bluuebunny/crossref_metadata_2025 huggingface dataset:
A method based on link prediction for identifying set of super-spreaders in complex networks
Authors: Hosseini Bayan , Veisi Farshid , Sheikhahmdi Amir
Published: March 2023

Identifying a group of key nodes with enormous capability for spreading information to other network nodes is one of the favourable research topics in complex networks. In most existing methods, only the current status of the network is used for identifying and selecting the member of these groups. The main weakness of these methods is a lack of attention to the highly dynamic nature of complex networks and continuous changes in them in terms of creating and eliminating nodes and links. This matter makes the selected group have no proper performance in spreading information relative to other nodes. Therefore, this article presents a novel method for identifying spreader nodes and selecting a superior set from them. In the proposed method, the diffusion power of network nodes is calculated in the first step, and some are selected as influential nodes. In the following steps, it is tried to modify the list of selected nodes by predicting the network variation. Six datasets gathered from real-world networks are utilized for evaluation. The proposed method and other methods are tested to evaluate their spread of influence and time complexity. Results show that using the link prediction in the proposed method can enhance the spread of influence by the selected set compared to other methods so that the spread of influence in some datasets is more than 30$\%$. On the other hand, the time complexity of the proposed method confirms its utility in very large networks.
Multimodality imaging in thoracic aortic diseases: a clinical consensus statement from the European Association of Cardiovascular Imaging and the European Society of Cardiology working group on aorta and peripheral vascular diseases
Authors: Evangelista Artur , Sitges Marta , Jondeau Guillaume , Nijveldt Robin , Pepi Mauro , Cuellar Hug , Pontone Gianluca , Bossone Eduardo , Groenink Maarten , Dweck Marc R , Roos-Hesselink Jolien W , Mazzolai L , van Kimmenade Roland , Aboyans Victor , Rodríguez-Palomares Jose
Published: March 2023

Imaging techniques play a pivotal role in the diagnosis, follow-up, and management of aortic diseases. Multimodality imaging provides complementary and essential information for this evaluation. Echocardiography, computed tomography, cardiovascular magnetic resonance, and nuclear imaging each have strengths and limitations in the assessment of the aorta. This consensus document aims to review the contribution, methodology, and indications of each technique for an adequate management of patients with thoracic aortic diseases. The abdominal aorta will be addressed elsewhere. While this document is exclusively focused on imaging, it is of most importance to highlight that regular imaging follow-up in patients with a diseased aorta is also an opportunity to check the patient’s cardiovascular risk factors and particularly blood pressure control.
Hereditary transthyretin amyloidosis presenting with spontaneous periorbital purpura: a case report
Authors: Jhawar Nikita , Reynolds Jordan , Nakhleh Raouf , Lyle Melissa
Published: March 2023

Background

Amyloidosis is a systemic disorder of abnormal protein folding and deposition resulting in a range of symptoms including neuropathy, heart failure, renal disease, and dermatologic findings. The two most common types of amyloidosis that affect the heart are transthyretin (ATTR) amyloidosis and light chain (AL) amyloidosis, which vary in clinical presentation. Skin findings such as periorbital purpura are considered more specific for AL amyloidosis. However, there are rare cases of ATTR amyloidosis causing the same dermatologic findings.

Case Summary

A 69-year-old female presented for evaluation of amyloidosis after cardiac imaging done at the time of a recent atrial fibrillation ablation showed signs of infiltrative disease. On examination, she had periorbital purpura which she reportedly had for years without receiving a diagnosis, as well as macroglossia with teeth indentation. These exam findings, in addition to her transthoracic echocardiogram showing apical sparing, are typically considered characteristic of AL amyloidosis. Subsequent workup revealed the presence of hereditary ATTR (hATTR) amyloidosis with a heterozygous pathogenic variant in the TTR gene producing the p.Thr80Ala mutation.

Conclusion

Spontaneous periorbital purpura is thought to be pathognomonic for AL amyloidosis. However, we describe a case of hereditary ATTR amyloidosis with the Thr80Ala TTR genetic variant presenting initially with periorbital purpura, the first case documented in the literature to our knowledge.
A novel breakthrough in wrist-worn transdermal troponin-I-sensor assessment for acute myocardial infarction
Authors: Sengupta Shantanu , Biswal Siddharth , Titus Jitto , Burman Atandra , Reddy Keshav , Fulwani Mahesh C , Khan Aziz , Deshpande Niteen , Shrivastava Smit , Yanamala Naveena , Sengupta Partho P
Published: March 2023

Aims

Clinical differentiation of acute myocardial infarction (MI) from unstable angina and other presentations mimicking acute coronary syndromes (ACS) is critical for implementing time-sensitive interventions and optimizing outcomes. However, the diagnostic steps are dependent on blood draws and laboratory turnaround times. We tested the clinical feasibility of a wrist-worn transdermal infrared spectrophotometric sensor (transdermal-ISS) in clinical practice and assessed the performance of a machine learning algorithm for identifying elevated high-sensitivity cardiac troponin-I (hs-cTnI) levels in patients hospitalized with ACS.

Methods and results

We enrolled 238 patients hospitalized with ACS at five sites. The final diagnosis of MI (with or without ST elevation) and unstable angina was adjudicated using electrocardiography (ECG), cardiac troponin (cTn) test, echocardiography (regional wall motion abnormality), or coronary angiography. A transdermal-ISS–derived deep learning model was trained (three sites) and externally validated with hs-cTnI (one site) and echocardiography and angiography (two sites), respectively. The transdermal-ISS model predicted elevated hs-cTnI levels with areas under the receiver operator characteristics of 0.90 [95% confidence interval (CI), 0.84–0.94; sensitivity, 0.86; and specificity, 0.82] and 0.92 (95% CI, 0.80–0.98; sensitivity, 0.94; and specificity, 0.64), for internal and external validation cohorts, respectively. In addition, the model predictions were associated with regional wall motion abnormalities [odds ratio (OR), 3.37; CI, 1.02–11.15; P = 0.046] and significant coronary stenosis (OR, 4.69; CI, 1.27–17.26; P = 0.019).

Conclusion

A wrist-worn transdermal-ISS is clinically feasible for rapid, bloodless prediction of elevated hs-cTnI levels in real-world settings. It may have a role in establishing a point-of-care biomarker diagnosis of MI and impact triaging patients with suspected ACS.
Prospective relationship between occupational physical activity and risk of ischaemic heart disease: are men and women differently affected?
Authors: Allesøe Karen , Aadahl Mette , Jacobsen Rikke Kart , Kårhus Line Lund , Mortensen Ole Steen , Korshøj Mette
Published: March 2023

Aims

High occupational physical activity (OPA) seems to increase risk of cardiovascular diseases among men. However, findings are mixed, and it is not known if women are differently affected. Therefore, the aim of this study is to investigate the relationship between OPA and risk for ischaemic heart disease (IHD), and whether it differs across sex.

Methods and results

This prospective cohort study was based on 1399 women and 1706 men, aged 30–61 years, participating in the Danish Monica 1 study in 1982–84, actively employed, without prior IHD and answering an OPA question. The information on incidence of IHD, before and during the 34-years follow-up, was retrieved by individual linkage to the Danish National Patient Registry. Cox proportional hazards models were used to investigate the association between OPA and IHD. Compared to women with sedentary work, women in all other OPA categories had lower hazard ratio (HR) for IHD. Among men, the risk of IHD was 22% higher among those with light OPA, and 42% and 46% higher among those with moderate OPA with some lifting or strenuous work with heavy lifting, respectively, compared to men with sedentary OPA. Compared to women with sedentary work, HR for IHD was higher among men in all OPA categories. There was statistically significant interaction between OPA and sex.

Conclusion

Demanding or strenuous OPA seems to be a risk factor for IHD among men, whereas a higher level of OPA seems to protect women from IHD. This emphasizes the importance of taking sex differences into account in studies of health effects of OPA.
Aging and Economic Preferences: Cumulative Meta-Analyses of Age Differences in Risk, Time, Social, and Effort Preferences
Authors: Bagaïni Alexandra , Liu Yunrui , Bajrami Arzie , Son Gayoung , Tisdall Loreen , Mata Rui
Published: March 2023

Objectives

Several theories predict changes in individuals’ economic preferences across the life span. To test these theories and provide a historical overview of this literature, we conducted meta-analyses on age differences in risk, time, social, and effort preferences as assessed by behavioral measures.

Methods

We conducted separate meta-analyses and cumulative meta-analyses on the association between age and risk, time, social, and effort preferences. We also conducted analyses of historical trends in sample sizes and citation patterns for each economic preference.

Results

The meta-analyses identified overall no significant effects of age for risk (r = −0.02, 95% CI [−0.06, 0.02], n = 39,832) and effort preferences (r = 0.24, 95% CI [−0.05, 0.52], n = 571), but significant effects of age for time (r = −0.04, 95% CI [−0.07, −0.01], n = 115,496) and social preferences (r = 0.11, 95% CI [0.01, 0.21], n = 2,997), suggesting increased patience and altruism with age, respectively. Equivalence tests, which compare these effects to practically important ones (i.e., r = |0.1|), however, suggest that all effects are of trivial significance. The analyses of temporal trends suggest that the magnitude of effects and sample sizes have not changed significantly over time, nor do they dramatically affect the extent that articles are cited.

Discussion

Overall, our results contrast with theories of aging that propose general age effects for risk and effort preferences, yet provide some but tenuous support for those suggesting age-related changes in time and social preferences. We discuss implications for theory development as well as future empirical work on economic preferences.
Using Item Response Times in Online Questionnaires to Detect Mild Cognitive Impairment
Authors: Schneider Stefan , Junghaenel Doertes U , Meijer Erik , Stone Arthur A , Orriens Bart , Jin Haomiao , Zelinski Elizabeth M , Lee Pey-Jiuan , Hernandez Raymond , Kapteyn Arie
Published: March 2023

Objectives

With the increase in web-based data collection, response times (RTs) for survey items have become a readily available byproduct in most online studies. We examined whether RTs in online questionnaires can prospectively discriminate between cognitively normal respondents and those with cognitive impairment, no dementia (CIND).

Method

Participants were 943 members of a nationally representative internet panel, aged 50 and older. We analyzed RTs that were passively recorded as paradata for 37 surveys (1,053 items) administered online over 6.5 years. A multilevel location-scale model derived 3 RT parameters for each survey: (1) a respondent’s average RT and 2 components of intraindividual RT variability addressing (2) systematic RT adjustments and (3) unsystematic RT fluctuations. CIND status was determined at the end of the 6.5-year period.

Results

All 3 RT parameters were significantly associated with CIND, with a combined predictive accuracy of area under the receiver-operating characteristic curve = 0.74. Slower average RTs, smaller systematic RT adjustments, and greater unsystematic RT fluctuations prospectively predicted a greater likelihood of CIND over periods of up to 6.5, 4.5, and 1.5 years, respectively.

Discussion

RTs for survey items are a potential early indicator of CIND, which may enhance analyses of predictors, correlates, and consequences of cognitive impairment in online survey research.
Geographic Patterns of Dementia in the United States: Variation by Place of Residence, Place of Birth, and Subpopulation
Authors: Zacher Meghan , Brady Samantha , Short Susan E
Published: March 2023

Objectives

The prevalence of dementia varies geographically in the United States. However, the extent to which this variation reflects contemporary place-based experiences versus embodied exposures from earlier in the life course remains unclear, and little is known regarding the intersection of place and subpopulation. This study, therefore, evaluates whether and how risk for assessed dementia varies by place of residence and birth, overall and by race/ethnicity and education.

Methods

We pool data from the 2000 to 2016 waves of the Health and Retirement Study, a nationally representative panel survey of older U.S. adults (n = 96,848 observations). We estimate the standardized prevalence of dementia by Census division of residence and birth. We then fit logistic regression models of dementia on region of residence and birth, adjusting for sociodemographic characteristics, and examine interactions between region and subpopulation.

Results

The standardized prevalence of dementia ranges from 7.1% to 13.6% by division of residence and from 6.6% to 14.7% by division of birth, with rates highest throughout the South and lowest in the Northeast and Midwest. In models accounting for region of residence, region of birth, and sociodemographic covariates, Southern birth remains significantly associated with dementia. Adverse relationships between Southern residence or birth and dementia are generally largest for Black and less-educated older adults. As a result, sociodemographic disparities in predicted probabilities of dementia are largest for those residing or born in the South.

Discussion

The sociospatial patterning of dementia suggests its development is a lifelong process involving cumulated and heterogeneous lived experiences embedded in place.
What is a vishwaguru? Indian civilizational pedagogy as a transformative global imperative
Authors: de Estrada Kate Sullivan
Published: March 2023

Ambitions for India to enact the role of vishwaguru or ‘world teacher’ are a conspicuous feature of foreign policy discourse under contemporary Hindu nationalist rule in India. This discourse, and India's foreign-policy practice, engage the international realm with a puzzling intensity given Hindu nationalism's inward-looking and exclusionary emphasis on majoritarian cultural unity. In this article, I leverage International Relations scholarship on social closure, international order and recognition struggles to examine the historical lineages and recent articulations of nineteenth-century religious reformist ideas about India's world mission and spiritual superiority. I argue that different Indian civilizational imaginaries across time produce a pedagogical imperative, aimed at the transformation of global social hierarchies. Centred on a quest to assert social superiority and remake the terms of recognition, any given vishwaguru project nonetheless relies on international recognition. The recent domestic and diasporic appeal of Hindu nationalist foreign policy stems from how it appears to intervene to rectify the longstanding misrecognition of India. In this context, western liberal states' instrumental recognition of India as a democratic partner and defender of liberal order in the face of a ‘China challenge’ works to endorse and bolster the vishwaguru project of India's current domestic political moment.
From Hinduism to Hindutva: civilizational internationalism and UNESCO
Authors: Singh Rani , Winter Tim
Published: March 2023

This article considers civilizational politics at the interface between nationalism and internationalism. It does this by focusing on some key trends in India's engagements with UNESCO and its flagship conventions for culture. The article builds on existing scholarship regarding the political appropriation of key religious and heritage sites within India by critically examining how Hinduism is presented to UNESCO and other organizations as a religious and civilizational heritage for global recognition and endorsement. We argue that UNESCO's programmes and conventions are being co-opted via a rewriting of history and in the creation of heritage imaginaries of a Hindu nation. From there, the discussion extends previous critiques regarding the conjoining of Hinduism to a Harappan civilization heritage by showing how this geographically extends outwards via a programme of Indian Ocean diplomacy conceived around environmental and historical connectivities. In pulling these various threads together, the article demonstrates the ways in which Hindu civilizational discourses circulate at the international level in seemingly benign and banal ways, and, yet, simultaneously advance the domestic cultural politics now familiar to the Hindutva movement.
Disciplining India: paternalism, neo-liberalism and Hindutva civilizationalism
Authors: Chacko Priya
Published: March 2023

Policy hybrids, which combine marketizing and liberalizing reforms with social welfare programmes and state support to boost domestic production, are fast becoming the norm globally. How are neo-liberal and national-developmentalist agendas reconciled as governing practices, and what are their national and international outcomes and implications? This article focuses on the understudied case of India, arguing that a paternalist political rationality, which melds paternalist logics in neo-liberalism and the government's Hindutva civilizationalist politics, underpins its flagship economic policy, the Atmanirbhar Bharat Abhiyan (Self-reliant India Mission). This policy, through production-linked incentives, aims to boost Indian manufacturing. India has benefited from a global push to diversify supply chains and forge new geopolitical partnerships, such as the Quad, to undermine China's manufacturing dominance and geopolitical assertiveness. Yet, its current approach consolidates the dominance of large firms, producing an elitist political economy, and does not address structural weaknesses through public investment in areas like research and education. This has implications for India's development, global trade and geopolitics. These arguments are made by identifying the paternalist logics in the theories and practices of neo-liberalism, and in Hindutva civilizationalist politics; assessing the aims of the Atmanirbhar Bharat Abhiyan as elaborated by government officials; and evaluating the early outcomes of production-linked incentive schemes.
What if? Counterfactual Trump and the western response to the war in Ukraine
Authors: Kaarbo Juliet , Oppermann Kai , Beasley Ryan K
Published: March 2023

Because of his personality, had Donald Trump won the 2020 election the remarkable and unexpected united response by NATO allies to the February 2022 Russian invasion of Ukraine would not have happened. Relying on leader personality research in foreign policy, we demonstrate this by using the counterfactual method of analysis. Specifying key differences between Biden's and Trump's personalities in terms of their experiences, traits and beliefs, we explicitly show that president Trump would have been very unlikely to share US intelligence, rally NATO allies in support of Ukraine or challenge Vladimir Putin. In contrast, these responses fit very well with Joe Biden's personality. We first present counterfactual analysis as a method before comparing Biden and Trump along personality characteristics known to significantly influence foreign-policy decisions. Through our case-study, we demonstrate the value of using systematic and theoretically grounded counterfactual methods for assessing the importance of individual differences between leaders and emphasizing their impact on international affairs.
A Longitudinal Study of Self-Disclosure in Human–Chatbot Relationships
Authors: Skjuve Marita , Følstad Asbjørn , Brandtzæg Petter Bae
Published: March 2023

Self-disclosure in human–chatbot relationship (HCR) formation has attracted substantial interest. According to social penetration theory, self-disclosure varies in breadth and depth and is influenced by perceived rewards and costs. While previous research has addressed self-disclosure in the context of chatbots, little is known about users' qualitative understanding of such self-disclosure and how self-disclosure develops in HCR. To close this gap, we conducted a 12-week qualitative longitudinal study (n = 28) with biweekly questionnaire-based check-ins. Our results show that while HCRs display substantial conversational breadth, with topics spanning from emotional issues to everyday activities, this may be reduced as the HCR matures. Our results also motivate a nuanced understanding of conversational depth, where even conversations about daily activities or play and fantasy can be experienced as personal or intimate. Finally, our analysis demonstrates that conversational depth can develop in at least four ways, influenced by perceived rewards and costs. Theoretical and practical implications are discussed.
Poverty and Frailty Are Not Related to Each Other With Regard to Outcomes in Middle-Aged and Older Patients with Burn Injuries
Authors: Wallace David , Sloan Keturah , Williams Deborah , Heard Jason , Sen Soman , Palmieri Tina , Greenhalgh David , Romanowski Kathleen
Published: March 2023

The purpose of this study was to determine the relationship between frailty and poverty in burn patients ≥50 years old, and their association with patient outcomes. This was a single-center retrospective chart review from 2009 to 2018 of patients ≥50 years old admitted with acute burn injuries. Frailty was assigned using the Canadian Study of Health and Aging Clinical Frailty Scale. Poverty was defined as a patient from a zip code that had >20% of people living in poverty. The relationship between frailty and poverty, as well as each variable independently on mortality, length of stay (LOS), and disposition location, was examined. Of 953 patients, the median age was 61 years, 70.8% were male, and the median total body surface area burn was 6.6%. Upon admission, 26.4% and 35.2% of patients were frail and from impoverished neighborhoods, respectively. The mortality rate was 8.8%. Univariate analysis demonstrated that nonsurvivors had significantly higher chances of living in poverty (P = .02) and were more likely to be frail compared to survivors. There was no significant correlation between poverty and frailty (P = .08). Multivariate logistic regression confirmed the relationship between lack of poverty and mortality (OR .47, 95% CI 0.25–0.89) and frailty and mortality (OR 1.62, 95% CI 1.24–2.12). Neither poverty (P = .26) nor frailty (P = .52) was associated with LOS. Both poverty and frailty were associated with a patient’s discharge location (P = .03; P < .0001). Poverty and frailty each independently predict mortality and discharge destination in burn patients ≥50, but they are not associated with LOS nor each other.
Race and Ethnicity Influences Outcomes of Adult Burn Patients
Authors: DiPaolo Nicola , Hulsebos Ian F , Yu Jeremy , Gillenwater Timothy Justin , Yenikomshian Haig A
Published: March 2023

Outcomes of burn survivors is a growing field of interest; however, there is little data comparing the outcomes of burn survivors by ethnicity. This study seeks to identify any inequities in burn outcomes by racial and ethnic groups. A retrospective chart review of an ABA Certified burn center at a large urban safety net hospital identified adult inpatient admissions from 2015 to 2019. A total of 1142 patients were categorized by primary ethnicity: 142 black or African American, 72 Asian, 479 Hispanic or Latino, 90 white, 215 other, and 144 patients whose race or ethnicity was unrecorded. Multivariable analyses evaluated the relationship between race and ethnicity and outcomes. Covariate confounders were controlled by adjustment of demographic, social, and prehospital clinical factors to isolate differences that might not be explained by other factors. After controlling for covariates, black patients had 29% longer hospital stays (P = .043). Hispanic patients were more likely to be discharged to home or to hospice care (P = .005). Hispanic ethnicity was associated with a 44% decrease in the odds of discharge to acute care, inpatient rehabilitation, or a ward outside the burn unit (P = .022). Black and Hispanic patients had a higher relative chance of having publicly assisted insurance, versus private insurance, than their white counterparts (P = .041, P = .011 respectively). The causes of these inequities are indeterminate. They may stem from socioeconomic status not entirely accounted for, ethnic differences in comorbidity related to stressors, or inequity in health care delivery.
A20 EARLY-LIFE FUNGAL COLONIZATION MEDIATES HOST METABOLISM AND WHITE ADIPOSE TISSUE INFLAMMATION IN MICE
Authors: Gutierrez M W , van Tilburg Bernardes E , Kalbfleisch K , Chleilat F , Arrieta M -C
Published: March 2023

Background

The gut microbiome has been linked to metabolic diseases including obesity, however the role of fungi (mycobiome) remains understudied. Recently, fungal taxa have been correlated with obesity in humans, though their causal contribution to obesity development, especially in the context of early life, is unknown. Obesity has been associated with metabolic inflammation, including alterations to the white adipose tissue (WAT) immune landscape, which has been shown to be influenced by the microbiome. Given the potent modulation of host immunity by the mycobiome, it is plausible that it also influences WAT inflammation.

Purpose

This research aimed to explore the role of early-life colonization by specific fungal taxa in obesity development and WAT inflammation.

Method

Gnotobiotic mice were colonized from birth with 12 mouse-derived bacteria (Oligo-MM12) alone or in combination with Candida albicans or Rhodotorula mucilaginosa. Mice were weaned onto a control or high-fat-high-sugar diet (HFHS) and evaluated at 12 weeks for metabolic and associated inflammatory outcomes.

Result(s)

C. albicans colonization reduced body weight in mice fed control diet, and induced resistance to weight and adiposity gain in mice fed HFHS. In contrast, R. mucilaginosa colonization was associated with increased adiposity in mice fed control diet, and elevated glycemia and LDL-cholesterol in mice fed HFHS. Fungal colonization had a broad impact on immune cells in white adipose tissue. C. albicans colonization was associated with increased adipose tissue inflammation with elevated Th1, Th17, ɣδT cells, ILC1, NK cells, cDC1 and neutrophils independently of diet. Additionally, vascular associated macrophages (VAM), CX3CR1+ macrophages and DCs, and ILC3 were elevated in mice fed control diet, while mice fed HFHS displayed elevated Th2, CD8+ T cells and eosinophils. In contrast, R. mucilaginosa colonized mice displayed decreased adipose tissue B cells and increased VAMs when fed control diet, and increased CX3CR1+ DCs when fed HFHS. Interestingly, C. albicans colonization was associated with increased relative expression of mPgc1⍺ in white adipose tissue of HFHS fed mice, indicative of enhanced mitochondrial biogenesis.

Conclusion(s)

Elevated adipose tissue inflammation with C. albicans colonization suggests dysfunction of energy storage and may explain the decreased body weight and resistance to diet-induced obesity, while the immune changes in R. mucilaginosa colonized mice may exacerbate obesity development. This work revealed that two common fungal colonizers have distinct and striking influences on obesity and metabolic inflammation and prompts for the inclusion of fungi in microbiome studies on host metabolism.

Please acknowledge all funding agencies by checking the applicable boxes below

CIHR, Other

Please indicate your source of funding

Cumming School of Medicine

Disclosure of Interest

None Declared
A27 DNA HYPOMETHYLATION INDUCED BY 5-AZA-CDR OR LOSS OF DNMT1 INHIBITS COLITIS-ASSOCIATED COLORECTAL CANCER
Authors: Larsen F , Good H , Shin A , Derouet M , Zhang L , Asfaha S
Published: March 2023

Background

Colorectal cancer is the second leading cause of cancer death in Canada. A major risk factor for the development of colorectal cancer is chronic inflammation leading to colitis-associated cancer (CAC). We previously described a CAC mouse model in which tumors arise from DCLK1+ tuft cells following loss of the tumor suppressor adenomatous polyposis coli (APC) and induction of colitis. Interestingly, both colitis and CAC display epigenetic changes that modulate gene expression. However, the impact of DNA methylation changes on colonic tumorigenesis is not known. Thus, we hypothesize that inhibition of DNA methylation in DCLK1+ tuft cells reduces colonic tumorigenesis.

Purpose

In this study, we aim to investigate the role of DNA methylation in CAC by inhibiting DNA methylation using genetic and pharmacologic means.

Method

Using a publicly available dataset (GSE75214) of gene expression data analyzed by microarray from colonic biopsies of patients with ulcerative colitis and Crohn’s Disease with active disease, we examined the expression of DNA methyltransferases (DNMTs). Expression of DNMTs in mice with colitis was additionally examined by RT-qPCR and global DNA methylation levels measured by 5-mC ELISA. In separate experiments, Dclk1-CreERT2/Apcf/f mice were crossed to DNMT1f/f mice to knock-out the DNA methyltransferase DNMT1 in DCLK1+ tuft cells. Dclk1/Apcf/f and Dclk1/Apcf/f/DNMT1f/f mice were then administered three doses of tamoxifen followed by 2.5% dextran sodium sulfate (DSS) for five days to induce colitis. Fourteen weeks later, we assessed colonic tumor number and size. In a separate cohort of Dclk1/Apcf/f mice, we induced colitis and treated the mice with six doses of the DNA de-methylating drug 5-AZA-2’-deoxycytidine (5-AZA) or vehicle, and assessed colonic tumor number. To examine DNA methylation changes, we then treated WT mice with 5-AZA and DSS and isolated intestinal epithelial cells. From the intestinal epithelial cell, we isolated DNA and ran the Infinium MouseMethylation BeadChip Array.

Result(s)

Patients with IBD were found to have increased expression of DNMT1 compared to healthy controls. Mice treated with DSS similarly had increased DNMT1 expression, as well as, global methylation levels compared to controls. Deletion of DNMT1 in DCLK1+ cells significantly inhibited the number and size of colonic tumors. Treatment of mice with 5-AZA decreased global and gene specific DNA methylation levels, and significantly reduced both the number of mice with tumors, and the average colonic tumor number and size per mouse.

Conclusion(s)

Our findings demonstrate that colitis in both patients and mice is associated with DNA methylation. Furthermore, DNA hypomethylation by 5-AZA treatment or loss of DNMT1 reduces CAC formation suggesting that altered DNA methylation plays a critical role in colonic tumorigenesis.

Disclosure of Interest

None Declared
A42 LIVE DONOR LIVER TRANSPLANTATION IN PRIMARY SCLEROSING CHOLANGITIS: AN INDICATOR OF AN ORGAN ALLOCATION SYSTEM NOT ADDRESSING PATIENT NEED
Authors: Zheng K , Onofrio F , Xu C , Chen S , Xu W , Vyas M , Bingham K , Patel K , Lilly L , Selzner N , Jaeckel E , Tsien C , Gulamhusein A , Hirschfield G M , Bhat M
Published: March 2023

Background

Liver transplantation is frequently lifesaving for people living with primary sclerosing cholangitis (PSC). However, patients are waitlisted for liver transplant (LT) according to the MELD-Na score, which may not accurately reflect the burden of living with PSC.

Purpose

We sought to describe and analyze the clinical trajectory for patients with PSC referred for LT, in a mixed deceased donor/live donor transplant programme.

Method

This was a retrospective cohort study from November 2012 to December 2019 including all patients with PSC referred for assessment at the University Health Network Liver Transplant Clinic. Patients who required multiorgan transplant or re-transplantation were excluded. Liver symptoms, hepatobiliary malignancy, MELD-Na progression, and death were abstracted from chart review. Competing Risk analysis was used for timing of LT, transplant type, and death.

Result(s)

Of 172 PSC patients assessed, 144 (84%) were listed, of whom 106/144 (74%) were transplanted. Mean age was 47.6 years and 66% were male. During follow-up through to 2021, 23/144 (16%) were removed from the waitlist due to infection, clinical deterioration, liver-related mortality or new cancer; 3 had clinical improvement. At the time of listing, 118/144 (81.95%) had a potential Living Donor (pLD) of whom 94 were transplanted: 64 live donor and 30 deceased donor. Patients with pLD had 79% lower mortality (p<0.001), and higher rates of transplantation (80% vs 46%). Exception points were granted to 13/172 (7.5%) patients.

Conclusion(s)

In a high-volume North American liver transplant centre, most patients with PSC assessed for transplant were listed and subsequently transplanted. However, this was a consequence of patients engaging in live donor transplantation. Our findings support the concern from patients with PSC that MELD-Na allocation does not adequately address their needs.

Please acknowledge all funding agencies by checking the applicable boxes below

CIHR, Other

Please indicate your source of funding;

This study was supported by PSC Partners Canada, Canadian Institutes of Health Research (CIHR), Toronto General and Western Hospital Foundation.

Disclosure of Interest

None Declared
A46 ENTEROBACTERIACEAE ENRICHMENT IN THE GUT MICROBIOME OF CRITICALLY ILL PATIENTS PROMOTES IMMUNE DYSFUNCTION AND SUSCEPTIBILITY TO NOSOCOMIAL INFECTIONS
Authors: Schlechte J M , Zucoloto A Z , Yu I -L , Doig C J , Dunbar M J , McCoy K D , McDonald B
Published: March 2023

NOT PUBLISHED AT AUTHOR’S REQUEST

Please acknowledge all funding agencies by checking the applicable boxes below

CIHR, Other

Please indicate your source of funding;

Government of Alberta

Disclosure of Interest

None Declared
A56 DEVELOPMENT OF A PROGNOSTIC SURVIVAL MODEL FOR PATIENTS DIAGNOSED WITH PANCREATIC CANCER IN ONTARIO
Authors: James P , Gayowsky A , Salim M , Seow H , Sutradhar R , Tanuseputro P , Coburn N , Hallet J , Hsu A , Mahar A , Webber C
Published: March 2023

Background

Pancreatic adenocarcinoma (PAC) is a deadly disease with an overall 5-year survival of less than 8%. The current literature on patient outcomes are limited by small samples sizes and patients enrolled in clinical trials. There are no prognostic tools for patients with pancreatic cancer.

Purpose

To develop a prognostic survival model for patients with pancreatic cancer

Method

All patients with a diagnosis of pancreatic cancer cancer from January 2007 to December 2020 were identified through the Ontario Cancer Registry. The primary outcome was survival. The cohort was used to develop a multivariable cox proportional hazards regression model with baseline characteristics under a backward stepwise variable selection process to predict the risk of mortality. Covariates included patient age, sex, tumour location, cancer stage, treatment types, distance to a cancer centre, hospitalizations, comorbidities, access to family physician, and symptoms as captured using the Edmonton Symptom Assessment System datasets.

Result(s)

There was a total of 17,450 pancreatic cancer patients in the cohort, 48% of which were female and the mean age was 72 years. 44% of patients presented with a tumor in the head of the pancreas. Among those with stage data (44%), 24% were stage IV at diagnosis. Mean survival was approximately 0.7 years. Approximately 60% were hospitalized in the 3 months prior to diagnosis. Almost all patients had a family doctor rostered (95%). In multivariate analysis, key predictors of survival assessed at the time of diagnosis were age, sex, tumour location in the pancreas, stage at diagnosis, pain, appetite functional status and treatment choice (all p<0.001). Using these variables, we created a prediction model that can estimate one-year probability of death with high discrimination (area under the curve = 0.82, c-statistic 0.76).

Conclusion(s)

Our model accurately predicts one-year pancreatic cancer survival risk using clinical symptom and performance status data. The model has the potential to be a useful prognostic tool that can be completed by patients and their caregivers in support of patient-centered care.

Please acknowledge all funding agencies by checking the applicable boxes below

CIHR

Disclosure of Interest

None Declared
A62 IDENTIFICATION OF SPECIFIC COLONIC DEEP MUSCLE LAYER MACROPHAGES SUBSETS BY THE CD64 (FCΓRI) MARKER
Authors: Nishihara Y , Zarwa S , Bai X , De Palma G , Collins S , Bercik P
Published: March 2023

Background

Although intestinal muscle layer macrophages have been suggested to play an important role in the colonic transit by interacting with the myenteric plexus neurons, they have not been fully characterized. CD64 (FcγRI) is one of the most generally used markers for intestinal macrophages, but several studies suggested existence of a subpopulation of macrophages that lack CD64. In addition, the muscle layer macrophage subsets currently identified are considered to be same in the small intestine and colon, although this has not been formally tested.

Purpose

In this study, we aim to identify and characterize the subsets of muscle layer macrophages by CD64 marker. We hypothesize that colon specific CD64-macrophages have a different role from CD64+ conventional macrophages.

Method

The muscle layers of small intestine (ileum) and colon were separated from SPF mice and cells from each muscle layer were analyzed by flow cytometry and fluorescent staining. The muscle layer macrophages were gated withCD45+, F4/80+, CD11b+ and Ly6c-, and analyzed with CD64 and MHCⅡmarkers by flow cytometry. In additional experiments, fluorescent staining with CD64 and F4/80 was assessed in whole-mount tissue of the separated muscle layer.

Result(s)

Within the macrophage population from the colon muscle layer, we found not only CD64+ cells, a conventional marker of macrophage, but also CD64- cell population (CD45+, F4/80+, CD11b+, Ly6c-). However, in the small intestine, this CD64- cell population was barely detectable. In addition, colonic CD64+ cells had mostly high expression of MHCⅡ marker, while CD64- cells had low expression of MHCⅡ. A similar pattern was found when we examined intestinal and colonic tissues by immunofluorescent staining.

Conclusion(s)

We identified a colon-specific CD64- subset of macrophage in muscle layer. Additional experiments are needed to characterize their immunomodulatory properties.

Please acknowledge all funding agencies by checking the applicable boxes below

None

Disclosure of Interest

None Declared

CLIINICAL PRACTICE
A94 EXPLORING THE SOCIOECONOMIC BURDEN OF PEDIATRIC INFLAMMATORY BOWEL DISEASE: A SURVEY OF FAMILIES AND PEDIATRIC PROVIDERS
Authors: Desai T , Yaskina M , Carroll M
Published: March 2023

Background

Rates of pediatric inflammatory bowel disease (IBD) have been increasing significantly over recent decades, contributing to the rising chronic disease burden across pediatrics. Currently, there is very limited literature exploring the financial burden on families of children with IBD. In fact, there is only one Canadian study in this area despite Canada having one of the highest rates of pediatric IBD in the world.

Purpose

The goal of this study is to better understand the socioeconomic burden of pediatric IBD at our institution and compare institutional practices across the country.

Method

The study took place at a large, tertiary care pediatric centre in Edmonton, Alberta, Canada between October 2022 and January 2023. Two separate electronic surveys were developed and distributed to all families of children with IBD at our institution (N= ~400) and pediatric IBD providers across the country (N= ~45) respectively. Surveys explored demographic information, financial impacts of IBD diagnosis and perceptions around pediatric IBD care and financial support.

Result(s)

Interim results (N=3) indicate dietary therapy costs, missed time off work and school and time off for IBD treatment as considerable burdens on families. Across the country, initial provider data (N=6) suggests significant variability in clinical practice, allied health support and financial support for families. There is overwhelming agreement among providers that the socioeconomic burdens on families is significant. Further data and regression analysis is ongoing.

Conclusion(s)

This is the first study in Canada to directly explore the socioeconomic burden on families of children with IBD. Results indicate good correlation between provider awareness and the increased financial burden on families but also considerable variation in practice across the country. Data suggest further research and advocacy is required to better support patients, however various quality improvement opportunities exist both locally and beyond.

Please acknowledge all funding agencies by checking the applicable boxes below

None

Disclosure of Interest

None Declared
A100 CAVERNOUS TRANSFORMATION OF THE PORTAL VEIN IN A PEDIATRIC PATIENT WITH GOLDENHAR SYNDROME: A CASE REPORT
Authors: Diaz F , Briglia F
Published: March 2023

Background

Goldenhar syndrome is a rare congenital condition thought to arise from the first and second branchial arches and typically asymmetrically affects the eyes, ears, and spine. Portal vein thrombosis/cavernous transformation is one of the main causes of portal hypertension in children. It is often associated with risk factors such as catheterization of the umbilical vein in the neonatal period, omphalitis, intra-abdominal infections in the neonatal period and prothrombotic conditions. This is a challenging clinical scenario as it leads to portal hypertension and variceal bleed with no chronic liver disease stigmata and liver function is essentially normal. While previous European literature from the early-2000s reported associated portal vein anomalies in Goldenhar syndrome, we are not aware of any recent and/or Canadian pediatric cases.

Purpose

We report a Canadian case of cavernous transformation of the portal vein with resulting gastrointestinal bleeding in a child with Goldenhar syndrome.

Method

Case report

Result(s)

A pediatric patient with a postnatal suspicion of Goldenhar syndrome, with confirmation by 6 months of age, presented with an acute 3-day history of melena, on the context of a recent viral illness and ibuprofen use. Laboratory testing showed a normocytic anemia (Hb 68) with a normal INR (1.1). The rest of the workup was unremarkable. There was no history of catheterization of the umbilical vein on the neonatal period nor other hematological complications. To assess for potential duplication cyst as differential diagnosis, a computerized tomography of the chest, abdomen and pelvis was ordered and revealed suspected cavernous transformation of the portal vein with suspected varices near the gastroesophageal junction and within the abdomen, and hepatomegaly with spleen size at the upper limit of normal. Octreotide was started after the CT results. A gastroscopy was done 24h after presentation and found portal hypertensive gastropathy and esophageal varices (2 Grade II and 1 Grade I). Sclerotherapy was performed. Post-gastroscopy ultrasound supported earlier radiographic findings of cavernous portal vein transformation and hepatosplenomegaly. Moreover, the ultrasound noted normal flow direction in the portal and hepatic veins. The patient has not re-presented for further episodes of gastrointestinal bleeding.

Conclusion(s)

This case report supports the previously reported association between Goldenhar syndrome and portal venous anomalies. Early consideration may lead to prompt diagnosis and management of the potentially life-threatening complications of portal hypertension in this population.

Please acknowledge all funding agencies by checking the applicable boxes below

None

Disclosure of Interest

None Declared
A111 CLINICAL AND PATHOLOGICAL OUTCOMES BETWEEN WATER EXCHANGE AND AIR INSUFFLATION USING NON-SEDATED EXTENDED FLEXIBLE SIGMOIDOSCOPY FOR AVERAGE RISK COLORECTAL CANCER SCREENING: PRELIMINARY FINDINGS FROM A RANDOMIZED CONTROL TRIAL
Authors: Aulakh A , Parker B , Sullivan B , Recsky M , Oliveira C , Richardson W , Hirschkorn P , Perini R , Bak A
Published: March 2023

Background

Colorectal cancer (CRC) is Canada's third most common cancer type and represents approximately 11% of all cancer deaths. While sedated colonoscopy or flexible sigmoidoscopy (FS) continues to be considered for CRC screening, these modalities have limitations and risks. Another unevaluated screening modality, known as an extended FS (EFS), attempts to capitalize on the benefits of a FS while minimizing the risks involved with a sedated colonoscopy. EFS provides a scope-based examination up to the splenic flexure and then attempts to examine beyond, often to the point of the caecum. Providing the option for EFS may produce improvements in the patient experience and performance, which may improve the feasibility of using scope-based screening more broadly in screening programs.

Purpose

To determine the extent non-sedated EFS using the water exchange method (WE) is associated with a complete colon examination compared to the traditional air insufflation (AI) method using CO2 in an average-risk screening population.

Method

This randomized control trial included 90 non-sedated participants, screened by trained general surgery and gastroenterology clinicians at Kelowna General Hospital, British Columbia, Canada, using two different scope insufflation techniques, WE and AI. The primary outcome of interest was the cecal intubation rates (CIR), while secondary outcomes included the adenoma detection rate (ADR) and reported pain scores. Other metrics, such as patient satisfaction rates, sessile serrated adenoma detection rates (SSADR), and serrated lesion detection rates (SLDR) were also recorded.

Result(s)

The demographic characteristics between the WE and AI groups were statistically similar, with the mean age of participants being 58 and 57, respectively. During the study period, four endoscopists performed the EFS. There were higher initial satisfaction rates in the WE group vs the AI (95% vs 77%, satisfaction of ≥ 9/10 p = 0.028). CIR and ADR were similar between the WE and AI group (CIR = 93% vs 91%, p = 0.710), (ADR = 40% vs 34%, p = 0.660). The SSADR and SLDR were also similar between the WE and AI group (SSADR = 21% vs 14%, p = 0.408), (SLDR = 42% vs 36%, p = 0.528).

Conclusion(s)

EFS without sedation using either technique exceeds quality benchmarks recommended for sedated screening colonoscopy while maintaining adequate patient safety and comfort. The WE method optimizes a patient's overall experience making a strategy of average risk colorectal cancer screening with non-sedated WE EFS feasible.

Please acknowledge all funding agencies by checking the applicable boxes below

CAG, Other

Please indicate your source of funding;

Kelowna General Hospital, Interior Health

Disclosure of Interest

None Declared