bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endometrial Receptivity Analysis (ERA) test: an unproven technology
Authors: Ben Rafael Zion 
Published: March 2021

ABSTRACT
This article addresses the limitations of the endometrial receptivity array (ERA) methodology to increase implantation. Such limitations vary from the assumed inconsistency of the endometrial biopsy, the variable number of genes found to be dysregulated in endometrium samples without the embryonal-induced effect, the failure to account for the simultaneous serum progesterone level, and the expected low percentage of patients who may need this add-on procedure, to the difficulties in synchronising the endometrium with hormone replacements in successive cycles and the inherent perinatal risks associated with routine cryopreservation of embryos. Without a gold standard to compare, the claim that the window of implantation (WOI) might be off by ±12 h only requires a good argument for the advantage it provides to human procreation, knowing that embryos can linger for days before actual embedding starts and that the window is actually a few days. The intra-patient variations in the test need to be addressed. In summary, like all other add-ons, it is doubtful whether the ERA test use can significantly enhance implantation success rates.
Heuristic mean-variance optimization in Markov decision processes using state-dependent risk aversion
Authors: Schlosser Rainer 
Published: March 2021

AbstractIn dynamic decision problems, it is challenging to find the right balance between maximizing expected rewards and minimizing risks. In this paper, we consider NP-hard mean-variance (MV) optimization problems in Markov decision processes with a finite time horizon. We present a heuristic approach to solve MV problems, which is based on state-dependent risk aversion and efficient dynamic programming techniques. Our approach can also be applied to mean-semivariance (MSV) problems, which particularly focus on the downside risk. We demonstrate the applicability and the effectiveness of our heuristic for dynamic pricing applications. Using reproducible examples, we show that our approach outperforms existing state-of-the-art benchmark models for MV and MSV problems while also providing competitive runtimes. Further, compared to models based on constant risk levels, we find that state-dependent risk aversion allows to more effectively intervene in case sales processes deviate from their planned paths. Our concepts are domain independent, easy to implement and of low computational complexity.
Yield dissection models to improve yield: a case study in tomato
Authors: Tsutsumi-Morita Yutaka , Heuvelink Ep , Khaleghi Sedighehsadat , Bustos-Korts Daniela , Marcelis Leo F M , Vermeer Kim M C A , van Dijk Hannelore , Millenaar Frank F , Van Voorn George A K , Van Eeuwijk Fred A 
Published: March 2021

AbstractYield as a complex trait may either be genetically improved directly, by identifying QTLs contributing to yield, or indirectly via improvement of underlying components, where parents contribute complementary alleles to different components. We investigated the utility of two yield dissection models in tomato for identifying promising yield components and corresponding QTLs. In a harvest dissection, marketable yield was the product of number of fruits and individual fruit fresh weight. In a biomass dissection, total yield was the product of fruit fresh-dry weight ratio and total fruit dry weight. Data came from a greenhouse experiment with a population of hybrids formed from four-way RILs. Trade-offs were observed between the component traits in both dissections. Genetic improvements were possible by increasing the number of fruits and the total fruit dry weight to offset losses in fruit fresh weight and fruit fresh-dry weight ratio. Most yield QTLs colocalized with component QTLs, offering options for the construction of high-yielding genotypes. An analysis of QTL allelic effects in relation to parental origin emphasized the complementary role of the parents in the construction of desired genotypes. Multi-QTL models were used for the comparison of yield predictions from yield QTLs and predictions from the products of components following multi-QTL models for those components. Component QTLs underlying dissection models were able to predict yield with the same accuracy as yield QTLs in direct predictions. Harvest and biomass yield dissection models may serve as useful tools for yield improvement in tomato by either or both of combining individual component QTLs and multi-QTL component predictions.
Concentrations of para-Fluorofuranylfentanyl in Paired Central and Peripheral Blood Collected during Postmortem Death Investigations
Authors: Rodriguez Salas Judith , Krotulski Alex J , Newman Reta , Thogmartin Jon R , Mohr Amanda L A , Logan Barry K 
Published: March 2021

Abstract
The opioid epidemic in the USA has been associated with an increasing mortality rate in large part due to the emergence and proliferation of synthetic opioids over the last 15 years. Fentanyl and its analogs have played a large part in these statistics due to their potency and toxicity. Fluorofuranylfentanyl (FFF) is a fentanyl analog that emerged in the USA in 2018 and was associated with numerous adverse events and deaths. During this study, a liquid chromatography tandem mass spectrometry workflow was developed to accurately identify the isomer of FFF present (ortho- vs. meta- vs. para-) in medicolegal death investigation cases from Pinellas County, Florida. FFF was quantified in central and peripheral blood samples collected at autopsy. In addition, the metabolism of FFF was studied using liquid chromatography quadrupole time-of-flight mass spectrometry. para-FFF was quantitatively confirmed in 29 postmortem cases; no other isomer of FFF was detected. Central blood concentrations ranged between 0.66 and 73 ng/mL (mean = 11 ± 14 ng/mL, median = 10 ng/mL) and peripheral blood concentrations ranged between 0.53 and 23 ng/mL (mean = 5.7 ± 6.4 ng/mL, median = 2.7 ng/mL). A comparison of central to peripheral blood concentrations was evaluated to determine the possibility of postmortem redistribution. The metabolism of ortho-FFF was studied and found to undergo metabolic processes similar to fentanyl, producing ortho-fluorofuranyl-norfentanyl, fluoro-4-anilino-N-phenethylpiperidine, and hydroxylated species. The results of this study demonstrate the toxicity of FFF and its implication in medicolegal death investigations. Laboratories must remain aware of new or re-emerging fentanyl analogs, as they pose significant risks to public health and public safety.
A3 THE LOSS OF THE CIRCADIAN CLOCK GENE BMAL1 INCREASES TUMOUR INITIATION IN APCMIN MICE
Authors: Nunes M , Trombley C , Flôres D E , Wu G , Curran C , Taleb Z , Hogenesch J B , Karpowicz P 
Published: March 2021

Abstract

Background
Circadian rhythms are autonomously running 24h cycles in bodily processes. In animals these rhythms are driven by a molecular time keeper known as the circadian clock. The clock is a transcription-translation feedback loop composed of the transcription factors Bmal1 and Clock as well as their repressors Per and Cry. The circadian clock regulates over 40% of the genome rhythmically. Chronic circadian disruption, in the case of shift work, can lead to pathologies including cancer. Colorectal cancer is most frequently initiated through a mutation in the Wnt pathway regulator, Apc. Several studies have attempted to provide a mechanistic link between cancer and circadian clock disruption but the use of mice on mixed genetic backgrounds and poor circadian models have made this link unclear.

Aims
We aim to determine if the circadian clock plays a role in intestinal tumourigenesis.

Methods
We crossed the Apcmin mouse strain, a common intestinal tumour model, with Bmal1 mutant mice, which lack a functioning circadian clock. After creating an isogenic strain, we examined the number of tumours in control (Bmal1+/+) and clock dead (Bmal1-/-) animals. We derived organoids, a 3D cell culture method, from Apc+/+; Bmal1+/+ (healthy, clock-live), Apc+/+, Bmal1-/-(healthy, clock-dead), Apcmin; Bmal1+/+(adenoma, clock-live), Apcmin; Bmal1-/- (adenoma, clock-live) mouse ileum and collected every 2h from 24-48h after synchronizing their circadian clock. Collected samples were sent for RNA sequencing and assessed for circadian regulated transcripts. This experiment was followed up by in vitro organoid assays.

Results
The circadian clock controls 41 genes in the intestinal epithelium, including genes like Tead4 which are known to be important in intestinal biology. There are twofold more tumours in Bmal1-/- mice than their Bmal1+/+ littermates, and Bmal1-/- tumours upregulate Tead4 and Hippo pathway targets and downregulate Wnt pathway targets. Bmal1-/- adenoma organoids show increased self-renewal when compared to Bmal1+/+ adenoma organoids. However, this increase in self-renewal is lost when organoids are treated with inhibitors of the hippo pathway.

Conclusions
The circadian clock is important in maintaining the health of an organism, and disruption of the clock can lead to many health consequences including cancer. We show for the first time that the circadian clock controls the hippo signaling mediator Tead4. Additionally, we show that the loss of the clock leads to an increase in the number of tumours present in the epithelium which are characterized by an increase in hippo signaling. This research shows the important of considering time of day when studying stem cells during homeostasis and in cancer.

Funding Agencies
CIHRNSERC
A6 THE ROLE OF TUFT CELLS IN INTESTINAL HOMEOSTASIS
Authors: Zhang A , Pang Y , Menzies S , Sly L M 
Published: March 2021

Abstract

Background
Intestinal epithelial cells may actively regulate homeostasis by recognizing and responding to extracellular signals. One of these cell types, tuft cells, has been proposed to have a role in secretion, absorption, and reception. However, their role in the intestine has not been fully characterized. We have found that tuft cells express the SH2 domain-containing inositol 5’-phosphatase (SHIP), which was formerly thought to be restricted to hematopoietic cells. SHIP negatively regulates PI3K-mediated cell growth, proliferation, and activation. Tuft cells secrete IL-25, which activates group 2 innate lymphoid cells (ILC2s), leading to type 2 immune responses. Tuft cells may contribute to inflammation in the intestine by increasing ILC2 numbers and/or activation, leading to type II inflammation.

Aims
My hypothesis is that SHIP inhibits tuft cell responses to innate immune stimuli by limiting PI3K activation. Moreover, SHIP deficiency will increase tuft cell responses to commensal microbes, causing ILC2-mediated type II inflammation. To investigate the role of SHIP in tuft cell responses in vivo, I will use a tuft cell-specific SHIP deficient mouse in the dextran sodium sulfate (DSS)-induced colitis model.

Methods
We created a mouse deficient in SHIP only in intestinal tuft cells (Fabpcre x SHIPfl/fl) to investigate the impact of SHIP deficiency in tuft cells on responses to luminal microbes. Tuft cell-specific SHIP deficient mice (8-week-old) and their wild type littermates were subjected to DSS-induced colitis for 7 days. Clinical disease activity was monitored daily and gross pathology, including total colon length, was examined at the experimental endpoint. The concentrations of pro-inflammatory type I and type II cytokines were assessed in colonic tissue homogenates via ELISA.

Results
During DSS-induced colitis, mice with SHIP deficient tuft cells had increased disease activity compared to their wild type littermates, particularly evident in their weight loss. Mice with SHIP deficient tuft cells also had significantly shorter colons than their wild type littermates. IL-25 concentrations (produced by tuft cells) were increased in full thickness colon homogenates from mice with SHIP deficient tuft cells. In contrast, pro-inflammatory cytokines IL-1β, IL-6, and TNF did not differ between genotypes. Thus, increased tuft cell activity due to SHIP deficiency correlated with increased disease severity during DSS-induced colitis.

Conclusions
SHIP deficiency in intestinal tuft cells leads to increased tuft cell activity and exacerbated colitis during DSS treatment. Tuft cells may contribute to inflammation via IL-25 production, leading to increased type II inflammation by ILC2s. In future studies, we will target IL-25 in this model to determine whether increased tuft cell IL-25 production plays a causal role in disease exacerbation.

Funding Agencies
NSERC
A10 FOOD ANTIGEN-STRESS INTERACTION LEADS TO INCREASE PAIN SIGNALING IN ILEUM AND COLON VIA STAT6 IN AN IBS MODEL
Authors: Lopez Lopez C , Jaramillo Polanco J , Yu Y , Tsang Q K , Vanner S , Reed D E 
Published: March 2021

Abstract

Background
Abdominal pain can be triggered by food ingestion in IBS patients. Previously we have shown that a food antigen induces local release of immune mediators in the colon that increase dorsal root ganglion (DRG) neuron excitability when there is previous antigen exposure in the presence of psychological stress. However, it is unknown if this effect is limited to the colon. Furthermore, the involvement of histamine in the neuronal hyperexcitability suggests that the stress-food antigen interaction evokes a Th2 immune response. Thus, we sought to investigate the role of STAT6, a transcription factor downstream of Th2 cytokines and important for IgE production.

Aims
1) Determine if stress-food antigen interaction leads to release of mediators within the small intestine that increase DRG neuron excitability. 2) Determine the involvement of STAT6 on neuronal hyperexcitability induced by the stress-food antigen interaction.

Methods
BALB/c mice were exposed to water avoidance stress (WAS) or sham stress (SHAM) for 1 hr daily for 10 days. On day 2–10, mice were exposed to ovalbumin (OVA) or saline (SAL). Seven days later, mice were re-exposed to either OVA or SAL every 2 days for 2 weeks yielding 3 groups: WAS/OVA+OVA, WAS/SAL+OVA, and SHAM/OVA+OVA. STAT6 deficient mice were also exposed to WAS/OVA+OVA protocol. Ileum or colonic supernatants were obtained 4 hours after tissue collection. DRG neurons were incubated overnight with supernatants prior to perforated patch clamp recordings. Neuronal excitability was evaluated by measuring the rheobase (minimum current to elicit an action potential, decreased rheobase indicates increased excitability). Mechanosensitivity of extrinsic afferent nerves innervating distal ileum was examined using ex vivo extracellular afferent nerve recordings. Data was analyzed by one or two-way ANOVA with Bonferroni post-hoc test.

Results
Ileum supernatants from WAS/OVA+OVA mice increased DRG neuron excitability compared to WAS/SAL+OVA and SHAM/OVA+OVA mice (63.3 ± 6.2 pA vs 83.2 ± 5.4 pA, 86.7 ± 4.5 pA, p&lt;0.05). Ileum afferent nerve response to distention was significantly augmented in WAS/OVA+OVA mice compared to WAS/SAL+OVA and SHAM/OVA+OVA (P&lt;0.05, n=4–7). DRG neurons incubated with WAS/OVA+OVA supernatant from STAT6 deficient mice were less excitable compared to neurons incubated with colonic supernatants from wild type mice (86.5 ± 4.1 pA vs 67.6 ± 4.8 pA, p&lt;0.05).

Conclusions
Stress-food antigen interaction releases mediators in both the small intestine and colon to increase nociceptive signaling, an important finding as IBS can involve both areas. The release of excitatory mediators within the gut appears to involve STAT6. Thus, a stress-food antigen interaction evoking a Th2 immune response in the gut may be a mechanism underlying food induced symptoms in IBS.

Funding Agencies
Queen’s University, Department of Medicine
A19 HEALTH CARE UTILIZATION DIFFERENCES BETWEEN FIRST NATIONS AND THE GENERAL POPULATION WITH INFLAMMATORY BOWEL DISEASE IN SASKATCHEWAN
Authors: Marques Santos J , Fowler S , Jennings D , Brass C , Porter L , Porter R , Sanderson R , Peña-Sánchez J 
Published: March 2021

Abstract

Background
Indigenous patients with inflammatory bowel disease (IBD) have expressed concerns about barriers to access IBD care. The limited evidence of IBD among Indigenous people highlights the need for studies evaluating access to IBD care in this population.

Aims
We aimed to compare health care utilization between First Nations (FNs) and individuals from the general population (GP) diagnosed with IBD in Saskatchewan (SK).

Methods
A population-based retrospective cohort study was conducted using administrative health databases of SK from 1998 to 2017 fiscal years. As a patient-oriented research initiative, outcomes of interest were chosen in collaboration with Indigenous patients and family advocates. A validated algorithm requiring multiple health care contacts was applied to identify incident IBD cases. The self-declared FN status variable was used to divide IBD cases between FNs and the general population (GP). To balance the groups, 1:5 age and sex matching was applied. Cox-proportional models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95%CI). Stratified analysis was completed for those diagnosed before and after 2008 (pre- and post-biologic eras).

Results
A matched cohort with 696 IBD incident cases was created (FN=116, GP=580). Comparing health care utilization of FNs and individuals from the GP with IBD, there were no statistically significant differences in outpatient gastroenterology visits (FNs=81.0%, GP=83.6%), colonoscopies (FNs=91.4%, GP=86.9%), and surgeries for IBD (FNs=31.0%, GP=33.5%). We observed differences in prescription claims for any medication for IBD (FNs=79.3%, GP=89.3%) and 5-aminosalicylic acid (5-ASA) claims (FNs=75.9%, GP=81.4%). The HRs adjusted by rural/urban residence and diagnostic type showed differences in prescription claims for any IBD medication (HR=0.52, 95%CI 0.41–0.65) and 5-ASA (HR=0.57, 95%CI 0.45–0.72). In the pre-biologic era, FNs had a lower risk of having a prescription claim for any IBD medication (HR=0.32, 95%CI 0.23–0.45) and 5-ASA (HR=0.33, 95%CI 0.24–0.47), respectively. These differences were not significant in the post-biologic era.

Conclusions
Our study identified an inverse association between FN status and having prescription medication claims for IBD in SK. We considered multiple confounding variables when evaluating this association but could not control by disease severity. Thus, this association might reflect a barrier to access IBD medications or that FNs with IBD might present a milder disease. Further studies should continue evaluating access to IBD care, medication use, and disease severity among FNs living with IBD.

Funding Agencies
Saskatchewan Centre for Patient-Oriented Research (SCPOR), Saskatchewan Health Research Foundation (SHRF), and College of Medicine, University of Saskatchewan.
A20 DIAGNOSTIC ACCURACY OF A LOW COST, WIDELY AVAILABLE TEST STRIP FOR PREDICTING A POSITIVE FECAL CALPROTECTIN TEST
Authors: Trasolini R , Wong S , Salh B 
Published: March 2021

Abstract

Background
Fecal calprotectin is a non-invasive test of colonic inflammation used for monitoring inflammatory bowel disease activity and for risk stratifying non-specific colonic symptoms. Calprotectin is a leukocyte specific enzyme. A similar test, leukocyte esterase is used to detect leukocytes in urine and is widely available as a low-cost point-of-care test strip. We hypothesize that an unmodified version of the urine test strip would be highly accurate in predicting a positive fecal calprotectin test in a real world sample of patients.

Aims
To explore a low cost, rapid alternative to the fecal calprotectin test

Methods
All inpatient and outpatient stool samples tested for calprotectin by the Vancouver General Hospital laboratory from February 2020 to November 2020 were included prospectively. Samples were simultaneously tested for fecal leukocyte esterase using an unmodified Roche Cobas Chemstrip urinalysis test strip by central lab personnel. An identical aliquot was sent to LifeLabs for calprotectin as per standard protocol. All samples were suspended in buffer using established laboratory protocols prior to testing. Fecal leukocyte esterase results were reported as 0–4+ based on visual interpretation, calprotectin results were reported as mcg/g of stool. REB review and approval was obtained prior to data collection. Sensitivity, Specificity and AUROC were calculated using Microsoft Excel and JROCFIT.

Results
26 samples were collected. Using a fecal calprotectin greater than 120 mcg/g as a gold standard an AUROC of 0.89 (SE= .06) was calculated. A leukocyte esterase reading of 2+ or greater had the best test characteristics based on ROC curve analysis. Using this cutoff, 21/26 samples were concordant, giving an accuracy of 80.8%, sensitivity of 90.9% and specificity of 73.3%. Positive likelihood ratio was 8.07 and negative likelihood ratio was 0.29. Assuming an AUROC of 0.8, the sample size N=26 is 90% powered (β=0.9) to predict the true AUROC within 0.1 with a type I error rate of .05 (α&lt;.05).

Conclusions
This study suggests application of a prepared stool sample to a urinalysis test strip gives a result highly predictive of a positive fecal calprotectin test. Further results are being collected prospectively to improve the robustness of these preliminary data. Secondary outcomes including comparison to endoscopy and biopsy results where available are planned if an adequate sample size can be accrued. Future studies justifying independent clinical use of leukocyte esterase would require a common gold standard comparator such as endoscopy. Fecal calprotectin testing is not universally insured and is not available as a rapid test strip. Use of fecal leukocyte esterase may reduce costs and shorten time to results if proven to be independently reliable.

Funding Agencies
None