University of Calgary

Galán-Madruga D., Broomandi P., Satyanaga A., Jahanbakhshi A., Bagheri M., Fathian A., Sarvestan R., Cárdenas-Escudero J., Cáceres J.O., Kumar P., Kim J.R.

Scientific evidence sustains PM2.5 particles' inhalation may generate harmful impacts on human beings' health; therefore, their monitoring in ambient air is of paramount relevance in terms of public health. Due to the limited number of fixed stations within the air quality monitoring networks, development of methodological frameworks to model ambient air PM2.5 particles is primordial to providing additional information on PM2.5 exposure and its trends. In this sense, this work aims to offer a global easily-applicable tool to estimate ambient air PM2.5 as a function of meteorological conditions using a multivariate analysis. Daily PM2.5 data measured by 84 fixed monitoring stations and meteorological data from ERA5 (ECMWF Reanalysis v5) reanalysis daily based data between 2000 and 2021 across the United Kingdom were attended to develop the suggested approach. Data from January 2017 to December 2020 were employed to build a mathematical expression that related the dependent variable (PM2.5) to predictor ones (sea-level pressure, planetary boundary layer height, temperature, precipitation, wind direction and speed), while 2021 data tested the model. Evaluation indicators evidenced a good performance of model (maximum values of RMSE, MAE and MAPE: 1.80 µg/m3, 3.24 µg/m3, and 20.63%, respectively), compiling the current legislation's requirements for modelling ambient air PM2.5 concentrations. A retrospective analysis of meteorological features allowed estimating ambient air PM2.5 concentrations from 2000 to 2021. The highest PM2.5 concentrations relapsed in the Mid- and Southlands, while Northlands sustained the lowest concentrations.

Tin E., Rutella S., Khatri I., Na Y., Yan Y., MacLean N., Vadakekolathu J., Minden M.D., Schimmer A.D., Lee J., Zhang L.

Abstract Despite the curative potential of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML), its efficacy is limited by intrinsic resistance of cancer cells to donor-derived T-cell cytotoxicity. Using a genome-wide CRISPR screen, we identified the SOCS1–JAK1–STAT1 pathway as a mediator of AML susceptibility to T cells. Knockdown of suppressors of cytokine signaling 1 (SOCS1) in AML cells sensitized them to killing by allogeneic T cells, whereas SOCS1 overexpression in AML cells induced resistance to T-cell antileukemic activity. Mechanistically, SOCS1 protected AML cells from T-cell killing by antagonizing IFNγ–JAK1—induced intercellular adhesion molecule 1 expression. Furthermore, primary AML cells with lower SOCS1 expression correlated with better overall survival in patients, especially those with a lower exhausted CD8+ T-cell score. Thus, this study reveals SOCS1 and its downstream mediators as a potential targetable pathway to enhance T cell–based immunotherapy for AML. Significance: Our investigation of the SOCS1 pathway in AML and T-cell interactions provides insights into potential mechanisms of resistance of AML to allogeneic hematopoietic stem cell transplantation and demonstrates the potential of targeting SOCS1 and its downstream mediators to enhance antileukemic T-cell activity. See related commentary by YYY, p. XX.

Krishnan A., Rajakumar I., Salmon J.

Background: Vancomycin resistant Enterococcus faecium (VRE) bacteremia and infective endocarditis (IE) are difficult to treat and associated with high mortality. Methods: We describe a case of a 78-year-old male with VRE prosthetic valve endocarditis treated with combined daptomycin/ampicillin. We review published literature on the treatment of VRE IE and summarize other published case reports of daptomycin combination therapy. Results: Prompt clearance of bacteremia was achieved. Cardiac valve replacement surgery was pursued but was followed by post-operative complications and ultimately the patient did not survive. Conclusion: There is limited published literature on the treatment of VRE IE and an optimal antibiotic regimen has not been established. This case adds to the growing body of literature demonstrating the use of daptomycin and beta-lactam combination therapy for VRE bacteremia and endocarditis. Combination therapy may be an appropriate choice for select cases; however, reports of treatment failure warrant caution.

Sun B., Ni M., Li Y., Song Z., Wang H., Zhu H., Wei J., Belke D., Cai S., Guo W., Yao J., Tian S., Estillore J.P., Wang R., Sondergaard M.T., et. al.

BACKGROUND: Ca 2+ mishandling in cardiac Purkinje cells is a well-known cause of cardiac arrhythmias. The Purkinje cell resident inositol 1,4,5-trisphosphate receptor 1 (ITPR1) is believed to play an important role in Ca 2+ handling, and ITPR1 gain-of-function (GOF) has been implicated in cardiac arrhythmias. However, nearly all known disease-associated ITPR1 variants are loss-of-function and are primarily linked to neurological disorders. Whether ITPR1 GOF has pathological consequences, such as cardiac arrhythmias, is unclear. This study aimed to identify human ITPR1 GOF variants and determine the impact of ITPR1 GOF on Ca 2+ handling and arrhythmia susceptibility. METHODS: There are a large number of rare ITPR1 missense variants reported in open data repositories. Based on their locations in the ITPR1 channel structure, we selected and characterized 33 human ITPR1 missense variants from open databases and identified 21 human ITPR1 GOF variants. We generated a mouse model carrying a human ITPR1 GOF variant, ITPR1-W1457G (W1447G in mice). RESULTS: We showed that the ITPR1-W1447G +/- and recently reported ITPR1-D2594K +/- GOF mutant mice were susceptible to stress-induced ventricular arrhythmias. Confocal Ca 2+ and voltage imaging in situ in heart slices and Ca 2+ imaging and patch-clamp recordings of isolated Purkinje cells showed that ITPR1-W1447G +/- and ITPR1-D2594K +/- variants increased the occurrence of stress-induced spontaneous Ca 2+ release, delayed afterdepolarization, and triggered activity in Purkinje cells. To assess the potential role of ITPR1 variants in arrhythmia susceptibility in humans, we looked up a gene-based association study in the UK Biobank data set and identified 7 rare ITPR1 missense variants showing potential association with cardiac arrhythmias. Remarkably, in vitro functional characterization revealed that all these 7 ITPR1 variants resulted in GOF. CONCLUSIONS: Our studies in mice and humans reveal that enhanced function of ITPR1 , a well-known movement disorder gene, increases the risk for cardiac arrhythmias.

Sattar A., Cook K.L., Rai S.K., Berthier E., Allen S., Rinzin S., Van Wyk de Vries M., Haeberli W., Kushwaha P., Shugar D.H., Emmer A., Haritashya U.K., Frey H., Rao P., Gurudin K.S., et. al.

On 3 October 2023, a multihazard cascade in the Sikkim Himalaya, India, was triggered by 14.7 million m 3 of frozen lateral moraine collapsing into South Lhonak Lake, generating an ~20 m tsunami-like impact wave, breaching the moraine, and draining ~50 million m 3 of water. The ensuing Glacial Lake Outburst Flood (GLOF) eroded ~270 million m 3 of sediment, which overwhelmed infrastructure, including hydropower installations along the Teesta River. The physical scale and human and economic impact of this event prompts urgent reflection on the role of climate change and human activities in exacerbating such disasters. Insights into multihazard evolution are pivotal for informing policy development, enhancing Early Warning Systems (EWS), and spurring paradigm shifts in GLOF risk management strategies in the Himalaya and other mountain environments.

Jiang C., Sun H., Feng D., Xie Z., Tan B., Liu K.

Convolutional neural networks (CNNs) successfully detect lithographic hotspots by learning from hand-designed features of layout patterns or entire layouts, as images, in an end-to-end fashion. However, compared to lithography simulation, CNN-based solutions demonstrate inferior hotspot detection accuracy and a high false-alarm rate. Moreover, the interpretability of the hotspot prediction process has yet to be considered due to the “black-box” nature of CNNs. In this work, inspired by conventional lithography simulation where defect regions are simulated as direct evidence for hotspot identification, we propose an explainable two-stage CNN-based hotspot detector that considers both the accuracy and interpretability of hotspot detection. Our architecture learns to locate the defect areas in the first stage as extracted hotspot features. In the second stage, we combine the strength of feature engineering and end-to-end learning, incorporating the original layout input, the learned defect location map from the first stage, and a fixed auxiliary region of interest (ROI) map for final hotspot detection. Experimental results for our technique exhibit the highest hotspot accuracy (98.1%) and the lowest false-alarm rate (4.0%) thus far compared to all prior CNN solutions. We also demonstrate the best overall qualitative and quantitative interpretability results with the highest increase in confidence (IC) and the lowest average drop (AD) in scores when CNN interpretation methods such as Grad-CAM-based approaches are applied. We further demonstrate use cases of our technique for successfully justifying and pinpointing hotspot mispredictions by examining the prediction evidence from our learned defect locations.

Rahman R., Fouhse J.M., Ju T., Fan Y., Bhardwaj T., Brook R.K., Nosach R., Harding J., Willing B.P.

ABSTRACT Colonization of co-evolved, species-specific microbes in early life plays a crucial role in gastrointestinal development and immune function. This study hypothesized that modern pig production practices have resulted in the loss of co-evolved species and critical symbiotic host-microbe interactions. To test this, we reintroduced microbes from wild boars (WB) into conventional piglets to explore their colonization dynamics and effects on gut microbial communities, metabolite profiles, and immune responses. At postnatal day (PND) 21, 48 piglets were assigned to four treatment groups: (i) WB-derived mixed microbial community (MMC), (ii) sow-derived MMC, (iii) a combination of WB and sow MMC (Mix), or (iv) Control (PBS). Post-transplantation analyses at PND 48 revealed distinct microbial communities in WB-inoculated piglets compared with Controls, with trends toward differentiation from Sow but not Mix groups. WB-derived microbes were more successful in colonizing piglets, particularly in the Mix group, where they competed with Sow-derived microbes. WB group cecal digesta enriched with Lactobacillus helveticus , Lactobacillus mucosae , and Lactobacillus pontis . Cecal metabolite analysis showed that WB piglets were enriched in histamine, acetyl-ornithine, ornithine, citrulline, and other metabolites, with higher histamine levels linked to Lactobacillus abundance. WB piglets exhibited lower cecal IL-1β and IL-6 levels compared with Control and Sow groups, whereas the Mix group showed reduced IFN-γ, IL-2, and IL-6 compared with the Sow group. No differences in weight gain, fecal scores, or plasma cytokines were observed, indicating no adverse effects. These findings support that missing WB microbes effectively colonize domestic piglets and may positively impact metabolite production and immune responses. IMPORTANCE This study addresses the growing concern over losing co-evolved, species-specific microbes in modern agricultural practices, particularly in pig production. The implementation of strict biosecurity measures and widespread antibiotic use in conventional farming systems may disrupt crucial host-microbe interactions that are essential for gastrointestinal development and immune function. Our research demonstrates that by reintroducing wild boar-derived microbes into domestic piglets, these microbes can successfully colonize the gut, influence microbial community composition, and alter metabolite profiles and immune responses without causing adverse effects. These findings also suggest that these native microbes can fill an intestinal niche, positively impacting immune activation. This research lays the groundwork for future strategies to enhance livestock health and performance by restoring natural microbial populations that produce immune-modulating metabolites.

Liu C., Huang Z., Wang X.

Hosseini-Yazdi S., Kuo A.D.

ABSTRACT Humans expend more energy walking on uneven terrain, but the amount varies across terrains. Few experimental characterizations exist, each describing terrain qualitatively without any relation to others or to flat ground. This precludes mechanistic explanation of the energy costs. Here, we show that energy costs vary smoothly and approximately quadratically as a function of terrain amplitude. We tested this with healthy adults (N=10) walking on synthetic uneven terrain with random step heights of parametrically controlled maximum amplitude (four conditions 0–0.045 m) and at four walking speeds (0.8–1.4 m s−1). Both net metabolic rate and the rate of positive work increased approximately with amplitude squared and speed cubed (R2=0.74, 0.82, respectively), as predicted by a simple walking model. The model requires work to redirect the body center of mass velocity between successive arcs described by pendulum-like legs, at proportional metabolic cost. Humans performed most of the greater work with terrain amplitude early in the single stance phase, and with speed later in stance during push-off. Work and energy rates changed with approximately linear proportionality, with a ratio or delta efficiency of 49.5% (R2=0.68). The efficiency was high enough to suggest substantial work performed passively by elastic tendon and not only by active muscle. Simple kinematic measures such as mid-swing foot clearance also increased with terrain amplitude (R2=0.65), possibly costing energy as well. Nevertheless, most of the metabolic cost of walking faster or on more uneven terrain can be explained mechanistically by the work performed.

He M., Wu H., Shen X., Zhuang W.

Caddey B., Fisher S., Barkema H.W., Nobrega D.B.

SUMMARY Numerous questions persist regarding the role of companion animals as potential reservoirs of antimicrobial-resistant organisms that can infect humans. While relative antimicrobial usage in companion animals is lower than that in humans, certain antimicrobial-resistant pathogens have comparable colonization rates in companion animals and their human counterparts, which inevitably raises questions regarding potential antimicrobial resistance (AMR) transmission. Furthermore, the close contact between pets and their owners, as well as pets, veterinary professionals, and the veterinary clinic environment, provides ample opportunity for zoonotic transmission of antimicrobial-resistant pathogens. Here we summarize what is known about the transmission of AMR and select antimicrobial-resistant organisms between companion animals (primarily dogs, cats, and horses) and humans. We also describe the global distribution of selected antimicrobial-resistant organisms in companion animals. The impact of interspecies AMR transmission within households and veterinary care settings is critically reviewed and discussed in the context of methicillin-resistant staphylococci, extended-spectrum β-lactamase and carbapenemase-producing bacteria. Key research areas are emphasized within established global action plans on AMR, offering valuable insights for shaping future research and surveillance initiatives.

Ghasoub M., Scholten C., Geeraert B., Long X., Joshi S., Wedderburn C.J., Roos A., Subramoney S., Hoffman N., Narr K., Woods R., Zar H.J., Stein D.J., Donald K., Lebel C.

Abstract Introduction: Prenatal alcohol exposure (PAE) is associated with various neurological, behavioral and cognitive deficits, including reading and language. Previous studies have demonstrated altered white matter in children and adolescents with PAE and associations with reading and language performance in children aged 3 years and older. However, little research has focused on the toddler years, despite this being a critical period for behavioral and neural development. We aimed to determine associations between structural brain connectivity and early language skills in toddlers, in the context of PAE. Methods: 88 toddlers (2–3 years, 56 males), 23 of whom had PAE, underwent a diffusion MRI scan in Cape Town, South Africa, with language skills assessed using the Expressive and Receptive Communication subtests from the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). Diffusion scans were preprocessed to create a structural network of regions associated with language skills using graph theory analysis. Linear regression models were used to examine moderation effects of PAE on structural network properties and language skills. Results: Toddlers with PAE had higher structural connectivity in language networks than unexposed children. PAE moderated the relationship between structural network properties and Expressive Communication scores. None of the effects survived correction for multiple comparisons. Conclusion: Our findings show weak moderation effects of PAE on structural language network properties and language skills. Our study sheds light on the structural connectivity correlates of early language skills in an understudied population during a critical neurodevelopmental period, laying the foundation for future research.

Rose J., Chong A., McKinley K., Meckler G., Van Rooij T., Görges M., Principi T., Gravel J., Singh D., Hurley K., Wright B., Turner T., Mater A., Burstein B., Doan Q.

Objectives: We aimed to develop a comprehensive list of patient care components performed by pediatric emergency department (PED) physicians that could be individually scored on their subjective workload using the National Aeronautics and Space Administration Task Load Index (NASA-TLX). These “care components,” alongside patient and environmental factors that influence workload (“modifiers”), will form the basis of the Standardized Workload Assessment Metric for Pediatric Emergency Departments (SWAMPED). We sought to obtain preliminary workload scores for each care component and assess the face validity of the NASA-TLX-derived workload tool. Methods: After establishing a working list of “care elements” and modifiers, we convened an expert panel during a 3-day workshop to curate a comprehensive list of PED patient care components and modifiers affecting physician workload using a modified Delphi process. Experts completed a pilot version of the NASA-TLX-derived workload survey for each care component. A virtual follow-up was held 5 months after the initial meeting to finalize the list of modifiers and care components. Results: Of the 93 initial care elements and 75 modifiers, 46 care components were retained, alongside 6 final modifiers. Preliminary workload scores showed “high acuity, low occurrence procedures (cricothyroidotomy, thoracotomy, pericardiocentesis, burr hole, etc.),” with the highest median workload score of 106, while “immobilization device simple (prefabricated)” had the lowest median workload score of 22. Conclusions: The SWAMPED, derived through expert consensus, holds promise as a standardized assessment tool for PED physician workload. Validation studies involving larger cohorts are crucial for refining the SWAMPED and allowing widespread adoption of this novel quantitative workload metric.

Stewart C., Owen C., Street L., Hay K., Perry S., Duggan P., Shafey M., Balogh A., Cao J., Chua N., Stewart D., Puckrin R.

Fukuchi C.A., Stefanyshyn D.J., Wannop J.W.