Open Access Publications
Permanent URI for this collection
Browse
Recent Submissions
Item Open Access A combination of calcium hydroxide and sodium hydrosulphate controls pathogens causing environmental mastitis in recycled manure solids(2024-10-08) Praveen, Selladurai; Kataktalware, Mukund A.; Meena, Priyanka; Lavanya, Maharajan; Patoliya, Priyanka; Jeyakumar, Sakthivel; Ravindra, Menon R.; Chauhan, Mamta; Ramesha, K. P.; Devi, G. L.; Kastelic, John P.; Dhali, ArindamAbstract Recycled manure solids (RMS) are dried cow dung processed using a manure dewatering machine and subsequently sun-dried to ~ 20% moisture. Benefits of RMS include abundant availability, low cost, and eco-friendliness, but its use as bedding material for cows is hindered by a moisture content that promotes microbial growth. This in vitro study evaluated impacts of calcium hydroxide (CH; 5 and 7.5%) and sodium hydrosulphate (SHS; 6 and 8%), independently and in combinations, at various depths of RMS, on physicochemical and microbial properties. The CH-treated groups had increased pH and reduced moisture on Day 0. Incorporating 7.5% CH + 6% SHS at 15–20 cm, and 7.5% CH + 8% SHS at all depths, effectively suppressed Escherichia coli and Klebsiella spp. Furthermore, a combination of 7.5% CH + 8% SHS at 20 cm inhibited coliform growth, whereas 7.5% CH with 6% SHS inhibited Streptococcus spp. In conclusion, a combination of 7.5% CH with either 6 or 8% SHS at a depth of 15 cm in RMS was particularly effective in controlling environmental mastitis-causing pathogens, specifically E. coli and Klebsiella spp. Graphical AbstractItem Open Access Spatiotemporal modeling reveals high-resolution invasion states in glioblastoma(2024-10-10) Manoharan, Varsha T.; Abdelkareem, Aly; Gill, Gurveer; Brown, Samuel; Gillmor, Aaron; Hall, Courtney; Seo, Heewon; Narta, Kiran; Grewal, Sean; Dang, Ngoc H.; Ahn, Bo Y.; Osz, Kata; Lun, Xueqing; Mah, Laura; Zemp, Franz; Mahoney, Douglas; Senger, Donna L.; Chan, Jennifer A.; Morrissy, A. S.Abstract Background Diffuse invasion of glioblastoma cells through normal brain tissue is a key contributor to tumor aggressiveness, resistance to conventional therapies, and dismal prognosis in patients. A deeper understanding of how components of the tumor microenvironment (TME) contribute to overall tumor organization and to programs of invasion may reveal opportunities for improved therapeutic strategies. Results Towards this goal, we apply a novel computational workflow to a spatiotemporally profiled GBM xenograft cohort, leveraging the ability to distinguish human tumor from mouse TME to overcome previous limitations in the analysis of diffuse invasion. Our analytic approach, based on unsupervised deconvolution, performs reference-free discovery of cell types and cell activities within the complete GBM ecosystem. We present a comprehensive catalogue of 15 tumor cell programs set within the spatiotemporal context of 90 mouse brain and TME cell types, cell activities, and anatomic structures. Distinct tumor programs related to invasion align with routes of perivascular, white matter, and parenchymal invasion. Furthermore, sub-modules of genes serving as program network hubs are highly prognostic in GBM patients. Conclusion The compendium of programs presented here provides a basis for rational targeting of tumor and/or TME components. We anticipate that our approach will facilitate an ecosystem-level understanding of the immediate and long-term consequences of such perturbations, including the identification of compensatory programs that will inform improved combinatorial therapies.Item Open Access A randomized controlled trial of a “Small Changes” behavioral weight loss treatment delivered in cardiac rehabilitation for patients with atrial fibrillation and obesity: study protocol for the BE-WEL in CR-AF study(2024-10-11) Williamson, Tamara M.; Rouleau, Codie R.; Wilton, Stephen B.; Valdarchi, A. B.; Moran, Chelsea; Patel, Stuti; Lutes, Lesley; Aggarwal, Sandeep G.; Arena, Ross; Campbell, Tavis S.Abstract Background Atrial fibrillation (AF) represents a global epidemic. Although international AF practice guidelines indicate weight loss for patients with AF and comorbid obesity (BMI ≥ 30 kg/m2) to alleviate symptom burden and improve prognosis, few cardiac rehabilitation (CR) programs include targeted weight loss treatment. Aims This RCT protocol will evaluate the efficacy of a “Small Changes” behavioral weight loss treatment (BWLT) to produce clinically relevant (≥ 10%) weight loss among patients with AF and obesity undergoing CR, relative to CR alone. Secondary aims are to establish efficacy of CR + BWLT for improving AF symptoms, AF risk factors, and health-related quality of life. Methods Adults (18 +) with AF and obesity will be recruited and randomized to receive CR + BWLT (intervention) or CR-only (control). Controls will receive CR consisting of supervised exercise and risk factor self-management for 12 weeks. The intervention group will receive CR plus BWLT (12 weekly, group-based virtual sessions, followed by 12 weeks of follow-up support). Weight and AF-risk factors will be assessed at pre-randomization, 12 weeks, 24 weeks, and 52 weeks. AF burden will be assessed using 30-s ECGs recorded bidaily and with AF symptoms. The primary endpoint of weight loss will be calculated from baseline to 52 weeks as a percentage of starting weight. Intention-to-treat analyses will compare the proportion in each group achieving ≥ 10% weight loss. Assuming success rates of 5% and 30% among controls and intervention groups, respectively, and a 30% loss to follow-up, 120 patients (60 per group) will provide 80% power to detect a difference using a two-sided independent test of proportions (alpha = 5%). Impact This clinical trial will be the first to demonstrate that adding BWLT to CR promotes clinically meaningful weight loss among patients with AF and comorbid obesity. Findings will inform design and execution of a large efficacy trial of long-term (e.g., 5-year) clinical endpoints (e.g., AF severity, mortality). Implementing weight control interventions designed to target the AF substrate in CR could dramatically reduce morbidity and enhance quality of life among patients living with AF in Canada. Trial registration ClinicalTrials.gov registration number: NCT05600829. Registered October 31, 2022.Item Open Access Use of implementation mapping to develop a multifaceted implementation strategy for an electronic prospective surveillance model for cancer rehabilitation(2024-10-01) Lopez, Christian J.; Neil-Sztramko, Sarah E.; Tanyoas, Mounir; Campbell, Kristin L.; Bender, Jackie L.; Strudwick, Gillian; Langelier, David M.; Reiman, Tony; Greenland, Jonathan; Jones, Jennifer M.Abstract Background Electronic Prospective Surveillance Models (ePSMs) remotely monitor the rehabilitation needs of people with cancer via patient-reported outcomes at pre-defined time points during cancer care and deliver support, including links to self-management education and community programs, and recommendations for further clinical screening and rehabilitation referrals. Previous guidance on implementing ePSMs lacks sufficient detail on approaches to select implementation strategies for these systems. The purpose of this article is to describe how we developed an implementation plan for REACH, an ePSM system designed for breast, colorectal, lymphoma, and head and neck cancers. Methods Implementation Mapping guided the process of developing the implementation plan. We integrated findings from a scoping review and qualitative study our team conducted to identify determinants to implementation, implementation actors and actions, and relevant outcomes. Determinants were categorized using the Consolidated Framework for Implementation Research (CFIR), and the implementation outcomes taxonomy guided the identification of outcomes. Next, determinants were mapped to the Expert Recommendations for Implementing Change (ERIC) taxonomy of strategies using the CFIR-ERIC Matching Tool. The list of strategies produced was refined through discussion amongst our team and feedback from knowledge users considering each strategy’s feasibility and importance rating via the Go-Zone plot, feasibility and applicability to the clinical contexts, and use among other ePSMs reported in our scoping review. Results Of the 39 CFIR constructs, 22 were identified as relevant determinants. Clinic managers, information technology teams, and healthcare providers with key roles in patient education were identified as important actors. The CFIR-ERIC Matching Tool resulted in 50 strategies with Level 1 endorsement and 13 strategies with Level 2 endorsement. The final list of strategies included 1) purposefully re-examine the implementation, 2) tailor strategies, 3) change record systems, 4) conduct educational meetings, 5) distribute educational materials, 6) intervene with patients to enhance uptake and adherence, 7) centralize technical assistance, and 8) use advisory boards and workgroups. Conclusion We present a generalizable method that incorporates steps from Implementation Mapping, engages various knowledge users, and leverages implementation science frameworks to facilitate the development of an implementation strategy. An evaluation of implementation success using the implementation outcomes framework is underway.Item Open Access Mobilizing strategic inflection points for sustainment of an effective intervention in an integrated learning health system: an interpretive description(2024-09-30) Benzies, Karen M.; Zanoni, Pilar; McNeil, Deborah A.Abstract Background Innovative models of care have the potential to improve the sustainability of health systems by improving patient and provider experiences and population outcomes while simultaneously reducing costs. Yet, it is challenging to recognize the distinctive points during research and quality improvement processes that contribute to sustainment of effective interventions. The business concept of an inflection point—the position on the curve of a trajectory where the progress in implementation of an intervention is accelerated or decelerated—may be useful to understand implementation and improve sustainability and ultimately sustainment of effective interventions. The purpose of this study was to retrospectively identify and describe strategic inflection points that accelerated the sustainability process and led to the sustainment of Alberta Family Integrated Care. Methods This qualitative study was conducted in Alberta, Canada and employed an interpretive description design. Purposively sampled documents (proposals, project management plans, reports to funders and sponsors, meeting minutes, and fidelity audit and feedback checklists) from the Alberta Family Integrated Care cluster randomized controlled trial and quality improvement project constituted data for this study. Results To accelerate sustainability in the research context, we identified (1) alignment with strategic priorities, (2) iterative, user-centered co-design, and (3) contextualization of implementation as strategic inflection points. To accelerate sustainability in the health system context, we identified (1) the learning health system, (2) enduring partnerships, (3) responsivity to societal and system change, (4) embedded governance, and (5) intentional integration into the health system as strategic inflection points. Capitalizing on these strategic inflection points led to sustainment of Alberta Family Integrated Care in the provincial health system. Conclusions We identified key inflection points in the research and health system contexts that led to sustainment of Alberta Family Integrated Care. By anticipating, recognizing, and leveraging inflection points in the sustainability process, researchers may be able to accelerate implementation and achieve sustainment of multi-component interventions in complex systems. Trial registration ClinicalTrials.gov: NCT02879799. Registration date: May 27, 2016. Protocol version: June 9, 2016; version 2. Protocol publication: https://doi.org/10.1186/s13063-017-2181-3 .Item Open Access Menopausal state and rheumatoid arthritis: a systematic review and meta-analysis(2024-09-30) Namavari, Negin; Jokar, Mohammad; Ghodsian, Arnoosh; Jahromi, Hossein K.; Rahmanian, VahidAbstract Background Rheumatoid arthritis (RA) is a chronic inflammatory condition primarily affecting the joints. The higher prevalence of RA among females, combined with the known effects of sex hormones on immune function, has led researchers to investigate the potential relationship between menopausal status and the risk, severity, or progression of RA. This systematic review and meta-analysis aimed to determine the association between menopause and rheumatoid arthritis. Methods In 2023, we conducted a comprehensive search across multiple databases, including Google Scholar, Scopus, PubMed/MEDLINE, Science Direct, Web of Science, EMBASE, Springer, and ProQuest. The search aimed to identify studies exploring the association between menopause and rheumatoid arthritis. Results Our analysis revealed that post-menopausal women had a higher risk of developing rheumatoid arthritis compared to pre-menopausal women, with an estimated odds ratio of 1.35 (95% CI: 1.04–1.67). Additionally, women who experienced early menopause (defined as onset before age 45) showed significantly higher odds of developing RA, with an odds ratio of 2.97 (95% CI: 1.73–4.22). Conclusion These findings highlight the importance of considering menopausal status when assessing the risk of RA development in women. The results suggest that post-menopausal women, particularly those who experience early menopause, may be at higher risk for developing RA. Further research in this area could provide valuable insights into potential preventive measures and targeted interventions for high-risk individuals.Item Open Access Educating patients about patient-reported outcomes—are we there yet?(2024-09-30) Unni, Elizabeth; van Muilekom, Maud M.; Absolom, Kate; Bajgain, Bishnu; Haverman, Lotte; Santana, MariaAbstract Background Using Patient Reported Outcome Measures (PROMs) in clinical settings can improve patient outcomes by enhancing communication between patient and provider. There has been significant improvements in the development of PROMs, their implementation in routine patient clinical care, training physicians and other healthcare providers to interpret the PROMs results to identify any issues reported by the patient, and to use the PROMs results to provide or modify the treatment. Main body Despite the increased use of PROMs, the lack of PROM completion by patients is a major concern in the optimal use of PROMs. Studies have shown several reasons why patients do not complete PROMs and one of the reasons is their lack of understanding of the significance of PROMs and their utility in their clinical care. While examining the various strategies that can be used to improve the uptake of PROM completion by patients, educating patients about the use of PROMs has been recommended. There is less evidence on how patients are trained or educated about PROMs. It may also be possible that the patient education strategies are not reported in the publications. This brings up the question of evaluation of the educational strategies used. Conclusion Our symposium at the 2023 ISOQOL conference brought together a range of experiences and learning around patient-centered PROMs educational activities used in the Netherlands, Canada, and the UK. This commentary is aimed to describe the lay of the land about educational activities around the use of PROMs in clinical care for patients, recognizing the gaps, and posing questions to be considered by the research and clinical community.Item Open Access Coupled THMC model-based prediction of hydraulic fracture geometry and size under self-propping phase-transition fracturing(2024-10-04) Zhang, Nanlin; Liu, Fushen; Jiang, Liangliang; Mo, Pinqiang; Xiao, Jingwen; Song, Qi; Luo, YuhaoAbstract The Self-Propping Phase-transition Fracturing Technology (SPFT) represents a novel and environmentally friendly approach for a cost-effective and efficient development of the world’s abundant unconventional resources, especially in the context of a carbon-constrained sustainable future. SPFT involves the coupling of Thermal, Hydraulic, Mechanical, and Chemical (THMC) fields, which makes it challenging to understand the mechanism and path of hydraulic fracture propagation. This study addresses these challenges by developing a set of THMC multifield coupling models based on SPFT parameters and the physical/chemical characteristics of the Phase-transition Fracturing Fluid System (PFFS). An algorithm, integrating the Finite Element Method, Discretized Virtual Internal Bonds, and Element Partition Method (FEM-DVIB-EPM), is proposed and validated through a case study. The results demonstrate that the FEM-DVIB-EPM coupling algorithm reduces complexity and enhances solving efficiency. The length of the hydraulic fracture increases with the quantity and displacement of PFFS, and excessive displacement may result in uncontrolled fracture height. Within the parameters considered, a minimal difference in fracture length is observed when the PFFS amount exceeds 130 m3, that means the fracture length tends to stabilize. This study contributes to understanding the hydraulic fracture propagation mechanism induced by SPFT, offering insights for optimizing hydraulic fracturing technology and treatment parameters.Item Open Access A chromosome level reference genome of Diviner’s sage (Salvia divinorum) provides insight into salvinorin A biosynthesis(2024-10-01) Ford, Scott A.; Ness, Rob W.; Kwon, Moonhyuk; Ro, Dae-Kyun; Phillips, Michael A.Abstract Background Diviner’s sage (Salvia divinorum; Lamiaceae) is the source of the powerful hallucinogen salvinorin A (SalA). This neoclerodane diterpenoid is an agonist of the human Κ-opioid receptor with potential medical applications in the treatment of chronic pain, addiction, and post-traumatic stress disorder. Only two steps of the approximately twelve step biosynthetic sequence leading to SalA have been resolved to date. Results To facilitate pathway elucidation in this ethnomedicinal plant species, here we report a chromosome level genome assembly. A high-quality genome sequence was assembled with an N50 value of 41.4 Mb and a BUSCO completeness score of 98.4%. The diploid (2n = 22) genome of ~ 541 Mb is comparable in size and ploidy to most other members of this genus. Two diterpene biosynthetic gene clusters were identified and are highly enriched in previously unidentified cytochrome P450s as well as crotonolide G synthase, which forms the dihydrofuran ring early in the SalA pathway. Coding sequences for other enzyme classes with likely involvement in downstream steps of the SalA pathway (BAHD acyl transferases, alcohol dehydrogenases, and O-methyl transferases) were scattered throughout the genome with no clear indication of clustering. Differential gene expression analysis suggests that most of these genes are not inducible by methyl jasmonate treatment. Conclusions This genome sequence and associated gene annotation are among the highest resolution in Salvia, a genus well known for the medicinal properties of its members. Here we have identified the cohort of genes responsible for the remaining steps in the SalA pathway. This genome sequence and associated candidate genes will facilitate the elucidation of SalA biosynthesis and enable an exploration of its full clinical potential.Item Open Access Validation of large language models for detecting pathologic complete response in breast cancer using population-based pathology reports(2024-10-03) Cheligeer, Ken; Wu, Guosong; Laws, Alison; Quan, May L.; Li, Andrea; Brisson, Anne-Marie; Xie, Jason; Xu, YuanAbstract Aims The primary goal of this study is to evaluate the capabilities of Large Language Models (LLMs) in understanding and processing complex medical documentation. We chose to focus on the identification of pathologic complete response (pCR) in narrative pathology reports. This approach aims to contribute to the advancement of comprehensive reporting, health research, and public health surveillance, thereby enhancing patient care and breast cancer management strategies. Methods The study utilized two analytical pipelines, developed with open-source LLMs within the healthcare system’s computing environment. First, we extracted embeddings from pathology reports using 15 different transformer-based models and then employed logistic regression on these embeddings to classify the presence or absence of pCR. Secondly, we fine-tuned the Generative Pre-trained Transformer-2 (GPT-2) model by attaching a simple feed-forward neural network (FFNN) layer to improve the detection performance of pCR from pathology reports. Results In a cohort of 351 female breast cancer patients who underwent neoadjuvant chemotherapy (NAC) and subsequent surgery between 2010 and 2017 in Calgary, the optimized method displayed a sensitivity of 95.3% (95%CI: 84.0–100.0%), a positive predictive value of 90.9% (95%CI: 76.5–100.0%), and an F1 score of 93.0% (95%CI: 83.7–100.0%). The results, achieved through diverse LLM integration, surpassed traditional machine learning models, underscoring the potential of LLMs in clinical pathology information extraction. Conclusions The study successfully demonstrates the efficacy of LLMs in interpreting and processing digital pathology data, particularly for determining pCR in breast cancer patients post-NAC. The superior performance of LLM-based pipelines over traditional models highlights their significant potential in extracting and analyzing key clinical data from narrative reports. While promising, these findings highlight the need for future external validation to confirm the reliability and broader applicability of these methods.Item Open Access Adaptive designs in clinical trials: a systematic review-part I(2024-10-04) Ben-Eltriki, Mohamed; Rafiq, Aisha; Paul, Arun; Prabhu, Devashree; Afolabi, Michael O. S.; Baslhaw, Robert; Neilson, Christine J.; Driedger, Michelle; Mahmud, Salaheddin M.; Lacaze-Masmonteil, Thierry; Marlin, Susan; Offringa, Martin; Butcher, Nancy; Heath, Anna; Kelly, Lauren E.Abstract Background Adaptive designs (ADs) are intended to make clinical trials more flexible, offering efficiency and potentially cost-saving benefits. Despite a large number of statistical methods in the literature on different adaptations to trials, the characteristics, advantages and limitations of such designs remain unfamiliar to large parts of the clinical and research community. This systematic review provides an overview of the use of ADs in published clinical trials (Part I). A follow-up (Part II) will compare the application of AD in trials in adult and pediatric studies, to provide real-world examples and recommendations for the child health community. Methods Published studies from 2010 to April 2020 were searched in the following databases: MEDLINE (Ovid), Embase (Ovid), and International Pharmaceutical Abstracts (Ovid). Clinical trial protocols, reports, and a secondary analyses using AD were included. We excluded trial registrations and interventions other than drugs or vaccines to align with regulatory guidance. Data from the published literature on study characteristics, types of adaptations, statistical analysis, stopping boundaries, logistical challenges, operational considerations and ethical considerations were extracted and summarized herein. Results Out of 23,886 retrieved studies, 317 publications of adaptive trials, 267 (84.2%) trial reports, and 50 (15.8%) study protocols), were included. The most frequent disease was oncology (168/317, 53%). Most trials included only adult participants (265, 83.9%),16 trials (5.4%) were limited to only children and 28 (8.9%) were for both children and adults, 8 trials did not report the ages of the included populations. Some studies reported using more than one adaptation (there were 390 reported adaptations in 317 clinical trial reports). Most trials were early in drug development (phase I, II (276/317, 87%). Dose-finding designs were used in the highest proportion of the included trials (121/317, 38.2 %). Adaptive randomization (53/317, 16.7%), with drop-the-losers (or pick-the-winner) designs specifically reported in 29 trials (9.1%) and seamless phase 2-3 design was reported in 27 trials (8.5%). Continual reassessment methods (60/317, 18.9%) and group sequential design (47/317, 14.8%) were also reported. Approximately two-thirds of trials used frequentist statistical methods (203/309, 64%), while Bayesian methods were reported in 24% (75/309) of included trials. Conclusion This review provides a comprehensive report of methodological features in adaptive clinical trials reported between 2010 and 2020. Adaptation details were not uniformly reported, creating limitations in interpretation and generalizability. Nevertheless, implementation of existing reporting guidelines on ADs and the development of novel educational strategies that address the scientific, operational challenges and ethical considerations can help in the clinical trial community to decide on when and how to implement ADs in clinical trials. Study protocol registration https://doi.org/10.1186/s13063-018-2934-7 .Item Open Access Comparison of patient-reported outcomes between alternative care provider-led and physician-led care for severe sleep disordered breathing: secondary analysis of a randomized clinical trial(2024-09-26) J. Santana, Maria; Jaja, Oyindamola; Duan, Qiuli; D. Penz, Erika; L. Fraser, Kristin; J. Hanly, Patrick; R. Pendharkar, SachinAbstract Background Previous research has suggested that alternative (respiratory) care providers (ACP) may provide affordable, accessible care for sleep-disordered breathing (SDB) that decreases wait-times and improves clinical outcomes. The objective of this study was to compare ACP-led and sleep physician-led care for SDB on patient reported outcome and experiences, with a focus on general and health-related quality of life, sleepiness, and patient satisfaction. Methods We conducted a secondary analysis of a randomized trial in which participants with severe SDB were assigned to either ACP-led or physician-led management. We created longitudinal linear mixed models to assess the impacts of treatment arm and timepoint on total and domain-level scores of multiple patient-reported outcome measures and patient-reported experience measures. Results Patients in both treatment arms (ACP-led n = 81; sleep-physician = 75) reported improved outcomes on the Sleep Apnea Quality of Life Index, Health Utilities Index, and Epworth Sleepiness Scale. Patients in each group had similar and clinically meaningful improvements on domains assessing cognition, emotion, and social functioning. The linear mixed models suggested no significant difference between treatment arms on the patient-reported outcomes. However, scores significantly improved over time. Conclusions Management of SDB using ACPs was comparable to physician-led care, as measured bypatient-reported outcome and experience measures. While loss to follow-up limits our findings, these results provide some support for the use of this novel health service delivery model to improve access to high quality SDB care. Clinical trial registration This is analysis of data from the study registered Clinicaltrials.gov (NCT02191085).Item Open Access Real-world outcomes of patients with hereditary angioedema with normal C1-inhibitor function and patients with idiopathic angioedema of unknown etiology in Canada(2024-09-27) Adatia, Adil; Boursiquot, Jean-Nicolas; Goodyear, Dawn; Kalicinsky, Chrystyna; Kanani, Amin; Waserman, Susan; Nguyen, Michelle M. L.; Wadhwa, Abhinav; Weiss, Jessica; El-Zoeiby, Ahmed; Betschel, StephenAbstract Background Hereditary angioedema with normal C1-inhibitor function (HAE nC1-INH) and idiopathic angioedema of unknown etiology (AE-UNK) are rare conditions that cause recurrent subcutaneous and submucosal swelling. The characteristics and clinical outcomes of patients with these conditions in Canada have not been studied. Methods The aim of this study was to extract real-world evidence from the electronic health records of patients with HAE nC1-INH or AE-UNK who were managed in selected practices of Canadian HAE-treating specialist physicians between 01-Jan-2012 and 01-Jan-2022, to examine case numbers, treatment, clinical outcomes, and healthcare utilization. Results Of 60 patients (37 with HAE nC1-INH, 23 with AE-UNK), median (range) age at symptom onset was 21.5 (5.0–57.0) and 23.0 (10.0–54.0) years, respectively. Time to diagnosis from onset of symptoms was 7.0 (0.0–43.0) and 2.0 (− 10.0 to 50.0) years. Significant differences were observed in terms of the predominant triggers for angioedema attacks between patients with HAE nC1-INH and AE-UNK: stress (65% vs. 26%, p = 0.007) and estrogen therapy (35% vs. 9%, p = 0.031). Before diagnosis, most patients received antihistamines (50% of HAE nC1-INH and 61% of AE-UNK patients). Post-diagnosis, 73% and 74% of HAE nC1-INH and AE-UNK patients received long-term prophylaxis (LTP), with the most common LTP treatments being subcutaneous pdC1-INH (43% of HAE nC1-INH patients and 39% of AE-UNK patients) and tranexamic acid (41% of HAE nC1-INH patients and 35% of AE-UNK patients). Of patients with HAE nC1-INH, and patients with AE-UNK, 22% and 13%, respectively, were taking more than one LTP treatment concurrently. Before HAE treatment initiation, significantly fewer patients with AE-UNK compared to patients with HAE nC1-INH had angioedema attacks affecting their extremities (13% vs. 38%, p = 0.045) and GI system (22% vs. 57%, p = 0.015). In the three months following treatment initiation, patients with AE-UNK experienced significantly fewer angioedema attacks compared to patients with HAE nC1-INH (median 2.0 attacks [0.0–48.0] vs. 6.0 attacks [0.0–60.0], p = 0.044). Additionally, fewer patients with AE-UNK compared to HAE nC1-INH experienced attacks affecting their GI system (26% vs. 57%, p = 0.032). Attack duration and frequency significantly decreased for patients with HAE nC1-INH from a median of 1.00 day (range: 0.00–7.00) to 0.29 day (range: 0.02–4.00; p = 0.001) and from 10.50 attacks (range: 0.00–90.00) to 6.00 attacks (range: 0.00–60.00; p = 0.004) in the three months following HAE treatment initiation. Conclusions Using Canadian real-world evidence, these data demonstrate differing clinical trajectories between patients with HAE nC1-INH and AE-UNK, including diagnostic delays, varied attack characteristics, treatment responses and healthcare utilization. Despite treatment response, many patients still experienced frequent angioedema attacks. These results suggest an unmet need for treatment guidelines and therapies specifically for patients with HAE nC1-INH and AE-UNK and better understanding of the pathophysiology accounting for the reported differences between the two.Item Open Access “Give me the reigns of taking care of myself with a home”: Healing environments in an Indigenous-led alcohol harm reduction program(2024-09-26) Brown, Meaghan; Hunt-Jinnouchi, Fran; Robinson, Jennifer; Clark, Nancy; Mushquash, Christopher; Milaney, Katrina; Pauly, BernieAbstract Background Distinct from western Managed Alcohol Programs (MAPs), Indigenous-led alcohol harm reduction programs can be defined by both ‘culture as healing’ and decolonized harm reduction philosophies. We sought to explore experiences of Indigenous ‘family members’ (participants) in an Indigenous-led alcohol harm reduction program and culturally supportive housing to identify appropriate supports according to family member perspectives, and to inform delivery of the program. Methods Situated within an Indigenous-western research partnership, we completed semi-structured interviews with seven family members of an Indigenous-led alcohol harm reduction and culturally supportive housing program. Community-guided protocols informed relational knowledge gathering practices including semi-structured in-depth interviews, qualitative thematic analysis, collaborative interpretation of findings, and development of knowledge products. Results Family members highlighted the importance of tailored Indigenous-led alcohol harm reduction in shifting their relationships to alcohol from survival to having choice and control of their drinking (It’s a choice I’m making right now). The provision of varied and incremental culture-based opportunities (Multiple pathways for connecting to culture) facilitated engagement with culture as healing. Policies that honour respect and autonomy were identified as supportive to healing and harm reduction, countering family members’ experiences in western spaces (Give me the reigns of taking care of myself with a home). Conclusions An Indigenous-led alcohol harm reduction program within a model of culture as healing facilitated shifts in relationships to alcohol, providing a space where family members could explore long term goals of healing and connection to culture. Family members’ experiences and recommendations offer key considerations for the design of Indigenous-led harm reduction and culture as healing models. Recommendations emphasize the provision of tailored alcohol harm reduction plans in parallel to multiple and accessible opportunities for connection to culture as healing in order to meet diverse participant goals and relationships to alcohol and culture.Item Open Access Factors influencing survival in sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional natural history study of 76 patients(2024-09-27) Keller, Nancy; Midgley, Julian; Khalid, Ehtesham; Lesmana, Harry; Mathew, Georgie; Mincham, Christine; Teig, Norbert; Khan, Zubair; Khosla, Indu; Mehr, Sam; Guran, Tulay; Buder, Kathrin; Xu, Hong; Alhasan, Khalid; Buyukyilmaz, Gonul; Weaver, Nicole; Saba, Julie D.Abstract Background Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a recently recognized inborn error of metabolism associated with steroid-resistant nephrotic syndrome as well as adrenal insufficiency and immunological, neurological, and skin manifestations. SPLIS is caused by inactivating mutations in SGPL1, encoding the pyridoxal 5’phosphate-dependent enzyme sphingosine-1-phosphate lyase, which catalyzes the final step of sphingolipid metabolism. Some SPLIS patients have undergone kidney transplantation, and others have been treated with vitamin B6 supplementation. In addition, targeted therapies including gene therapy are in preclinical development. In anticipation of clinical trials, it will be essential to characterize the full spectrum and natural history of SPLIS. We performed a retrospective analysis of 76 patients in whom the diagnosis of SPLIS was established in a proband with at least one suggestive finding and biallelic SGPL1 variants identified by molecular genetic testing. The main objective of the study was to identify factors influencing survival in SPLIS subjects. Results Overall survival at last report was 50%. Major influences on survival included: (1) age and organ involvement at first presentation; (2) receiving a kidney transplant, and (3) SGPL1 genotype. Among 48 SPLIS patients with nephropathy who had not received a kidney transplant, two clinical subgroups were distinguished. Of children diagnosed with SPLIS nephropathy before age one (n = 30), less than 30% were alive 2 years after diagnosis, and 17% were living at last report. Among those diagnosed at or after age one (n = 18), ~ 70% were alive 2 years after diagnosis, and 72% were living at time of last report. SPLIS patients homozygous for the SPL R222Q variant survived longer compared to patients with other genotypes. Kidney transplantation significantly extended survival outcomes. Conclusion Our results demonstrate that SPLIS is a phenotypically heterogeneous condition. We find that patients diagnosed with SPLIS nephropathy in the first year of life and patients presenting with prenatal findings represent two high-risk subgroups, whereas patients harboring the R222Q SGPL1 variant fare better than the rest. Time to progression from onset of proteinuria to end stage kidney disease varies from less than one month to five years, and kidney transplantation may be lifesaving.Item Open Access Coding rules for uncertain and “ruled out” diagnoses in ICD-10 and ICD-11(2024-09-27) Atolagbe, Oluseun O.; Romano, Patrick S.; Southern, Danielle A.; Wongtanasarasin, Wachira; Ghali, William A.Abstract The International Classification of Diseases, 11th Revision (ICD-11) has significantly improved the ability to navigate coding challenges beyond prior iterations of the ICD. Commonly encountered sources of complexity in clinical documentation include coding of uncertain and “ruled out” diagnoses. Assessing official international guidelines and rules, this paper documents extensive variation across countries in existing practices for coding and reporting unconfirmed and “ruled out” clinical concepts in ICD-10 (and modifications thereof). The design of ICD-11 is intended to mitigate these coding challenges by introducing postcoordination, expanding the range of codable clinical concepts, and offering clearer guidance in the ICD-11 Reference Guide. ICD-11 offers substantial progress towards more precise capture of uncertain and “ruled out” diagnoses, including international consensus on coding rules for these historically challenging clinical concepts. However, we identify the need for further clarification of the concepts of “provisional diagnosis” and “differential diagnosis.”Item Open Access Rapid normalization of vitamin D deficiency in PICU (VITdALIZE-KIDS): study protocol for a phase III, multicenter randomized controlled trial(2024-09-19) O’Hearn, Katie; Menon, Kusum; Albrecht, Lisa; Amrein, Karin; Britz-McKibbin, Philip; Cayouette, Florence; Choong, Karen; Foster, Jennifer R.; Fergusson, Dean A.; Floh, Alejandro; Fontela, Patricia; Geier, Pavel; Gilfoyle, Elaine; Guerra, Gonzalo G.; Gunz, Anna; Helmeczi, Erick; Khamessan, Ali; Joffe, Ari R.; Lee, Laurie; McIntyre, Lauralyn; Murthy, Srinivas; Parsons, Simon J.; Ramsay, Tim; Ryerson, Lindsay; Tucci, Marisa; McNally, DayreAbstract Background The rate of vitamin D deficiency (VDD) in critically ill children worldwide has been estimated at 50%. These children are at risk of multiple organ dysfunction, chronic morbidity, and decreased health related quality of life (HRQL). Pediatric and adult ICU clinical trials suggest that VDD is associated with worse clinical outcomes, although data from supplementation trials are limited and inconclusive. Our group’s phase II multicenter dose evaluation pilot study established the efficacy and safety of an enteral weight-based cholecalciferol loading dose to rapidly restore vitamin D levels in critically ill children. Methods Our aim is to evaluate the impact of this dosing regimen on clinical outcomes. VITdALIZE-KIDS is a pragmatic, phase III, multicenter, double-blind RCT aiming to randomize 766 critically ill children from Canadian PICUs. Participants are randomized using a 1:1 scheme to receive a single dose at enrollment of enteral cholecalciferol (10,000 IU/kg, max 400,000 IU) or placebo. Eligibility criteria include critically ill children aged newborn (> 37 weeks corrected gestational age) to < 18 years who have blood total 25-hydroxyvitamin D < 50 nmol/L. The primary objective is to determine if rapid normalization of vitamin D status improves HRQL at 28 days following enrollment. The secondary objective is to evaluate the impact of rapid normalization of vitamin D status on multiple organ dysfunction. The study includes additional tertiary outcomes including functional status, HRQL and mortality at hospital discharge and 90 days, PICU and hospital length of stay, and adverse events related to vitamin D toxicity. Additionally, we are performing comprehensive vitamin D speciation and non-targeted metabolite profiling as part of a sub-study for the first 100 participants from whom an enrollment and at least one post-intervention blood and urine sample were obtained. Discussion The VITdALIZE-KIDS trial is the first phase III, multicenter trial to evaluate whether rapid normalization of vitamin D status could represent a simple, inexpensive, and safe means of improving outcomes following pediatric critical illness. Recruitment was initiated in June 2019 and is expected to continue to March 2026. Trial registration Clinicaltrials.gov, NCT03742505. Study first submitted on November 12, 2018 https://clinicaltrials.gov/study/NCT03742505Item Open Access Diurnal timing of physical activity and risk of colorectal cancer in the UK Biobank(2024-09-18) Stein, Michael J.; Baurecht, Hansjörg; Bohmann, Patricia; Fervers, Béatrice; Fontvieille, Emma; Freisling, Heinz; Friedenreich, Christine M.; Konzok, Julian; Peruchet-Noray, Laia; Sedlmeier, Anja M.; Leitzmann, Michael F.; Weber, AndreaAbstract Background Physical activity reduces colorectal cancer risk, yet the diurnal timing of physical activity in colorectal cancer etiology remains unclear. Methods This study used 24-h accelerometry time series from UK Biobank participants aged 42 to 79 years to derive circadian physical activity patterns using functional principal component analysis. Multivariable Cox proportional hazard models were used to examine associations with colorectal cancer risk. Results Among 86,252 participants (56% women), 529 colorectal cancer cases occurred during a median 5.3-year follow-up. We identified four physical activity patterns that explained almost 100% of the data variability during the day. A pattern of continuous day-long activity was inversely associated with colorectal cancer risk (hazard ratio (HR) = 0.94, 95% confidence interval (CI) = 0.89–0.99). A second pattern of late-day activity was suggestively inversely related to risk (HR = 0.93, 95% CI = 0.85–1.02). A third pattern of early- plus late-day activity was associated with decreased risk (HR = 0.89, 95% CI = 0.80–0.99). A fourth pattern of mid-day plus night-time activity showed no relation (HR = 1.02, 95% CI = 0.88–1.19). Our results were consistent across various sensitivity analyses, including the restriction to never smokers, the exclusion of the first 2 years of follow-up, and the adjustment for shift work. Conclusions A pattern of early- plus late-day activity is related to reduced colorectal cancer risk, beyond the benefits of overall activity. Further research is needed to confirm the role of activity timing in colorectal cancer prevention.Item Open Access Trained immunity: a revolutionary immunotherapeutic approach(2024-09-14) Salauddin, Md.; Nath, Sabuj K.; Saha, Sukumar; Zheng, Qingcong; Zheng, Chunfu; Hossain, Md. G.Abstract Trained immunity is a phenomenon in which brief exposure to an infectious agent or a vaccine can induce long-lasting changes in the host's immune system, enhancing protection against subsequent infections. The concept of trained immunity has a significant impact on the field of immunology and has the potential to revolutionize how we approach vaccination and infectious disease control. Investigations into trained immunity are rapidly advancing and have led to the development of new vaccines and immunotherapeutic strategies that harness the power of this phenomenon. While more investigations are needed to fully understand the mechanisms of trained immunity and its potential limitations, the prospects for its future application in clinical practice are promising. Here, we describe trained immunity as a biological process and explore the innate cues, epigenetic changes, and metabolic reprogramming activities that affect how trained immunity is induced.Item Open Access In vitro and ex vivo metabolism of chemically diverse fructans by bovine rumen Bifidobacterium and Lactobacillus species(2024-09-09) King, Marissa L.; Xing, Xiaohui; Reintjes, Greta; Klassen, Leeann; Low, Kristin E.; Alexander, Trevor W.; Waldner, Matthew; Patel, Trushar R.; Wade Abbott, D.Abstract Background Inulin and inulin-derived fructooligosaccharides (FOS) are well-known prebiotics for use in companion animals and livestock. The mechanisms by which FOS contribute to health has not been fully established. Further, the fine chemistry of fructan structures from diverse sources, such as graminan-type fructans found in cereal crops, has not been fully elucidated. New methods to study fructan structure and microbial responses to these complex carbohydrates will be key for evaluating the prebiotic potency of cereal fructans found in cattle feeds. As the rumen microbiome composition is closely associated with their metabolic traits, such as feed utilization and waste production, prebiotics and probiotics represent promising additives to shift the microbial community toward a more productive state. Results Within this study, inulin, levan, and graminan-type fructans from winter wheat, spring wheat, and barley were used to assess the capacity of rumen-derived Bifidobacterium boum, Bifidobacterium merycicum, and Lactobacillus vitulinus to metabolize diverse fructans. Graminan-type fructans were purified and structurally characterized from the stems and kernels of each plant. All three bacterial species grew on FOS, inulin, and cereal crop fructans in pure cultures. L. vitulinus was the only species that could metabolize levan, albeit its growth was delayed. Fluorescently labelled polysaccharides (FLAPS) were used to demonstrate interactions with Gram-positive bacteria and confirm fructan metabolism at the single-cell level; these results were in agreement with the individual growth profiles of each species. The prebiotic potential of inulin was further investigated within naïve rumen microbial communities, where increased relative abundance of Bifidobacterium and Lactobacillus species occurred in a dose-dependent and temporal-related manner. This was supported by in situ analysis of rumen microbiota from cattle fed inulin. FLAPS probe derived from inulin and fluorescent in situ hybridization using taxon-specific probes confirmed that inulin interacts with Bifidobacteria and Lactobacilli at the single-cell level. Conclusion This research revealed that rumen-derived Bifidobacteria and Lactobacilli vary in their metabolism of structurally diverse fructans, and that inulin has limited prebiotic potential in the rumen. This knowledge establishes new methods for evaluating the prebiotic potential of fructans from diverse plant sources as prebiotic candidates for use in ruminants and other animals.