Search

We derive and numerically implement various asymptotic approximations for the lowest or principal eigenvalue of the Laplacian with a periodic arrangement of localised traps of small \[\mathcal{O}(\varepsilon)\] spatial extent that are centred at the lattice points of an arbitrary Bravais lattice in \[{\mathbb{R}^2}\]. The expansion of this principal eigenvalue proceeds in powers of \[\nu \equiv - 1/\log (\varepsilon {d_c})\] , where dc is the logarithmic capacitance of the trap set. An explicit three-term approximation for this principal eigenvalue is derived using strong localised perturbation theory, with the coefficients in this series evaluated numerically by using an explicit formula for the source-neutral periodic Green's function and its regular part. Moreover, a transcendental equation for an improved approximation to the principal eigenvalue, which effectively sums all the logarithmic terms in powers of v, is derived in terms of the regular part of the periodic Helmholtz Green's function. By using an Ewald summation technique to first obtain a rapidly converging infinite series representation for this regular part, a simple Newton iteration scheme on the transcendental equation is implemented to numerically evaluate the improved 'log-summed' approximation to the principal eigenvalue. From a numerical computation of the PDE eigenvalue problem defined on the fundamental Wigner–Seitz (WS) cell for the lattice, it is shown that the three-term asymptotic approximation for the principal eigenvalue agrees well with the numerical result only for a rather small trap radius. In contrast, the log-summed asymptotic result provides a very close approximation to the principal eigenvalue even when the trap radius is only moderately small. For a circular trap, the first few transcendental correction terms that further improves the log-summed approximation for the principal eigenvalue are derived. Finally, it is shown numerically that, amongst all Bravais lattices with a fixed area of the primitive cell, the principal eigenvalue is maximised for a regular hexagonal arrangement of traps. [ABSTRACT FROM AUTHOR]

Objective: This study aims to present and analyze the results of the French cohort in a European Board of Ophthalmology (EBO) survey on cataract surgical training in Europe, highlighting the particularities of French training., Materials and Methods: A 23-question electronic questionnaire was sent to interns applying for the EBO examination from 2018 to 2022. Responses from French participants were specifically collected and analyzed., Results: Of 122 responding French ophthalmologists, the mean age was 31.0±2.8 years with an equal distribution between men and women. The most frequent pre-patient training sessions were on virtual reality simulators (8.6±8.2 sessions). French respondents reported a higher average number of partial (124.1±94.8) and complete (96.4±93.1) surgeries, with increased confidence (0-10 scale) in performing simple (7.3±2.4) and complex (5.51±2.6) surgeries, as well as in managing posterior capsular ruptures (7.2±2.5) or performing corneal sutures (3.9±2.7)., Discussion: Within the European landscape, French cataract surgery training is part of a model of "surgery for all", without gender disparity. Regional variations, however, mark the French landscape, in contrast to other European nations such as Spain and Germany. Standardization of pre-patient training sessions is proposed as a means of equalization., Conclusion: To standardize cataract surgery training in Europe, it is advisable to establish recommendations and educational strategies, including the standardization of pre-patient training sessions to ensure validation of surgical skills., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: This study, part of a series, analyses the Swiss cohort from an EBO survey on cataract surgery training in Europe, focusing on Switzerland's unique program. The survey identifies two models: training all residents in surgery, and a "high-volume surgeon" model where only some learn CS post-residency., Methods: This study analyses the survey results of Swiss participants in the EBO examinations (2018-2022) and compared them with the most important cohorts (Germany, France and Spain)., Results: Out of 251 respondents, 87 (34.7%) answered the questionnaire. Most (70.1%) had taken the EBO exam between 2021-2022, with the majority of study participants being men (55.2%) with a median age of 34 years and came from 12 different cantons. Two third (68.8%) of respondents had not performed any steps of cataract surgery on patients during their residency. Notably, 22.1% stated that they had carried out 10 or more training sessions on virtual reality simulator, 5.8% on synthetic eyes and 21% on animal eyes. A notable discrepancy was observed between participants with 10 or more training sessions and those without specific training in four key areas: self-assessed confidence and ability to perform cataract surgery (p = 0.006), management of challenging cases (p = 0.027), handling complications like posterior capsular tear (p = 0.031) and in performing corneal sutures (p = 0.023)., Discussion: Switzerland fits into the "high-volume surgeon" model group; extensive simulation-based training there significantly boosts self-confidence in performing CS, an effect less noticeable in countries offering hands-on training during residency., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Bronchial thermoplasty (BT) is a bronchoscopic procedure for patients with severe uncontrolled asthma, but randomized controlled studies of its efficacy in severe asthma with frequent exacerbations are lacking. The current aim was to assess BT efficacy in this patient population., Methods: Thirty patients with asthma (GINA 5) who had experienced at least four severe exacerbations in the preceding year were randomized to BT (n = 15) or control groups (n = 15). All patients had four follow-up visits over the following 15 months, corresponding to 3, 6, 9, and 12 months after the last procedure for the BT group. The primary outcome was number of exacerbations at 15 months after inclusion (i.e. 12 months after bronchial thermoplasty)., Results: All but three patients had received an asthma biologic without receiving benefit. In the year preceding enrollment, patients in the BT group had an average of five exacerbations, compared with six among controls. For patients in the BT group, oral steroid intake was 9.3 mg/d, compared with 11.0 mg/d among controls. The BT group had 1.58 fewer severe exacerbations (mean, 6.09) compared with controls (mean, 8.28) in the 12-month period after the therapy (p = 0.047). Oral steroid intake during follow-up after BT was significantly lower in the BT group (ratio vs controls: 0.61; p = 0.0002). Quality-of-life measures between inclusion and the last visit were significantly improved in the BT group, but not among controls. Few mild to moderate adverse events were reported, and all were controlled within days., Conclusion: In patients with severe asthma and frequent severe exacerbations, BT significantly decreased the rate of severe exacerbations and oral steroid intake and led to improved quality of life during the 15 months after inclusion. BT appears to offer a therapeutic option for severe asthma with frequent exacerbations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pr F. De Blay reports financial support was provided by ADIRAL. Pr F. De Blay reports financial support was provided by SOS Oxygène. Pr F. De Blay reports financial support was provided by France Oxygen. Pr F. De Blay reports financial support was provided by Elivie SAS. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Introduction: Faced to the growing development of collecting systematic molecular analyses in relapsed pediatric cancers to transform their targeted matched therapies, this study aimed to assess the clinical and therapeutic indications of systematic diagnostic genomic explorations performed in pediatric solid cancers to determine which type of screening and if it afford at relapse time an accurate targeted strategy., Methods: A total of 280 patients less than 22 years, referred at the University Hospitals of Strasbourg for a newly diagnosed solid tumor from January 2015 to December 2021, were prospectively genomically investigated since diagnosis. Using 7 different molecular tests going from single-gene methods (IHC, FISH, RT-PCR, Sanger sequencing, droplet digital PCR) to largescale analyses (Next-Generation sequencing, RNAsequencing and FoundationOne®CDx), we explored retrospectively the molecular findings in those pediatric solid tumors (except hematolymphoid cancers) to improve diagnosis, prognosis assessment and relapse therapeutics., Results: One hundred and ninety-eight patients (71%) underwent molecular biology (MB) at diagnosis. Thirty-eight different histologies were grouped into cerebral tumors (30%), sarcomas (26%, bone and soft tissues), various blastomas (27%), and other entities (17%). Over a median 40-month follow-up, the overall survival rate of patients was 85% and the relapse rate 28%. Of the 326 analyses carried out, 245 abnormalities (single nucleotide variations: 50%, fusions: 25%, copy number alteration: 20%) concerning 70 oncogenes were highlighted. The overall clinical impact rate was 84%. Broad-spectrum analyses had a higher therapeutic impact (57%) than the targeted analyses (28%). 75% of broad-spectrum tests found an actionable variant conducting 23% of patients to receive rapidly a matched targeted therapy since first relapse., Conclusion: Our experience highlighted the clinical utility of molecular profiling of solid tumors as soon as at diagnosis in children to expect improving access to innovative agents at relapse., (© 2024. The Author(s).)

Difficulties in controlling emotions - a proxy for emotion dysregulation (ED)-and difficulties in expressing feelings in words-'absence of emotion labelling' or alexithymia-co-exist in autism and contribute to elevated levels of impulsive and suicidal behaviour. To date, studies linking the two phenomena have relied on retrospective self-reported measures, lacking support for generalizability to real-life situations. The present study investigated in vivo emotion labelling and its impact on emotion control in 29 autistic adults without intellectual disability (ASC) and 28 neurotypical (NT) individuals of similar age, sex, and educational level. Participants were trained in an Ecological Momentary Assessment (EMA) to label their emotions, the arousal dimension, and their emotion control via smartphone over a one-week period. Findings showed that the ASC group experienced more instances of 'having an emotion that I cannot name' and, when they were able to label their emotions, they reported higher rates of negative and conflicting (simultaneously positive and negative) emotions. In both groups, the absence of emotion labelling, and intense negative emotions were associated with impaired emotion control. However, the association between lack of emotional awareness-'I have no emotion'-and impaired emotion control was only evident in ASC individuals. Our study highlights a nuanced facet of emotional processing in the ASC population. Further research is needed to gain a deeper understanding of the complex relationship between ED and alexithymia in autism., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: To determine the prevalence of root resorption of teeth adjacent to permanent maxillary canines on both sides, by cone-beam computed tomography (CBCT), in pretreatment adolescent subjects with unilaterally impacted maxillary canines, and to define predictive factors for the root resorption., Materials and Methods: This retrospective sample included 76 adolescents (38 boys, 38 girls, mean age 12.3 ± 2.1 years; range 8-17 years) who had CBCT after detection of a unilateral impacted maxillary canine before any active orthodontic treatment. Both ipsilateral and contralateral sides were examined, and 14 qualitative and quantitative variables were collected. Descriptive statistics were calculated, and multiple logistic regression was used to predict root resorption., Results: On the impaction side, 57.9% of canines resorbed at least one adjacent tooth compared with 13.2% on the contralateral side (P < .001). On the impaction side, resorption was slight in 59.6%, moderate in 5.8%, and severe in 34.6% of the cases. On the contralateral side, resorption was slight in 91.7%, moderate in 0%, and severe in 8.3% of the cases. On both sides, upper lateral incisors were the teeth most frequently resorbed, followed by the upper first premolars and upper central incisors. The presence of contact between the canine and the adjacent roots was the only statistically significant risk factor for resorption for both ipsilateral and contralateral sides., Conclusions: Orthodontists should look for root resorption on both sides in cases of unilaterally impacted maxillary canines., (© 2024 by The EH Angle Education and Research Foundation, Inc.)

Background: In early atherosclerosis, circulating LDLs (low-density lipoproteins) traverse individual endothelial cells by an active process termed transcytosis. The CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) treated advanced atherosclerosis using a blocking antibody for IL-1β (interleukin-1β); this significantly reduced cardiovascular events. However, whether IL-1β regulates early disease, particularly LDL transcytosis, remains unknown., Methods: We used total internal reflection fluorescence microscopy to quantify transcytosis by human coronary artery endothelial cells exposed to IL-1β. To investigate transcytosis in vivo, we injected wild-type and knockout mice with IL-1β and LDL to visualize acute LDL deposition in the aortic arch., Results: Exposure to picomolar concentrations of IL-1β induced transcytosis of LDL but not of albumin by human coronary artery endothelial cells. Surprisingly, expression of the 2 known receptors for LDL transcytosis, ALK-1 (activin receptor-like kinase-1) and SR-BI (scavenger receptor BI), was unchanged or decreased. Instead, IL-1β increased the expression of the LDLR (LDL receptor); this was unexpected because LDLR is not required for LDL transcytosis. Overexpression of LDLR had no effect on basal LDL transcytosis. However, knockdown of LDLR abrogated the effect of IL-1β on transcytosis rates while the depletion of Cav-1 (caveolin-1) did not. Since LDLR was necessary but overexpression had no effect, we reasoned that another player must be involved. Using public RNA sequencing data to curate a list of Rab (Ras-associated binding) GTPases affected by IL-1β, we identified Rab27a. Overexpression of Rab27a alone had no effect on basal transcytosis, but its knockdown prevented induction by IL-1β. This was phenocopied by depletion of the Rab27a effector JFC1 (synaptotagmin-like protein 1). In vivo, IL-1β increased LDL transcytosis in the aortic arch of wild-type but not Ldlr -/- or Rab27a-deficient mice. The JFC1 inhibitor nexinhib20 also blocked IL-1β-induced LDL accumulation in the aorta., Conclusions: IL-1β induces LDL transcytosis by a distinct pathway requiring LDLR and Rab27a; this route differs from basal transcytosis. We speculate that induction of transcytosis by IL-1β may contribute to the acceleration of early disease., Competing Interests: None.

Objective: Subclinical hyperthyroidism (SCH) is common and associated with atrial fibrillation (AF) risk in the elderly. Current guidelines rely on a low level of evidence., Methods: Randomized clinical trial including patients 50 years and older, with TSH <0.4 mU/L and normal thyroid hormone concentrations. All patients showed autonomy on thyroid scan. They were randomized either to receive radioiodine (I131) or to be monitored and treated only if they underwent AF or evolved towards overt hyperthyroidism. Primary outcome was the onset of new AF. Secondary outcomes were treatment-induced hypothyroidism rate and health-related quality of life., Results: 144 patients (mean age 65.3±8.9y, 76% female) were randomized, 74 to surveillance and 70 to treatment. Four patients in the surveillance group and one in the treatment group developed AF (p=0.238). However, the patient who developed AF in the treatment group maintained TSH <0.4 mU/L at AF onset. A post-hoc analysis was carried out and showed that when normalization of TSH was considered, the risk of AF was significantly reduced (p=0.0003). In the surveillance group, several patients showed no classical characteristics associated with AF risk, including age>65y or TSH<0.1mU/L. Of 94 patients treated using radioiodine, 25% developed hypothyroidism during follow-up., Conclusions: Due to recruitment difficulties this study failed to demonstrate that SCH treatment can reduce significantly the incidence of AF in patients older than 50 years with thyroid autonomy even if all the patients who developed AF maintained TSH <0.4 mU/L. This result must be balanced with the increased risk of radioiodine-induced hypothyroidism.

Voltage distribution in sub-cellular micro-domains such as neuronal synapses, small protrusions, or dendritic spines regulates the opening and closing of ionic channels, energy production, and thus, cellular homeostasis and excitability. Yet how voltage changes at such a small scale in vivo remains challenging due to the experimental diffraction limit, large signal fluctuations, and the still limited resolution of fast voltage indicators. Here, we study the voltage distribution in nano-compartments using a computational approach based on the Poisson-Nernst-Planck equations for the electro-diffusion motion of ions, where inward and outward fluxes are generated between channels. We report a current-voltage (I-V) logarithmic relationship generalizing Nernst law that reveals how the local membrane curvature modulates the voltage. We further find that an influx current penetrating a cellular electrolyte can lead to perturbations from tens to hundreds of nanometers deep, depending on the local channel organization. Finally, we show that the neck resistance of dendritic spines can be completely shunted by the transporters located on the head boundary, facilitating ionic flow. To conclude, we propose that voltage is regulated at a subcellular level by channel organization, membrane curvature, and narrow passages., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Incidental capture of non-target species poses a pervasive threat to many marine species, with sometimes devastating consequences for both fisheries and conservation efforts. Because of the well-known importance of vocalizations in cetaceans, acoustic deterrents have been extensively used for these species. In contrast, acoustic communication for sea turtles has been considered negligible, and this question has been largely unexplored. Addressing this challenge therefore requires a comprehensive understanding of sea turtles' responses to sensory signals. In this study, we scrutinized the avenue of auditory cues, specifically the natural sounds produced by green turtles (Chelonia mydas) in Martinique, as a potential tool to reduce bycatch. We recorded 10 sounds produced by green turtles and identified those that appear to correspond to alerts, flight or social contact between individuals. Subsequently, these turtle sounds-as well synthetic and natural (earthquake) sounds-were presented to turtles in known foraging areas to assess the behavioral response of green turtles to these sounds. Our data highlighted that the playback of sounds produced by sea turtles was associated with alert or increased the vigilance of individuals. This therefore suggests novel opportunities for using sea turtle sounds to deter them from fishing gear or other potentially harmful areas, and highlights the potential of our research to improve sea turtles populations' conservation., (© 2024. The Author(s).)

Background: Cystic fibrosis related diabetes (CFRD) is commonly associated with declining lung function and nutritional status. We aimed to evaluate the pulmonary impact of early glucose abnormalities by using 2-h standard oral glucose tolerance testing (OGTT) and continuous glucose monitoring (CGM) in people with cystic fibrosis (PwCF)., Methods: PwCF aged ≥10 years old without known CFRD were included in a five-year prospective multicentre study. Annual evaluation of nutritional status, lung function, OGTT and CGM was set up. Associations between annual rate changes (Δ) in lung function, ΔFEV1 (forced expiratory volume in 1 s) percentage predicted (pp) and ΔFVC (forced vital capacity) pp., and annual rate changes in OGTT or CGM variables were estimated with a mixed model with a random effect for subject., Results: From 2009 to 2016, 112 PwCF (age: 21 ± 11 years, BMI (body mass index) z-score: -0.55 ± 1.09, FEV1pp: 77 ± 24 %, 2-h OGTT glucose: 122 ± 44 mg/dL, AUC (area under curve) >140 mg/dL: 1 mg/dL/day (0.2, 3.0) were included. A total of 428 OGTTs and 480 CGMs were collected. The participants presented annual decline of FVCpp and FEV1pp at -1.0 % per year (-1.6, -0.4), p < 0.001 and - 1.9 % per year (-2.5, -1.3), p < 0.001 respectively without change in BMI z-score during the study. Variation of two-hour OGTT glucose was not associated with declining lung function, as measured by ΔFEV1pp (p = 0.94) and ΔFVCpp (p = 0.90). Among CGM variables, only increase in AUC >140 mg/dL between two annual visits was associated with a decrease in ΔFVCpp (p < 0.05) and ΔFEV1pp (p < 0.05)., Conclusions: This prospective study supports the fact that early glucose abnormalities revealed by CGM predict pulmonary function decline in PwCF, while 2-h standard OGTT glucose is not associated with pulmonary impairment., Competing Interests: Declaration of competing interest No potential conflicts of interest relevant to this article were reported., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Takayasu arteritis (TA) leads to stenotic disease. Aneurysmal lesions are rarer. This study assessed the main characteristics of aneurysmal disease in a Canadian cohort of patients with TA., Methods: This monocentric retrospective study included patients with TA followed at the Mount Sinai Hospital Vasculitis Clinic in Toronto. Diagnosis of TA was based on clinical findings and/or satisfied the 1990 American College of Rheumatology classification criteria., Results: Seventy-four patients were included. At any time, aneurysmal disease was found in 23 (31%) patients. Median disease duration was 9.0 (IQR 7.0-19.0) years. Prior hypertension ( P = 0.02), fever ( P = 0.04), and seizure disorders ( P = 0.03) were more common. Limb claudication was less frequent ( P = 0.01). Persistent and/or new aneurysms were demonstrated in 22/23 patients at follow-up. Thoracic aorta aneurysm (13/22) was most common, followed by abdominal aorta (8/22), subclavian (7/22), and carotid (6/22) artery disease. Aortic valve regurgitation was more frequent (9/23 vs 3/48; P = 0.001). Twenty-one patients had been treated with glucocorticoids (median 6.1 years [IQR 3.7-8.1]). Methotrexate, azathioprine, and leflunomide were repeatedly used. Infliximab (7/23) was used more often ( P = 0.04), whereas tocilizumab was received by only 4 patients with aneurysmal disease ( P = 0.01). Patients with aneurysms suffered more frequent relapses (2.0 [IQR 0.0-4.0] vs 1.0 [IQR 0.0-2.0], P = 0.04)., Conclusion: Aneurysmal disease was found in a significant proportion of patients with TA. Given that aneurysms may carry a risk of rupture, and are associated with a higher rate of relapse, this finding should be reported systematically in TA studies., (Copyright © 2024 by the Journal of Rheumatology.)

FKBP12.6, a binding protein to the immunosuppressant FK506, which also binds the ryanodine receptor (RyR2) in the heart, has been proposed to regulate RyR2 function and to have antiarrhythmic properties. However, the level of FKBP12.6 expression in normal hearts remains elusive and some controversies still persist regarding its effects, both in basal conditions and during β-adrenergic stimulation. We quantified FKBP12.6 in the left ventricles (LV) of WT (wild-type) mice and in two novel transgenic models expressing distinct levels of FKBP12.6, using a custom-made specific anti-FKBP12.6 antibody and a recombinant protein. FKBP12.6 level in WT LV was very low (0.16 ± 0.02 nmol/g of LV), indicating that <15% RyR2 monomers are bound to the protein. Mice with 14.1 ± 0.2 nmol of FKBP12.6 per g of LV (TG1) had mild cardiac hypertrophy and normal function and were protected against epinephrine/caffeine-evoked arrhythmias. The ventricular myocytes showed higher [Ca 2+ ] i transient amplitudes than WT myocytes and normal SR-Ca 2+ load, while fewer myocytes showed Ca 2+ sparks. TG1 cardiomyocytes responded to 50 nM Isoproterenol increasing these [Ca 2+ ] i parameters and producing RyR2-Ser2808 phosphorylation. Mice with more than twice the TG1 FKBP12.6 value (TG2) showed marked cardiac hypertrophy with calcineurin activation and more arrhythmias than WT mice during β-adrenergic stimulation, challenging the protective potential of high FKBP12.6. RyR2 R420Q CPVT mice overexpressing FKBP12.6 showed fewer proarrhythmic events and decreased incidence and duration of stress-induced bidirectional ventricular tachycardia. Our study, therefore, quantifies for the first time endogenous FKBP12.6 in the mouse heart, questioning its physiological relevance, at least at rest due its low level. By contrast, our work demonstrates that with caution FKBP12.6 remains an interesting target for the development of new antiarrhythmic therapies., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Whole genome sequencing (WGS) at high-depth (30X) allows the accurate discovery of variants in the coding and non-coding DNA regions and helps elucidate the genetic underpinnings of human health and diseases. Yet, due to the prohibitive cost of high-depth WGS, most large-scale genetic association studies use genotyping arrays or high-depth whole exome sequencing (WES). Here we propose a cost-effective method which we call "Whole Exome Genome Sequencing" (WEGS), that combines low-depth WGS and high-depth WES with up to 8 samples pooled and sequenced simultaneously (multiplexed). We experimentally assess the performance of WEGS with four different depth of coverage and sample multiplexing configurations. We show that the optimal WEGS configurations are 1.7-2.0 times cheaper than standard WES (no-plexing), 1.8-2.1 times cheaper than high-depth WGS, reach similar recall and precision rates in detecting coding variants as WES, and capture more population-specific variants in the rest of the genome that are difficult to recover when using genotype imputation methods. We apply WEGS to 862 patients with peripheral artery disease and show that it directly assesses more known disease-associated variants than a typical genotyping array and thousands of non-imputable variants per disease-associated locus., (© 2024. The Author(s).)

Ca 2+ signaling is essential for cardiac contractility and excitability in heart function and remodeling. Intriguingly, little is known about the role of a new family of ion channels, the endo-lysosomal non-selective cation "two-pore channel" (TPCs) in heart function. Here we have used double TPC knock-out mice for the 1 and 2 isoforms of TPCs (Tpcn1/2 -/- ) and evaluated their cardiac function. Doppler-echocardiography unveils altered left ventricular (LV) systolic function associated with a LV relaxation impairment. In cardiomyocytes isolated from Tpcn1/2 -/- mice, we observed a reduction in the contractile function with a decrease in the sarcoplasmic reticulum Ca 2+ content and a reduced expression of various key proteins regulating Ca 2+ stores, such as calsequestrin. We also found that two main regulators of the energy metabolism, AMP-activated protein kinase and mTOR, were down regulated. We found an increase in the expression of TPC1 and TPC2 in a model of transverse aortic constriction (TAC) mice and in chronically isoproterenol infused WT mice. In this last model, adaptive cardiac hypertrophy was reduced by Tpcn1/2 deletion. Here, we propose a central role for TPCs and lysosomes that could act as a hub integrating information from the excitation-contraction coupling mechanisms, cellular energy metabolism and hypertrophy signaling., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Ltd.)

Photoactivation is a paradigm consisting in local molecular fluorescent activation by laser illumination in a chosen region (source) while measuring the concentration at a target region. Data-driven modeling is concerned with the following questions: how from the measurement in these two regions is it possible to infer the properties of molecular propagation? How is it possible to use such responses to infer motions occurring in networks such as the endoplasmic reticulum? In this book chapter, we shall review the data-driven analysis based on diffusion-transport models and numerical simulations to interpret the photoactivation dynamics and extract biophysical parameters. We will discuss modeling approaches to reconstruct local network properties from photoactivation transients., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Vulnerable populations such as low-income older adults in social housing suffer from poor quality of life and are impacted by chronic diseases. These populations are also high users of emergency services, which contribute to high healthcare costs. Community-based, patient-centred interventions, such as community paramedicine (CP) programs, can address the healthcare gaps for these underserved populations. Community Paramedicine at Clinic (CP@clinic) is an innovative, evidence-based, chronic disease prevention/management program that improves patient health and quality of life, connects them with health and community services, preserves healthcare resources and yields cost savings for the emergency care system. The program also works with other community organizations, facilitating interprofessional engagement and supporting other disciplines in providing care. Known barriers to implementing CP programs highlight the importance of standard practices and training as exemplified by the CP@clinic program., (Copyright © 2024 Longwoods Publishing.)

Transition to novel environments, such as groundwater colonization by surface organisms, provides an excellent research ground to study phenotypic evolution. However, interspecific comparative studies on evolution to groundwater life are few because of the challenge in assembling large ecological and molecular resources for species-rich taxa comprised of surface and subterranean species. Here, we make available to the scientific community an operational set of working tools and resources for the Asellidae, a family of freshwater isopods containing hundreds of surface and subterranean species. First, we release the World Asellidae database (WAD) and its web application, a sustainable and FAIR solution to producing and sharing data and biological material. WAD provides access to thousands of species occurrences, specimens, DNA extracts and DNA sequences with rich metadata ensuring full scientific traceability. Second, we perform a large-scale dated phylogenetic reconstruction of Asellidae to support phylogenetic comparative analyses. Of 424 terminal branches, we identify 34 pairs of surface and subterranean species representing independent replicates of the transition from surface water to groundwater. Third, we exemplify the usefulness of WAD for documenting phenotypic shifts associated with colonization of subterranean habitats. We provide the first phylogenetically controlled evidence that body size of males decreases relative to that of females upon groundwater colonization, suggesting competition for rare receptive females selects for smaller, more agile males in groundwater. By making these tools and resources widely accessible, we open up new opportunities for exploring how phenotypic traits evolve in response to changes in selective pressures and trade-offs during groundwater colonization., (© 2023 John Wiley & Sons Ltd.)

Purpose: To survey recently graduated European ophthalmologists concerning cataract surgery (CS) training opportunities., Setting: Countries affiliated to the European Board of Ophthalmology (EBO)., Design: Cross-sectional study of anonymous survey results., Methods: A 23-question online survey was emailed to candidates who sat the EBO Diploma Examination as residents between 2018 and 2022., Results: 821 ophthalmologists from 30 countries completed the survey. The mean residency duration was 4.73 (SD 0.9) years. The mean reported number of entire CS procedures performed was 80.7 (SD 100.6) at the end of residency, but more than 25% of respondents (n = 210) had received no live CS training during their residency. The self-confidence (scale, 1 to 10) to perform a simple case or challenging case, manage posterior capsular rupture, and realize a corneal stitch were rated 4.1, 3.2, 4.2, 2.4, respectively. We observed extensive variation in clinical exposure to CS and self-reported confidence to perform CS between European trainees. Females reported a mean of 18% fewer entire procedures than their male colleagues and were also less confident in their surgical skills (P < .05). Trainees in residency programs longer than 5 years performed fewer procedures and were less confident than trainees in residences of shorter duration (P < .001). The importance of fellowships to complete surgical education was rated 7.7 out of 10., Conclusions: CS training across European countries lacks harmony. Female ophthalmology trainees continue, as in other specialties, to experience apparent gender bias. European level recommendations seem necessary to raise and harmonize competency-based CS training programs and promote post-residency fellowship training programs., (Copyright © 2023 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Soybean is an important global source of plant-based protein. A persistent trend has been observed over the past two decades that soybeans grown in western Canada have lower seed protein content than soybeans grown in eastern Canada. In this study, 10 soybean genotypes ranging in average seed protein content were grown in an eastern location (control) and three western locations (experimental) in Canada. Seed protein and oil contents were measured for all lines in each location. RNA-sequencing and differential gene expression analysis were used to identify differentially expressed genes that may account for relatively low protein content in western-grown soybeans. Differentially expressed genes were enriched for ontologies and pathways that included amino acid biosynthesis, circadian rhythm, starch metabolism, and lipid biosynthesis. Gene ontology, pathway mapping, and quantitative trait locus (QTL) mapping collectively provide a close inspection of mechanisms influencing nitrogen assimilation and amino acid biosynthesis between soybeans grown in the East and West. It was found that western-grown soybeans had persistent upregulation of asparaginase (an asparagine hydrolase) and persistent downregulation of asparagine synthetase across 30 individual differential expression datasets. This specific difference in asparagine metabolism between growing environments is almost certainly related to the observed differences in seed protein content because of the positive correlation between seed protein content at maturity and free asparagine in the developing seed. These results provided pointed information on seed protein-related genes influenced by environment. This information is valuable for breeding programs and genetic engineering of geographically optimized soybeans., Competing Interests: The 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 Hooker, Smith, Zapata, Charette, Luckert, Mohr, Daba, Warkentin, Hadinezhad, Barlow, Hou, Lefebvre, Golshani, Cober and Samanfar.)

Patient reported outcomes measures (PROMS) are important endpoints to measure patient health status in the perioperative setting. However, there are no good tools to measure PROMS in the pediatric surgical population. Patients 7 to 17 years old undergoing surgery were included and followed up for 1 day after surgery (POD1). At POD1 the patients were asked to rate their overall postoperative recovery using a 100-mm visual analog scale (VAS). The primary outcome was the pediatric QoR-15 score on postoperative day 1 (POD1). 150 patients completed the study. The mean (SD) pediatric QoR-15F scores were 132.1 (14.1) and 111.0 (27.0), preoperatively and on POD1, respectively. Convergent validity confirmed with Pearson (r) correlation between the postoperative pediatric QoR-15F and the patient-rated global recovery assessment was 0.72 (95% confidence interval [0.63-0.79]; p < 10 -16 ). Concerning reliability, internal consistency of the pediatric QoR-15 assessed by Cronbach's alpha was 0.90. The test-retest concordance correlation coefficient was 0.92; 95% CI [0.83-0.96]. Split-half alpha was 0.74. The pictorial pediatric version of the QoR-15F showed good validity, reliability, responsiveness, acceptability and feasibility. This PROMS should be considered for clinical care and research in the perioperative pediatric patient setting.Trial Registration: NCT04453410 on clinicaltrials.gov., (© 2023. Springer Nature Limited.)

Anthracyclines, such as doxorubicin (Dox), are widely used chemotherapeutic agents for the treatment of solid tumors and hematologic malignancies. However, they frequently induce cardiotoxicity leading to dilated cardiomyopathy and heart failure. This study sought to investigate the role of the exchange protein directly activated by cAMP (EPAC) in Dox-induced cardiotoxicity and the potential cardioprotective effects of EPAC inhibition. We show that Dox induces DNA damage and cardiomyocyte cell death with apoptotic features. Dox also led to an increase in both cAMP concentration and EPAC1 activity. The pharmacological inhibition of EPAC1 (with CE3F4) but not EPAC2 alleviated the whole Dox-induced pattern of alterations. When administered in vivo , Dox-treated WT mice developed a dilated cardiomyopathy which was totally prevented in EPAC1 knock-out (KO) mice. Moreover, EPAC1 inhibition potentiated Dox-induced cell death in several human cancer cell lines. Thus, EPAC1 inhibition appears as a potential therapeutic strategy to limit Dox-induced cardiomyopathy without interfering with its antitumoral activity., Competing Interests: MM, AB, MR, DD, AL, ML, TB, PM, MG, FL, JC, CB, CR, FL, BC, JB, MV, RF, AG, CL, EM No competing interests declared, (© 2023, Mazevet et al.)

Objective: In 2020, the Canadian Vasculitis Research Network (CanVasc) published their updated recommendations for the management of ANCA-associated vasculitides (AAV). The current addendum provides further recommendations regarding the use of avacopan in AAV based on a review of newly available evidence., Methods: An updated systematic literature review on avacopan (formerly, CCX168) using Medline, Embase, and the Cochrane Library was performed for publications up to September 2022. New recommendations were developed and categorized according to the EULAR grading levels, as done for previous CanVasc recommendations. A modified Delphi procedure and videoconferences were used to reach ≥80% consensus on the inclusion, wording and grading of each recommendation., Results: Three new recommendations were developed. They focus on avacopan therapy indication and duration, as well as timely glucocorticoid tapering., Conclusion: These 2022 addended recommendations provide rheumatologists, nephrologists and other specialists caring for patients with AAV with guidance for the use of avacopan, based on current evidence and consensus from Canadian experts., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The prevalence of post-surgical lumbar neuropathic radiculopathy is approximately 30%. Poor response to the recommended treatments for neuropathic pain, namely antidepressants and/or gabapentinoids, requires the development of new techniques to prevent chronic pain. One such well-tolerated technique is the administration of autologous plasma enriched in platelets and fibrin (PRF). This approach is largely used in regenerative medicine owing to the anti-inflammatory and analgesic properties of PRF. It could also be an interesting adjuvant to surgery, as it reduces neurogenic inflammation and promotes nerve recovery, thereby reducing the incidence of residual postoperative chronic pain. The aim of the present study is to evaluate the benefit of periradicular intraoperative application of PRF on the residual postsurgical neuropathic pain after disc herniation surgery., Methods: A randomized, prospective, interventional, controlled, single-blind study with evaluation by a blind outcome assessor will be performed in Strasbourg University Hospital. We will compare a control group undergoing conventional surgery to an experimental group undergoing surgery and periradicular administration of PRF (30 patients in each arm). The primary outcome is the intensity of postoperative neuropathic radicular pain, measured by a visual analog scale (VAS) at 6 months post-surgery. The secondary outcomes are the characteristics of neuropathic pain (NPSI), the quality of life (SF-12 and PGIC), the presence of anxiety/depression symptoms (HAD), and the consumption of analgesics. We will also carry out transcriptomic analysis of a panel of pro- and anti-inflammatory cytokines in blood samples, before surgery and at 6 months follow-up. These gene expression results will be correlated with clinical data, in particular, with the apparition of postoperative neuropathic pain., Discussion: This study is the first randomized controlled trial to assess the efficacy of PRF in the prevention of neuropathic pain following surgery for herniated disc. This study addresses not only a clinical question but will also provide information on the physiopathological mechanisms of neuropathic pain., Trial Registration: This study is registered at ClinicalTrials.gov: NCT05196503 , February 24, 2022., (© 2023. The Author(s).)

Local translation in neurons is partly mediated by the reactivation of stalled polysomes. Stalled polysomes may be enriched within the granule fraction, defined as the pellet of sucrose gradients used to separate polysomes from monosomes. The mechanism of how elongating ribosomes are reversibly stalled and unstalled on mRNAs is still unclear. In the present study, we characterize the ribosomes in the granule fraction using immunoblotting, cryogenic electron microscopy (cryo-EM), and ribosome profiling. We find that this fraction, isolated from 5-d-old rat brains of both sexes, is enriched in proteins implicated in stalled polysome function, such as the fragile X mental retardation protein (FMRP) and Up-frameshift mutation 1 homologue. Cryo-EM analysis of ribosomes in this fraction indicates they are stalled, mainly in the hybrid state. Ribosome profiling of this fraction reveals (1) an enrichment for footprint reads of mRNAs that interact with FMRPs and are associated with stalled polysomes, (2) an abundance of footprint reads derived from mRNAs of cytoskeletal proteins implicated in neuronal development, and (3) increased ribosome occupancy on mRNAs encoding RNA binding proteins. Compared with those usually found in ribosome profiling studies, the footprint reads were longer and were mapped to reproducible peaks in the mRNAs. These peaks were enriched in motifs previously associated with mRNAs cross-linked to FMRP in vivo , independently linking the ribosomes in the granule fraction to the ribosomes associated with FMRP in the cell. The data supports a model in which specific sequences in mRNAs act to stall ribosomes during translation elongation in neurons. SIGNIFICANCE STATEMENT Neurons send mRNAs to synapses in RNA granules, where they are not translated until an appropriate stimulus is given. Here, we characterize a granule fraction obtained from sucrose gradients and show that polysomes in this fraction are stalled on consensus sequences in a specific state of translational arrest with extended ribosome-protected fragments. This finding greatly increases our understanding of how neurons use specialized mechanisms to regulate translation and suggests that many studies on neuronal translation may need to be re-evaluated to include the large fraction of neuronal polysomes found in the pellet of sucrose gradients used to isolate polysomes., (Copyright © 2023 the authors.)