bluuebunny/crossref_metadata_2025 huggingface dataset:
A213 A NOVEL PH-SENSITIVE OPIOID ANALGESIC THAT IS SELECTIVELY ACTIVATED IN ACIDIC INFLAMMATORY ENVIRONMENTS
Authors: Yu Y , Jiménez-Vargas N N , Lopez Lopez C D , Jaramillo Polanco J O , Bunnett N W , Vanner S
Published: February 2020

Background

Opioids drugs are effective analgesics for inflammatory disorders such as inflammatory bowel disease (IBD) but their effects at non-inflammed sites can cause serious morbidity and even death. Exploiting the knowledge that tissue pH in inflamed tissues is acidic (e.g. 6.5–7.0), a novel opioid analgesic, ±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenylpropionamide (NFEPP), with a low acid dissociation constant, was developed that selectively activates peripheral µ-opioid receptor (MOPr) at acidic pH. Thus, pH-sensitive binding of NFEPP could selectively inhibit nociceptive nerves in the inflamed colon and have no effect on non-inflamed tissues outside the GI tract.

Aims

Evaluate whether NFEPP causes inhibition of colonic nociceptors at acidic pH’s, which mimic the inflamed colon.

Methods

To evaluate pH sensitive property of NFEPP to activate MOPr, dorsal root ganglia (DRG) neurons from C57BL/6 mice were exposed to the MOPr agonists NFEPP (300nM, 15 min) or DAMGO (100nM, 15 min) or vehicle at pH 6.5 or 6.8 or 7.4. Neuronal excitability was measured by recording the rheobase (minimum current to fire an action potential) using patch clamp recordings of isolated dorsal root ganglia neurons. In parallel ex vivo studies of mouse colon, extracellular recordings were obtained from afferent nerves innervating the distal colon. Afferent responses to probing with von Frey hair (1 gm) were examined before and after exposure to NFEPP (300nM, 5 min superfusion) at pH 6.5 and 7.4 respectively. Oneway ANOVA and post hoc Dunnett and Bonferroni tests were used to analyze the data.

Results

In patch clamp studies, NFEPP caused a decrease in DRG excitability at pH 6.5 and 6.8 (increased rheobase 21.3%, p<0.05 and 28.9%, p<0.05 respectively compared to vehicle) but had no effect at physiological pH 7.4. DAMGO, a MOPr agonist, caused inhibition of nociceptor excitability at pH 7.4 (increased rheobase 25.2%, p<0.05 compared to vehicle) as shown in previous experiments, but had no effect at pH 6.5 and 6.8. Vehicle had no effect at the different pH’s. In colonic afferent nerve recordings, NFEPP significantly attenuated afferent response (28.9% P<0.01) to probing at pH 6.5 and this effect was reversed after a 15 min washout. At pH 7.4 NFEPP had no effect on afferent nerve firing.

Conclusions

NFEPP activated MOPr at acidic pH causing inhibition of colonic nociceptors. This pH-selective agonist provides a new strategy to relieve pain at the site of inflammation while being devoid of any of unwanted activity in non-inflamed organs.

Funding Agencies

CCC
A214 GENETIC VARIATION IN THE FARNESOID X RECEPTOR PREDICTS CROHN’S DISEASE SEVERITY IN FEMALE PATIENTS
Authors: Wilson A , Wang Q , Almousa A , Jansen L , Choi Y , Schwarz U I , Kim R
Published: February 2020

Background

Crohn’s disease (CD) is an immune-mediated inflammatory bowel disease defined by episodes of intestinal inflammation. There is now an increasing appreciation of the bile acid-sensing nuclear receptor, FXR, as an important regulator of intestinal inflammation, intestinal permeability and response to bacterial overgrowth. Many of these processes are dysregulated in CD. It is unclear how genetic variation in FXR impacts on CD severity. FXR deficiency is rare. Loss of function mutations in FXR as contributors to CD are unlikely; however, partial loss of function of FXR may contribute to CD progression or severity. Our group demonstrated that FXR-1G>T, a SNV adjacent to the ATG start codon, is linked to reduced transactivation of FXR gene targets. We hypothesized that changes in the intestinal barrier as a result of reduced FXR expression among those who harbor the FXR-1T allele are more likely to exhibit a severe CD phenotype compared to G (reference) allele carriers, and thereby experience a more rapid progression to surgery. Alterations in FXR activity may in part be secondary to genetic variation in the FXR gene.

Aims

To evaluate FXR-1G>T as a genomic biomarker of severity in CD and propose a plausible molecular mechanism.

Methods

A retrospective study (n=542) was conducted in a Canadian cohort of CD patients. Blood samples were obtained for genotypic analysis (FXR-1G>T), as well as determination of the FXR downstream product, fibroblast growth factor (FGF) 19. Primary outcomes included risk and time to first CD-related surgery. To better elucidate a potential molecular basis for the observed effect of FXR-1G>T genotype on CD prognosis (more frequent and early surgery) in female CD patients, we explored a connection between the estrogen receptor (ER)-mediated pathway and genetic variation in FXR using a cell-based model. .

Results

The FXR-1GT genotype was associated with the risk of (odds ratio, OR=3.34, 95%CI=1.58–7.05, p=0.002) and early progression to surgery (hazard ratio, HR=3.00, 95%CI=1.86–4.83, p<0.0001) in CD. Female carriers of the FXR-1GT genotype had the greatest risk of surgery (OR=14.87 95%CI=4.22–52.38, p<0.0001) and early progression to surgery (HR=6.28, 95%CI=3.62–10.90, p<0.0001). Furthermore, women carriers of FXR-1GT polymorphism had a nearly three-fold lower FGF19 plasma concentration compared to women with wildtype FXR-1GG genotype (p<0.0001). In HepG2 cells cotransfected with estrogen receptors (ERα and β) and FXR, presence of estradiol further attenuated variant FXR activity.

Conclusions

FXR-1GT is deleterious to women with CD through ER-mediated attenuation of FXR activation. Female CD FXR-1GT carriers should be considered for more aggressive medical management.

Funding Agencies

CAG, CCC, CIHR
A223 THE GEM PROJECT: ASSOCIATIONS OF DIETARY PATTERNS WITH MICROBIOME AND FECAL CALPROTECTIN IN HEALTHY FIRST-DEGREE RELATIVES OF CROHN’S DISEASE PATIENTS
Authors: Sasson G , Raygoza Garay J , Turpin W , Power N , Smith M , Guttman D S , Research Consortium T , Croitoru K
Published: February 2020

Background

Crohn’s disease (CD) is thought to be due to an interaction between environmental factors and the gut microbiome that activates an immune response in genetically susceptible hosts. Epidemiologic studies suggest diet is an important variable in CD development; however, little is known about the mechanism by which diet contributes to pathogenesis. It has recently been shown that diet plays a substantial role in shaping microbiome composition (MC). We hypothesize that specific diet patterns are associated with differences in MC that may be related to CD risk.

Aims

To characterize associations between diet patterns with MC and fecal calprotectin (FC) in healthy first-degree relatives (FDR’s) of CD patients in the Genetic, Environmental, Microbial (GEM) Project.

Methods

A validated food frequency questionnaire (FFQ) was used to assess diet for North American FDR’s at recruitment. Each question was summarized as a score based on weekly consumption frequency. The Dirichlet method of unsupervised clustering was used to generate dominant diet clusters. Diet-microbiome associations were assessed using the two-part microbiome model. Stool microbiota at recruitment was characterized by 16s RNA sequencing of V4 region using MiSeq platform. Baseline FC was measured by BUHLMANN ELISA test.

Results

2766 FDR’s had FFQ’s at recruitment; mean age 18.52 years, 53% female. The Dirichlet method identified 4 clusters, some of which resembled known diet patterns: Superbowl (mainly organ meats, non-red meat, beer, spirits), High Carbohydrate (HC), Mediterranean (MD) and Western (WD) diets. HC was associated with increased relative abundance of V. veillonella (P=2.68E-4). Both HC and MD were associated with decreased abundance of E. klebsiella (P=2.64E-5 and P=1.02E-5 respectively). WD was associated with decreased abundance of L. dorea (P=5.74E-5), a genus considered high risk for CD. A per question analysis demonstrated significant associations between several taxa and individual foods. Diet clusters were then correlated with FC, and a decrease in FC was observed with MD (estimate -16.96, P=0.012). There were no associations with FC in a per question analysis.

Conclusions

Dominant dietary patterns and certain individual foods are associated with specific gut MC. As well, MD is inversely associated with FC and therefore has potential use as an intervention for lowering inflammation. Understanding relationships between diet, MC and FC in individuals at high risk for CD would be beneficial in defining new dietary strategies in predictably modulating future risk of CD.

Funding Agencies

CCCHelmsley Charitable Trust
A224 THE MANITOBA LIVING WITH IBD STUDY: MEDICATION ADHERENCE AND MARS-5 VALIDATION
Authors: Stone J , Witges K , Shafer L , Targownik L E , Lix L M , Haviva C , Walker J , Graff L A , Vagianos K , Sargent M , Bernstein C N
Published: February 2020

Background

Medication non-adherence in IBD has previously been reported to be quite variable, ranging from 7 to 73%, and is considered to be an important contributor to disease flares. While there is currently no gold standard for medication adherence reporting in IBD, the Medication Adherence Reporting Scale 5 (MARS-5) has frequently been used in this population, but never validated.

Aims

This study aimed to analyze medication adherence rates in a cohort of persons with IBD in Manitoba, report predictors of medication non-adherence on self-reported symptoms, and validate the MARS-5 as a medication adherence tool.

Methods

55 subjects were prospectively followed with biweekly online surveys in the Manitoba Living with IBD Study. Subjects not taking any medications for IBD or only taking as needed, missing adherence data and those lost to follow-up were excluded, leaving 112 subjects. Descriptive data on demographics, surgeries, IBD medications, medication adherence, and measures of disease activity utilizing IBDSI-SF scores were collected. Mean annual medication adherence percentage, IBDSI-SF(>14=active for Crohn’s,>13=active for UC) and MARS-5 scores were calculated. Logistic regression analysis was performed to determine variables associated with medication adherence and to validate the MARS-5.

Results

Mean age was 42.9 years (SD 12.8), with 71.4% being female. Crohn’s disease (CD) was diagnosed in 67.9%, with 37.5% having undergone at least one abdominal surgery. 70.5% of patients were on 2 or more IBD medications. Mean IBDSI score was 15.5 and mean MARS-5 score was 22.5. 20 (17.9%) patients reported a mean adherence of <90% across all medications- 18 were oral medication users, 1 was on an infusion biologic and 1 on subcutaneous adalimumab. 10 (9.8%) had adherence <80%, all of which were to oral medications. Multivariate regression analysis revealed only a diagnosis of Crohn’s disease (OR 4.62; 95% CI 1.37–15.7; p=0.014) to be a predictor of adherence. Disease activity as defined by IBDSI (OR 0.43, 95% CI 0.13–1.45; p=0.139) and fecal calprotectin >250ug/L (OR 1.04, 95% CI 0.35–3.11; p=0.724), age >55 (OR 2.37, 95% CI 0.65–8.65; p=0.476), female sex (OR 0.38, 95% CI 0.097–1.52; p=0.150) and stress (OR 0.67, 95% CI 0.19–2.32; p=0.498) were not shown to be predictors. MARS-5 was compared to percentage adherence, showing moderate correlation (Pearson r=0.46). Logistic regression analysis showed each additional MARS-5 point was associated with a 1.7 times greater odds of >90% adherence.

Conclusions

We report a highly adherent Manitoba IBD cohort. A diagnosis of CD was the only predicitor of adherence. MARS-5 showed moderate correlation with mean percentage adherence values, suggesting it is a valid assessment tool for determining medication adherence in an IBD population.

Funding Agencies

None
A233 VEDOLIZUMAB FOR STEROID & INFLIXIMAB-REFRACTORY ICI-COLITIS
Authors: Klemm N K , Trasolini R , Chahal D , Donnellan F
Published: February 2020

Background

Immune checkpoint inhibitors (ICI), such as anti-PD1, improve survival in melanoma, renal carcinoma and prostate cancer. However, by disinhibiting the immune system, these treatments cause significant immune-related adverse events (irAE), including colitis. For ICI-colitis, guidelines suggest escalating from observation to steroids to infliximab, without strong evidence for additional options should these fail. Vedolizumab has been used in a small number of cases for steroid-refractory or dependent ICI-colitis; only 9 cases have been reported in patients who failed infliximab therapy with a response rate of 67%.

Aims

To discuss a case of ICI-colitis that failed multiple steroid courses and infliximab infusions, but achieved remission with vedolizumab.

Methods

A 65-year-old male with malignant melanoma was randomized to adjuvant nivolumab +/- ipilimumab and developed non-bloody diarrhea. Despite loperamide, diarrhea worsened to 4–5 bowel movements daily. Stool cultures and C. diff were negative and 85mg of daily prednisone was started, while the ICI was held for 8 weeks. After a 2nd steroid taper, diarrhea recurred and the patient received 2 infliximab infusions 18 days apart. Despite initial improvement, biopsies demonstrated colitis and he underwent a 3rd infusion with little response. Clinical and biopsy-confirmed remission was only achieved once 2 vedolizumab infusions were given.

Results

Colitis is the most common ICI irAE, ranging in severity from mild to perforation and death. The incidence of grade 3 and 4 colitis, which require ICI discontinuation, is 1.3% for anti-PD1 and 13.6% in combination therapy. The severity of irAE is positively correlated with malignancy response and stopping ICI risks recurrence. Those that fail irAE medical management may require surgery. Thus, there is an impetus to continue the ICI and provide effective medical management for irAE.

ICI-colitis guidelines are based on the CTCAE diarrhea classification and suggest supportive management and ICI continuation for grade 1. For grade 2, the ICI is held and steroids are started; infliximab is added for grades 3 and 4. However, 33–66% of patients are steroid-refractory or dependent; and patients may be infliximab non-responders, or unable to tolerate systemic side effects.

Vedolizumab, an anti-α4β7-integrin, acts locally to inhibit T cells in the bowel wall, reducing inflammation in IBD. Recent reports, including ours, suggest usefulness in steroid and infliximab-refractory ICI colitis after only 2–4 infusions. When the inflammatory burden is high, the response rate is >80% and given its gut-specificity, side effects are minimal compared to infliximab. Although further evaluation is required, using vedolizumab as second-line therapy is reasonable.

Conclusions

Given vedolizumab’s safety and gut-specificity, it should readily be considered in the treatment of ICI irAE.

Funding Agencies

None
A235 THE INFLUENCE OF IL10 ON COLITIS DEVELOPMENT IN NOD2 DEFICIENT MICE
Authors: Gryfe M D , Croitoru K , Goethel A , Luchak A
Published: February 2020

Background

Inflammatory bowel disease (IBD) risk genes include interleukin-10 (IL10) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2). Although their specific roles in intestinal inflammation are unclear, these proteins are involved in modulating host-microbe interactions and intestinal homeostasis.

Aims

Since IL10 is an anti-inflammatory cytokine that maintains intestinal homeostasis, we hypothesized that mice deficient for both IL10 and NOD2 would be more susceptible to colitis than mice with only the NOD2 deletion.

Methods

In-house generated NOD2-/- x IL10-/- (double knockout) and NOD2-/- x IL10+/+ littermate mice of varying ages (3–20 weeks of age) were weighed and stools samples were collected at weekly intervals. Lipocalin-2 (LCN-2) levels were quantified in stool by ELISA. A subset of mice from each genotype received 3.5% dextran sulfate sodium (DSS) supplemented water for 5 days starting at eight weeks of age. Mice were sacrificed after two days of regular water, on day 8.

Results

Untreated NOD2-/- x IL10+/+ mice showed higher fecal LCN-2 compared to NOD2-/- x IL10-/- mice at all ages, although this trend was not significant. Within DSS-treated mice, LCN-2 levels in stool collected at sacrifice (on day 8) were significantly higher in NOD2-/- x IL10+/+ mice, compared to NOD2-/- x IL10-/- mice. Moreover, only 50% (2 of 4) of the NOD2-/- x IL10+/+ DSS-treated mice survived to day 8, whereas all four NOD2-/- x IL10-/- DSS-treated mice survived.

Conclusions

Fecal LCN-2 indicates the extent of neutrophil infiltration, which is reflective of the severity of intestinal inflammation. As such, LCN-2 levels suggest that NOD2-/- x IL10+/+ mice have higher baseline inflammation and are more susceptible to DSS-induced colitis than double knockout NOD2-/- x IL10-/- mice. These results are contrary to our hypothesis that combining IL10 and NOD2 deficiency would increase colitis susceptibility as compared to NOD2 deficiency alone. This suggests that the absence of IL10 may actually reduce the severity of DSS-induced colitis in NOD2 deficient mice. The role of IL10 in modulating the gut microbiome using this model remains to be assessed.

Funding Agencies

CAG
A236 REAL LIFE HEALTH CARE UTILIZATION IN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE IN THE ERA OF BIOLOGICS
Authors: Tchogna S A , Yang X , Deslandres C , Jantchou P
Published: February 2020

Background

The burden associated with the management of pediatric patients with inflammatory bowel disease (IBD) has been rising over the past years as the incidence of IBD is increasing in children. In addition, the widespread use of biologics and a treat-to-target approach also contributes to the increase of healthcare utilization.

Aims

The purpose of this study was to assess the health care services utilization and the associated factors in a prospective cohort of children diagnosed with IBD in Quebec.

Methods

Patients diagnosed from 2013 to 2015 and followed up until the transfer to adult care were identified in our IBD database. Data on IBD related services and treatments: imaging procedures, hospitalizations and outpatient visits, medications from diagnosis to transition was extracted. We analyzed the healthcare utilization according to the baseline disease severity (pediatric Crohn’s disease activity index (PCDAI) or pediatric ulcerative colitis activity index (PUCAI)) at diagnosis, and according to exposition to intravenous biologics.

Results

A total of 144 patients were included in the study [(77 males), Crohn’s disease (98), Ulcerative Colitis (31) and IBD-unclassified (15); median (interquartile(IQR)) age at diagnosis 15.2(14.3–16.3)]. The median(IQR) duration of follow up at the IBD clinic was 2.9 (1.8–3.9) years. The median (min-max) number of imaging procedures varied largely: esophagogastroduodenoscopy 1(0–2), Colonoscopy 1(1–6), abdominal ultrasound 1(0–13), abdominal MRI 1(0–4), tomodensitometry 0(0–2), Bone densitometry 1(0–5). Patients had various follow-up encounters (median (min-max)): outpatient visits 9 (1–28), IBD nurses phone follow-up 4(0–33). A total of 64.6% of patients had at least one hospitalization [median(min-max) number 1(0–10); median duration 4(0–150 days)] and 35.41% had at least one emergency room visit. Baseline disease severity did not predict the disease burden: the mean number of encounters was 3.0 /year in the moderate/severe group as compared to 2.5/year in the mild group; P= 0.61. Among the, 63.5% of patients exposed to an intravenous biologic (Infliximab or Vedolizumab), those exposed earlier (<3 months after diagnosis) used more health care services (mean = 3.3/year) than those exposed later (mean =2.23/year); P <0.0001. In addition, the median (interquartile (IQR)) cumulative days of healthcare utilization (missing school days) for patients treated with intravenous biologics was 48.5 (32.4–67.9) days during pediatric care.

Conclusions

Adolescents with IBD have several encounters between the diagnosis and transition to adult care. Disease severity at diagnosis was not related to a higher level of health services utilization during follow-up. However, treatment with intravenous biologics was associated with a high health service utilization and school missing during follow-up.

Funding Agencies

None
A239 INFLAMMATORY BOWEL DISEASE PSYCHOTHERAPY PROTOCOL: GUT-DIRECTED COGNITIVE BEHAVIOURAL THERAPY, CLINICAL HYPNOSIS, AND EMOTION REGULATION COPING SKILLS DEVELOPMENT
Authors: Paulton J P , Prevost J
Published: February 2020

Background

IBD patients have a heightened risk for mental health illness, but general psychotherapy has shown mixed results. This psychotherapy protocol specialized for IBD patients uses recommended mental health therapies to treat specific chronic mental health illness. Therapy focuses on practicing CBT, clinical hypnosis, and emotion regulation healthy coping skills to self-manage chronic mental health symptoms. Standard therapies for acute mental illness, e.g. anxiety, depression, and suicidality, should be used as appropriate.

Aims

Aims of psychotherapy in IBD include improvement of mental health, symptoms management, quality of life (QOL), and adherence to medical treatments. Cognitive behavioural therapy (CBT) changes maladaptive coping behaviours and thinking. Clinical hypnosis improves somatic symptoms, e.g. chronic pain, nausea, and cramping. Emotion regulation improves ability to process stressful emotions, and has been shown to be affected by chronic diseases, including moderate to severe Crohn’s disease.

Methods

Patients learn to self-manage chronic mental health symptoms with healthy coping skills. CBT allows patients to identify maladaptive coping behaviours and thinking. Healthy coping behaviours and thinking patterns are chosen, supported, and adapted to. Clinical hypnosis uses relaxation techniques, e.g. progressive muscle relaxation, visualizations, and positive suggestions as a complimentary therapy for somatic symptoms. Emotion regulation develops tolerance and healthy processing of stressors.

Results

Therapy effectiveness is evaluated by improvements in patients’ mental health, symptoms management, QOL, and adherence to medical treatments. Mental health improvement, QOL, and emotion regulation are monitored by patient self-report, e.g. questionnaires. Maladaptive coping behaviours and thinking changed using CBT are individual to each patient. Somatic symptoms improved using clinical hypnosis are determined by monitoring or patient self-report. Adherence to medical treatments, as appropriate, is monitored.

Conclusions

This IBD psychotherapy protocol uses gut-directed CBT, clinical hypnosis, and emotion regulation therapies, designed to improve mental health, symptoms management, QOL, and adherence to medical treatments. Healthy coping skills treat maladaptive coping behaviours and thinking, somatic symptoms, and emotion dysregulation. Chronic mental health illness associated with IBD, is treated using this specialized psychotherapy.

Funding Agencies

None
A246 POPULATION WIDE STUDY OF THE EPIDEMIOLOGY AND OUTCOMES OF ANTI-TNF DOSE AUGMENTATION IN INFLAMMATORY BOWEL DISEASE
Authors: Elias E , Singh H , Bernstein C N , Targownik L
Published: February 2020

Background

Inflammatory bowel disease (IBD) patients who experience loss of response to anti-tumor necrosis factor (anti-TNF) therapy are often treated with augmented doses of anti-TNF to recapture response. Despite this, factors associated with dose augmentation and treatment outcomes following dose augmentation remain largely undefined.

Aims

To examine the epidemiology of anti-TNF dose augmentation and determine the associated treatment outcomes among a province-wide cohort of anti-TNF treated IBD subjects.

Methods

The University of Manitoba Inflammatory Bowel Disease Epidemiological Database was used to identify patients receiving infliximab or adalimumab maintenance therapy for IBD in the Canadian province of Manitoba. Anti-TNF dose augmentation was defined as a ≥50% increase in anti-TNF dose or a shortening of dosing interval to ≤42 days for infliximab or ≤10 days for adalimumab. Anti-TNF failure was defined as corticosteroid use, IBD-related hospitalization, resective IBD surgery, or change in anti-TNF agent. Competing risks regression using a proportional subhazards model was used to determine the associations between dose augmentation, anti-TNF failure, anti-TNF discontinuation and a number of patient, disease, and treatment factors.

Results

871 persons (624 Crohn’s disease (CD), 247 ulcerative colitis (UC)) using anti-TNF maintenance therapy were identified. Cumulative incidence of dose augmentation among continued users was 25.7% at 90 days, 52.3% at 1 year, and 72.8% at 5 years. Anti-TNF failure occurred in 261 of 575 dose augmented subjects, with corticosteroid use the most common failure-defining event. Failure of standard dose anti-TNF in the 90 days preceding dose augmentation was strongly associated with failure of dose augmentation (HR 2.98 (2.27–3.93); p<0.0001). Persons with CD were less likely to receive corticosteroids but more likely to switch anti-TNF agents than persons with UC.

Conclusions

Rates of adverse IBD outcomes remain high after dose augmentation, particularly when dose augmentation is undertaken shortly after (or in response to) one of these adverse events. Our data suggest that dose augmentation may not be as effective as uncontrolled observational studies have indicated.

Funding Agencies

None
A263 MICE CHALLENGED WITH DNBS FOUR DAYS AFTER INFECTION WITH THE RAT TAPEWORM HYMENOLEPIS DIMINUTA ARE PROTECTED FROM COLITIS
Authors: Li S , Wang A , McKay D M
Published: February 2020

Background

Helminth therapy for colitis is supported by data from murine models, including infection with H. diminuta inhibiting dinitrobenzene sulphonic-acid (DNBS)-induced colitis. Considering H. diminuta as a candidate helminth therapy the kinetics of infection in the context of inflammation should be addressed. Reciprocally, it is important to know if colitis alters the immune response to the helminth.

Aims

1) Assess DNBS-colitis in mice infected 4-days previously with H. diminuta. 2) Determine in DNBS-induced colitis affects the outcome of infection with H. diminuta.

Methods

Male BALB/c mice were infected by gavage with five H. diminuta and four days later were challenged with DNBS (3 mg, ir.). Disease was assessed 3 days later (i.e. day 7-post H. diminuta) by colon length, disease activity score and histopathology (n=9–14 mice, 3 experiments). Alternatively, on day three post-DNBS, mice were infected with H. diminuta and worm infectivity and splenocyte Th2-cytokine production assessed at 8 days post-infection (n=5–9 mice, 1 experiment).

Results

Mice challenged with DNBS at 4-days post-infection were significantly protected from colitis, with 2/14 mice requiring humane euthanization for disease severity compared to 6/13 in the DNBS-only group. Splenocyte production of IL-4, IL-5 and IL-10 was increased in the H. diminuta-only group compared to control mice: DNBS-only treated mice showed reduced levels of all three cytokines and H. diminuta+DNBS mice had cytokine levels not different from H. diminuta-only infected mice. DNBS-colitis prior to infection did not affect the increase in systemic TH2 immunity evoked by H. diminuta, but did result in greater intestinal worm burdens.

Conclusions

The data suggest (1) the window of opportunity for H. diminuta to suppress colitis in a prophylactic regimen is at least 4–8 days post-infection, and (2) H. diminuta administered to mice at the peak of colitis severity mobilizes TH2 immunity that could promote quicker recovery from colitis.

Funding Agencies

CAG, CCC, NRCNSERC
A264 HELMINTH-INFECTION MOBILIZES HOST AND MICROBIAL FACTORS THAT CO-OPERATE TO SUPPRESS CHEMICAL-INDUCED COLITIS IN MICE
Authors: Shute A J , Callejas Pina B E , Jayme T S , Wang A , Buret A , McKay D M
Published: February 2020

Background

Infection with helminth parasites suppresses inflammation in murine model systems; for example, IL-10 is important in Hymenolepis diminuta-inhibition of DNBS-induced colitis. Bacteria-derived products can have anti-inflammatory effects. Given that infection with H. diminuta, or other parasitic worms, results in perturbation of the gut microbiota, the present study tested a role for bacteria in helminth-suppression of colitis by assessing reciprocity between IL-10 and butyrate signaling in the amelioration of colitis.

Aims

To determine if a functional relationship exists between IL-10 and butyrate in the inhibition of colitis observed following infection with the lumen-dwelling tapeworm, Hymenolepis diminuta.

Methods

Colitis was induced in male BALB/c mice by intra-rectal dinitrobenzene sulphonic acid (DNBS) (3 mg/~22g mouse), with necropsy and assessment 3 days later. Mice received either infection with five H. diminuta cysticercoids by gavage or daily butyrate enemas or acetate in their drinking water. Immunostaining assessed IL-10R protein expression on formalin-fixed sections of colon. The murine IEC4.1 epithelial cell line and epithelial organoids were treated with butyrate and mRNA for the IL10Rα chain assessed, as was colonic tissue from mice.

Results

Mice infected with H. diminuta or receiving butyrate enemas (n=8–12) were protected from DNBS-induced colitis as gauged by colon length, and macroscopic disease and histopathology scores. Addition of acetate to the drinking water resulted in a more modest anti-colitic effect. Suppression of colitis was accompanied by increased epithelial expression of IL-10 in butyrate- and H. diminuta-treated mice, with the later also showing upregulation of the IL-10R on lamina propria cells; an effect negated by co-treating the mice with broad spectrum antibiotics. In vitro analyses revealed increased IL10Rα mRNA in butyrate-treated epithelia (n=4).

Conclusions

This study begins to tease apart the host (i.e. IL-10) and bacterial (i.e. butyrate) molecules that mediate H. diminuta-evoked suppression of colitis in a murine model. These proof-of-principle data suggest that knowledge of the individual patient (i.e. immunological basis of their disease and their microbiota) may be a critical determinant of the success or failure of helminth therapy.

Funding Agencies

CAG, CCCNSERC
A265 SERIAL FECAL MICROBIOTA TRANSPLANT PLUS FIDAXOMICIN IN THE TREATMENT OF SEVERE OR FULMINANT CLOSTRIDIOIDES DIFFICILE INFECTION
Authors: Russell L , Roach B , Yang D Y , Wang C , Wine E , Saxinger L , Wong K , Kao D H
Published: February 2020

Background

Severe and fulminant Clostridioides Difficile infection(CDI) is associated with increased mortality and morbidity. Current guidelines recommend high dose vancomycin with metronidazole for treatment. Surgery is a high risk for patients failing medical therapy partly due to multiple comorbidities. Emerging evidence suggests efficacy of sequential fecal microbiota transplantation(FMT) by colonoscopy combined with vancomycin in patients failing maximal medical therapy. Fidaxomicin is non-inferior to vancomycin in treating CDI; however, it has not been studied in severe/fulminant cases. It is not known if FMT by enema combined with fidaxomicin is efficacious and safe in this patient population.

Aims

This single center, prospective, open-label pilot study aimed to determine the efficacy and safety of combined sequential FMT by enema plus fidaxomicin in severe or fulminant CDI not responding to maximal medical therapy. Primary outcome was resolution of diarrhea 2 weeks following final FMT. Secondary outcomes were resolution of diarrhea 8 weeks following final FMT, safety of proposed treatment protocol and colectomy rate.

Methods

Consecutive patients with severe or fulminant CDI, who fulfilled study inclusion criteria were recruited. Sequential cycles of FMT, administered by enema daily over three days(720cc followed by 360cc and 180cc), plus fidaxomicin 200mg PO BID were given. Clinical symptoms and inflammatory markers were monitored during the study and subsequent cycles of FMT were administered when clinical or biochemical improvement plateaued. A final FMT was administered with CDI resolution.

Results

A total of three patients were enrolled between Jan 22 to Aug 8, 2019, shown in Table 1. One patient had fulminant CDI due to shock, and the others had severe CDI. All had severe pseudomembranous colitis seen on endoscopy at enrollment. Two of three patients reached both primary and secondary outcomes with 2 FMT cycles. The only patient who did not reach the primary was successfully managed with long term vancomycin suppression. This patient had failed multiple FMTs prior to enrollment. There were no adverse events noted and no colectomy was required during this study.

Conclusions

This pilot study is the first to demonstrate efficacy and safety of combined sequential FMT by enema and fidaxomicin in treating severe or fulminant CDI patients. An adequately powered study is required to validate these findings.

Funding Agencies

CIHRAlberta Health Services, University of Alberta Hospital Foundation
A275 REVISITING THE DIAGNOSTIC YIELD OF ERCP BRUSH CYTOLOGY FOR INDETERMINATE BILIARY STRICTURES
Authors: Nur A , Boerner S , Edwards L , Ryan K , James P
Published: February 2020

Background

Endoscopic Retrograde Cholangiopancreatography (ERCP) brush cytology is the most frequently used tool for sampling indeterminate biliary strictures. Previous studies have demonstrated that the diagnostic yield of brush cytology for malignant biliary strictures is 60%. With improved diagnostic tools, sampling techniques and specimen processing, the yield of ERCP brush cytology may be higher.

Aims

To assess the diagnostic yield of ERCP brush cytology in patients with indeterminate biliary strictures and to determine factors associated with positive diagnosis.

Methods

This is a retrospective study of all patients who underwent ERCP with brush cytology at University Health Network (UHN) from October 2016 to September 2019. The cytological samples were taken as follows: the cytology brush is introduced into the stricture ten times under direct fluoroscopy guidance. The brush was cut and placed into a methanol based buffered solution (CytoLyt®). Residual sample was then flushed out of the catheter with the solution and into the sample container. Patient demographic, clinical, procedural and pathological data was collected by chart review. All patients were followed for a minimum of three months after their index ERCP. Post-ERCP sampling via repeat ERCP brushings, endoscopic ultrasound fine needle biopsy, percutaneous biopsy or surgical resection was recorded.

Results

A total of 97 patients underwent ERCP with brush cytology during the study period (43 females, median age 69 years). Fifty-nine patients (84%) were diagnosed with malignancy via ERCP brush cytology. Using follow up sampling, surgical resection and clinical follow up as the gold standard, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 84%, 100%, 100%, and 71% respectively. Patient demographics, degree of cholestasis or stricture location had no significant impact on these outcomes.

Conclusions

This study shows a high diagnostic yield for ERCP with brush cytology for patients with indeterminate biliary strictures. Large prospective studies using updated tools, techniques and specimen handling processes are needed to confirm our observations.

Funding Agencies

None
Efficacy and safety of abiraterone acetate plus prednisone in Japanese patients with newly diagnosed, metastatic hormone-naive prostate cancer: final subgroup analysis of LATITUDE, a randomized, double-blind, placebo-controlled, phase 3 study
Authors: Suzuki Hiroyoshi , Shin Toshitaka , Fukasawa Satoshi , Hashine Katsuyoshi , Kitani Sumiko , Ohtake Noriyuki , Shibayama Kazuhiro , Tran Namphuong , Mundle Suneel , Fizazi Karim , Matsubara Nobuaki
Published: February 2020

Background

LATITUDE was a randomized, double-blind, international and phase 3 study of abiraterone acetate plus prednisone in patients with high-risk metastatic hormone-naïve prostate cancer. In the first interim analysis of LATITUDE (clinical cutoff date: 31 October 2016), significant prolongation in overall survival and radiographic progression-free survival (co-primary endpoints) was observed when compared with placebo. The results of the Japanese subgroup analysis of LATITUDE first interim analysis were consistent with those of the overall population. In this study, overall survival and safety results from the final analysis of the Japanese subgroup of the LATITUDE study are presented (clinical cutoff date: 15 August 2018).

Methods

Abiraterone acetate (1000 mg/day) and prednisone (5 mg/day) were administered orally in the abiraterone acetate plus prednisone group, and matching placebos in the placebo group.

Results

Of the 1199 patients included in LATITUDE, 70 constituted the Japanese subgroup (abiraterone acetate plus prednisone: n = 35, placebo: n = 35). Following a median (range) follow-up of 56.6 (2.5, 64.2) months, the median overall survival was not reached in both the treatment arms of the Japanese subgroup (hazard ratio: 0.61; 95% confidence interval: 0.27–1.42; nominal P = 0.2502). A total of 23 deaths (abiraterone acetate plus prednisone: 9 [25.7%], placebo group: 14 [40.0%]) were reported in Japanese subgroup. Grade 3/4 adverse events were reported in 24 (68.6%) and 9 (25.7%) patients in the abiraterone acetate plus prednisone and placebo groups, respectively.

Conclusions

In this Japanese subgroup analysis, addition of abiraterone acetate plus prednisone to androgen-deprivation therapy demonstrated favorable efficacy and safety outcomes in patients with newly diagnosed, high-risk metastatic hormone-naïve prostate cancer. Survival benefits observed in the Japanese subgroup first interim analysis were sustained long-term and were consistent with the overall population.
Ultrastructural Dendritic Changes Underlying Diaschisis After Capsular Infarct
Authors: Lee Min-Cheol , Kim Ra Gyung , Lee Taebum , Kim Jo-Heon , Lee Kyung-Hwa , Choi Yoo-Duk , Kim Hyung-Seok , Cho Jongwook , Park Ji-Young , Kim Hyoung-Ihl
Published: February 2020

Diaschisis has been described as functional depression distant to the lesion. A variety of neuroscientific approaches have been used to investigate the mechanisms underlying diaschisis. However, few studies have examined the pathological changes in diaschisis at ultrastructural level. Here, we used a rat model of capsular infarct that consistently produces diaschisis in ipsilesional and contralesional motor and sensory cortices. To verify the occurrence of diaschisis and monitor time-dependent changes in diaschisis, we performed longitudinal 2-deoxy-2-[18F]-fluoro-d-glucose microPET (FDG-microPET) study. We also used light and electron microscopy to identify the microscopic and ultrastructural changes at the diaschisis site at 7, 14, and 21 days after capsular infarct modeling (CIM). FDG-microPET showed the occurrence of diaschisis after CIM. Light microscopic examinations revealed no significant histopathological changes at the diaschisis site except a mild degree of reactive astrogliosis. However, electron microscopy revealed swollen, hydropic degeneration of axial dendrites and axodendritic synapses, although the neuronal soma (including nuclear chromatin and cytoplasmic organelles) and myelinated axons were relatively well preserved up to 21 days after injury. Furthermore, number of axodendritic synapses was significantly decreased after CIM. These data indicate that a circumscribed subcortical white-matter lesion produces ultrastructural pathological changes related to the pathogenesis of diaschisis.
Stress and the Home Environment in Caregivers of Children with Sickle Cell
Authors: Varughese Taniya E , Hoyt Catherine R , L’Hotta Allison J , Ikemenogo Princess A , Howdeshell Seth G , Housten Ashley J , Abel Regina A , King Allison A
Published: February 2020

Objective

Caregivers of young children with chronic illnesses are at high risk for elevated levels of stress and mental health symptoms. This study examined stress and mental health symptoms as well as the socioeconomic status (SES) and home environments of a cohort of caregivers of infants and toddlers with sickle cell disease (SCD).

Methods

Forty-two caregivers of infants and toddlers (aged 1–34 months) with SCD completed the Brief Symptom Inventory (BSI) and Parent Stress Index (PSI). The Home Observation for Measurement of the Environment (HOME) was used to assess family living environments.

Results

Compared to test norms, caregivers reported high levels of situational/demographic life stress [mean difference (MD) 5.7, p = .003] and child distractibility/hyperactivity (MD 3.62, p = .001) on the PSI. However, no significant differences in psychological symptoms of distress were noted on the BSI. Caregivers scored significantly lower than norms on PSI subdomains of acceptability (MD −1.88, p = .03), competence (MD −3.11, p = .002), depression (MD −3.94, p < .001), and the overall parent domain (MD −12.55, p = .005). Significant correlations were found between PSI scores and the HOME and between SES and the HOME.

Conclusion

Caregivers of infants and toddlers with SCD experience elevated levels of life stress but, in turn, endorse high acceptance of their child and self-competence in parenting. Although life stress may be high in this population, symptoms of psychological distress were not identified. Caregivers reporting elevated life and illness-specific stressors may benefit from environmental supports and interventions.
Desiccation tolerance in streptophyte algae and the algae to land plant transition: evolution of LEA and MIP protein families within the Viridiplantae
Authors: Becker Burkhard , Feng Xuehuan , Yin Yanbin , Holzinger Andreas
Published: February 2020

The present review summarizes the effects of desiccation in streptophyte green algae, as numerous experimental studies have been performed over the past decade particularly in the early branching streptophyte Klebsormidium sp. and the late branching Zygnema circumcarinatum. The latter genus gives its name to the Zygenmatophyceae, the sister group to land plants. For both organisms, transcriptomic investigations of desiccation stress are available, and illustrate a high variability in the stress response depending on the conditions and the strains used. However, overall, the responses of both organisms to desiccation stress are very similar to that of land plants. We highlight the evolution of two highly regulated protein families, the late embryogenesis abundant (LEA) proteins and the major intrinsic protein (MIP) family. Chlorophytes and streptophytes encode LEA4 and LEA5, while LEA2 have so far only been found in streptophyte algae, indicating an evolutionary origin in this group. Within the MIP family, a high transcriptomic regulation of a tonoplast intrinsic protein (TIP) has been found for the first time outside the embryophytes in Z. circumcarinatum. The MIP family became more complex on the way to terrestrialization but simplified afterwards. These observations suggest a key role for water transport proteins in desiccation tolerance of streptophytes.
Deciphering aquaporin regulation and roles in seed biology
Authors: Hoai Phan T T , Tyerman Stephen D , Schnell Nicholas , Tucker Matthew , McGaughey Samantha A , Qiu Jiaen , Groszmann Michael , Byrt Caitlin S
Published: February 2020

Seeds are the typical dispersal and propagation units of angiosperms and gymnosperms. Water movement into and out of seeds plays a crucial role from the point of fertilization through to imbibition and seed germination. A class of membrane intrinsic proteins called aquaporins (AQPs) assist with the movement of water and other solutes within seeds. These highly diverse and abundant proteins are associated with different processes in the development, longevity, imbibition, and germination of seed. However, there are many AQPs encoded in a plant’s genome and it is not yet clear how, when, or which AQPs are involved in critical stages of seed biology. Here we review the literature to examine the evidence for AQP involvement in seeds and analyse Arabidopsis seed-related transcriptomic data to assess which AQPs are likely to be important in seed water relations and explore additional roles for AQPs in seed biology.
Chemical diversity of super-Earths as a consequence of formation
Authors: Scora Jennifer , Valencia Diana , Morbidelli Alessandro , Jacobson Seth
Published: February 2020

Recent observations of rocky super-Earths have revealed an apparent wider distribution of Fe/Mg ratios, or core to mantle ratios, than the planets in our Solar system. This study aims to understand how much of the chemical diversity in the super-Earth population can arise from giant impacts during planetary formation. Planet formation simulations have only recently begun to treat collisions more realistically in an attempt to replicate the planets in our Solar system. We investigate planet formation more generally by simulating the formation of rocky super-Earths with varying initial conditions using a version of symba, a gravitational N-body code, that incorporates realistic collisions. We track the maximum plausible change in composition after each impact. The final planets span a range of Fe/Mg ratios similar to the Solar system planets, but do not completely match the distribution in super-Earth data. We only form a few planets with minor iron-depletion, suggesting other mechanisms are at work. The most iron-rich planets have a lower Fe/Mg ratio than Mercury, and are less enriched than planets such as Kepler-100b. This indicates that further work on our understanding of planet formation and further improvement of precision of mass and radius measurements are required to explain planets at the extremes of this Fe/Mg distribution.
The Gaia DR2 parallax zero-point: hierarchical modelling of red clump stars
Authors: Chan Victor C , Bovy Jo
Published: February 2020

The systematic offset of Gaia parallaxes has been widely reported with Gaia’s second data release, and it is expected to persist in future Gaia data. In order to use Gaia parallaxes to infer distances to high precision, we develop a hierarchical probabilistic model to determine the Gaia parallax zero-point offset along with the calibration of an empirical model for luminosity of red clump stars by combining astrometric and photometric measurements. Using a cross-matched sample of red clump stars from the Apache Point Observatory Galactic Evolution Experiment and Gaia Data Release 2 (DR2), we report the parallax zero-point offset in DR2 to be $\varpi _0 = -48 \pm 1\,\mu \text{as}$. We infer the red clump absolute magnitude to be −1.622 ± 0.004 in Ks, 0.435 ± 0.004 in G, −1.019 ± 0.004 in J, and −1.516 ± 0.004 in H. The intrinsic scatter of the red clump is ∼0.09 mag in J, H, and Ks, or ∼ 0.12 mag in G. We tailor our models to accommodate more complex analyses such as investigating the variations of the parallax zero-point with each source’s observed magnitude, observed colour, and sky position. In particular, we find fluctuations of the zero-point across the sky to be of order or less than a few 10s of $\mu \text{as}$.