Canada Research Chair Research Articles

Factor XI/XIa Inhibitors: What We Now Know

The emerging class of agents targeting factor XI/XIa offers the paradigm-shifting possibility of ‘haemostasis-sparing anticoagulation’: protection from stroke and other thromboembolic events with a benign bleeding profile. With three investigational agents now into late-phase development, two presentations delivered at the European Society of Cardiology (ESC) Congress 2024, held in London, UK, have added to our knowledge of this innovative and diverse class. The first of these presentations shared the full data from the OCEANIC-AF Phase III trial, in which the small molecule factor XIa inhibitor asundexian was compared with the factor Xa inhibitor apixaban for stroke prevention in atrial fibrillation, and reviewed the probable reasons for the failure of this trial to meet its efficacy endpoint. The second presentation was a secondary analysis from the AZALEA-TIMI 71 Phase II trial, in which the safety of the monoclonal antibody factor XI inhibitor abelacimab was compared with that of the factor Xa inhibitor rivaroxaban in patients with atrial fibrillation undergoing invasive procedures. This article is based on a post-ESC interview with Jeffrey I. Weitz, Professor of Medicine and Biochemistry and Biomedical Sciences at McMaster University, Canada; Canada Research Chair (Tier 1) in Thrombosis and the Heart and Stroke Foundation; J.F. Mustard Chair in Cardiovascular Research; Executive Director of the Thrombosis and Atherosclerosis Research Institute (TaARI), in Hamilton, Canada; and Secretary General of the International Society on Thrombosis and Haemostasis (ISTH). It assesses the current status and future prospects of the factor XI/XIa inhibitor class in light of these recent developments.

The contribution of intimate partner violence to vertical HIV transmission: a modelling analysis of 46 African countries

Addressing gender inequities could be key to the elimination of vertical transmission of HIV. Women experiencing intimate partner violence (IPV) might be at an increased risk of vertical transmission due to their vulnerability to HIV acquisition and barriers to access to and retention in care. Sub-Saharan Africa, where IPV burden is among the highest globally, accounts for most new paediatric HIV infections. We aimed to examine the proportion of excess vertical transmission attributable to IPV in this region. In this modelling analysis, we created a probability tree model of vertical HIV transmission among women aged 15-49 years in 46 African countries. We estimated the proportion of vertical transmission attributable to past-year physical or sexual IPV, or both, as an age-standardised population attributable fraction (PAF) and as excess vertical transmission risk per 1000 births among women experiencing IPV. We incorporated perinatal and postnatal vertical transmission among women who acquired HIV before pregnancy, during pregnancy, and during breastfeeding. Fertility, HIV prevalence, HIV incidence, antiretroviral therapy (ART) uptake, and ART retention varied in the model by women's IPV experience. The model was parameterised using UNAIDS' 2023 Spectrum model data, WHO's Global Database on Violence Against Women, and the peer-reviewed literature. Uncertainty intervals (95% UI) were calculated through 1000 Monte Carlo simulations. Across 46 countries 13% (95% UI 6-21) of paediatric HIV infections in 2022 were attributed to IPV, corresponding to over 22 000 paediatric infections. The PAF ranged from 4% (2-7) in Niger to 28% (13-43) in Uganda. The PAF was highest among girls aged 15-19 years (20%, 8-33) and lowest among women aged 45-49 years (6%, 3-9). In southern Africa, where women's HIV prevalence is highest (23%), IPV led to 11 (5-20) additional infections per 1000 births among women affected by IPV. IPV might be responsible for one in eight paediatric HIV infections in sub-Saharan Africa. Ending IPV could accelerate vertical transmission elimination, especially among young women who bear the highest burden of violence. Canadian Institutes of Health Research, Canada Research Chair, and Fonds de recherche du Québec-Santé. For the French, Georgian and Spanish translations of the abstract see Supplementary Materials section.

A Model-Free Approach for Solving Choice-Based Competitive Facility Location Problems Using Simulation and Submodularity

This paper considers facility location problems in which a firm entering a market seeks to open facilities on a subset of candidate locations so as to maximize its expected market share, assuming that customers choose the available alternative that maximizes a random utility function. We introduce a deterministic equivalent reformulation of this stochastic problem as a maximum covering location problem with an exponential number of demand points, each of which is covered by a different set of candidate locations. Estimating the prevalence of these preference profiles through simulation generalizes a sample average approximation method from the literature and results in a maximum covering location problem of manageable size. To solve it, we develop a partial Benders reformulation in which the contribution to the objective of the least influential preference profiles is aggregated and bounded by submodular cuts. This set of profiles is selected by a knee detection method that seeks to identify the best tradeoff between the fraction of the demand that is retained in the master problem and the size of the model. We develop a theoretical analysis of our approach and show that the solution quality it provides for the original stochastic problem, its computational performance, and the automatic profile-retention strategy it exploits are directly connected to the entropy of the preference profiles in the population. Computational experiments on existing and new benchmark sets indicate that our approach dominates the classical sample average approximation method on large instances of the competitive facility location problem, can outperform the best heuristic method from the literature under the multinomial logit model, and achieves state-of-the-art results under the mixed multinomial logit model. We characterize a broader class of problems, which includes assortment optimization, to which the solving methodology and the analyses developed in this paper can be extended. History: Accepted by Andrea Lodi, Area Editor for Design & Analysis of Algorithms—Discrete. Funding: This research was supported by Fonds de Recherche du Québec-Nature et Technologies and Institut de Valorisation des Données through scholarships to R. Legault. E. Frejinger was partially supported by the Canada Research Chair program [Grant 950-232244]. Supplemental Material: The online appendices are available at https://doi.org/10.1287/ijoc.2023.0280 .

Hybrid immunity from severe acute respiratory syndrome coronavirus 2 infection and vaccination in Canadian adults: A cohort study.

Few national-level studies have evaluated the impact of 'hybrid' immunity (vaccination coupled with recovery from infection) from the Omicron variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). From May 2020 to December 2022, we conducted serial assessments (each of ~4000-9000 adults) examining SARS-CoV-2 antibodies within a mostly representative Canadian cohort drawn from a national online polling platform. Adults, most of whom were vaccinated, reported viral test-confirmed infections and mailed self-collected dried blood spots (DBSs) to a central lab. Samples underwent highly sensitive and specific antibody assays to spike and nucleocapsid protein antigens, the latter triggered only by infection. We estimated cumulative SARS-CoV-2 incidence prior to the Omicron period and during the BA.1/1.1 and BA.2/5 waves. We assessed changes in antibody levels and in age-specific active immunity levels. Spike levels were higher in infected than in uninfected adults, regardless of vaccination doses. Among adults vaccinated at least thrice and infected more than 6 months earlier, spike levels fell notably and continuously for the 9-month post-vaccination. In contrast, among adults infected within 6 months, spike levels declined gradually. Declines were similar by sex, age group, and ethnicity. Recent vaccination attenuated declines in spike levels from older infections. In a convenience sample, spike antibody and cellular responses were correlated. Near the end of 2022, about 35% of adults above age 60 had their last vaccine dose more than 6 months ago, and about 25% remained uninfected. The cumulative incidence of SARS-CoV-2 infection rose from 13% (95% confidence interval 11-14%) before omicron to 78% (76-80%) by December 2022, equating to 25 million infected adults cumulatively. However, the coronavirus disease 2019 (COVID-19) weekly death rate during the BA.2/5 waves was less than half of that during the BA.1/1.1 wave, implying a protective role for hybrid immunity. Strategies to maintain population-level hybrid immunity require up-to-date vaccination coverage, including among those recovering from infection. Population-based, self-collected DBSs are a practicable biological surveillance platform. Funding was provided by the COVID-19 Immunity Task Force, Canadian Institutes of Health Research, Pfizer Global Medical Grants, and St. Michael's Hospital Foundation. PJ and ACG are funded by the Canada Research Chairs Program.

The neurophysiological brain-fingerprint of Parkinson’s disease

Research in healthy young adults shows that characteristic patterns of brain activity define individual "brain-fingerprints" that are unique to each person. However, variability in these brain-fingerprints increases in individuals with neurological conditions, challenging the clinical relevance and potential impact of the approach. Our study shows that brain-fingerprints derived from neurophysiological brain activity are associated with pathophysiological and clinical traits of individual patients with Parkinson's disease (PD). We created brain-fingerprints from task-free brain activity recorded through magnetoencephalography in 79 PD patients and compared them with those from two independent samples of age-matched healthy controls (N=424 total). We decomposed brain activity into arrhythmic and rhythmic components, defining distinct brain-fingerprints for each type from recording durations of up to 4min and as short as 30s. The arrhythmic spectral components of cortical activity in patients with Parkinson's disease are more variable over short periods, challenging the definition of a reliable brain-fingerprint. However, by isolating the rhythmic components of cortical activity, we derived brain-fingerprints that distinguished between patients and healthy controls with about 90% accuracy. The most prominent cortical features of the resulting Parkinson's brain-fingerprint are mapped to polyrhythmic activity in unimodal sensorimotor regions. Leveraging these features, we also demonstrate that Parkinson's symptom laterality can be decoded directly from cortical neurophysiological activity. Furthermore, our study reveals that the cortical topography of the Parkinson's brain-fingerprint aligns with that of neurotransmitter systems affected by the disease's pathophysiology. The increased moment-to-moment variability of arrhythmic brain-fingerprints challenges patient differentiation and explains previously published results. We outline patient-specific rhythmic brain signaling features that provide insights into both the neurophysiological signature and symptom laterality of Parkinson's disease. Thus, the proposed definition of a rhythmic brain-fingerprint of Parkinson's disease may contribute to novel, refined approaches to patient stratification. Symmetrically, we discuss how rhythmic brain-fingerprints may contribute to the improved identification and testing of therapeutic neurostimulation targets. Data collection and sharing for this project was provided by the Quebec Parkinson Network (QPN), the Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer's Disease (PREVENT-AD; release 6.0) program, the Cambridge Centre for Aging Neuroscience (Cam-CAN), and the Open MEG Archives (OMEGA). The QPN is funded by a grant from Fonds de Recherche du Québec - Santé (FRQS). PREVENT-AD was launched in 2011 as a $13.5 million, 7-year public-private partnership using funds provided by McGill University, the FRQS, an unrestricted research grant from Pfizer Canada, the Levesque Foundation, the Douglas Hospital Research Centre and Foundation, the Government of Canada, and the Canada Fund for Innovation. The Brainstorm project is supported by funding to SB from the NIH (R01-EB026299-05). Further funding to SB for this study included a Discovery grant from the Natural Sciences and Engineering Research Council of Canada of Canada (436355-13), and the CIHR Canada research Chair in Neural Dynamics of Brain Systems (CRC-2017-00311).

Sex differences in houselessness, injection drug use, and mental health conditions among people newly diagnosed with HIV in Manitoba, Canada from 2018 to 2021: a retrospective cohort study

Manitoba saw the highest number of new HIV diagnoses in the province's history in 2021 and is the only Canadian province not meeting any of the previous UNAIDS 90-90-90 targets. Our goal was to describe sex differences and syndemic conditions within an incident HIV cohort in Manitoba, and the HIV treatment initiation and undetectable viral load outcomes. This was a retrospective cohort study of all people 18 years and older newly diagnosed with HIV in Manitoba, Canada between January 1st, 2018 and December 31st, 2021. Data was collected as follows: before HIV diagnosis: chlamydia, gonorrhoea, syphilis, and/or hepatitis C antibodies. At the time of HIV diagnosis: age, sex, gender, race/ethnicity, sexual orientation. During follow-up: CD4 counts, viral load, HIV treatment, hospitalizations, and number of visits to HIV care. Main exposures evaluated: methamphetamine use, injection drug use, houselessness, and mental health conditions. Outcomes: started antiretroviral treatment and achieved an undetectable viral load. A descriptive statistical analysis was used. There were 404 new HIV diagnoses in Manitoba from 2018 to 2021; 44.8% were female, 55.2% male; 76.% self-identified as Indigenous, 13.4% white/European, 4.7% African/black; 86.6% cis-gender; 60.9% heterosexual, 13.4% gay, bisexual and men who have sex with men, and 1.7% lesbian. Injection drug use was reported by 71.8% and 43.5% of females and males respectively. Methamphetamine was the most frequently injected drug (62.4%). Amongst females, 81.8% experienced at least one of the following: houselessness (43.1%), mental health comorbidities (46.4%), and injection drug use (71.8%). Only 64.9% of all individuals had an undetectable viral load (61.1% females and 67.9% males), 56.5% among people experiencing houselessness, 59% among young people (≤29 years), and 60.1% among people who inject drugs. People newly diagnosed with HIV in Manitoba are disproportionately experiencing houselessness, mental illness, and injection drug use (mostly methamphetamine). This pattern is more pronounced for female individuals. These findings highlight the need for syndemic and gender-specific approaches, simultaneously addressing social and health conditions, to treat HIV. This work was supported by the Canadian Institutes of Health Research, The Manitoba Medical Service Foundation, The James Farley Memorial Fund and the Canada Research Chairs Program.

Autoimmunities after COVID: An Interview with Cindy Patton

Cindy Patton is Professor Emeritus of Sociology and Anthropology at Simon Fraser University in Vancouver, Canada. An early AIDS activist in Boston, she holds a PhD in Communications from the University of Massachusetts, Amherst. After inaugurating her academic career at Temple University (Rhetoric and Community) and Emory University (Graduate Institute of the Liberal Arts), she accepted a Canada Research Chair in Community, Culture and Health at Simon Fraser (2003-15). In that capacity, she worked with more than two dozen groups to develop small community-driven projects related to HIV/AIDS, housing, social welfare, mental health, while achieving, culminating in the creation of the Community Health Online Digital Research Resource, a catalogued, open-access, full-text collection of the materials from those groups (www.chodarr.org). Her academic publications span the social study of medicine, especially AIDS; social movement theory; gender studies; and media studies. She is the coeditor of Queer Diasporas (2000) and a special issue of Cultural Studies on Pierre Bourdieu (2003). She is the author of such works as Globalizing AIDS (2002), Cinematic Identity: Anatomy of a Problem Film (1997), Fatal Advice: How Safe-Sex Education Went Wrong (1996), Inventing AIDS (1990), and LA Plays Itself/Boys in the Sand: A Queer Film Classic (2014). Taken collectively, Patton’s scholarship and activism has laid the foundation for insights in the health humanities, particularly AIDS studies, that consider the inextricable connections between epidemiology and ideology. Patton’s theorizations of stigma and discrimination patterns, her deconstruction of “truth” discourses subtending science, her critical re-evaluations of axioms associated with risk, safe sex, community, and knowledge production have been crucial interventions in the understanding of health and illness as cultural and discursive scripts. Among Patton’s most enduring contributions has been her theorization of how “African AIDS” was invented and circulated—that is, the notion of geographically bifurcated HIV pandemics split by the essential linkage between Africa and blackness generally with pathogenesis. Equally influential has been her elaboration of the insurgent queer research practices that fused with antiracist struggle to combat this split. In the interview below, Travis Alexander and Nishant Shahani engage Patton in a discussion on a range of topics—from (dis)continuities between the HIV/AIDS and COVID pandemics to the role of queer activism in forging epidemiological counter-publics and the geopolitics of medical bureaucracy.

COVID-19 hospitalization, mortality and premature mortality by a history of immigration in Ontario, Canada: a population-based cohort study

Immigrants in high-income countries experienced inequities in COVID-19 severe outcomes. We examined hospitalization and death throughout the pandemic, and change during the vaccine era, in Ontario, Canada. We conducted a population-based study using linked immigration and health data, following two cohorts for 20 months from January 1, 2020 (pre-vaccine) and September 1, 2021 (vaccine era). We used multivariable Poisson generalized estimating equation regression to estimate adjusted rate ratios (aRR) with 95% confidence intervals (CI), accounting for age, sex and co-morbidities. We calculated age-standardized years of life lost (ASYRs) rates by immigrant category. Of 11,692,387 community-dwelling adults in the pre-vaccine era cohort and 11,878,304 community-dwelling adults in the vaccine era cohort, 21.6% and 21.4% of adults in each era respectively were immigrants. Females accounted for 57.9% and 57.8% of sponsored family, and 68.4% and 67.6% of economic caregivers, in each era respectively. Compared to other Ontarians in the pre-vaccine era cohort, hospitalization rates were highest for refugees (aRR [95% CI] 3.41 [3.39-3.44]) and caregivers (3.13 [3.07-3.18]), followed by sponsored family and other economic immigrants. Compared to other Ontarians, aRRs were highest for immigrants from Central America (5.00 [4.92-5.09]), parts of South Asia (3.95 [3.89-4.01]) and Jamaica (3.56 [3.51-3.61]) with East Asians having lower aRRs. Mortality aRRs were similar to hospitalization aRRs. In the vaccine era, all aRRs were attenuated and most were similar to or lower than other Ontarians, with refugees and a few regions maintaining higher rates. In the pre-vaccine era ASYRs were higher for all immigrant groups. ASYRs dropped in the vaccine era with only refugees continuing to have higher rates. Immigrants, particularly refugees, experienced greater premature mortality. aRRs for most immigrant groups dropped substantially after high vaccine coverage was achieved. Vaccine outreach and improvements in the social determinants of health are needed. Canadian Institutes of Health Research, Canada Research Chairs Program.

Does ovariectomy exacerbate the cardiorespiratory and metabolic consequences of moderate intermittent hypoxia in female rats?

Intermittent hypoxia (IH) is a major consequence of sleep apnea (SA). IH causes respiratory dysfunction and contributes to numerous co-morbidities of SA including hypertension and obesity. The fact that menopause increases the prevalence of SA and related diseases in women indicates the importance of loss of ovarian function in the pathophysiology. Here, we determined whether experimental loss of ovarian function (ovariectomy; OVX) exacerbates the cardiorespiratory and metabolic consequences of IH. We explored neuroendocrine changes by assessing hormones known to be involved in energy balance, respiratory control, and stress responses (leptin, ACTH and corticosterone). We subjected adult (8 weeks) Sprague Dawley female rats to bilateral OVX (n = 13) or sham operation (n = 14). Rats were housed in pairs, and after two weeks of recovery, animals were exposed to room air (control; n = 16) or to a 7-day moderate IH protocol (n = 11). Within their cage, rats intermittently received a nitrogen-enriched hypoxic mixture, followed by room air for reoxygenation. Each bout of hypoxia lasted 30 seconds (nadir FIO2 = 0.10) and was followed by 5-minutes of reoxygenation (10 cycles/h, for 8hrs between 10h-18h). Apnea frequency, acute responses to hypoxia (FIO2 = 0.12; 120 sec) and hypercapnia (FICO2 = 0.05; 10 min) were measured by whole-body plethysmography. Blood pressure was assessed by the tail cuff method, and body weight was followed throughout the protocol. Plasma corticosterone and leptin were measured by multiplex assays. OVX increased apneic events, whereas IH reduced them; with the highest frequency observed in OVX females maintained in normoxia. Ventilatory responses (hypoxia and CO2) and blood pressure were not affected by IH or OVX. Over the course of the protocol, OVX increased weight gain whereas IH induced weight loss. OVX (but not IH) increased ACTH and corticosterone. IH (but not OVX) reduced leptin. Correlation matrix analysis showed that weight gain was the best predictor of apnea frequency (r = 0.759; p = 0.03). We conclude that loss of ovarian function and related weight gain have the greatest impact on respiratory function during sleep. Additionally, OVX-related activation of the stress pathways may contribute to this process. These results fail to demonstrate a role for OVX in exacerbating the cardiorespiratory and metabolic consequences of IH. Lack of weight gain following IH likely contributes to this finding. This study is supported by operating grants from the Canadian Institutes of Health Research (RK and VJ). NJM is supported by a Sentinel North Partnered Research Chair in Sleep Pharmacometabolism and a Canada Research Chair in Metabolism and Sleep Neurobiology. MG received a doctoral scholarship from the Fonds de Recherche du Québec — Santé (FRQS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A Better Estimate of Internally Generated Intangible Capital

Internally developed intangibles are not included in reported assets under U.S. generally accepted accounting principles. The omission of this increasingly important class of assets reduces the usefulness and relevance of financial statement analysis, conducted with reported values of equity and assets. Recent studies overcome this deficiency by capitalizing research and development (R&D) expenses to estimate the value of knowledge capital and by capitalizing selling, general, and administrative (SG&A) expenses to estimate the value of organization capital. Those two estimates are then added to reported values for financial statement analysis. For convenience, many studies rely on two rules of thumb and assume them to be equally applicable in all instances: (1) 30% of SG&A and 100% of R&D expenses are investments, and (2) the useful life of SG&A and R&D investments is three and five years, respectively. We propose a more flexible approach by estimating the capitalization and amortization parameters on an industry–year–specific basis. Our modified values of total assets and equity, inclusive of the value of capitalized intangibles, exhibit greater association with future returns and investments compared with as-reported values and values estimated with uniform rules of thumb. We provide a better estimate of intangible capital for the consumers of financial statements. This paper was accepted by Ranjani Krishnan, accounting. Funding: A. Srivastava and R. Zhao acknowledge financial support from the Social Sciences and Humanities Research Council of Canada. A. Srivastava acknowledges financial support from the Canada Research Chairs Program of the Government of Canada. A. Iqbal acknowledges financial support from the Canadian Securities Institute Research Foundation and Chartered Professional Accountants (Alberta) Education Foundation. Supplemental Material: The data files are available at https://doi.org/10.1287/mnsc.2022.01703 .

Crowdkeeping in Last-Mile Delivery

In order to improve the efficiency of the last-mile delivery system when customers are possibly absent for deliveries, we propose the idea of employing the crowd to work as keepers and to provide storage services for their neighbors. Crowd keepers have extra flexibility, more availability, and lower costs than fixed storage options such as automated lockers, and this leads to a more efficient and a more profitable system for last-mile deliveries. We present a bilevel program that jointly determines the assignment, routing, and pricing decisions while considering customer preferences, keeper behaviors, and platform operations. We develop an equivalent single-level program, a mixed-integer linear program with subtour elimination constraints, that can be solved to optimality using a row generation algorithm. To improve the efficiency of the solution procedure, we further derive exact best response sets for both customers and keepers, and approximate optimal travel times using linear regression. We present a numerical study using a real-world data set from Amazon. The fixed-storage and no-storage systems are used as benchmarks to assess the performance of the crowdkeeping system. The results show that the crowdkeeping delivery system has the potential to generate higher profits because of its ability to consolidate deliveries and to eliminate failed deliveries. Funding: Funding provided by the Natural Sciences and Engineering Research Council of Canada [Grants 2022-04979 and 2022-05261], the Canada Research Chair program [Grant CRC-2018-00105], and the China Scholarship Council [Grant 202006190051] is gratefully acknowledged. Supplemental Material: The online appendix is available at https://doi.org/10.1287/trsc.2022.0323 .

“Hope, but also Danger”: A Conversation with Larissa Lai on not Going Back and the ‘Re’ of Recuperation

Larissa Lai is a poet, fiction writer and academic who holds a Canada Research Chair at the University of Calgary, where she directs The Insurgent Architects’ House for Creative Writing. She has authored nine books. Her most recent works are The Tiger Flu, Iron Goddess of Mercy and The Lost Century. She is a recipient of the Jim Duggins Novelist’s Prize, the Lambda Literary Award, and the Otherwise Honor Book. She was recently awarded a Maria Zambrano Fellowship at the University of Huelva in Spain and has been actively engaged in cultural organizing, experimental poetry and speculative fiction communities since the 1980s. Her work often explores themes of identity intertwined with elements of science fiction and the fantastical imagination. This interview took place in Parque García Sanabria on 24th March 2023 during a visit of Larissa Lai to the University of La Laguna. This interview focuses on the convergence of history, myth and affects, providing a reflection on the circularity of time and the promise of happiness.

Feature-Based Inventory Control with Censored Demand

Problem definition: We study stochastic periodic-review inventory systems with lost sales, where the decision maker has no access to the true demand distribution a priori and can only observe historical sales data (referred to as censored demand) and feature information about the demand. In an inventory system, excess demand is unobservable because of inventory constraints, and sales data alone cannot fully recover the true demand. Meanwhile, feature information about the demand is abundant to assist inventory decisions. We incorporate features for inventory systems with censored demand. Methodology/results: We propose two feature-based inventory algorithms called the feature-based adaptive inventory algorithm and the dynamic shrinkage algorithm. Both algorithms are based on the stochastic gradient descent method. We measure the performance of the proposed algorithms through the average expected regret in finite periods: that is, the difference between the cost of our algorithms and that of a clairvoyant optimal policy with access to information, which is acting optimally. We show that the average expected cost incurred under both algorithms converges to the clairvoyant optimal cost at the rate of [Formula: see text] for the perishable inventory case and [Formula: see text] for the nonperishable inventory case. The feature-based adaptive inventory algorithm results in high volatility in the stochastic gradients, which hampers the initial performance of regret. The dynamic shrinkage algorithm uses a shrinkage parameter to adjust the gradients, which significantly improves the initial performance. Managerial implications: This paper considers feature information. The idea of dynamic shrinkage for the stochastic gradient descent method builds on a fundamental insight known as the bias-variance trade-off. Our research shows the importance of incorporating the bias-variance in a dynamic environment for inventory systems with feature information. Funding: W. T. Huh acknowledges support from the NSERC Discovery Grants [Grant RGPIN 2020-04213] and the Canada Research Chair Program. The work of Y. Rong was supported by the National Natural Science Foundation of China [Grants 72025201, 72331006, and 72221001]. Supplemental Material: The online appendix is available at https://doi.org/10.1287/msom.2021.0135 .

A10 PROLINE METABOLISM AFFECTS CANCER STEM CELLS IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background Esophageal squamous cell carcinoma (ESCC) is highly deadly with a 5-year survival rate of only 16%, partly due to treatment resistance. Resistance is associated, among others, with the presence of cancer stem cells (CSC). Previous work in the laboratory has shown that prolonged exposure to anticancer treatments such as radiation and/or 5-FU leads to increased number of CSCs. Interestingly, disruption of amino acid metabolism, especially decreased proline levels, has been observed in treated cells. Proline is a non-essential amino acid that can either be uptake from the environment or synthesized from glutamate or ornithine. However, its role in cancer cells remains poorly understood and controversial. Aims Therefore, my project aims at determining the role of proline metabolism in CSC abundance and tumoral properties in ESCC. Methods Using ESCC cell lines, TE11 and TE15, we stimulated proline metabolism by adding proline to the media or inhibited its catabolism using L-THFA. L-THFA forces proline accumulation in the cell. We then conducted flow cytometry to quantify CSC proportion, proliferation assay, spheroid formation assay and spheroids included in collagen for migration and invasion assay. Results First, the stimulation of proline metabolism decreased the proportion of CSCs in flow cytometry. These results align with our initial observations, where CSC-enriched cells exhibited reduced proline levels. Second, the inhibition of proline catabolism by L-THFA had the opposite effect, namely an increase in the proportion of CSC. Interestingly, these changes in the proportion of CSCs induced by proline or L-THFA translated into changes in clonogenic potential, a capacity typically associated with stem cells. Indeed, limiting dilution spheroids formation assays showed that proline decreased while L-THFA increased the number of formed spheroids. Since spheroids formation is linked to the presence of CSC, this provides new evidence of the impact of proline metabolism on CSC characteristics. Finally, L-THFA treatments drastically increased migratory and invasive abilities in 3D spheroid models compared to untreated or proline-treated conditions. Conclusions In conclusion, our results suggest that proline metabolism is implicated in the enrichment of cancer stem cells as well as in their functions. Funding Agencies CAG, CIHRinnovation.ca ; Centre de recherche CHUS ; FMSS ; Canada Research Chairs

A158 DEVELOPMENT OF MODELS TO SUDY THE INTERACTION BETWEEN CANCER STEM CELLS AND THE MICROENVIRONMENT IN COLON CANCER

Abstract Background Colon cancer affects 1 in 15 people and is the 3rd deadliest cancer worldwide. The standard of care consists of surgical resection combined with 5-fluorouracil (5-FU) chemotherapy. However, relapses remain frequent due to a partial or complete loss of sensitivity to treatment, also known as chemoresistance. Over the last decades, studies have revealed the importance of intratumoral heterogeneity in this phenomenon, and in particular of two components: cancer stem cells (CSCs) and the microenvironment. CSCs are cells with a high capacity of self-renewal, potency (ability to give rise to different cell types) and resistance to anti-cancer treatments. The microenvironment, for its part, comprises all the components surrounding tumour cells, such as cancer-associated fibroblasts (CAFs). Although their respective importance in resistance has been well studied, it is important to better understand their respective modulation during resistance as well as their interactions. Aims Identify the specific changes occurring in CSCs and CAFs, as well as their interactions, during the induction of 5-FU resistance in colon cancer. Methods To achieve this goal, we are establishing 5-FU resistant models using organoid lines from colon cancer patients. First, we validated that parental organoids maintain their expected cellular heterogeneity by immunofluorescence. We also confirmed that our parental organoids are sensitive to 5-FU by measuring the survival through a WST1 assay. Results Indeed, we showed the presence of CSCs (ALDH1+) and proliferative cells (Ki67+), among others. With a baseline IC50 of 5µM, we concluded that they can be used to generate a 5-FU resistant line. In addition, our initial findings suggest that the conditioned media of CAF cultures decreases the sensitivity of parental organoids to 5-FU, emphasizing the need to study deeper the interaction between these two tumor components Conclusions In summary, our preliminary results suggest that the interaction between tumor cells and CAFs modulates the response to chemotherapy. We are currently exploring whether CSCs are particularly involved in this phenomenon. In addition, we are developing patient-derived xenograft models (PDX) sensitive or resistant to 5-FU in order to study in vivo the interactions between CAFs and CSCs. At the end, this project will provide a better understanding of the changes required for resistance, paving the way for new targeted therapies Funding Agencies Canada foundation for innovation, Canada Research Chairs

A261 INVESTIGATING THE RELATIONSHIP BETWEEN AIR POLLUTION AND BIOMARKERS OF CROHN’S DISEASE IN CANADA

Abstract Background The cause of Crohn's disease (CD) remains unclear. Studies suggest a potential connection between CD and air pollution, with a higher occurrence of CD found in areas with higher pollution levels. Aims Our study sought to explore this potential connection by investigating the relationship between components of air pollution and biomarkers indicative of CD risk. Methods In total, 2,256 healthy first-degree relatives of patients with CD were recruited as part of the CCC-GEM Project. We assessed baseline samples of gut permeability using the urinary fractional excretion ratio of lactulose-to-mannitol (LMR), subclinical inflammation via fecal calprotectin (FCP), and stool microbiome using 16S-rRNA sequencing. Air pollutant (n=8) concentrations were obtained from the National Air Pollution Surveillance Database. We used postal code to estimate air pollutant exposure via inverse distance weighting, averaging data for one (pollutant1-month), three (pollutant3-months), and twelve months (pollutant12-months) prior to recruitment. We used generalized estimating equation models to find associations between pollutant exposure and LMR, FCP, and microbiome composition, adjusting for age, sex, air pollutant seasonality, familial income, and familial relationships. Significance was set at pampersand:003C0.05, and false discovery rate (q) correction was applied to microbiome analysis. Results We observed a negative association between particulate matter (PMµg/m3), PM101-month, and PM103-months and LMR (β=-0.06[-0.09, -0.01], p=6.0×10-3 and β=-0.05[-0.07, -0.01], p=7.6×10-4), and a positive association between PM103-months and FCP (β=0.05[0.001, 0.10], p=0.04). 12-month pollutant exposure was associated with seven microbial taxa in a logit model. Notably, Carbon monoxide (CO)12-months was associated with Oscillospiraceae UCG_003 (β=3.49[1.53, 5.46], q=0.03). PM2512-months was associated with Marvinbryantia (β=0.12[0.06, 0.18], q=0.02). PM1012-months was associated with Moryella (β=0.07[0.03, 0.10], q=0.02). Nitrogen dioxide (NO)12-months was associated with Coprobacter and Ruminococcaceae UBA1819 (β=0.05[0.02, 0.07], q=0.03 and β=0.05[0.02, 0.08], q=0.04). NOX12-months was also associated with Ruminococcaceae_UBA1819 as well as Intestinimonas (β=0.03[0.01, 0.04], q=0.04 and β=0.03[0.01, 0.04], q=0.02). Conclusions Air pollutant exposure was associated with biomarkers of gut inflammation, barrier function, and microbiome composition. A shorter exposure (1/3 months) primarily affected FCP and LMR, while longer-term exposure (12 months) exerted a discernible impact on the microbiome. These findings suggest that exposure to air pollution may modulate the gut barrier function, inflammation, and the gut microbiome, biomarkers that are associated with the development of CD. Funding Agencies Crohn’s and Colitis Canada Genetics Environment Microbial (CCC-GEM) III, Leona M. and Harry B. Helmsley Charitable Trust, Dr. Croitoru is the recipient of the Canada Research Chair in Inflammatory Bowel Diseases

Will psychedelic research and the ‘psychedelic renaissance’ create another generational divide?

Will psychedelic research and the ‘psychedelic renaissance’ create another generational divide? Erika Dyck, Canada Research Chair in History of Health & Social Justice at the University of Saskatchewan, discusses changing attitudes to psychedelics and the challenges in forming a strong evidence base from available psychedelic research. As psychedelics re-emerge in the 21st century, their storied past continues to haunt their future. Tales have circulated of their entanglement in unethical medical research and implication in violent behaviours, including suicides and homicides. Psychedelics have even been blamed for turning an entire generation of young people to question authority and the values of a post-World War culture. Are psychedelics really to blame for these social divisions? I do not think that psychedelics are the problem, but they may be a symptom.

A Column Generation Scheme for Distributionally Robust Multi-Item Newsvendor Problems

This paper studies a distributionally robust multi-item newsvendor problem, where the demand distribution is unknown but specified with a general event-wise ambiguity set. Using the event-wise affine decision rules, we can obtain a conservative approximation formulation of the problem, which can typically be further reformulated as a linear program. In order to efficiently solve the resulting large-scale linear program, we develop a column generation-based decomposition scheme and speed up the computational efficiency by exploiting a special column selection strategy and stopping early based on a Karush-Kuhn-Tucker condition test. Focusing on the Wasserstein ambiguity set and the event-wise mean absolute deviation set, a computational study demonstrates both the computational efficiency of the proposed algorithm, which significantly outperforms a commercial solver and a Benders decomposition method, and the out-of-sample superiority of distributionally robust solutions relative to their sample average approximation counterparts. History: Accepted by Nicola Secomandi, Area Editor for Stochastic Models & Reinforcement Learning. Funding: This work was supported by the Natural Sciences and Engineering Research Council of Canada [492997-2016, RGPIN-2016-05208], the National Natural Science Foundation of China [71972012], Alliance de recherche numérique du Canada, and Canada Research Chairs [CRC-2018-00105]. It was also supported by Groupe d’études et de recherche en analyse des décisions (GERAD). Finally, this research was enabled in part by support provided by Digital Research Alliance of Canada ( https://alliancecan.ca/en ). Supplemental Material: The software that supports the findings of this study is available within the paper and its supplemental information ( https://pubsonline.informs.org/doi/suppl/10.1287/ijoc.2022.0010 ) as well as from the IJOC GitHub software repository ( https://github.com/INFORMSJoC/2022.0010 ). The complete IJOC Software and Data Repository is available at https://informsjoc.github.io/ .

MULTILINEAGE DIFFERENTIATION OF C2C12 CELLS AND MONOCYTES IN VITRO WITHIN A 6-BROMOINDIRUBIN-3’-OXIME-INCORPORATED CHITOSAN-BASED SCAFFOLD FOR ENHANCED BONE REGENERATION

Critical size bone defects deriving from large bone loss are an unmet clinical challenge1. To account for disadvantages with clinical treatments, researchers focus on designing biological substitutes, which mimic endogenous healing through osteogenic differentiation promotion. Some studies have however suggested that this notion fails to consider the full complexity of native bone with respect to the interplay between osteoclast and osteoblasts, thus leading to the regeneration of less functional tissue2. The objective of this research is to assess the ability of our laboratory's previously developed 6-Bromoindirubin-3’-Oxime (BIO) incorporated guanosine diphosphate crosslinked chitosan scaffold in promoting multilineage differentiation of myoblastic C2C12 cells and monocytes into osteoblasts and osteoclasts1, 3, 4. BIO addition has been previously demonstrated to promote osteogenic differentiation in cell cultures5, but implementation of a co-culture model here is expected to encourage crosstalk thus further supporting differentiation, as well as the secretion of regulatory molecules and cytokines2.Biocompatibility testing of both cell types is performed using AlamarBlue for metabolic activity, and nucleic acid staining for distribution. Osteoblastic differentiation is assessed through quantification of ALP and osteopontin secretion, as well as osteocalcin and mineralization staining. Differentiation into osteoclasts is verified using SEM and TEM, qPCR, and TRAP staining.Cellular viability of C2C12 cells and monocytes was maintained when cultured separately in scaffolds with and without BIO for 21 days. Both scaffold variations showed a characteristic increase in ALP secretion from day 1 to 7, indicating early differentiation but BIO-incorporated sponges yielded higher values compared to controls. SEM and TEM imaging confirmed initial aggregation and fusion of monocytes on the scaffold's surface, but BIO addition appeared to result in smoother cell surfaces indicating a change in morphology. Late-stage differentiation assessment and co-culture work in the scaffold are ongoing, but initial results show promise in the material's ability to support multilineage differentiation.Acknowledgements: The authors would like to acknowledge the financial support of the Collaborative Health Research Program (CHRP) through CIHR and NSERC, as well as Canada Research Chair – Tier 1 in Regenerative Medicine and Nanomedicine, and the FRQ-S.

MESENCHYMAL STEM CELL-DERIVED EXTRACELLULAR VESICLE MIMETICS AS OSTEOINDUCTIVE MEDIATORS: AN IN VITRO INVESTIGATION

Mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) have great promise in the field of orthopaedic nanomedicine due to their regenerative, as well as immunomodulatory and anti-inflammatory properties. Researchers are interested in harnessing these biologically sourced nanovesicles as powerful therapeutic tools with intrinsic bioactivity to help treat various orthopaedic diseases and defects. Recently, a new class of EV mimetics has emerged known as nanoghosts (NGs). These vesicles are derived from the plasma membrane of ghost cells, thus inheriting the surface functionalities and characteristics of the parent cell while at the same time allowing for a more standardized and reproducible production and significantly greater yield when compared to EVs. This study aims to investigate and compare the osteoinductive potential of MSC-EVs and MSC-NGs in vitro as novel tools in the field of bone tissue engineering and nanomedicine. To carry out this investigation, MSC-EVs were isolated from serum-free MSC conditioned media through differential ultracentrifugation. The remaining cells were treated with hypotonic buffer to produce MSC-ghosts that were then homogenized and serially extruded through 400 and 200 nm polycarbonate membranes to form the MSC-NGs. The concentration, size distribution, zeta potential, and protein content of the isolated nanoparticles were assessed. Afterwards, MSCs were treated with either MSC-EVs or MSC-NGs under osteogenic conditions, and their differentiation was assessed through secreted ALP assay, qPCR, and Alizarin Red mineralization staining. Isolation of MSC-EVs and MSC-NGs was successful, with relatively similar mean diameter size and colloidal stability. No effect on MSC viability and metabolic activity was observed with either treatment. Both MSC-EV and MSC-NG groups had enhanced osteogenic outcomes compared to the control; however, a trend was observed that suggests MSC-NGs as better osteoinductive mediators compared to MSC-EVs.Acknowledgements: The authors would like to acknowledge Canada Research Chair – Tier 1 in Regenerative Medicine and Nanomedicine, CHRP, and McGill's Faculty of Dental Medicine and Oral Health Sciences for their financial support.