Lawson Health Research Institute

Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly non-alcoholic fatty liver disease) is a prevalent and progressive condition closely linked to gut microbiota composition. Fecal microbiota transplantation (FMT) may help restore a health-associated microbiome, but its efficacy is often limited by inconsistent engraftment of beneficial taxa. Prebiotics may selectively support keystone microbes associated with reduced MASLD risk. This study evaluated two prebiotics, inulin and xylooligosaccharides (XOS), for their ability to modulate the microbiota of healthy FMT donors in an in vitro gut model, focusing on enriching beneficial taxa and functions associated with MASLD resilience. Stool from eight clinically qualified FMT donors was cultured anaerobically for 24 h with or without prebiotics. Microbiota composition was assessed by 16S rRNA gene sequencing and short-chain fatty acid (SCFA) concentrations were measured using nuclear magnetic resonance. Functional potential was inferred using predictive metagenomic analysis. Prebiotic responses were highly donor-specific, yet both inulin and XOS consistently enriched Bifidobacterium and Bacteroides-genera associated with SCFA production and metabolic health. XOS preferentially enriched Lactobacillus and Parabacteroides, while inulin enhanced Holdemanella and Mediterraneibacter. Functional pathways relevant to MASLD pathophysiology were enriched, including carbohydrate metabolism, vitamin biosynthesis, fatty acid metabolism, and tryptophan degradation. Both prebiotics significantly increased acetate levels, while butyrate showed a donor-dependent increasing trend. These findings suggest that prebiotic supplementation can selectively enrich MASLD-relevant microbial taxa and functions in donor-derived FMT material, supporting their potential as adjuvants to enhance the efficacy and disease-specificity of FMT interventions for MASLD.

Acute kidney injury (AKI) is a known immune-related adverse event of cancer immune checkpoint inhibitor (ICI) therapy. Further population-based data on AKI incidence, risk factors and practice patterns post-ICI therapy are needed. We measured the cumulative incidence of AKI among advanced cancer patients while receiving ICI therapy and non-ICI systemic therapy in Ontario, Canada (2012-18). An increase in serum creatinine was used to define AKI and graded according to event severity. Time to event modeling was used to compare the risk of developing AKI, pre-disposing factors and survival outcomes. We studied 16 425 patients with advanced cancer receiving either ICI or non-ICI systemic therapy. Among 4380 patients receiving ICI therapy, the overall crude 4-year incidence of AKI (any stage) was 29% and severe AKI (stage ≥2) was 7%. Characteristics associated with a higher risk of AKI included male sex, genitourinary (versus other) malignancy, the presence of hypertension, diabetes or chronic kidney disease, and prescription of a non-steroidal anti-inflammatory drug. The risk of experiencing AKI was significantly lower among patients treated with ICI versus non-ICI systemic therapy [adjusted hazards ratio (aHR) 0.80, 95% confidence interval (CI) 0.74-0.86, P-value <.0001]. Among the 587 patients who experienced an AKI and were both alive and discontinued ICI therapy within 30days, 54 (9%) were re-challenged with ICI in the following 6months and 24 (44%) had a recurrent AKI event. Patients who were re-challenged with ICI therapy had improved overall survival as compared with patients that received other non-ICI systemic therapy (aHR 0.38, 95% CI 0.22-0.67, P-value <.001). Our real-world study demonstrates a modest risk for severe AKI among cancer patients receiving ICI therapy, lower than with exposure to other systemic cancer therapies. Among patients who developed AKI and stopped ICI therapy, re-challenge was uncommon but may warrant consideration for select patients.

Target-to-background ratio (TBR) is commonly reported in fluorescence molecular imaging (FMI) as a surrogate for detection accuracy. While intuitive, TBR does not explicitly account for image noise or spatial variability, both of which strongly influence object detectability. In this work, we use a simple simulation framework to examine the relationship between TBR, contrast-to-variability ratio (CVR), and detection accuracy quantified by the area under the receiver operating characteristic curve (AUC). Across a broad range of simulated imaging conditions, CVR exhibits a substantially stronger and more monotonic relationship with AUC than TBR. These results demonstrate that TBR is a weak and potentially misleading indicator of detection performance, whereas CVR provides a more reliable and interpretable surrogate when ground truth is unavailable. We recommend adoption of AUC-based metrics when ground truth is known and CVR when it is not, avoiding reliance on TBR alone.

BackgroundUnilateral spatial neglect (USN) is a common post-stroke deficit that adversely affects activities of daily living and functional independence. Despite advancements in stroke rehabilitation research, USN-specific rehabilitation studies remain relatively limited, contributing to a gap in evidence-based clinical practice.ObjectiveTo characterize randomized controlled trials (RCTs) evaluating post-stroke USN rehabilitation interventions and to provide an overview of the intervention types studied and gaps in the current literature.MethodsSystematic searches of MEDLINE, Embase, Scopus, CINAHL, and PsycINFO were conducted from inception to December 31, 2024. The methodological quality of included RCTs was assessed using the PEDro scale.ResultsA total of 123 RCTs were included, collectively enrolling 3,419 participants. The annual number of trials has remained stable in recent years. The mean sample size was 27.8, and the majority of RCTs (60.2%) were conducted in the subacute phase post-stroke. A total of 44 unique types of intervention were examined across the 123 RCTs. Top-down interventions were evaluated in 49 RCTs (39.8%), while bottom-up therapies were examined in 82 RCTs (66.6%), and pharmacological interventions were used in only 6 studies (4.9%).ConclusionsFuture RCTs on neglect should recruit larger sample sizes, evaluate the efficacy of combined interventions, and implement time-sensitive treatment strategies to maximize gains in the earlier post stroke phase. Additionally, RCTs are needed to specifically address the impact of treatment timing on outcomes, and the long-term effects.

We evaluated whether age modifies treatment efficacy and safety of advanced therapies in patients with moderate-to-severe ulcerative colitis (UC). Through an individual patient-level data (IPD) meta-analysis of 10 RCTs of advanced therapies (TNF antagonists: infliximab, adalimumab, golimumab; vedolizumab; ustekinumab; tofacitinib) in patients with moderate-to-severe UC, we compared the efficacy (induction of clinical remission, endoscopic improvement, endoscopic remission, and symptomatic remission) and safety (serious adverse events [SAEs] and infections) of induction therapy in older (≥ 60y) vs younger adults (< 60y). Modified Poisson regression was used to estimate the ratio of risk ratios (RRR) of treatment effects by age, adjusting for baseline endoscopic severity, disease duration, disease extent, prior biologic exposure, C-reactive protein, albumin, hemoglobin, concomitant corticosteroid use, and clustering effect by studies. Among 6192 patients (mean age 39.6years, 41% female), 634 (10.2%) were aged ≥ 60years. Efficacy of all advanced therapies over placebo was similar in older vs younger adults, with no significant treatment effect modification (induction of clinical remission: TNF antagonists, RRR of older vs younger adults, 0.94 [95% CI, 0.41-2.15]; non-TNF-targeting agents, RRR, 1.26 [0.60-2.62]). However, older adults were significantly more likely to experience infections with advanced therapies vs placebo, compared with younger adults (TNF antagonists, RRR, 1.52 [1.12-2.05]; non-TNF-targeting agents, RRR, 2.04 [1.45-2.87]). In patients with moderate-to-severe UC, older age did not modify the magnitude of efficacy but was associated with higher magnitude of infection during induction with advanced therapies.

Introduction: Recent multidomain intervention trials for dementia show it is possible to improve cognition by targeting combinations of risk factors. We aimed to identify the most prevalent co-occurring risk factor combinations that are strongly associated with low cognition. Methods: This cross-sectional analysis included 30,097 participants aged 45 to 85 in the Canadian Longitudinal Study on Aging. The five most prevalent dyad, triad, and tetrad combinations of 12 modifiable risk factors were identified. Neuropsychological test battery composite Z score was calculated to assess cognition. Multivariable linear regression was used to explore the association between the prevalent combinations of risk factors and cognition. Synergistic interaction between risk factors was assessed using interaction terms. Results: The most prevalent dyadic combination was physical inactivity and sleep disturbance, with hypertension added for the triad, and obesity added for the tetrad. The dyadic combination associated with both high prevalence and the strongest association with low cognition was hearing loss and physical inactivity (prevalence 27%; mean difference −0.12 [95% CI: −0.14 to −0.09]). For the triad, it was hearing loss, physical inactivity, and hypertension (14%; −0.14 [−0.16 to −0.11]), and with the addition of obesity for the tetrad (5.1%; −0.15 [−0.19 to −0.12]). Synergistic interaction was observed between hypertension and physical inactivity (p < 0.001). Conclusion: Prevalent and detrimental combinations of modifiable risk factors for dementia were identified to inform targeted intervention strategies. The synergistic interaction between hypertension and physical inactivity highlights the benefit of addressing both risk factors simultaneously to maximize cognitive benefits.

Rationale: Chimeric antigen receptor (CAR) T cell therapies have shown remarkable success in treating hematological cancers and are increasingly demonstrating potential for solid tumors. CRISPR-based genome editing offers a promising approach to enhance CAR-T cell potency and safety, yet challenges such as inefficient tumor homing and toxicities in normal tissues, limit broader adoption. Advanced imaging technologies, including bioluminescence imaging (BLI) and positron emission tomography (PET), provide real-time visualization of CAR-T cell behavior in vivo. Here, we developed Trackable Reporter Adaptable CRISPR-Edited CAR (tRACE-CAR) T cells, a modular system for site-specific integration of CARs and imaging reporters.Methods: The luciferase reporter AkaLuciferase (AkaLuc) or the human sodium iodide symporter (NIS) was cloned downstream of the CAR in adeno-associated virus (AAV) donors for imaging. CAR-reporter cassettes were inserted into the T-cell receptor α constant locus of primary human T cells via CRISPR editing and AAV transduction. Editing efficiency was assessed by flow cytometry. In vitro cytotoxicity was evaluated across multiple effector-to-target ratios. In vivo, BLI and PET imaging were used for tracking CAR-T cells in tumor-bearing immunodeficient mice.Results: T cell receptor (TCR) knockout efficiency exceeded 85% and CAR expression reached 70-80%. Reporter-engineered CAR-T cells exhibited significant cytotoxicity and outperformed naïve T cells. In vivo, AkaLuc BLI and 18F-tetrafluoroborate PET enabled non-invasive tracking of viable CAR-T cells. Administration route (intravenous, peritumoral, or intraperitoneal) significantly influenced CAR-T cell distribution and therapeutic effectiveness.Conclusion: tRACE-CAR enables precise optical and PET tracking of CRISPR-edited CAR-T cells in models of leukemia and ovarian cancer, allowing dynamic, non-invasive monitoring of cell distribution in both tumors and off-target tissues. This imaging-enabled platform could lead to more personalized, effective CRISPR-edited CAR cell therapies.