bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of the electrocardiographic phenotype in risk stratification for sudden cardiac death in childhood hypertrophic cardiomyopathy
Authors: Norrish Gabrielle , Topriceanu Cristian , Qu Chen , Field Ella , Walsh Helen , Ziółkowska Lidia , Olivotto Iacopo , Passantino Silvia , Favilli Silvia , Anastasakis Aris , Vlagkouli Vasiliki , Weintraub Robert , King Ingrid , Biagini Elena , Ragni Luca , Prendiville Terrence , Duignan Sophie , McLeod Karen , Ilina Maria , Fernández Adrian , Bökenkamp Regina , Baban Anwar , Drago Fabrizio , Kubuš Peter , Daubeney Piers E F , Chivers Sian , Sarquella-Brugada Georgia , Cesar Sergi , Marrone Chiara , Medrano Constancio , Alvarez Garcia-Roves Reyes , Uzun Orhan , Gran Ferran , Castro Fernandez J , Gimeno Juan R , Barriales-Villa Roberto , Rueda Fernando , Adwani Satish , Searle Jonathan , Bharucha Tara , Siles Ana , Usano Ana , Rasmussen Torsten B , Jones Caroline B , Kubo Toru , Mogensen Jens , Reinhardt Zdenka , Cervi Elena , Elliott Perry M , Omar Rumana Z , Kaski Juan P
Published: March 2021

Aims

The 12-lead electrocardiogram (ECG) is routinely performed in children with hypertrophic cardiomyopathy (HCM). An ECG risk score has been suggested as a useful tool for risk stratification, but this has not been independently validated. This aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events.

Methods and results

Data from 356 childhood HCM patients with a mean age of 10.1 years (±4.5) were collected from a retrospective, multi-centre international cohort. Three hundred and forty-seven (97.5%) patients had ECG abnormalities at baseline, most commonly repolarization abnormalities (n = 277, 77.8%); left ventricular hypertrophy (n = 240, 67.7%); abnormal QRS axis (n = 126, 35.4%); or QT prolongation (n = 131, 36.8%). Over a median follow-up of 3.9 years (interquartile range 2.0–7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93–2.04). No ECG variables were associated with 5-year arrhythmic event on univariable or multivariable analysis. The ECG risk score threshold of >5 had modest discriminatory ability [C-index 0.60 (95% CI 0.484–0.715)], with corresponding negative and positive predictive values of 96.7% and 6.7%

Conclusion

In a large, international, multi-centre cohort of childhood HCM, ECG abnormalities were common and varied. No ECG characteristic, either in isolation or combined in the previously described ECG risk score, was associated with 5-year sudden cardiac death risk. This suggests that the role of baseline ECG phenotype in improving risk stratification in childhood HCM is limited.
Criterion validity of a single-item question for assessment of daily breaks in sedentary time in adults
Authors: Júdice Pedro B , Rosa Gil B , Magalhães João P , Hetherington-Rauth Megan , Correia Inês R , Sardinha Luís B
Published: March 2021

Background

As the implementation of sensor-based assessment for sedentary time (ST) and physical activity (PA) has practical limitations when applied on a large-scale, most studies rely on subjective data. We aimed to examine the criterion validity of a single-item question to assess daily breaks in ST and other PA-related outcomes for the first time using sensor-based data as the criterion.

Methods

In a sample of 858 adults, breaks in ST and other PA-related parameters were assessed through sensor-based accelerometry and subjective data, which included a comprehensive questionnaire with a specific question (‘During the day, do you usually sit for a long time in a row or interrupt frequently?’) with a three-level closed answer. The Spearman’s rank correlation coefficient was used to determine the agreement between the single-item question and sensor-based data.

Results

Positive correlations were found for self-reported breaks in ST with sensor-based breaks in ST in both women (ρ=0.37; 95% CI=0.29–0.44) and men (ρ=0.15; 95% CI=0.04–0.26). Self-reported breaks in ST were inversely correlated with ST in women (ρ =−0.33; 95% CI=−0.40 to 0.25). For both sexes, self-reported breaks in ST showed a positive correlation with light-intensity PA (ρ=0.39; 95% CI=0.31–0.46 women; ρ=0.13; 95% CI=0.02–0.24 men), however, positive correlations between self-reported breaks in ST and moderate-to-vigorous PA (ρ=0.13; 95% CI=0.02–0.24) were found only in men.

Conclusions

Our single-item question can be used as an indication for ranking people’s breaks in ST during the waking day, although acknowledging that some misclassification will occur, especially in men. There must be an effort to include this question in future national and international surveys to replicate these findings.
Rickettsia-host interaction: strategies of intracytosolic host colonization
Authors: Voss Oliver H , Rahman M Sayeedur
Published: March 2021

Bacterial infection is a highly complex biological process involving a dynamic interaction between the invading microorganism and the host. Specifically, intracellular pathogens seize control over the host cellular processes including membrane dynamics, actin cytoskeleton, phosphoinositide metabolism, intracellular trafficking and immune defense mechanisms to promote their host colonization. To accomplish such challenging tasks, virulent bacteria deploy unique species-specific secreted effectors to evade and/or subvert cellular defense surveillance mechanisms to establish a replication niche. However, despite superficially similar infection strategies, diverse Rickettsia species utilize different effector repertoires to promote host colonization. This review will discuss our current understandings on how different Rickettsia species deploy their effector arsenal to manipulate host cellular processes to promote their intracytosolic life within the mammalian host.
On the relationship between strain rate and seismicity in the India–Asia collision zone: implications for probabilistic seismic hazard
Authors: Stevens V L , Avouac J-P
Published: March 2021

The increasing density of geodetic measurements makes it possible to map surface strain rate in many zones of active tectonics with unprecedented spatial resolution. Here we show that the strain tensor rate calculated from GPS in the India–Asia collision zone represents well the strain released in earthquakes. This means that geodetic data in the India–Asia collision zone region can be extrapolated back in time to estimate strain buildup on active faults, or the kinematics of continental deformation. We infer that the geodetic strain rates can be assumed stationary through time on the timescale needed to build up the elastic strain released by larger earthquakes, and that they can be used to estimate the probability of triggering earthquakes. We show that the background seismicity rate correlates with the geodetic strain rate. A good fit is obtained assuming a linear relationship ($\dot{N} = \lambda \ \cdot \dot{\epsilon }$, where $\dot{N}$ is the density of the rate of Mw ≥ 4 earthquakes, $\dot{\epsilon }$ is strain rate and λ = 2.5 ± 0.1 × 10−3 m−2), as would be expected from a standard Coulomb failure model. However, the fit is significantly better for a non-linear relationship ($\dot{N} = \gamma _1 \cdot \dot{\epsilon }^{\gamma _2}$ with γ1 = 2.5 ± 0.6 m−2 and γ2 = 1.42 ± 0.15). The b-value of the Gutenberg–Richter law, which characterize the magnitude–frequency distribution, is found to be insensitive to the strain rate. In the case of a linear correlation between seismicity and strain rate, the maximum magnitude earthquake, derived from the moment conservation principle, is expected to be independent of the strain rate. By contrast, the non-linear case implies that the maximum magnitude earthquake would be larger in zones of low strain rate. We show that within areas of constant strain rate, earthquakes above Mw 4 follow a Poisson distribution in time and and are uniformly distributed in space. These findings provide a framework to estimate the probability of occurrence and magnitude of earthquakes as a function of the geodetic strain rate. We describe how the seismicity models derived from this approach can be used as an input for probabilistic seismic hazard analysis. This method is easy to automatically update, and can be applied in a consistent manner to any continental zone of active tectonics with sufficient geodetic coverage.
The monks of Rochester and the hospital of St. Mary of Strood: a twelfth-century dispute reassessed
Authors: Barnaby James
Published: March 2021

This article assesses the twelfth-century Rochester dispute concerning St. Mary’s hospital at Strood. Bishop Gilbert Glanville’s plan to endow the hospital with monastic estates was vigorously resisted by the cathedral monks, with Gilbert traditionally being seen as an anti-monastic bishop. This article reassesses the events of the conflict and places it in the context of other twelfth-century disputes. It argues that Gilbert was not trying to supplant his cathedral chapter, but was instead trying to establish a hospital to care for the needs of the sick and poor pilgrims.
Micronations: A lacuna in the law
Authors: Hobbs Harry , Williams George
Published: March 2021

Around 100 active micronations exist across the globe. Led by committed and eccentric individuals, these aspirant or wannabe states assert their claims to sovereignty in myriad ways. In dressing in the language of statehood, they challenge understandings of, and approaches to, international legal personality. In this article we provide the first legal survey of micronations. We develop a conceptual framework to understand what it means to be a micronation, explore their various forms, and analyze key public law issues. Our survey reveals that, although public law has not engaged with this phenomenon, states respond to the assertion of sovereignty by micronations in both benign and violent ways.
Mechanical circulatory support in coronavirus disease-2019-positive patients with severe respiratory failure
Authors: Natanov Ruslan , Wiesner Olaf , Haverich Axel , Kühn Christian
Published: March 2021

OBJECTIVES

Treatment of severe acute respiratory distress syndrome (ARDS) induced by severe acute respiratory syndrome coronavirus 2 has been heavily debated. Our goal was to describe our findings in patients with severe ARDS due to severe coronavirus disease 2019 (sCOVID-19) treated with venovenous extracorporeal membrane oxygenation (vv-ECMO).

METHODS

We retrospectively examined all patients treated with vv-ECMO for severe ARDS due to acute respiratory syndrome coronavirus 2.

RESULTS

In total, 13 patients were treated with vv-ECMO in our medical centre. The mean patient age was 48.1 years. Most patients were obese (69%) and male (85%). All patients were mechanically ventilated before ECMO. The mean time from intubation to proning was 16.6 h; the time from start of prone therapy to vv-ECMO implantation was 155.1 h. The mean total ECMO run time was 358 h. Significant reduction of positive end-expiratory pressure (P = 0.02), peak pressure (P = 0.001) and minute volume (P = 0.03) could be achieved after implantation of vv-ECMO. All patients showed an inflammatory response. Overall mortality was 30.7%: 1 patient died of mesenteric ischaemia; 3 patients died of multiple organ failure. A worse prognosis was seen in patients with highly elevated concentrations of interleukin-6.

CONCLUSIONS

The use of vv-ECMO in patients with sCOVID-19-induced ARDS is safe and associated with improved respiratory ventilation settings. The rate of immune system involvement plays a pivotal role in the development and outcome of sCOVID-19.
Accuracy and reliability of injury coding in the national Dutch Trauma Registry
Authors: Twiss Eric , Krijnen Pieta , Schipper Inger
Published: March 2021

Objective

Injury coding is well known for lack of completeness and accuracy. The objective of this study was to perform a nationwide assessment of accuracy and reliability on Abbreviated Injury Scale (AIS) coding by Dutch Trauma Registry (DTR) coders and to determine the effect on Injury Severity Score (ISS). Additionally, the coders’ characteristics were surveyed.

Methods

Three fictional trauma cases were presented to all Dutch trauma coders in a nationwide survey (response rate 69%). The coders were asked to extract and code the cases’ injuries according to the AIS manual (version 2005, update 2008). Reference standard was set by three highly experienced coders. Summary statistics were used to describe the registered AIS codes and ISS distribution. The primary outcome measures were accuracy of injury coding and inter-rater agreement on AIS codes. Secondary outcome measures were characteristics of coders: profession, work setting, experience in injury coding and training level in injury coding.

Results

The total number of different AIS codes used to describe 14 separate injuries in the three cases was 89. Mean accuracy per AIS code was 42.2% (range 2.4–92.7%). Mean accuracy on number of AIS codes was 23%. Overall inter-rater agreement per AIS code was 49.1% (range 2.4–92.7%). The number of assigned AIS codes varied between 0 and 18 per injury. Twenty-seven percentage of injuries were overlooked. ISS was correctly scored in 42.4%. In 31.7%, the AIS coding of the two more complex cases led to incorrect classification of the patient as ISS < 16 or ISS ≥ 16. Half (47%) of the coders had no (para)medical degree, 26% were working in level I trauma centers, 37% had less than 2 years of experience and 40% had no training in AIS coding.

Conclusions

Accuracy of and inter-rater agreement on AIS injury scoring by DTR coders is limited. This may in part be due to the heterogeneous backgrounds and training levels of the coders. As a result of the inconsistent coding, the number of major trauma patients in the DTR may be over- or underestimated. Conclusions based on DTR data should therefore be drawn with caution.
Antibiotics and healthcare facility-associatedClostridioides difficileinfection: systematic review and meta-analysis 2020 update
Authors: Slimings Claudia , Riley Thomas V
Published: March 2021

Background

Antibiotic use is the most important modifiable risk factor for healthcare facility-associated Clostridioides difficile infection (HCFA-CDI). Previous systematic reviews cover studies published until 31 December 2012.

Objectives

To update the evidence for associations between antibiotic classes and HCFA-CDI to 31 December 2020.

Methods

PubMed, Scopus, Web of Science Core Collection, WorldCat and Proquest Dissertations & Theses were searched for studies published since 1 January 2013. Eligible studies were those conducted among adult hospital inpatients, measured exposure to individual antibiotics or antibiotic classes, included a comparison group and measured the occurrence of HCFA-CDI as an outcome. The Newcastle–Ottawa Scale was used to appraise study quality. To assess the association between each antibiotic class and HCFA-CDI, a pooled random-effects meta-analysis was undertaken. Meta-regression and subgroup analysis was used to investigate study characteristics identified a priori as potential sources of heterogeneity.

Results

Carbapenems and third- and fourth-generation cephalosporin antibiotics remain the most strongly associated with HCFA-CDI, with cases more than twice as likely to have recent exposure to these antibiotics prior to developing HCFA-CDI. Modest associations were observed for fluoroquinolones, clindamycin and β-lactamase inhibitor combination penicillin antibiotics. Individual study effect sizes were variable and heterogeneity was observed for most antibiotic classes.

Conclusions

This review provides the most up-to-date synthesis of evidence in relation to the risk of HCFA-CDI associated with exposure to specific antibiotic classes. Studies were predominantly conducted in North America or Europe and more studies outside of these settings are needed.
Goals, life events, and transitions: examining fertility apps for holistic health tracking
Authors: Costa Figueiredo Mayara , Huynh Thu , Takei Anna , Epstein Daniel A , Chen Yunan
Published: March 2021

Objective

Fertility is becoming increasingly supported by consumer health technologies, especially mobile apps that support self-tracking activities. However, it is not clear whether the apps support the variety of goals and life events of those who menstruate, especially during transitions between them.

Methods

Thirty-one of the most popular fertility apps were evaluated, analyzing data from three sources: the content of app store pages, app features, and user reviews.

Findings

Results suggest that fertility apps are designed to support specific life goals of people who menstruate, offering several data collection features and limited feedback options. However, users often desire holistic tracking that encompasses a variety of goals, life events, and the transitions among them.

Discussion

These findings suggest fertility patients can benefit more from holistic self-tracking and provide insights for future design of consumer health technologies that better support holistic fertility tracking.

Conclusion

Fertility apps have the potential to support varied experiences of people who menstruate. But to achieve that, apps need to expand their support by offering ways for more users to perform holistic, personalized, and personally meaningful tracking, so they can derive long-term benefit from the data they collect.
A12 PRE-TREATMENT HLADQA1-HLADRB1 TESTING FOR THE PREVENTION OF AZATHIOPRINE-INDUCED PANCREATITIS IN INFLAMMATORY BOWEL DISEASE: A PROSPECTIVE COHORT STUDY
Authors: Wilson A , Wang M , Ponich T , Gregor J C , Chande N , Yan B , Sey M , Beaton M D , Kim R
Published: March 2021

Background

Azathioprine (AZA) therapy has a long history of use in IBD. The need to promote its safe use in this population is ensured by governmental health policy requiring IBD patients to fail low cost drugs, such as AZA, prior to approving funding for more potent biologic therapies. AZA-induced pancreatitis is an idiosyncratic and unpredictable response, occurring in up to 7% of AZA-exposed patients that can lead to patient morbidity, hospitalization, delay in effective IBD management, as well as result in substantial additional health-related costs. There are no tools in clinical practice to identify individuals at risk of AZA-induced pancreatitis. Genetic variation in the HLADQA1-HLADRB1*07:01 haplotype is strongly associated with azathioprine (AZA)-induced pancreatitis in inflammatory bowel disease (IBD).

Aims

To evaluate whether HLA DQA1-HLADRB1*07:01A>C pre-treatment genotype testing in an adult IBD population prior to AZA therapy to guide AZA selection would result in a lower incidence of AZA-induced pancreatitis.

Methods

Participants with IBD (n=599) were screened for HLADQA1-HLADRB1*07:01A>C and participants with a variant genotype were excluded from azathioprine treatment (n=271). Wildtype participants (n=328) were started on azathioprine and followed for 3 months. The incidence of pancreatitis was compared to unscreened historical controls (n=373).

Results

The minor allele frequency of HLADQA1-HLADRB1*07:01 was 30.4% and 30.0% in the screened and unscreened populations respectively. Up to 45.2% of participants were excluded from AZA therapy based on genotype in the HLADQA1-HLADRB1*07:01A>C screened cohort. HLADQA1-HLADRB1*07:01A>C screening resulted in an 11-fold reduction in the odds of azathioprine-induced pancreatitis (0.30% versus 3.4%, OR=0.085, 95%CI=0.011–0.651, p=0.002).

Conclusions

HLA DQA1-HLADRB1*07:01A>C screening substantially reduced the risk of pancreatitis during AZA treatment in patients with IBD. However, using this strategy as a tool for guiding the use of AZA therapy in IBD may eliminate a large proportion of patients from being eligible for treatment with AZA. In regions, where there is access to other IBD therapies, and given the short and long term toxicities associated with AZA, HLA DQA1-HLADRB1*07:01A>C screening may be a clinically-relevant strategy for enhancing the safe use of AZA in IBD. Additionally, cost-effectiveness analyses are needed to further solidify the utility of HLA DQA1-HLADRB1*07:01A>C-screening in IBD populations.

Funding Agencies

Academic Medical Organization of Southwestern Ontario Innovation Fund
A16 FIBER SUPPLEMENTATION DIFFERENTIALLY MODULATES RESPONSES TO FECAL MICROBIAL TRANSPLANTATION IN PATIENTS WITH METABOLIC SYNDROME AND SEVERE OBESITY: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PILOT TRIAL
Authors: Mocanu V , Zhang Z , Deehan E , Samarasinghe K , Hotte N , Kao D H , Karmali S , Birch D W , Walter J , Madsen K
Published: March 2021

Background

Fecal microbial transplantation (FMT) from lean donors to obese patients with metabolic syndrome (MS) has been associated with promising yet short-term metabolic improvements. The concept of using dietary or fiber supplementation to enhance effects induced by FMT has been much discussed in the literature, but to date no human trials have examined this concept.

Aims

The aim of this study was to determine if fiber supplementation following FMT was able to enhance or sustain FMT-mediated metabolic benefits.

Methods

We performed a 12-wk double-blind randomized placebo-controlled trial in patients with severe obesity and MS recruited from Edmonton’s Bariatric Clinic from 2018 to 2019. Patients were stratified by sex and block randomized 1:1:1:1 amongst one of four groups: (1) Placebo FMT and a non-fermentable fiber (NF) (2) Placebo FMT and fermentable fiber (FF); (3) FMT and non-fermentable fiber (FMT-NF); and (4) FMT and fermentable fiber (FMT-FF). Patients received a single dose of FMT (50g donor stool) with 20 oral capsules followed by a 6-wk period of daily fiber. The primary outcome was evaluating mean differences (MD) in insulin sensitivity from baseline to 6-wks using the homeostatic model assessment of insulin resistance (HOMA2-IR).

Results

Sixty-eight patients were randomized with 61 completing the primary outcome (NF = 17; FF = 15; FMT-NF = 14; FMT-FF = 15) and evaluated using a modified intent-to-treat analysis. Baseline characteristics were similar with a mean BMI 45 ± 7 kg/m2, a female predominance (83.6%), and a HOMA2-IR of 3.43 ± 2.2. There were no baseline differences in clinical characteristics, metabolic parameters, medications, or dietary intake. FMT-NF had improvements in HOMA2-IR (MD -24.0% ± 12.0%; p=0.02), insulin sensitivity (MD 27.6% ± 12.3%; p=0.02), and insulinemia (MD -25.4% ± 12.3%; p=0.02) from baseline to 6-wks (Figure 1). These benefits were associated with increased microbial richness and improvements in GLP-1 metabolism. Linear mixed model regression revealed that select bacterial taxa including Phascolarctobacterium, Ruminococcaeceae, and B. stercoris correlated with increased insulin sensitivity. Findings occurred in the absence of changes in anthropometric parameters, dietary intake, medication regimen and were not observed in groups receiving fermentable fiber or in any group following cessation of fiber.

Conclusions

This proof-of-concept trial provides evidence that a single FMT dose combined with daily non-fermentable fiber supplementation can successfully improve insulin resistance in patients with metabolic syndrome and severe obesity on optimized medical therapy.

Funding Agencies

W. Garfield Weston Foundation
A17 EFFICACY AND SAFETY OF FILGOTINIB AS MAINTENANCE THERAPY FOR PATIENTS WITH MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS: RESULTS FROM THE PHASE 2B/3 SELECTION STUDY
Authors: Peyrin-Biroulet L , Loftus E V , Danese S , Vermeire S , Sandborn W J , Fogel R , Nijhawan S , Kempinski R , Filip R , Hospodarskyy I , McNally J , Yun C , Zhao S , Liu X , Tasset C , Besuyen R , Watanabe M , Schreiber S , Rogler G , Hibi T , Feagan B G
Published: March 2021

Aims

SELECTION (NCT02914522) Maintenance evaluated filgotinib (FIL), a preferential JAK1 inhibitor, as maintenance therapy for patients (pts) with moderately to severely active ulcerative colitis (UC) who achieved clinical remission or Mayo Clinic Score (MCS) response after 10 weeks of FIL 200mg QD, FIL 100mg QD or placebo (PBO) induction.

Methods

Pts randomized to FIL induction were rerandomized 2:1 to their induction FIL dose or PBO; pts randomized to PBO induction continued PBO maintenance. Steroid tapering was mandatory. The primary endpoint was clinical remission at Week 58. Key secondary endpoints and exploratory endpoints were assessed at Week 58.

Results

664 pts were treated in the Maintenance Study (n=93, 270, and 301 from induction with PBO, FIL 100mg and FIL 200mg); efficacy analyses included only FIL induction pts. Baseline demographics and disease characteristics were generally balanced across treatment arms; 40% were biologic experienced. Significantly higher proportion of pts on FIL 200mg or FIL 100mg were in clinical remission vs PBO. Significantly higher proportions of pts achieved key secondary endpoints with FIL 200mg vs PBO. More pts on FIL 200 mg or FIL 100mg achieved an MCS response and endoscopic improvement vs PBO.

Incidences of adverse events (AEs), serious AEs and discontinuations due to AEs were similar across arms. Serious infection (<2%) and herpes zoster (<1%) were infrequent among FIL-treated patients. There were no venous thromboses, including pulmonary embolism, among FIL-treated pts. Two pts on FIL 200mg died, both AEs leading to death were considered unrelated to FIL.

Conclusions

FIL 200mg and FIL 100mg were effective as maintenance treatment for pts with moderately to severely active UC who had achieved clinical response to FIL induction treatment. FIL 200 mg met all key secondary endpoints including endoscopic, histologic and 6-month corticosteroid-free remission. FIL was well tolerated in pts with moderate to severely active UC.

Funding Agencies

None
A24 FCGBP MAINTAINS MUC2 MUCUS STRUCTURAL INTEGRITY BY STABILIZING THE MUCUS LAYER IN RESPONSE TO THE COLONIC PATHOGEN, ENTAMOEBA HISTOLYTICA
Authors: Gorman H , Moreau F , Kim A , Chadee K
Published: March 2021

Background

MUC2 mucin is the major component of the colonic mucus bilayer that serves as the first line of innate host defense against pathogens while supporting a healthy microbiota and regulating epithelial barrier function. Proteomic studies of colonic mucus have identified various mucus-associated proteins. One of the most abundant is FCGBP, similar to MUC2 mucin, but its interaction with MUC2 or function is not known. Here, we elucidated FCGBP functional role in stabilizing MUC2 mucus and in innate host defence against Entamoeba histolytica (Eh).

Aims

Hypothesis: MUC2 mucin and FCGBP are coordinately produced and play an important role in innate host defense. The specific aims are:

1. To determine if FCGBP alters the structural integrity of the mucus layer

2. To determine the role of FCGBP in Eh infection

Methods

FCGBP mRNA and protein expression induced by Eh, in WT and FCGBP CRISPR/Cas9 LS174T goblet cells were analysed by RT-PCR and Western blotting. To compare integrity of the mucus layer, fluorescent Eh and 1μM fluorescent beads were inoculated on WT and KO monolayers and adherent Eh and bead penetrability analyzed. To quantify MUC2 and FCGBP degradation by Eh, purified MUC2 and recombinant FCGBP were incubated with Eh proteases (SPs) and Western blotted using highly specific antibodies against various regions of the proteins.

Results

In response to live Eh, FCGBP and MUC2 mRNA and protein expressions were significantly increased in a time-dependent manner. Surprisingly, FCGBP KO cells elicited robust expression of pro-inflammatory cytokine mRNA and protein as compared to WT cells. More fluorescent Eh were attached to the mucus layer of FCGBP KO cells as compared to WT or MUC2 KO cells. Fluorescent beads penetrated further towards the epithelial cell surface in KO as compared to WT cells. Interestingly, while both MUC2 and FCGBP from purified polymeric mucins were degraded by Eh SPs, FCGBP cleavage occurred at a faster rate than MUC2. Degradation of FCGBP and MUC2 was mediated by EhCP-A5 cysteine proteinase using purified MUC2 and recombinant FCGBP.

Conclusions

In WT goblet cells, FCGBP and MUC2 were upregulated temporally in response to Eh. The increase in pro-inflammatory cytokine expression in FCGBP KO cells in response to Eh suggests that Eh directly interacted with the cell surface suggesting an impaired protective mucus layer. In support of this, fluorescent beads penetrated the mucus layer close to the cell surface and more Eh were attached to FCGBP KO mucus demonstrating that FCGBP was critical in providing structural integrity of the mucus layer. In response to Eh, FCGBP degradation was a prerequisite for MUC2 cleavage, providing direct evidence that FCGBP and MUC2 interactions conferred biophysical properties of the protective functions of the mucus gel.

Funding Agencies

CIHR
A43 LONG-TERM EFFICACY AND SAFETY OF OBETICHOCLIC ACID IN PRIMARY BILIARY CHOLANGITIS: RESPONDER ANALYSIS OF OVER 5 YEARS OF TREATMENT IN THE POISE TRIAL
Authors: Hirschfield G , Jones D , Carbone M , Bowlus C L , Nevens F , Kremer A E , Liberman A , MacConell L , Hansen B E
Published: March 2021

Background

Obeticholic acid (OCA), a potent farnesoid X receptor agonist, is approved as second-line treatment for primary biliary cholangitis (PBC) in patients with an incomplete response or intolerance to ursodeoxycholic acid.

Aims

We evaluated the effect of OCA in PBC patients enrolled in the POISE trial, comparing those who did or did not achieve the POISE response criteria.

Methods

The phase 3, randomized, double-blind, 1-year POISE trial evaluated the efficacy and safety of OCA 5 and 10 mg vs placebo in patients with PBC; a 5-year open-label extension followed in which all patients received OCA. This analysis evaluated longer-term efficacy and safety in patients who achieved the POISE primary endpoint of alkaline phosphatase (ALP) <1.67 × upper limit of normal (ULN), total bilirubin 15% from baseline after 1 year of OCA and in patients who were incomplete responders.

Results

The analysis included 86 patients who achieved the POISE primary endpoint at year 1 of OCA treatment and 107 incomplete responders (mean baseline ALP, 268 vs 356 U/L, respectively; P<0.0001). Mean change from baseline in ALP at year 5 was –101 U/L for responders and –121 U/L for incomplete responders (P<0.0001; Figure). Median (Q1, Q3) baseline GLOBE 10-year risk of event scores were 16 (11, 23) for responders and 25 (15, 43) for incomplete responders. Change from baseline in median (Q1, Q3) GLOBE 10-year risk of event at year 1, which includes age and thus increases with time, was –2 (–4, 2) for responders and –2 (–6, 4) for incomplete responders; at year 5, these changes were 2 (–2, 7) and 4 (–4, 11), respectively. Median (Q1, Q3) baseline UK-PBC 10-year risk of event scores were 5 (3, 8) for responders and 8 (4, 16) for incomplete responders. Change from baseline in median (Q1, Q3) UK-PBC 10-year risk of event at year 1 was –1 (–3, 0.2) for responders and –1 (–3, 1) for incomplete responders; at year 5, these changes were –0.8 (–2, 0.2) and –0.05 (–2, 2), respectively. The most frequently reported AEs among responders and incomplete responders were pruritus (67%, 86%) and fatigue (35%, 31%).

Conclusions

OCA treatment improved key biochemical markers of PBC, regardless of achieving the POISE primary endpoint after 1 year of OCA treatment. Changes in biochemical parameters over time were often similar between groups.

Funding Agencies

Intercept Pharmaceuticals
A48 USE OF ENDOSCOPIC ULTRASOUND FINE NEEDLE ASPIRATE AND ENDOSCOPIC ULTRASOUND FINE NEEDLE BIOPSY FOR DETECTION OF GATA6 EXPRESSON IN PANCREATIC DUCTAL ADENOCARINCOMA
Authors: Law C , Fischer S , Knox J , Gallinger S , Ramotar S , Anna D , May G , James P D
Published: March 2021

Background

GATA6 is a transcription factor that can be used to distinguish between the basal-like and classical subtypes of pancreatic ductal adenocarcinoma (PDAC). The basal-like subtype has been demonstrated to be less responsive to modified FOLFIRINOX chemotherapy and thus can be used to predict response to specific chemotherapies. To date, GATA6 expression has only been evaluated in surgically resected PDAC specimens. Less than 15% of patients with PDAC are eligible for surgery. Endoscopic ultrasound guided fine-needle aspirate (EUS-FNA) and biopsy (EUS-FNB) can potentially help assess GATA6 expression in PDAC and in turn, help guide personalized treatment selection in all cases of PDAC.

Aims

The primary objective of this study was to explore the yield of EUS-FNA and EUS-FNB for the detection of GATA6 among patients with PDAC. The study also aimed to explore the impact of lesion location on sample adequacy and type of fixative on validity of GATA6 staining.

Methods

This study was conducted from November 2017 to October 2019. Consecutive patients with a diagnosis of PDAC confirmed by biopsy were included. Patients underwent either EUS-FNB or EUS-FNA to obtain tissues samples. Samples were fixed in either neutral buffered formalin (NBF) or a methanol based buffered solution (Cytolyt) and evaluated by a specialized cytopathology team. Fisher’s exact test was used and a p-value ≤0.05 was considered to indicate statistical significance.

Results

Forty-four patients were included in the study. Twenty-three (52%) patients were male and the median age of patients was 67.5 years. Twenty-five lesions were located in the head and neck of the pancreas, 14 were located in the body, and 4 were located in the tail. One patient was found to have a local recurrence of PDAC at the surgical bed of a previous Whipple procedure.

Eighteen lesions were sampled by EUS-FNA and 26 were sampled using EUS-FNB. Thirty-eight (86%) samples were adequate for assessment of GATA6. Sampling technique (p=0.68) and fixative type (p=1.00) did not appear to affect sample adequacy. Compared to pancreatic body or tail specimens, samples obtained from the head or neck of the pancreas were more likely to be inadequate for analysis (p=0.03).

Conclusions

EUS-FNA and EUS-FNB samples are efficacious methods of assessing GATA6 expression in PDAC. This is the first predictor of treatment response that has been demonstrated to be obtained without surgical resection. Neither EUS needle type or alcohol fixation before cell block preparation appear to impact GATA6 detection. Lesions in the pancreatic head or neck appear to be associated with higher rates of sample inadequacy. Larger, prospective studies are required to confirm our findings.

Funding Agencies

None
A61 USE OF ADJUNCTIVE REMOVAL TECHNIQUES FOR ENDOSCOPIC MUCOSAL RESECTION OF LARGE NON-PEDUNCULATED COLONIC POLYPS IS PREDICTIVE OF POLYP RECURRENCE
Authors: Li S , Mosko J , May G , Kandel G , Kortan P , Marcon N , Teshima C
Published: March 2021

Background

Endoscopic mucosal resection (EMR) allows for safe and effective removal of large non-pedunculated colon polyps. However, prior studies have shown significant recurrence rates between 10–30% after EMR, which have led to recommendations for close endoscopic follow-up and the use of techniques such as snare tip soft coagulation (STSC) to EMR margins to prevent recurrence. Models such as the Size/Morphology/Site/Access score (SMSA) have been developed to aid in identifying polyp complexity and patients at high risk of recurrence. Numerous individual risk factors for recurrence have previously been reported, however the significance of these factors have varied between studies, with limited data from Canadian centres.

Aims

To evaluate predictors of recurrence for large non-pedunculated polyps following EMR.

Methods

Consecutive patients between April 1, 2017 to March 1, 2019 who underwent EMR were retrospectively identified from endoscopy unit administrative records. Patients with non-pedunculated colorectal polyps ≥ 2 cm that were removed by EMR were included if follow-up endoscopy data were available. Polyps found to contain invasive adenocarcinoma on histology and/or were referred for surgical resection were excluded. Patient demographic, pre-procedural, intra-procedural, and post-procedural data to time of first follow-up colonoscopy were extracted. Recurrence was defined as a positive pathology specimen from the EMR scar at follow-up. Adjunctive techniques were defined as the use of any non-snare resection or ablation technique for removal of visible adenoma at the time of the EMR. Chi-square and multivariate regression analyses were conducted for variables of interest.

Results

517 patients underwent large polyp EMR during the study time period with 265 patients satisfying inclusion criteria. Median age of patients was 67 years (IQR 14); 48% were female. STSC was performed to EMR margins in 94% of cases. 30.9% and 69.1% of polyps were SMSA grade 3 and grade 4 respectively. Adjunctive removal techniques were utilized in 31% of patients, 95% of which was hot avulsion. 15% of patients had recurrence on follow-up endoscopy. Higher SMSA grade was associated with the use of adjunctive techniques (20% vs. 37%, p=0.006). The use of adjunctive removal techniques (OR 2.92, p=0.007) and male gender (OR 3.45, p=0.002) were the only factors found to be significantly predictive of recurrence on multivariate analysis.

Conclusions

Male gender and the use of adjunctive removal techniques, particularly hot avulsion, are independently predictive of recurrence after EMR of large complex colorectal polyps. Male patients and those who require hot avulsion may be considered high risk for recurrence and warrant closer follow-up.

Funding Agencies

None
A62 THE UTILITY OF FECAL IMMUNOCHEMICAL TEST IN HOSPITALIZED PATIENTS: A RETROSPECTIVE CHART REVIEW
Authors: Vantomme E , Chetty K , Ho K , O’Byrne M
Published: March 2021

Background

Fecal immunochemical test (FIT) is a colorectal cancer (CRC) screening tool that uses antibodies to detect the globin moiety of human hemoglobin. On average, one test costs approximately $35 CAD. It has been widely validated as an effective screening tool that is both more sensitive than fecal occult blood testing, and less likely to react to non-human sources of blood, such as from dietary sources. Despite an absence of evidence for use in hospitalized patients, it is commonly ordered in this setting.

Aims

To assess the value and appropriateness of FIT in hospitalized patients in an urban health authority.

Methods

All FITs ordered for hospitalized patients between August 1, 2017 and June 1, 2018 in one academic hospital in Regina, Saskatchewan were examined. Of the 626 cases that were identified, information regarding demographics, clinical presentation, consultations, laboratory values, and endoscopy results were recorded.

Results

Of all 626 FITs ordered, 204 were positive and 422 were negative. Hospitalist physicians ordered 41% of these FITs. Of the 197 patients with negative FITs whose clinical data were available, 39% proceeded to gastroscopy and 23% proceeded to colonoscopy/flexible sigmoidoscopy during admission. Of the 201with positive FITs whose clinical data were available, 58% proceeded to gastroscopy and 40% proceeded to colonoscopy/flexible sigmoidoscopy during admission. FIT had a sensitivity of 100% (95% CI: 94–100%) and specificity of 3% (95% CI: 0–15%) to detect abnormal colonoscopy/flexible sigmoidoscopy results while having a sensitivity of 67% (95% CI: 57–78%) and specificity of 45% (95% CI:36–55%) to detect abnormal gastroscopy. Using a composite of uninvestigated iron deficiency, age >75 or <50 years, clinically overt bleeding, endoscopy despite negative FIT, and up-to-date CRC screening as a definition for inappropriate use of FIT, we found that 7% of negative FITsand 4% of positive FITs were appropriately ordered.

Conclusions

FIT tests had excellent sensitivity for lower gastrointestinal bleeding but had a high false positive rate in this population. FIT tests performed poorly in upper gastrointestinal bleeding. Using FIT for its validated purpose of CRC screening was done in a minority of cases. Importantly, 60% of patients with negative FIT tests proceeded to endoscopy, which may suggest that FITs in hospitalized patients does not significantly alter clinical decision making in a majority of cases.

Funding Agencies

None
A66 GASTRIC HETEROTOPIA OF THE COLON IN A PATIENT WITH A POSITIVE FECAL IMMUNOCHEMICAL TEST
Authors: Nassiri S , Emery J S , Lee L H
Published: March 2021

Background

Gastric heterotopia (GH), indicates the presence of ectopic gastric tissue and is a rare entity outside of the small intestine. Abdominal pain and bleeding are described but most colonic GH is found incidentally.

Aims

We report a case of colonic GH found on routine screening colonoscopy.

Methods

Case report and review of the literature.

Results

Case Report: A 60-year-old woman with a history of alcohol use disorder, chronic Hepatitis C, and gastroesophageal reflux disease was referred for colonoscopy after a positive fecal immunochemical test. Remote colonoscopy was notable for a large tubular adenoma with low-grade dysplasia. The patient denied constitutional symptoms, change in bowel habits, or evidence of gastrointestinal (GI) bleeding. No family history of colorectal cancer was reported. Complete blood count, renal function, electrolytes, and carcinoembryonic antigen were normal.

At colonoscopy, a 2 cm sessile polyp (0-Is Paris classification) was identified with a normal vascular pattern, but unclassifiable pit pattern. Submucosal injection was suboptimal suggesting tethering. However, given the history of previous polypectomy and favorable endoscopic appearance, piecemeal resection was attempted and achieved fair results. Histology showed abundant pyloric-type glands with overlying foveolar epithelium (Figure 1). Endoscopic follow-up at 8 months confirmed complete resection.

Literature Review

GH is observed throughout the GI tract but is predominantly seen in the esophagus and duodenum. Colonic involvement is uncommon with only 12 cases reported. Despite the lack of epidemiological studies, there is a male predominance across all age groups. Pathogenesis is thought to be either congenital, with deposition as the stomach descends during embryogenesis, or acquired secondary to metaplasia following injury to normal intestinal mucosa.

Presenting complaints may include altered bowel habits or haematochezia, but most lesions are detected incidentally on surveillance colonoscopy. Endoscopic descriptions are diverse with variations in size (1-60mm), Paris classification (sessile or pedunculated), and appearance (erythematous patch, ulcer, or diverticulum). Endoscopic resection is recommended given association with bleeding but may be technically difficult due to submucosal involvement which may theoretically increase risk of complications such as perforation. Definitive diagnosis rests on histological examination. The risk of malignant transformation of GH in the colon is unknown with only two such cases reported. However, some propose the incidence of malignant change is underestimated as the growing tumor may eliminate the focus of heterotopic gastric mucosa.

Conclusions

GH in the colon is a rare entity with diverse endoscopic appearances and poorly understood natural history. Careful endoscopic resection is feasible in the absence of other high-risk endoscopic features.

Funding Agencies

None
A67 DELAYED PRESENTATION AND SURGICAL MANAGEMENT OF PRIMARY PNEUMOCOCCAL PERITONITIS
Authors: Klemm N K , Trasolini R , Chatur N
Published: March 2021

Background

S. pneumoniae intraabdominal infections are rare in healthy individuals, but the literature reveals a female dominance for primary peritonitis in the early post-partum period. Limited studies exist evaluating the timing of surgical management.

Aims

We present a case of primary pneumococcal peritonitis in which the presentation and surgical intervention was delayed.

Methods

A case chart review and literature review was conducted.

Results

A 41-year-old female with a spontaneous vaginal delivery 4 months prior presented with progressive abdominal pain, distention, and emesis over 10 days. She was septic with a firm, distended abdomen and rebound tenderness. A CT revealed significant panenteritis and ascites. She received intravenous fluids and was empirically started on ceftriaxone, vancomycin and metronidazole. The gastrointestinal virus panel, stool cultures and C. difficile toxin were negative. However, her blood cultures revealed Strep. pneumoniae and the purulent peritoneal fluid contained gram-positive cocci. Despite sensitivity to ceftriaxone, and several paracenteses, her ascites, pain and new fever continued. Twenty-eight days after admission, she underwent a laparoscopic abdominal lysis of adhesions and drainage of three intraabdominal abscess collections. Cultures of the purulent peritoneal fluid were negative. She was stepped down to amoxicillin-clavulanate and discharged six weeks after symptom onset.

Despite the development of pneumococcal vaccines, worldwide S. pneumoniae is a common pathogen with high morbidity and mortality. It is a rare cause of intraabdominal infections; however, primary peritonitis has been widely recognized in children. Prior to antibiotics, the mortality of pneumococcal peritonitis was 31.5–100%. Secondary pneumococcal peritonitis is established in adult patients with cirrhosis, nephrotic syndrome and immunocompromised conditions. In healthy individuals, pneumococcal peritonitis often mimics appendicitis and is diagnosed with positive blood cultures. The majority of primary pneumococcal peritonitis cases occur in females, are associated with the early post-partum period (less than two months), IUD placement, and pelvic inflammatory disease. Theories of pathogenesis include direct hematogenous spread or translocation. Transient colonization of the genital tract after IUD placement or during the post-partum period may allow for ascension from the fallopian tubes into the peritoneum. The majority of cases undergo surgery within one week of symptom onset. While it has not been studied in randomized trials, early surgical intervention for source control may decrease morbidity and hospital stay.

Conclusions

Primary pneumococcal peritonitis has a female predominance and can occur later in the post-partum period than previously reported. Surgery should be considered early to achieve source control and improve patient outcomes.

Funding Agencies

None