Checkpoint inhibitors and the gut

Checkpoint inhibitors have revolutionized treatments in modern oncology, including many conditions previously relegated to palliative therapies only. However, emerging recognition of checkpoint inhibitor-related adverse events has complicated the status of checkpoint inhibitor-related therapies. This review article discusses gastrointestinal adverse events as a result of checkpoint inhibitor therapy, as well as limitations of current guidelines, thus providing recommendations for guideline revision and future study direction

Semi-solid and solid bolus swallows in high-resolution oesophageal manometry for the detection of motility disorders

Background/Aims: High-resolution oesophageal manometry utilises water swallows to evaluate oesophageal function. However, small volumes of water are not representative of normal eating and as a result often produce normal manometry studies in patients with dysphagia. This study sets out to establish optimal diagnostic thresholds for semi-solid solid swallows and evaluate their ability to uncover motility abnormalities in patients with motility disorders. Method: Manometry was performed using ten 5-mL single water swallows followed by two semi-solid and two solid swallows in the upright position. Normative values for the adjunctive tests were obtained from patient controls while patients with major motility disorders were used to establish the optimal diagnostic thresholds. Diagnostic thresholds identified were prospectively tested in patients with normal water swallows but oesophagus related symptoms and in those with minor and major motility disorders. Results: Normal values for semi-solid and solid were determined in patient controls (n = 100). Development of diagnostic thresholds included 120 patients with major motility disorders. Optimal diagnostic thresholds identified for oesophagogastric junction dysfunction in semi-solid and solid swallows (IRP > 15.5 mmHg). Hypercontractilty and spasm used existing thresholds (>8000 mmHg-s-cm and < 4.5 s, respectively) but modified frequency of ≥50% of adjunctive swallows. Diagnostic thresholds were applied to symptomatic patients with normal water swallows (n = 70) identifying 12/70 (17%) to have abnormal adjunctive swallows. One of 30 patients (3%) with ineffective motility had abnormal adjunctive swallow and 12 patients with oesophageal spasm, oesophagogastric junction obstruction, and hypercontractility had abnormal adjunctive swallows that moved them up the motility disorder hierarchy. Conclusions: Semi-solid and solid challenge increase diagnostic yield of motility disorders

Cirrhotic cardiomyopathy

Cirrhotic cardiomyopathy (CCM), cardiac dysfunction in end-stage liver disease in the absence of prior heart disease, is an important clinical entity that contributes significantly to morbidity and mortality. The original definition for CCM, established in 2005 at the World Congress of Gastroenterology (WCG), was based upon known echocardiographic parameters to identify subclinical cardiac dysfunction in the absence of overt structural abnormalities. Subsequent advances in cardiovascular imaging and in particular myocardial deformation imaging have rendered the WCG criteria outdated. A number of investigations have explored other factors relevant to CCM, including serum markers, electrocardiography, and magnetic resonance imaging. CCM characteristics include a hyperdynamic circulatory state, impaired contractility, altered diastolic relaxation, and electrophysiological abnormalities, particularly QT interval prolongation. It is now known that cardiac dysfunction worsens with the progression of cirrhosis. Treatment for CCM has traditionally been limited to supportive efforts, but new pharmacological studies appear promising. Left ventricular diastolic dysfunction in CCM can be improved by targeted heart rate reduction. Ivabradine combined with carvedilol improves left ventricular diastolic dysfunction through targeted heart rate reduction, and this regimen can improve survival in patients with cirrhosis. Orthotopic liver transplantation also appears to improve CCM. Here, we canvass diagnostic challenges associated with CCM, introduce cardiac physiology principles and the application of echocardiographic techniques, and discuss the evidence behind therapeutic interventions in CCM

New Internet of Medical Things for home-based treatment of anorectal disorders

Home-based healthcare provides a viable and cost-effective method of delivery for resource and labour-intensive therapies, such as rehabilitation therapies, including anorectal biofeedback. However, existing systems for home anorectal biofeedback are not able to monitor patient compliance or assess the quality of exercises performed, and as a result have yet to see wide spread clinical adoption. In this paper, we propose a new Internet of Medical Things (IoMT) system to provide home-based biofeedback therapy, facilitating remote monitoring by the physician. We discuss our user-centric design process and the proposed architecture, including a new sensing probe, mobile app, and cloud-based web application. A case study involving biofeedback training exercises was performed. Data from the IoMT was compared against the clinical standard, high-definition anorectal manometry. We demonstrated the feasibility of our proposed IoMT in providing anorectal pressure profiles equivalent to clinical manometry and its application for home-based anorectal biofeedback therapy

Rheological characteristics of soluble fibres during chemically simulated digestion and their suitability for gastroparesis patients

Dietary fibres are an integral part of a balanced diet. Consumption of a high-fibre diet confers many physiological and metabolic benefits. However, fibre is generally avoided by individuals with gastrointestinal motility disorders like gastroparesis due to increased likelihood of exacerbated symptoms. Low-viscosity soluble fibres have been identified as a possible source of fibre tolerable for these individuals. The aim of this study is to determine the rheological properties of 10 common commercially available soluble fibres in chemically simulated digestive conditions and evaluate their suitability for individuals with mild to moderate gastroparesis, a gastric motility disorder. Rheological testing under neutral condition (distilled water pH 7) and chemically simulated gastric digestion were evaluated to determine the yield point and relative viscosity of each fibre. Our results reveal two rheological categories of soluble fibres; pseudoplastic and dilatant.Simulated digestion was shown to significantly alter the yield-points of psyllium husk, iotacarrageenan, beta-glucan, apple-fibre pectin, and inulin. Gum Arabic and partially hydrolysed guar gum showed the lowest viscosities and were not affected under simulated digestion, characteristics that make them potential candidate fibres for patients with gastroparesis. Altogether, our results demonstrate that digestion can have a significant impact on fibre viscosity and should be taken into consideration when evaluating the suitability of fibres for patients with gastric motility disorders

Prevalence and effects of gastro-oesophageal reflux during spirometry in subjects undergoing reflux assessment

Variability during spirometry can persist despite control of technical and personal factors. We postulate spirometry induces gastro-oesophageal reflux (GOR), which may cause variability and affect results of spirometry. Fifty-eight (58) subjects undergoing GOR investigation with oesophageal manometry and 24hr pH monitoring were recruited. Oesophageal dysmotility and GOR were assessed as part of clinical care. Subjects performed 2 sets of spirometry separated by a 10-minute rest period. The assessment of GOR during spirometry procedure (defined by a lower oesophageal pH<4) started from the first set of spirometry and concluded when the second set of spirometry was completed. We calculated variability (%) of FEV1, FVC and PEFR within each set as well as changes over 10-minutes. Twenty-six subjects (45%) recorded GOR during assessment. Of these, 23 subjects recorded GOR during the 10-minute rest period. Four subjects had GOR recorded only during spirometry tests. We did not find variability of spirometry parameters between the groups with and without GOR during spirometry procedure. However, in subjects with GOR, we found small but significant reductions of PEFR (0.5L/s, 8%, p<0.001) and FEV1 (84 mL, 3%, p = 0.048) in the second set of spirometry compared to the first spirometry set. This pilot study demonstrates that GOR can occur during and following spirometry. Presence of GOR during spirometry in this patient population caused small decreases in PEFR and FEV1 when it is repeated 10-minutes later however not increase variability in a single series of measurements

A HPLC-ESI-Q-ToF-MS method for the analysis of monomer constituents in PHGG, gum arabic and psyllium husk prebiotic dietary fibre supplements

“Soluble” type dietary fibre contains polysaccharides with monomer constituents that play a major role in lowering the glycemic index of food (“low-GI”) and improving colonic health through gut microbiome fermentation. Soluble fibres such as partially hydrolysed guar gum (PHGG), gum Arabic and psyllium husk are of particular interest in gastrointestinal research, exploring their effects in motility disorders such as gastroparesis, constipation, diarrhea and irritable bowel syndrome (IBS) is important. The primary aim of this research was to develop a rapid pre-column derivatized HPLC-ESI-Q-ToF-MS method for the identification and quantification of monomer sugar constituents in commercial dietary fibre supplements of PHGG, gum Arabic and psyllium husk. Polysaccharides in the samples were hydrolysed and derivatized using 1-phenyl-3-methyl-5-pyrazolone (PMP). A rapid 21 min HPLC-ESI-Q-ToF-MS method separated nine different PMP-labelled monomer sugars. Five different sugars (i.e., Galactose, Arabinose, Rhamnose, Mannose and Xylose) were identified and quantified. Standard curve linearity was excellent (R2 > 0.999), with good intra-laboratory precision (< ±5% SD for concentrations, ≤ ±0.02 min peak shifting for retention times). The average three-level (50%, 75% and 100%) spiking recoveries for the analytes was acceptable (96.22–109.49%). Positive scanning mode ESI-MS/MS was used to generate [M + H]+ precursor ions and three (m/z) product ion fragments to provide identity confirmation. The concentrations of monomer sugars in gum Arabic and psyllium husk dietary fibres were consistent with literature reports. In PHGG, the concentration of galactose was unexpectedly higher than mannose, indicating that the commercial hydrolysis process of guar gum during PHGG manufacturing affected monomer composition. The method presented here provides the basis for the standardisation and labelling of commercial PHGG, gum Arabic and psyllium husk supplements. Future research will need to explore the monomer variability in other prebiotic soluble fibres and their efficacy in the production of beneficial short-chain fatty acids (SCFA) in the colonic environment

The use of two-dimensional shear wave elastography in people with obesity for the assessment of liver fibrosis in non-alcoholic fatty liver disease

Obesity is associated with significant comorbidities, including non-alcoholic fatty liver disease (NAFLD). Given its potential to progress to advanced liver disease, monitoring the extent and progress of liver fibrosis and assessing its fibrosis stage are essential. Although liver biopsy is considered to be the gold standard for liver fibrosis staging, it is an invasive procedure with risk of complications. Considering the rising prevalence of obesity and NAFLD globally, developing non-invasive diagnostic methods is a priority. Transient elastography (TE) is increasingly being used to assess the severity of liver disease. However, in the presence of severe obesity, the increased thickness of subcutaneous adipose tissue and changes in anatomy may affect its diagnostic accuracy. Two-dimensional shear wave elastography (2D-SWE) assesses the liver stiffness in real time along with simultaneous anatomic B-mode ultrasound imaging and allows selection of the region of interest. This would suggest that 2D-SWE has several advantages over TE in patients with severe obesity. The purpose of this review is to examine the current literature addressing the use of 2D-SWE in the assessment of liver fibrosis in patients with NAFLD. This review also examines the evidence on the use of 2D-SWE in patients with obesity and NAFLD and compares it to TE as a novel and non-invasive method of assessing liver fibrosis

Understanding the biology of human interstitial cells of Cajal in gastrointestinal motility

Millions of patients worldwide suffer from gastrointestinal (GI) motility disorders such as gastroparesis. These disorders typically include debilitating symptoms, such as chronic nausea and vomiting. As no cures are currently available, clinical care is limited to symptom management, while the underlying causes of impaired GI motility remain unaddressed. The efficient movement of contents through the GI tract is facilitated by peristalsis. These rhythmic slow waves of GI muscle contraction are mediated by several cell types, including smooth muscle cells, enteric neurons, telocytes, and specialised gut pacemaker cells called interstitial cells of Cajal (ICC). As ICC dysfunction or loss has been implicated in several GI motility disorders, ICC represent a potentially valuable therapeutic target. Due to their availability, murine ICC have been extensively studied at the molecular level using both normal and diseased GI tissue. In contrast, relatively little is known about the biology of human ICC or their involvement in GI disease pathogenesis. Here, we demonstrate human gastric tissue as a source of primary human cells with ICC phenotype. Further characterisation of these cells will provide new insights into human GI biology, with the potential for developing novel therapies to address the fundamental causes of GI dysmotility

Placental abnormalities in type 1 and type 2 diabetes mellitus : a systematic review and metaanalysis of shear wave elastography

OBJECTIVE: This study aimed to describe the placental changes occurring in women with preexisting diabetes mellitus and to determine if elastography can detect placental changes in vivo. DATA SOURCES: PubMed, Embase, Medline, and Cochrane were searched to identify English language studies published until July 2020. STUDY ELIGIBILITY CRITERIA: 1) For key question 1, studies that described histopathologic changes in placentas from women with known diabetes mellitus and 2) for key question 2, those that described structural–placental changes detectable by elastography in high-risk pregnancies (eg, those complicated by preeclampsia and/or fetal growth restriction), were included. METHODS: For key question 1, we grouped placental pathologies using the Amsterdam International Consensus Group definitions. For key question 2, we conducted a metaanalysis including all data from studies reporting placental stiffness in meters per second (m/s) or kilopascals (kPa). The mean difference (95% confidence interval) was calculated using a random effects model. RESULTS: Data were extracted from 14 studies of placental histopathology in women with known diabetes. In this group, a wide variety of placental histopathologic changes are described, though none are considered pathognomonic. The histopathologic changes including maternal vascular malperfusion, fetal vascular malperfusion, and/or infectious/inflammatory/other changes were divided into 3 broad categories on the basis of presumed etiology. A total of 15 studies reported the placental stiffness scores in women with a high-risk pregnancy vs those with a normal pregnancy. Only 1 reported stiffness scores for placentas in women with preexisting diabetes mellitus (N<10 women). Pooled analysis of 14 studies with available data included 478 “high-risk pregnancies” and 828 control or healthy pregnancies. Maternal-derived pathologies resulted in higher placental stiffness (mean difference 4.5 kPa [95% confidence interval, 3.16–5.87]) compared with control or healthy pregnancies. Fetal-derived pathologies also resulted in higher placental stiffness (mean difference of 6.5 kPa [95% confidence interval, 1.08–11.86]) compared with control or healthy pregnancies. CONCLUSION: Shear wave elastography may provide an in vivo approximation of placental histopathology in women with certain kinds of high-risk pregnancies. A high-risk pregnancy may involve maternal- and fetal-derived pathologies. Further studies, particularly in women with preexisting diabetes, are needed to confirm this observation