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Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3am-/p+ were reduced in the maternal inherited deletion group with no observable change in the Ube3am+/p- paternal transmission cohort. We also discovered Ube3am-/p+ exhibited delayed reflex development, motor deficits in rearing and fine motor skills, aberrant social communication, and impaired touchscreen learning and memory in young adults. These behavioral deficits were large in effect size and easily apparent in the larger rodent species. Low social communication was detected using a playback task that is unique to rats. Structural imaging illustrated decreased brain volume in Ube3am-/p+ and a variety of intriguing neuroanatomical phenotypes while Ube3am+/p- did not exhibit altered neuroanatomy. Our report identifies, for the first time, unique AS relevant functional phenotypes and anatomical markers as preclinical outcomes to test various strategies for gene and molecular therapies in AS.

The topics of verification and validation have increasingly been discussed in the field of computational biomechanics, and many recent articles have applied these concepts in an attempt to build credibility for models of complex biological systems. Verification and validation are evolving techniques that, if used improperly, can lead to false conclusions about a system under study. In basic science, these erroneous conclusions may lead to failure of a subsequent hypothesis, but they can have more profound effects if the model is designed to predict patient outcomes. While several authors have reviewed verification and validation as they pertain to traditional solid and fluid mechanics, it is the intent of this paper to present them in the context of computational biomechanics. Specifically, the task of model validation will be discussed, with a focus on current techniques. It is hoped that this review will encourage investigators to engage and adopt the verification and validation process in an effort to increase peer acceptance of computational biomechanics models. [ABSTRACT FROM AUTHOR]

1 During chronic treatment of hypertensive patients observed mean steady-state plasma labetalol levels in ten patients were consistently and significantly higher than predicted from initial acute pharmacokinetic analysis. 2 Mean steady-state levels varied from 36 to 183 ng/ml on a chronic dose of 200 mg twice daily. 3 Patients with lower steady-state levels on a fixed dose of labetalol usually required higher maintenance doses to control blood pressure. [ABSTRACT FROM AUTHOR]

1 The pharmacokinetics of labetalol were studied in twelve hypertensive patients, ten of whom were not receiving other therapy. 2 Following intravenous administration there was a three- to fourfold variation in terminal elimination half-life, volume of distribution and total plasma clearance. The mean elimination half-life was 3.25 hours. 3 Following oral administration the drug was absorbed rapidly. Systemic availability varied from 11-86% (mean 33%). 4 Plasma levels correlated poorly with the acute effect on BP, raising the possibility of labetalol acting in a deep tissue compartment or alternatively an active metabolite contributing to its effect. [ABSTRACT FROM AUTHOR]

Background: The prevalence of femoroacetabular impingement may be greater in athletes than in the general population because of increased loading of the hip during sports. This study evaluated the radiographs of collegiate football players in order to quantify the prevalence of femoroacetabular impingement in asymptomatic athletes.Methods: Sixty-seven male collegiate football players (age, 21 ± 1.9 years) participated in this prospective study. Both hips (n = 134) were evaluated independently by two orthopaedic surgeons for radiographic signs of femoroacetabular impingement. The alpha angle and femoral head-neck offset were measured on frog-leg lateral radiographs. The lateral center-edge angle, acetabular index, crossover sign, and alpha angle were measured on anteroposterior radiographs. Data for continuous variables were averaged between observers prior to assessing prevalence. Cam femoroacetabular impingement was considered to be present if the femoral head-neck offset was <8 mm and/or the alpha angle was >50° on either radiograph. Pincer femoroacetabular impingement was considered to be present if the lateral center-edge angle was >40°, the acetabular index was <0°, and/or a positive crossover sign was detected by both observers.Results: Ninety-five percent of the 134 hips had at least one sign of cam or pincer impingement, and 77% had more than one sign. Twenty-one percent had only one sign of cam femoroacetabular impingement and 57% had both signs. Fifty-two percent had only one sign of pincer femoroacetabular impingement, 10% had two, and 4% had all three signs. Specifically, 72% had an abnormal alpha angle, 64% had a decreased femoral head-neck offset, 61% had a positive crossover sign, 16% had a decreased acetabular index, and 7% had an increased lateral center-edge angle. Fifty percent of all hips had at least one sign of pincer femoroacetabular impingement and at least one sign of cam impingement. Interobserver and intraobserver repeatability was moderate or better for each measure (range, 0.59 to 0.85).Conclusions: Morphologic abnormalities associated with cam and pincer femoroacetabular impingement were common in these collegiate football players. The prevalence of cam and pincer femoroacetabular impingement was substantially higher than the previously reported prevalence in the general population. [ABSTRACT FROM AUTHOR]

Purpose: The pathomorphology of Legg-Calvé-Perthes disease (LCPD) is a key contributor to poor long-term outcomes such as hip pain, femoroacetabular impingement, and early-onset osteoarthritis. Plain radiographs, commonly used for research and in the clinic, cannot accurately represent the full extent of LCPD deformity. The purpose of this study was to develop and evaluate a methodological framework for three-dimensional (3D) statistical shape modeling (SSM) of the proximal femur in LCPD., Methods: We developed a framework consisting of three core steps: segmentation, surface mesh preparation, and particle-based correspondence. The framework aims to address challenges in modeling this rare condition, characterized by highly heterogeneous deformities across a wide age range and small sample sizes. We evaluated this framework by producing a SSM from clinical magnetic resonance images of 13 proximal femurs with LCPD deformity from 11 patients between the ages of six and 12 years., Results: After removing differences in scale and pose, the dominant shape modes described morphological features characteristic of LCPD, including a broad and flat femoral head, high-riding greater trochanter, and reduced neck-shaft angle. The first four shape modes were chosen for the evaluation of the model's performance, together describing 87.5% of the overall cohort variance. The SSM was generalizable to unfamiliar examples with an average point-to-point reconstruction error below 1mm. We observed strong Spearman rank correlations (up to 0.79) between some shape modes, 3D measurements of femoral head asphericity, and clinical radiographic metrics., Conclusion: In this study, we present a framework, based on SSM, for the objective description of LCPD deformity in three dimensions. Our methods can accurately describe overall shape variation using a small number of parameters, and are a step toward a widely accepted, objective 3D quantification of LCPD deformity., (© 2024. CARS.)

AB598 is a CD39 inhibitory antibody being pursued for the treatment of solid tumors in combination with chemotherapy and immunotherapy. CD39 metabolizes extracellular adenosine triphosphate (eATP), an alarmin capable of promoting antitumor immune responses, into adenosine, an immuno-inhibitory metabolite. By inhibiting CD39, the consumption of eATP is reduced, resulting in a proinflammatory milieu in which eATP can activate myeloid cells to promote antitumor immunity. The preclinical characterization of AB598 provides a mechanistic rationale for combining AB598 with chemotherapy in the clinic. Chemotherapy can induce ATP release from tumor cells and, when preserved by AB598, both chemotherapy-induced eATP and exogenously added ATP promote the function of monocyte-derived dendritic cells via P2Y11 signaling. Inhibition of CD39 in the presence of ATP can promote inflammasome activation in in vitro-derived macrophages, an effect mediated by P2X7. In a MOLP8 murine xenograft model, AB598 results in full inhibition of intratumoral CD39 enzymatic activity, an increase in intratumoral ATP, a decrease of extracellular CD39 on tumor cells, and ultimately, control of tumor growth. In cynomolgus monkeys, systemic dosing of AB598 results in effective enzymatic inhibition in tissues, full peripheral and tissue target engagement, and a reduction in cell surface CD39 both in tissues and in the periphery. Taken together, these data support a promising therapeutic strategy of harnessing the eATP generated by standard-of-care chemotherapies to prime the tumor microenvironment for a productive antitumor immune response., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objective: We sought to examine the effects of acute seizures and respiratory derangement on the cardiac electrical properties reflected on the electrocardiogram (ECG); and to analyze their potential interactions with a diagnosis of epilepsy in children., Methods: Emergency center (EC) visits with seizure or epilepsy diagnostic codes from 1/2011-12/2013 were included if they had ECG within 24 h of EC visit. Patients were excluded if they had pre-existing cardiac conditions, ion channelopathy, or were taking specific cardiac medications. Control subjects were 1:1 age and gender matched. Abnormal ECG was defined as changes in rhythm, PR, QRS, or corrected QT intervals; QRS axis or morphology; ST segment; or T wave morphology from normal standards. We identified independent associations between clinical factors and abnormal ECG findings using multivariable logistic regression modeling., Results: Ninety-five children with epilepsy presented to the EC with seizures, respiratory distress, and other concerns. Three hundred children without epilepsy presented with seizures. There was an increased prevalence of minor ECG abnormalities in children with epilepsy (49 %) compared to the control subjects (29 %) and those without epilepsy (36 %). Epilepsy (OR: 1.61, 95 %CI: 1.01-2.6), need for supplemental oxygen (OR 3.06, 95 % CI: 1.45-6.44) or mechanical ventilation (OR: 2.5, 95 % CI: 1.03-6.05) were independently associated with minor ECG abnormalities. Secondary analyses further demonstrated an independent association between level of respiratory support and ECG abnormalities only in the epilepsy group., Significance: Independent association of increased respiratory support with minor ECG abnormalities suggests a potential respiratory influence on the hearts of children with epilepsy., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest to disclose. We confirm that we have read journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The Baylor College of Medicine Institutional Review Board approved the study with waiver of consent (H-34453)., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Summary: Cochlear implants to aid sensorineural hearing loss are becoming commonplace. In this study, we describe two cases that showed artifacts related to the cochlear implant device during scalp EEG recording. To our knowledge, cochlear implant artifacts have not been reported previously. Recognizing cochlear implant artifacts will avoid misinterpretation and resultant inappropriate treatment., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 by the American Clinical Neurophysiology Society.)

Objectives: Extracellular vesicles (EVs) are abundant in body fluids, contributing to intercellular signalling by transferring cargo that includes microRNAs (miRs)-themselves implicated in pathobiology. For the first time we evaluated the potential of EV miRs to contribute diagnostic information in early RA, predict methotrexate (MTX) efficacy or shed light on the drug's mechanism of action., Methods: Seven hundred and ninety-eight miRs isolated from serum-derived EVs of 46 patients with untreated RA, 23 with untreated polymyalgia rheumatica (PMR; inflammatory disease control group) and 12 in whom significant inflammatory disease had been excluded (non-inflammatory controls; NICs) were profiled (NanoString); the same measurements were made for RA patients after 6 months' MTX treatment. Analyses took multiple testing into account., Results: Twenty-eight EV miRs were robustly differentially expressed between early RA (but not PMR) patients and NICs after correction for age and sex, suggesting discriminatory value. Cross-validated partial least squares-discriminant analysis also indicated the predictive potential of a distinct baseline EV miR signature with respect to MTX-induced remission at 6 months. The change in expression of 13 miRs over the course of MTX treatment differed significantly between responders and non-responders, and four of those exhibiting increased relative abundance amongst responders have known roles in regulating the pathogenic potential of synovial fibroblasts, namely miR-212-3p, miR-338-5p, miR-410-3p and miR-537., Conclusion: Our data highlight the potential of serum EV miRs as diagnostic and therapeutic biomarkers, highlighting a novel potential mechanism by which MTX may exert its therapeutic effect in early RA that warrants further investigation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor on immune cells that outcompetes an activating receptor, CD226, for shared ligands. Tumor-infiltrating lymphocytes express TIGIT and CD226 on regulatory T cells (Treg) and on CD8+ T cells with tumor-reactive or exhausted phenotypes, supporting the potential of therapeutically targeting TIGIT to enhance antitumor immunity. To optimize the efficacy of therapeutic antibodies against TIGIT, it is necessary to understand IgG Fc (Fcγ) receptor binding for therapeutic benefit. In this study, we showed that combining Fc-enabled (Fce) or Fc-silent (Fcs) anti-TIGIT with antiprogrammed cell death protein 1 in mice resulted in enhanced control of tumors by differential mechanisms: Fce anti-TIGIT promoted the depletion of intratumoral Treg, whereas Fcs anti-TIGIT did not. Despite leaving Treg numbers intact, Fcs anti-TIGIT potentiated the activation of tumor-specific exhausted CD8+ populations in a lymph node-dependent manner. Fce anti-TIGIT induced antibody-dependent cell-mediated cytotoxicity against human Treg in vitro, and significant decreases in Treg were measured in the peripheral blood of patients with phase I solid tumor cancer treated with Fce anti-TIGIT. In contrast, Fcs anti-TIGIT did not deplete human Treg in vitro and was associated with anecdotal objective clinical responses in two patients with phase I solid tumor cancer whose peripheral Treg frequencies remained stable on treatment. Collectively, these data provide evidence for pharmacologic activity and antitumor efficacy of anti-TIGIT antibodies lacking the ability to engage Fcγ receptor., Significance: Fcs-silent anti-TIGIT antibodies enhance the activation of tumor-specific pre-exhausted T cells and promote antitumor efficacy without depleting T regulatory cells., (©2024 American Association for Cancer Research.)

Background: Checkpoint inhibitors (CPIs) are widely used in cancer treatment, with transformative impacts on survival. They nonetheless carry a significant risk of toxicity in the form of immune-related adverse events (IrAEs), which may be sustained and life-altering. IrAEs may require high-dose and/or prolonged steroid use and represent a significant healthcare burden. They mimic immune-mediated inflammatory diseases (IMIDs) but understanding of their pathogenesis is limited. The MEDALLION project aims to determine targetable mechanisms of immune dysregulation in IrAE development, employing an immune monitoring approach to determine changes in circulating and tissue resident cells of CPI recipients who do/do not develop them and assessing the contribution of the microbiome in parallel., Methods: MEDALLION is a non-randomised longitudinal cohort study aiming to recruit 66 cancer patient recipients of anti-PD1/PD-L1, anti-CTLA-4 or combination therapy. Eligible participants include those with malignant melanoma in the adjuvant or metastatic setting, mesothelioma and non-small cell lung carcinoma (NSCLC) treated in the metastatic setting. Comprehensive clinical evaluation is carried out alongside blood, skin swab and stool sampling at the time of CPI initiation (baseline) and during subsequent routine hospital visits on 6 occasions over a 10-month follow-up period. It is conservatively anticipated that one third of enrolled patients will experience a "significant IrAE" (SirAE), defined according to pre-determined criteria specific to the affected tissue/organ system. Those developing such toxicity may optionally undergo a biopsy of affected tissue where appropriate, otherwise being managed according to standard of care. Peripheral blood mononuclear cells will be analysed using multi-parameter flow cytometry to investigate immune subsets, their activation status and cytokine profiles. Stool samples and skin swabs will undergo DNA extraction for 16 S ribosomal RNA (rRNA) sequencing and internal transcribed spacer (ITS) gene sequencing to determine bacterial and fungal microbiome diversity, respectively, including species associated with toxicity. Stored tissue biopsies will be available for in situ and single-cell transcriptomic evaluation. Analysis will focus on the identification of biological predictors and precursors of SirAEs., Discussion: The pathogenesis of IrAEs will be assessed through the MEDALLION cohort, with the potential to develop tools for their prediction and/or strategies for targeted prevention or treatment., Trial Registration: The study was registered on 18/09/2023 in the ISRCTN registry (43,419,676)., (© 2024. The Author(s).)

Purpose: Cardiac abnormalities resulting from chronic epilepsy ("the epileptic heart") constitute a well-recognized comorbidity. However, the association of cardiac alterations with epilepsy duration remains understudied. We sought to evaluate this association using electrocardiogram (ECG)., Methods: We prospectively enrolled children between 1 months and 18 years of age without known cardiac conditions or ion channelopathies during routine clinic visits. ECGs were categorized as abnormal if there were alterations in rhythm; PR, QRS, or corrected QT interval; QRS axis or morphology; ST segment or T wave. An independent association between ECG abnormalities and epilepsy duration was evaluated using multivariable logistic regression modeling., Results: 213 children were enrolled. 100 ECGs (47%) exhibited at least one alteration; most commonly in the ST segment (37, 17%) and T wave (29, 11%). Children with normal ECGs had shorter epilepsy duration as compared to those with ECG abnormalities (46 [18-91] months vs. 73 [32-128 months], p = 0.004). A multivariable logistic regression model demonstrated that increasing epilepsy duration was independently associated with the presence of ECG abnormalities (OR=1.09, 95% CI=1.02-1.16, p = 0.008), adjusted for seizure frequency, generalized tonic-clonic/focal to bilateral tonic-clonic seizures as the predominant seizure type, and number of channel-modifying anti-seizure medications. Increasing epilepsy duration was also independently associated with the presence of ST/T wave abnormalities (OR=1.09, 95% CI=1.01-1.16, p = 0.017), adjusted for the same covariates., Significance: Increasing epilepsy duration is independently associated with the presence of minor ECG abnormalities. Additional studies are needed to evaluate whether this finding may represent a manifestation of the "epileptic heart"., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest to disclose. We confirm that we have read journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objectives: Long-term outcomes in rheumatoid arthritis (RA) depend on early and effective disease control. Methotrexate (MTX) remains the first-line disease modifying therapy, however there are no biomarkers with which to identify those most likely to achieve remission. To address this unmet need we explored metabolic pathways involved in MTX mechanism of action within circulating CD4+T cells in a cohort of treatment naive patients with early RA., Methods: Purified CD4+T cells were isolated from peripheral blood of 68 patients with early RA commencing MTX. The expression of a range of putative MTX metabolism and mechanism of action targets were explored by flow-cytometry and transcriptional analysis. From these data significant predictors of Disease Activity Score 28-C reactive protein (DAS28-CRP) remission (<2.4 at 6 months) were determined by logistic regression (clinical; flow-cytometry data) and linear modelling (gene expression data)., Results: Low baseline DAS28-CRP was associated with remission at 6 months (p=0.02). Expression of the ectonucleotidase CD39, involved in ATP-ADP conversion during adenosine synthesis, was higher on CD4+CD25 High regulatory T cells at baseline in those achieving remission (molecules of equivalent fluorescence 1264 vs 847; p=0.007). Expression of other adenosine signalling elements in CD4+T cells were also upregulated at baseline in patients achieving remission: AMPD1 (p<0.001), ADORA2b (p=0.039) and ADORA3 (p=0.047). When combined into a single predictive metric, a combination of these variables outperformed baseline DAS28-CRP in prediction of early remission (area under the curve 0.92 vs 0.67, p=0.001) CONCLUSIONS: Adenosine signalling is important in the achievement of early remission with MTX in RA and biomarkers of adenosine activity may hold utility for the stratification of therapy in early disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune-mediated inflammatory diseases (IMIDs) are typically characterised by relapsing and remitting flares of inflammation. However, the unpredictability of disease flares impedes their study. Addressing this critical knowledge gap, we use the experimental medicine approach of immunomodulatory drug withdrawal in rheumatoid arthritis (RA) remission to synchronise flare processes allowing detailed characterisation. Exploratory mass cytometry analyses reveal three circulating cellular subsets heralding the onset of arthritis flare - CD45RO + PD1 hi CD4 + and CD8 + T cells, and CD27 + CD86 + CD21 - B cells - further characterised by single-cell sequencing. Distinct lymphocyte subsets including cytotoxic and exhausted CD4 + memory T cells, memory CD8 + CXCR5 + T cells, and IGHA1+ plasma cells are primed for activation in flare patients. Regulatory memory CD4 + T cells (Treg cells) increase at flare onset, but with dysfunctional regulatory marker expression compared to drug-free remission. Significant clonal expansion is observed in T cells, but not B cells, after drug cessation; this is widespread throughout memory CD8 + T cell subsets but limited to the granzyme-expressing cytotoxic subset within CD4 + memory T cells. Based on our observations, we suggest a model of immune dysregulation for understanding RA flare, with potential for further translational research towards novel avenues for its treatment and prevention., (© 2024. The Author(s).)

Methods for statistically analyzing patient-specific data that vary both spatially and over time are currently either limited to summary statistics or require elaborate surface registration. We propose a new method, called correspondence-based network analysis, which leverages particle-based shape modeling to establish correspondence across a population and preserve patient-specific measurements and predictions through statistical analysis. Herein, we evaluated this method using three published datasets of the hip describing cortical bone thickness of the proximal femur, cartilage contact stress, and dynamic joint space between control and patient cohorts to evaluate activity- and group-based differences, as applicable, using traditional statistical parametric mapping (SPM) and our proposed spatially considerate correspondence-based network analysis approach. The network approach was insensitive to correspondence density, while the traditional application of SPM showed decreasing area of the region of significance with increasing correspondence density. In comparison to SPM, the network approach identified broader and more connected regions of significance for all three datasets. The correspondence-based network analysis approach identified differences between groups and activities without loss of subject and spatial specificity which could improve clinical interpretation of results., (© 2023. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Microvertebrate assemblages of the Upper Cretaceous (late Cenomanian to mid-Turonian) Favel Formation of Manitoba are formally described for the first time. New vertebrate occurrences from the Favel Formation include the actinopterygians Caturidae indet., cf. Albulidae incertae sedis , Micropycnodon kansasensis , Pachyrhizodus minimus , Protosphyraena sp., Thryptodus loomisi , chondrichthyans Ischyrhiza cf. mira , I. texana , Ptychodus marginalis , P. occidentalis , and P. rhombodus , the avian cf. Ichthyornis sp., the reptile Testudines indet., and an unknown taxon referred to as Vertebrate A. Changes in faunal occurrences throughout the formation suggest an offshore open marine environment for the lower and middle horizons and nearshore marine for the upper horizon, represent ing mid- and late stages of the Greenhorn third-order marine cycle. This newly described diversity increases biogeographic affinities of the late Cenomanian to mid-Turonian vertebrate assemblages of Manitoba with central WIS localities in South Dakota and Kansas, providing additional support for a central vertebrate biogeographic subprovince during late Cenomanian to early Turonian times, as well as WIS localities further south in Texas decreasing the gradient of the north-south or central-south community boundary during early and mid-Turonian times., Competing Interests: The authors declare that they have no competing interests., (© 2023 Kilmury et al.)

Expression of immediate early genes (IEGs) in the brain is important for synaptic plasticity, and probably also in neurodegenerative conditions. To understand the cellular mechanisms of the underlying neuropathophysiological processes in epilepsy, we need to pinpoint changes in concentration of synaptic plasticity-related proteins at subsynaptic levels. In this study, we examined changes in synaptic expression of Activity-regulated cytoskeleton-associated (Arc) and Brai Derived Neurotrophic Factor (BDNF) in a rat model of kainate-induced temporal lobe epilepsy (TLE). Western blotting showed reduced concentrations of Arc and increased concentrations of BDNF in hippocampal synaptosomes in chronic TLE rats. Then, using quantitative electron microscopy, we found corresponding changes in subsynaptic regions in the hippocampus. Specifically, we detected significant reductions in the concentrations of Arc in the presynaptic terminal of Schaffer collateral glutamatergic synapses in the stratum radiatum of the CA1 area in TLE, as well as in their adjacent postsynaptic spines. In CA3, there was a significant reduction of Arc only in the presynaptic terminal cytoplasm. Conversely, in CA3, there was a significant increase in the expression of BDNF in the presynaptic terminal, but not in the postsynaptic spine. Significant increase in BDNF concentration in the CA1 postsynaptic density was also obtained. We hypothesize that the observed changes in Arc and BDNF may contribute to both cognitive impairment and increased excitotoxic vulnerability in chronic epilepsy., Competing Interests: Competing interest The authors declare that the study was conducted without any relationship that could be considered as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Computer simulations of joint contact mechanics have great merit to improve our current understanding of articular ankle pathology. Owed to its computational simplicity, discrete element analysis (DEA) is an encouraging alternative to finite element analysis (FEA). However, previous DEA models lack subject-specific anatomy and may oversimplify the biomechanics of the ankle. The objective of this study was to develop and validate a personalized DEA framework that permits movement of the fibula and incorporates personalized cartilage thickness as well as ligamentous constraints., Methods: A linear and non-linear DEA framework, representing cartilage as compressive springs, was established, verified, and validated. Three-dimensional (3D) bony ankle models were constructed from cadaveric lower limb CT scans imaged during application of weight (85 kg) and/or torque (10 Nm). These 3D models were used to generate cartilage thickness and ligament insertion sites based on a previously validated statistical shape model. Ligaments were modelled as non-linear tension-only springs. Validation of contact stress prediction was performed using a simple, axially constrained tibiotalar DEA model against an equivalent FEA model. Validation of ligamentous constraints compared the final position of the ankle mortise to that of the cadaver after application of torque and sequential ligament sectioning. Finally, a combined ligamentous-constraining DEA model was validated for predicted contact stress against an equivalent ligament-constraining FEA model., Results: The linear and non-linear DEA model reproduced a mean articular contact stress within 0.36 MPa and 0.39 MPa of the FEA calculated stress, respectively. With respect to the ligamentous validation, the DEA ligament-balancing algorithm could reproduce the position of the distal fibula within the ankle mortise to within 0.97 mm of the experimental observed distal fibula. When combining the ligament-constraining and contact stress algorithm, DEA was able to reproduce a mean articular contact stress to within 0.50 MPa of the FEA calculated contact stress., Conclusion: The DEA framework presented herein offers a computationally efficient alternative to FEA for the prediction of contact stress in the ankle joint, manifesting its potential to enhance the mechanical understanding of articular ankle pathologies on both a patient-specific and population-wide level. The novelty of this model lies in its personalized nature, inclusion of the distal tibiofibular joint and the use of non-linear ligament balancing to maintain the physiological ankle joint articulation., Competing Interests: Declaration of Competing Interest Matthias Peiffer, MD, has nothing to disclose; Kate Duquesne, Eng, has nothing to disclose; Aline Van Oevelen, MD, has nothing to disclose; Arne Burssens, MD, PhD, has nothing to disclose; Sophie De Mits, PhD, has nothing to disclose; Steve A. Maas, Eng, PhD, has nothing to disclose; Penny R. Atkins, Eng, Phd, has nothing to disclose; Andrew A. Anderson, Eng, PhD, has nothing to disclose; Emmanuel. Audenaert, MD, PhD, has nothing to disclose, (Copyright © 2023. Published by Elsevier B.V.)