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Neurosignaling is increasingly recognized as a critical factor in cancer progression, where neuronal innervation of primary tumors contributes to the disease's advancement. This study focuses on segmenting individual axons within the prostate tumor microenvironment, which have been challenging to detect and analyze due to their irregular morphologies. We present a novel deep learning-based approach for the automated segmentation of axons, AxonFinder, leveraging a U-Net model with a ResNet-101 encoder, based on a multiplexed imaging approach. Utilizing a dataset of whole-slide images from low-, intermediate-, and high-risk prostate cancer patients, we manually annotated axons to train our model, achieving significant accuracy in detecting axonal structures that were previously hard to segment. Our analysis includes a comprehensive assessment of axon density and morphological features across different CAPRA-S prostate cancer risk categories, providing insights into the correlation between tumor innervation and cancer progression. Our paper suggests the potential utility of neuronal markers in the prognostic assessment of prostate cancer in aiding the pathologist's assessment of tumor sections and advancing our understanding of neurosignaling in the tumor microenvironment.

Mapping the spatial interactions of cancer, immune, and stromal cell states presents novel opportunities for patient stratification and for advancing immunotherapy. While single-cell studies revealed significant molecular heterogeneity in prostate cancer cells, the impact of spatial stromal cell heterogeneity remains poorly understood. Here, we used cyclic immunofluorescent imaging on whole-tissue sections to uncover novel spatial associations between cancer and stromal cells in low- and high-grade prostate tumors and tumor-adjacent normal tissues. Our results provide a spatial map of single cells and recurrent cellular neighborhoods in the prostate tumor microenvironment of treatment-naive patients. We report unique populations of mast cells that show distinct spatial associations with M2 macrophages and regulatory T cells. Our results show disease-specific neighborhoods that are primarily driven by androgen receptor-positive (AR+) stromal cells and identify inflammatory gene networks active in AR+ prostate stroma., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Challenging behaviours are a long-term burden for people with traumatic brain injury (TBI) and their families. Families frequently shoulder the responsibility alone, but little is known about the strategies they use to manage these behaviours. This study aimed to 1) identify the coping strategies used by people with TBI living in the community and their family caregivers to manage challenging behaviours; and 2) describe the similarities and differences between strategies used by people with TBI and caregivers. In this qualitative descriptive design, individual semi-structured interviews were conducted with adults with TBI and their caregivers and were inductively analyzed. The sample included 10 dyads and two triads, totalling 12 caregivers (8 women) and 14 individuals with TBI (6 women; 21.71 ± 10.84 years post-injury). Participants' strategies were proactive (prevention), reactive (response), or retroactive (aftercare). Most strategies were described by caregivers. Some of them were effective and lasting, others not, reflecting how they adapted their approaches over time. Families put in place various strategies in their life's journey, such as giving feedback or adapting the environment. Despite these strategies supporting long-term community living, the need for ongoing support is underscored, as crises may still occur, impacting families' quality of life.

Wound infections are highly prevalent and can lead to delayed or failed healing, causing significant morbidity and adverse economic impacts. These infections occur in various contexts, including diabetic foot ulcers, burns, and surgical sites. Enterococcus faecalis is often found in persistent non-healing wounds, but its contribution to chronic wounds remains understudied. To address this, we employed single-cell RNA sequencing (scRNA-seq) on infected wounds in comparison to uninfected wounds in a mouse model. Examining over 23,000 cells, we created a comprehensive single-cell atlas that captures the cellular and transcriptomic landscape of these wounds. Our analysis revealed unique transcriptional and metabolic alterations in infected wounds, elucidating the distinct molecular changes associated with bacterial infection compared to the normal wound healing process. We identified dysregulated keratinocyte and fibroblast transcriptomes in response to infection, jointly contributing to an anti-inflammatory environment. Notably, E. faecalis infection prompted a premature, incomplete epithelial-mesenchymal transition in keratinocytes. Additionally, E. faecalis infection modulated M2-like macrophage polarization by inhibiting pro-inflammatory resolution in vitro, in vivo, and in our scRNA-seq atlas. Furthermore, we discovered macrophage crosstalk with neutrophils, which regulates chemokine signaling pathways, while promoting anti-inflammatory interactions with endothelial cells. Overall, our findings offer new insights into the immunosuppressive role of E. faecalis in wound infections., Competing Interests: CC, SL, FT, MV, KK, GT No competing interests declared, (© 2024, Celik et al.)

Challenging behaviours significantly impact the lives of people with traumatic brain injury (TBI) and their family caregivers. However, these behaviours are rarely defined from the perspectives of both individuals, a necessary step to developing interventions targeting meaningful goals for individuals and caregivers. This study aimed to (1) explore and confirm the perspective of individuals with TBI living in the community and their family caregivers on behaviours they consider challenging and, (2) identify overlapping or distinct views on challenging behaviours. A qualitative descriptive design was used. Twelve caregivers (8 females; 59.67  ±  11.64 years old) and 14 participants with mild-severe TBI (6 females; 43.21  ±  10.98 years old; time post-injury: 21.71  ±  10.84 years) were interviewed (10 dyads and two triads). Data were analysed using inductive qualitative analysis. Challenging behaviours most frequently reported by all participants were aggressive/impulsive behaviours, inappropriate social behaviours, and behavioural manifestations of cognitive impairments. Overlapping perspectives were identified regarding aggressive behaviours. Distinctions exist as inappropriate social behaviours and cognitive difficulties were mainly reported by caregivers. Our results confirm that perspectives may vary between dyad members. Interventions should include dyad inputs to formulate goals that are significant to the person with TBI and their caregiver.

Focused ion beam-scanning electron microscopy (FIB-SEM) images can provide a detailed view of the cellular ultrastructure of tumor cells. A deeper understanding of their organization and interactions can shed light on cancer mechanisms and progression. However, the bottleneck in the analysis is the delineation of the cellular structures to enable quantitative measurements and analysis. We mitigated this limitation using deep learning to segment cells and subcellular ultrastructure in 3D FIB-SEM images of tumor biopsies obtained from patients with metastatic breast and pancreatic cancers. The ultrastructures, such as nuclei, nucleoli, mitochondria, endosomes, and lysosomes, are relatively better defined than their surroundings and can be segmented with high accuracy using a neural network trained with sparse manual labels. Cell segmentation, on the other hand, is much more challenging due to the lack of clear boundaries separating cells in the tissue. We adopted a multi-pronged approach combining detection, boundary propagation, and tracking for cell segmentation. Specifically, a neural network was employed to detect the intracellular space; optical flow was used to propagate cell boundaries across the z-stack from the nearest ground truth image in order to facilitate the separation of individual cells; finally, the filopodium-like protrusions were tracked to the main cells by calculating the intersection over union measure for all regions detected in consecutive images along z-stack and connecting regions with maximum overlap. The proposed cell segmentation methodology resulted in an average Dice score of 0.93. For nuclei, nucleoli, and mitochondria, the segmentation achieved Dice scores of 0.99, 0.98, and 0.86, respectively. The segmentation of FIB-SEM images will enable interpretative rendering and provide quantitative image features to be associated with relevant clinical variables., Competing Interests: JG has licensed technologies to Abbott Diagnostics; has ownership positions in Convergent Genomics, Health Technology Innovations, Zorro Bio, and PDX Pharmaceuticals; serves as a paid consultant to New Leaf Ventures; has received research support from Thermo Fisher Scientific (formerly FEI), Zeiss, Miltenyi Biotec, Quantitative Imaging, Health Technology Innovations, and Micron Technologies; and owns stock in Abbott Diagnostics, AbbVie, Alphabet, Amazon, Amgen, Apple, General Electric, Gilead, Intel, Microsoft, NVIDIA, and Zimmer Biomet. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Machireddy, Thibault, Loftis, Stoltz, Bueno, Smith, Riesterer, Gray and Song.)

Electron microscopy (EM) enables imaging at a resolution of nanometers and can shed light on how cancer evolves to develop resistance to therapy. Acquiring these images has become a routine task.However, analyzing them is now a bottleneck, as manual structure identification is very time-consuming and can take up to several months for a single sample. Deep learning approaches offer a suitable solution to speed up the analysis. In this work, we present a study of several state-of-the-art deep learning models for the task of segmenting nuclei and nucleoli in volumes from tumor biopsies. We compared previous results obtained with the ResUNet architecture to the more recent UNet++, FracTALResNet, SenFormer, and CEECNet models. In addition, we explored the utilization of unlabeled images through semi-supervised learning with Cross Pseudo Supervision. We have trained and evaluated all of the models on sparse manual labels from three fully annotated in-house datasets that we have made available on demand, demonstrating improvements in terms of 3D Dice score. From the analysis of these results, we drew conclusions on the relative gains of using more complex models, and semi-supervised learning as well as the next steps for the mitigation of the manual segmentation bottleneck., Competing Interests: JG has licensed technologies to Abbott Diagnostics; has ownership positions in Convergent Genomics, Health Technology Innovations, Zorro Bio and PDX Pharmaceuticals; serves as a paid consultant to New Leaf Ventures; has received research support from Thermo Fisher Scientific (formerly FEI), Zeiss, Miltenyi Biotech, Quantitative Imaging, Health Technology Innovations and Micron Technologies; and owns stock in Abbott Diagnostics, AbbVie, Alphabet, Amazon, Amgen, Apple, General Electric, Gilead, Intel, Microsoft, Nvidia, and Zimmer Biomet. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Pagano, Thibault, Bousselham, Riesterer, Song and Gray.)

Context In the exercise of his practice, the psychiatrist is commonly called upon to assess the suicidal risk of a patient and may, under the circumstances, engage his professional liability and become the subject of a civil suit in the event of the death of the patient. Despite the existence of guidelines and tools for the assessment and management of suicide risk, the practice often remains unstandardized. Few studies have focused on the assessment and management of this risk from a legal perspective. Some knowledge of case law could be useful to psychiatrists in making future decisions, both from a medico-legal point of view and to improve the care offered. Objectives This article aims to study the civil liability of the psychiatrist following the suicide of a patient by analyzing Canadian case law from a perspective of continuous improvement of practice with particular attention to the assessment and management of suicide risk. Method A systematic review of the judgments was carried out on CanLII.org, a virtual library of Canadian legal information allowing access to the judgments rendered by the courts of first instance, the Courts of Appeal as well as those of the Supreme Court of Canada. The search strategy consisted in using the key words "suicide," "psychiatrie," "faute" and "responsabilité" as well as their English translation to retain the recourses where a judgment was rendered by the court and where at least one psychiatrist acted as a defendant or co-defendant following the suicide of a patient. Results Nine judgments met our inclusion criteria. Since elements were of interest for our research question, it seemed wise to us to also include three decisions where the patient did not die of his suicidal attempt but kept significant sequelae. The analysis of the judgments made it possible to identify the alleged faults most often reproached to the psychiatrist by the plaintiff and to present the usual position of the courts, and the arguments which underlie them. The alleged faults can be grouped into three categories: an assessment of the suicide risk deemed faulty, a management of the suicide risk by supervisory measures deemed faulty and an omission to have used legal custody measures when they should have been applied. In nearly all cases, Canadian courts render a decision in favor of the psychiatrist, demonstrating sensitivity to the reality of psychiatrists' practice. The recommendations resulting from our analysis of Canadian case law support the guidelines of the American Psychiatric Association and the Ontario Hospital Association practice guidelines for suicide risk assessment and management, particularly in terms of the content of evaluation, specific moments of re-evaluation and documentation. Conclusion Knowledge of Canadian case law on civil liability for the suicide of a patient represents an additional asset for the practice of responsible and quality psychiatry.

The ErbB family of receptor tyrosine kinases is a primary target for small molecules and antibodies for pancreatic cancer treatment. Nonetheless, the current treatments for this tumor are not optimal due to lack of efficacy, resistance, or toxicity. Here, using the novel BiXAb™ tetravalent format platform, we generated bispecific antibodies against EGFR, HER2, or HER3 by considering rational epitope combinations. We then screened these bispecific antibodies and compared them with the parental single antibodies and antibody pair combinations. The screen readouts included measuring binding to the cognate receptors (mono and bispecificity), intracellular phosphorylation signaling, cell proliferation, apoptosis and receptor expression, and also immune system engagement assays (antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity). Among the 30 BiXAbs™ tested, we selected 3Patri-1Cetu-Fc, 3Patri-1Matu-Fc and 3Patri-2Trastu-Fc as lead candidates. The in vivo testing of these three highly efficient bispecific antibodies against EGFR and HER2 or HER3 in pre-clinical mouse models of pancreatic cancer showed deep antibody penetration in these dense tumors and robust tumor growth reduction. Application of such semi-rational/semi-empirical approach, which includes various immunological assays to compare pre-selected antibodies and their combinations with bispecific antibodies, represents the first attempt to identify potent bispecific antibodies against ErbB family members in pancreatic cancer., Competing Interests: Authors EAZ and P-EG were employed by company Biomunex Pharmaceuticals. AP and CL report a patent regarding a combination of anti-HER2 and anti-EGFR antibodies PCT/EP2009/012133. AP, CL, P-EG and EAZ report a patent regarding anti-EGFR/HER2 bispecific antibodies WO2017/186950. MC and SC-T report a patent regarding multi-specific antibodies WO2013/005194. P-EG and EAZ report a patent regarding polypeptide linkers and stable multi-specific antibodies WO2018/127608, WO2018/178101. One patent is pending regarding this work application number EP22305242.4. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rabia, Garambois, Dhommée, Larbouret, Lajoie, Buscail, Jimenez-Dominguez, Choblet-Thery, Liaudet-Coopman, Cerutti, Jarlier, Ravel, Gros, Pirot, Thibault, Zhukovsky, Gérard, Pèlegrin, Colinge and Chardès.)

New developments in electron microscopy technology, improved efficiency of detectors, and artificial intelligence applications for data analysis over the past decade have increased the use of volume electron microscopy (vEM) in the life sciences field. Moreover, sample preparation methods are continuously being modified by investigators to improve final sample quality, increase electron density, combine imaging technologies, and minimize the introduction of artifacts into specimens under study. There are a variety of conventional bench protocols that a researcher can utilize, though most of these protocols require several days. In this work, we describe the utilization of an automated specimen processor, the mPrep™ ASP-2000™, to prepare samples for vEM that are compatible with focused ion beam scanning electron microscopy (FIB-SEM), serial block face scanning electron microscopy (SBF-SEM), and array tomography (AT). The protocols described here aimed for methods that are completed in a much shorter period of time while minimizing the exposure of the operator to hazardous and toxic chemicals and improving the reproducibility of the specimens' heavy metal staining, all without compromising the quality of the data acquired using backscattered electrons during SEM imaging. As a control, we have included a widely used sample bench protocol and have utilized it as a comparator for image quality analysis, both qualitatively and using image quality analysis metrics., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The endoplasmic reticulum (ER) is a complex and dynamic organelle that regulates many cellular pathways, including protein synthesis, protein quality control, and lipid synthesis. When one or multiple ER roles are dysregulated and saturated, the ER enters a stress state, which, in turn, activates the highly conserved unfolded protein response (UPR). By sensing the accumulation of unfolded proteins or lipid bilayer stress (LBS) at the ER, the UPR triggers pathways to restore ER homeostasis and eventually induces apoptosis if the stress remains unresolved. In recent years, it has emerged that the UPR works intimately with other cellular pathways to maintain lipid homeostasis at the ER, and so does at cellular levels. Lipid distribution, along with lipid anabolism and catabolism, are tightly regulated, in part, by the ER. Dysfunctional and overwhelmed lipid-related pathways, independently or in combination with ER stress, can have reciprocal effects on other cellular functions, contributing to the development of diseases. In this review, we summarize the current understanding of the UPR in response to proteotoxic stress and LBS and the breadth of the functions mitigated by the UPR in different tissues and in the context of diseases., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cold affects many aspects of biology, medicine, agriculture, and industry. Here, we identify a conserved endoplasmic reticulum (ER) stress response, distinct from the canonical unfolded protein response, that maintains lipid homeostasis during extreme cold. We establish that the ER stress sensor IRE-1 is critical for resistance to extreme cold and activated by cold temperature. Specifically, neuronal IRE-1 signals through JNK-1 and neuropeptide signaling to regulate lipid composition within the animal. This cold-response pathway can be bypassed by dietary supplementation with unsaturated fatty acids. Altogether, our findings define an ER-centric conserved organism-wide cold stress response, consisting of molecular neuronal sensors, effectors, and signaling moieties, which control adaptation to cold conditions in the organism. Better understanding of the molecular basis of this stress response is crucial for the optimal use of cold conditions on live organisms and manipulation of lipid saturation homeostasis, which is perturbed in human pathologies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Human proteins expressed in yeast are common to enhance protein production while the expression of functional human pathways remain challenging. Here, we propose a simple and economical high-throughput gene assembly method to create a yeast megaplasmid library from human cDNA to screen for minimal human functional pathways. We introduced artificial promoters followed by symmetric loxP sites into the megaplasmids using Golden Gate assembly coupled with streptavidin-bead-based purification. The isolated high molecular weight, randomly assembled cDNA megaplasmid library may be useful for high-throughput directed evolution experiments and may be adapted for use in other model organisms., (Copyright: © 2022 by the authors.)

Metabolic diseases often share common traits, including accumulation of unfolded proteins in the endoplasmic reticulum (ER). Upon ER stress, the unfolded protein response (UPR) is activated to limit cellular damage which weakens with age. Here, we show that Caenorhabditis elegans fed a bacterial diet supplemented high glucose at day 5 of adulthood (HGD-5) extends their lifespan, whereas exposed at day 1 (HGD-1) experience shortened longevity. We observed a metabolic shift only in HGD-1, while glucose and infertility synergistically prolonged the lifespan of HGD-5, independently of DAF-16. Notably, we identified that UPR stress sensors ATF-6 and PEK-1 contributed to the longevity of HGD-5 worms, while ire-1 ablation drastically increased HGD-1 lifespan. Together, we postulate that HGD activates the otherwise quiescent UPR in aged worms to overcome ageing-related stress and restore ER homeostasis. In contrast, young animals subjected to HGD provokes unresolved ER stress, conversely leading to a detrimental stress response., (© 2022. The Author(s).)

Bispecific antibodies (BsAbs) represent an important advance in innovative therapeutic strategies. Among the countless formats of BsAbs, fusion with molecules such as anticalins linked to a monoclonal antibody (mAb), represents an easy and low-cost way to obtain innovative molecules. We fused an anticalin against human fibronectin to a molecule biosimilar to trastuzumab (H0) or rituximab (R0), in four different positions, two on the N terminal region of heavy or light chains and two on the C terminal region. The eight BsAbs (H family (HF) 1 to 4 and R family (RF) 1 to 4) were produced and their affinity parameters and functional properties evaluated. The presence of anticalin did not change the glycosylation of the BsAb, shape or yield. The antigenic recognition of each BsAb family, Her2 for HF1 to 4 and CD20 for RF1 to 4, was slightly decreased (HF) or absent (RF) for the anticalin N-terminal in the light chain position. The anticalin recognition of FN was slightly decreased for the HF family, but a dramatic decrease was observed for RF members with lowest affinity for RF1. Moreover, functional properties of Abs, such as CD16 activation of NK, CD32-dependent phagocytosis and FcRn transcytosis, confirmed that this anticalin position leads to less efficient BsAbs, more so for RF than HF molecules. Nevertheless, all BsAbs demonstrated affinities for CD16, CD32 and FcRn, which suggests that more than affinity for FcRs is needed for a functioning antibody. Our strategy using anticalin and Abs allows for rapid generation of BsAbs, but as suggested by our results, some positions of anticalins on Abs result in less functionality.

Protein folding and quality control is tightly regulated at the endoplasmic reticulum (ER), and its disruption is associated with many diseases. In eukaryotes, the accumulation of unfolded protein in the ER is sensed by the three sensors, IRE1, PERK, and ATF6 to activate the unfolded protein response (UPR) to restore ER homeostasis. However, uncoupling the sensing of each sensor and their respective downstream pathways has been challenging as the absence of one is compensated by the remaining two sensors. Here, we report a fully functional human PERK (hPERK) chimeric protein expressed in Saccharomyces cerevisiae that could be used for high throughput screen to identify new PERK inhibitory or activating compounds as well as to characterize the PERK stress sensing mechanisms., (Copyright: © 2022 by the authors.)

Mechanisms of therapeutic resistance and vulnerability evolve in metastatic cancers as tumor cells and extrinsic microenvironmental influences change during treatment. To support the development of methods for identifying these mechanisms in individual people, here we present an omic and multidimensional spatial (OMS) atlas generated from four serial biopsies of an individual with metastatic breast cancer during 3.5 years of therapy. This resource links detailed, longitudinal clinical metadata that includes treatment times and doses, anatomic imaging, and blood-based response measurements to clinical and exploratory analyses, which includes comprehensive DNA, RNA, and protein profiles; images of multiplexed immunostaining; and 2- and 3-dimensional scanning electron micrographs. These data report aspects of heterogeneity and evolution of the cancer genome, signaling pathways, immune microenvironment, cellular composition and organization, and ultrastructure. We present illustrative examples of how integrative analyses of these data reveal potential mechanisms of response and resistance and suggest novel therapeutic vulnerabilities., Competing Interests: D.S. is employed by Quantitative Imaging Systems. L.M.C. is a paid consultant for Cell Signaling Technologies, Shasqi, and AbbVie; received reagent and/or research support from Plexxikon, Pharmacyclics, Acerta Pharma, Deciphera Pharmaceuticals, Genentech, Roche Glycart AG, Syndax Pharmaceuticals, Innate Pharma, and NanoString Technologies; and is a member of the scientific advisory boards of Syndax Pharmaceuticals, Carisma Therapeutics, Zymeworks, Verseau Therapeutics, Cytomix Therapeutics, and Kineta. G.B.M. has licensed technologies to Myriad Genetics and NanoString; is on the SAB or is a consultant to Amphista, AstraZeneca, Chrysallis Biotechnology, GSK, ImmunoMET, Ionis, Lilly, PDX Pharmaceuticals, Signalchem Lifesciences, Symphogen, Tarveda, Turbine, and Zentalis Pharmaceuticals; and has stock/options/financial interests in Catena Pharmaceuticals, ImmunoMet, SignalChem, and Tarveda. J.W.G. has licensed technologies to Abbott Diagnostics, Zorro Bio, and PDX Pharmaceuticals; has ownership positions in Convergent Genomics, Health Technology Innovations, Zorro Bio, and PDX Pharmaceuticals; serves as a paid consultant to New Leaf Ventures; has received research support from Thermo Fisher Scientific (formerly FEI), Zeiss, Miltenyi Biotech, Cepheid (Danaher), Quantitative Imaging, Health Technology Innovations, and Micron Technologies; and owns stock in Abbott Diagnostics, AbbVie, Alphabet, Amazon, Amgen, Apple, General Electric, Gilead, Intel, Microsoft, Nvidia, and Zimmer Biomet., (© 2022 The Authors.)

High-Intensity Interval Training (HIIT) is a time-efficient training method suggested to improve health and fitness for the clinical population, healthy subjects, and athletes. Many parameters can impact the difficulty of HIIT sessions. This study aims to highlight and explain, through logical deductions, some limitations of the Skiba and Coggan models, widely used to prescribe HIIT sessions in cycling. We simulated 6198 different HIIT training sessions leading to exhaustion, according to the Skiba and Coggan-Modified (modification of the Coggan model with the introduction of an exhaustion criterion) models, for three fictitious athlete profiles (Time-Trialist, All-Rounder, Sprinter). The simulation revealed impossible sessions (i.e., requiring athletes to surpass their maximal power output over the exercise interval duration), characterized by a few short exercise intervals, performed in the severe and extreme intensity domains, alternating with long recovery bouts. The fraction of impossible sessions depends on the athlete profile and ranges between 4.4 and 22.9% for the Skiba model and 0.6 and 3.2% for the Coggan-Modified model. For practitioners using these HIIT models, this study highlights the importance of understanding these models' inherent limitations and mathematical assumptions to draw adequate conclusions from their use to prescribe HIIT sessions.

Background: Rabbit antithymocyte globulins (rATGs) are polyclonal antibodies used to prevent acute cellular rejection in kidney transplantation. Their dosing remains largely empirical and the question of an individualized dose is still unresolved., Methods: Data from a prospective study in 17 kidney transplant patients were used to develop a model describing the dose-concentration-response relationship of rATG with T-lymphocyte subpopulation counts over time. The model was validated using an independent cohort of kidney transplant patients treated by rATG in the same center., Results: Pharmacokinetics of rATG was described using a two-compartment model integrating a third compartment and a target-mediated elimination for active rATG. The kinetics of CD3 + , CD4 + , CD8 + , and CD3 - CD56 + cell counts over time were described by a pharmacokinetic-pharmacodynamic model with transit compartments, integrating both CD3 - CD56 + -independent and CD3 - CD56 + -dependent rATG-mediated lymphocyte depletion, and a positive feedback. Elimination of rATG was influenced by age and body surface area, while its distribution was also influenced by body surface area. CD3 + proliferation rate decreased with age and CD3 - CD56 + -mediated elimination was influenced by the V158F-FCGR3A polymorphism. Binary efficacy and tolerance endpoints were defined as a CD3 + count < 20 mm -3 for at least 7 days and a CD4 + count > 200 mm -3 at 1 year, respectively. Simulations showed that increasing or decreasing the standard 6-mg/kg dose will impact both tolerance and efficacy, while a dose decrease may be beneficial in elderly patients., Conclusions: Our results can be used to design prospective clinical trials testing dose individualization based on patients' characteristics., Clinical Trial Registration: Eudract No. 2009-012673-35., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Traumatic brain injury (TBI) is a leading cause of death and disability among adults. Falls and motor vehicle collisions (MVCs) are the most common causes of TBI hospitalizations in Canada. The purpose of this study was to determine whether, at the provincial level, there have been significant changes in the injury rate and causes of major TBI. This was a retrospective cohort study of all patients in Nova Scotia who presented with major TBI (Abbreviated Injury Scale Head score ≥ 3) between 2002 and 2018. Prospectively entered data were collected from the Nova Scotia Trauma Registry. Annual injury rates were calculated based on 100,000 population (all ages) using population estimates from Statistics Canada. Linear regression was performed to analyze annual trends of major TBI within the province. There were 5590 major TBI patients in Nova Scotia during the 16-year study period. The overall annual rate of major TBI was 37 per 100,000 population. There was a 39% increase in the rate of major TBI over the study period (r =  - 0.72, R2 = 0.51, p < 0.002). Patients had a mean age of 51 ± 25 years; 72% were male. The proportion of TBIs in males decreased significantly from 76% in 2002 to 69% in 2017 (p < 0.001). Mechanisms of injury were predominantly falls (45%) and MVCs (29%); the proportion of violent injuries was 11.5%. The rate of fall-related TBIs more than doubled between 2002 and 2017, increasing from 9.1 to 20.5 injuries per 100,000 (p < 0.001). Our findings demonstrate an increasing incidence of major TBI over a 16-year period with a greater than two-fold increase in the rate of fall-related TBI. These results are important for targeting TBI prevention efforts in reducing falls, especially in older adults., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)