warranted