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Nutrient availability is a key determinant of tumor cell behavior. While nutrient‐rich conditions favor proliferation and tumor growth, scarcity, and particularly glutamine starvation, promotes cell dedifferentiation and chemoresistance. Here, linking ribosome biogenesis plasticity with tumor cell fate, we uncover that the amino acid sensor general control non‐derepressible 2 (GCN2; also known as eIF‐2‐alpha kinase 4) represses the expression of the precursor of ribosomal RNA (rRNA), 47S, under metabolic stress. We show that blockade of GCN2 triggers cell death by an irremediable nucleolar stress and subsequent TP53‐mediated apoptosis in patient‐derived models of colon adenocarcinoma (COAD). In nutrient‐rich conditions, a cell‐autonomous GCN2 activity supports cell proliferation by stimulating 47S rRNA transcription, independently of the canonical integrated stress response (ISR) axis. Impairment of GCN2 activity prevents nuclear translocation of methionyl‐tRNA synthetase (MetRS), resulting in nucleolar stress, mTORC1 inhibition and, ultimately, autophagy induction. Inhibition of the GCN2–MetRS axis drastically improves the cytotoxicity of RNA polymerase I (RNA pol I) inhibitors, including the first‐line chemotherapy oxaliplatin, on patient‐derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls ribosome biogenesis according to the nutritional context. Furthermore, pharmacological co‐inhibition of the two GCN2 branches and RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically stressed COAD cells.

Abstract Autism spectrum disorders (ASD) are complex, polygenic and heterogenous neurodevelopmental conditions. The severity of autism-associated variants is influenced by environmental factors, particularly social experiences during the critical neurodevelopmental period. While early behavioral interventions have shown efficacy in some children with autism, pharmacological support for core features — impairments in social interaction and communication, and stereotyped or restricted behaviors — is currently lacking. In this study, we examined how the social environment influences both wild-type (WT) and Shank3 knockout (KO) mice, a model reflecting core autism-like traits. Our findings revealed that chronic social isolation enhanced social interaction and olfactory neuron responses in WT animals. Furthermore, it restored impairments in social novelty preference and olfactory function, as well as self-grooming in Shank3 KO mice. Conversely, an enriched social environment heightened social interest toward novel conspecifics in WT mice, but elicited the opposite effect in Shank3 KO mice. Notably, Shank3 KO mice displayed distinct social responses when exposed to WT or Shank3 KO mice. These results offer novel insights that could favor the implementation of behavioral interventions and inclusive classroom programs for children with ASD.

Characterizing the epidemiology of circulating respiratory pathogens during the COVID-19 pandemic could clarify the burden of acute respiratory infections and monitor outbreaks of public health and military relevance. The US Department of Defense supported 2 regions for influenza-like illness and severe acute respiratory infections surveillance, one in the Middle East through US Naval Medical Research Unit EURAFCENT, and another in Latin America through US Naval Medical Research Unit SOUTH. During 2020‒2022, coinciding with the COVID-19 pandemic, we collected a total of 16,146 nasopharyngeal and oropharyngeal swab samples from sentinel sites in Jordan (n = 11,305) and Latin America (n = 4,841). Samples were tested for SARS-CoV-2, influenza, and other respiratory pathogens. SARS-CoV-2 was the most frequently detected pathogen during 2020; other respiratory pathogens had distinct temporal and frequency distributions according to geographic location. Our findings support the need for continued sentinel surveillance as a vital tool for assessing the burden of respiratory diseases globally.

Abstract Photonics offers a transformative approach to artificial intelligence (AI) and neuromorphic computing by enabling low-latency, high-speed, and energy-efficient computations. However, conventional photonic tensor cores face significant challenges in constructing large-scale photonic neuromorphic networks. Here, we propose a fully integrated photonic tensor core, consisting of only two thin-film lithium niobate (TFLN) modulators, a III-V laser, and a charge-integration photoreceiver. Despite its simple architecture, it is capable of implementing an entire layer of a neural network with a computational speed of 120 GOPS, while also allowing flexible adjustment of the number of inputs (fan-in) and outputs (fan-out). Our tensor core supports rapid in-situ training with a weight update speed of 60 GHz. Furthermore, it successfully classifies (supervised learning) and clusters (unsupervised learning) 112 × 112-pixel images through in-situ training. To enable in-situ training for clustering AI tasks, we offer a solution for performing multiplications between two negative numbers.

Abstract Understanding Mercury’s magnetosphere is crucial for advancing our comprehension of how the solar wind interacts with the planetary magnetospheres. Despite previous missions, several gaps remain in our knowledge of Mercury’s plasma environment. Here, we present findings from BepiColombo’s third flyby, offering a synoptic view of the large scale structure and composition of Mercury’s magnetosphere. The Mass Spectrum Analyzer (MSA), Mass Ion Analyzer (MIA), and Mass Electron Analyzer (MEA) on the magnetospheric orbiter reveal insights, including the identification of trapped energetic hydrogen (H+) with energies around 20 keV e−1 evidencing a ring current, and a cold ion plasma with energies below 50 eV e−1. Additionally, we observe a Low-Latitude Boundary Layer (LLBL), which is a region of turbulent plasma at the edge of the magnetosphere, characterized by bursty ion enhancements, indicating an ongoing injection process in the duskside magnetosphere flank. These observations during cruise phase provide a tantalizing glimpse of future discoveries expected from the Mercury Plasma Particle Experiment (MPPE) instruments after orbit insertion, promising broader impacts on our understanding of planetary magnetospheres.

Purpose: To summarize the results of Chile's 2022 Report Card (RC) on physical activity (PA) for Children and Adolescents. Methods: Chile's 2022 RC included ten core PA indicators common to the Global Matrix 4.0. Evidence from scientific articles, reports, and databases published between 2018 and January 2022 was included for each indicator. The data were collected and analyzed by a national scientific committee, which assigned letter grades (A to F) using a consensus based on benchmarks defined and revised by the Active Healthy Kids Global Alliance. Results: The committee assigned the following grades: Overall PA, D−; Organized Sports and Physical Activity Participation, C−; Active Play, Incomplete; Active Transportation, D; Sedentary Behavior, D−; Physical Fitness, Incomplete; Family and Peers, D; School, C; Community and Environment, D+; Government, A−. Conclusions: Chile's 2022 RC, like its previous versions, shows persistently low grades for most indicators. Overall PA remained nearly unchanged, while Community and Environment scored lower. Slight improvements were seen in Organized Sports, Family and Peers, and School Environment. While Chile has endeavored to increase children's activity levels, policies require implementation through a systemic, coherent framework to promote sustainable changes and reach a larger portion of children and youth.

Abstract Background In Germany, the telephone patient service 116,117 for callers with non-life-threatening health issues is available 24/7. Based on structured initial assessment, urgency and placement of suitable medical care offer have been offered since 2020. The service has been in increasing demand for several years: Depending on time and residence, this can result in longer waiting times. Methods Prospective, two-armed cohort study with two intervention groups and one control group, alternating between blinding and unblinding for employees of 116,117 regarding prioritization status. Two interventions based on automated voice dialogues (1: Simple self-rating tool, 2: Automated brief query of emergency symptoms). In case of high level of urgency, callers are prioritized. Validation of urgency and need for care is carried out routinely based on structured initial assessment. Discussion By creating and providing a largely reproducible documentation of the implemented solutions for a waiting queue management, the developed approach would be available for comparable projects in the German health care system or in the European context. This potentially leads to a reduction in the use of resources in the development of comparable technical solutions based on automated voice dialogs. Trial registration DRKS00031235, registered on 10th November 2023, https://drks.de/search/de/trial/DRKS00031235 .

Abstract Prematurity is associated with lower exercise capacity, which relies on the integrity of the cardiovascular, pulmonary, and skeletal muscle systems. Our animal model mimicking prematurity-associated conditions showed altered muscle composition and atrophy in adulthood. This study aimed to compare muscle composition and strength in adults born preterm versus full-term controls. This observational cohort study recruited 55 adults born preterm, ≤ 29 weeks’ of gestation and 53 full-term controls who underwent musculoskeletal ultrasound imaging to assess morphology of the rectus femoris at rest and during a maximal voluntary contraction. Maximal voluntary contraction of the hands and legs were measured by manual dynamometry. In adults born preterm, there was lower muscle strength (handgrip: − 4.8 kg, 95% CI − 9.1, − 0.6; knee extensor: − 44.6 N/m, 95% CI − 63.4, − 25.8) and smaller muscle area (− 130 mm2, 95% CI − 207, − 53), which was more pronounced with a history of bronchopulmonary dysplasia. Muscle stiffness was increased in the preterm versus term group (0.4 m/s, 95% CI 0.04, 0.7). Prematurity is associated with alterations in skeletal muscle composition, area, and function in adulthood. These findings highlight the necessity to implement preventive and/or curative approaches to improve muscle development and function following preterm birth to enhance overall health in this population.

Abstract Molluscum contagiosum (MC) is a common skin infection affecting children globally, including in Israel, which has a diverse population comprising mainly Jews (73.2%) and Arabs (21.1%). Despite documented disparities in various diseases between these groups, research on differences in dermatological care is scarce. This study aimed to investigate MC as a potential differentiator between Arab and Jewish children. A retrospective analysis of MC cases among children (0–18 years) from 2013 to 2022 was performed at Soroka University Medical Center, a tertiary hospital serving over a million patients. 615 patients participated in our study, with 95.2% Jewish and 4.8% Arab. Both groups showed similar characteristics in lesion quantity (P = 0.535), diameter (P = 0.341), inflammation markers, and lesion location. Additionally, management, treatment response, and outcomes were found to be similar between the two groups. In conclusion, the Arab representation in the study was disproportionately low compared to their population in the area. While Jewish patients may rely more on medical specialists, we believe Arabs may prefer self-management practices, such as the use of traditional medicine, possibly hindering effective physician-led care. Understanding such disparities could improve dermatological care by tailoring approaches to diverse populations.

Abstract This study aims to evaluate the applicability of the high-resolution WaveFront Phase Imaging Sensor (WFPI) in eyes with Fuchs’ Endothelial Corneal Dystrophy (FECD) through qualitative and quantitative analysis using a custom-designed Automatic Guttae Detection Method (AGDM). The ocular phase was measured using the t $$\cdot$$ · eyede aberrometer and then was processed to obtain its High-Pass Filter Map (HPFM). The subjects were pathological and healthy patients from the Fundación Jiménez-Díaz Hospital (Madrid, Spain). The AGDM was developed and applied in pupils with 3 and 5 mm of diameter. A set of metrics were extracted and evaluated like the Root-Mean-Square error (RMS), Number of guttae, Guttae Area, and Area of Delaunay Triangulation (DT). Finally, a Support Vector Machine (SVM) model was trained to classify between pathological and healthy eyes. Quantitatively, the HPFM reveals a dark spots pattern according to the ophthalmologist’s description of the slit-lamp examination of guttae distribution. There were significant statistical differences in all the metrics when FECD and Healthy groups were compared using the same pupil size; but comparing both pupil sizes for the same group there were significant differences in most of the variables. This sensor is a value tool to objectively diagnose and monitor this pathology through wavefront phase changes.

Background: Guidelines recommend that adolescents should accumulate an average of 60 min per day of moderate-to-vigorous physical activity (MVPA). However, using only this cut-off could hide important information. For instance, from a population-level point of view, increasing physical activity for those with no or low physical activity could provide more health benefits than increasing physical activity for those with intermediate levels. Also, including a more sensitive cut-point of ≥1 days per week could be an additional strategy for identifying those with low access/opportunities for physical activity practice. Thus, the current study aims to estimate the prevalence of ≥60 min of MVPA ≥1 days per week among adolescents globally, and to describe any relevant gender inequalities. Methods: We used representative datasets from 146 countries/territories collected between 2003 and 2019. MVPA was self-reported. Participants were grouped into younger (≤14 years old) and older (>14 years old) adolescents. Crude Poisson regression models were used to identify the relative differences in ≥60 min of MVPA ≥1 days per week between boys and girls, and random-effects meta-analysis models were used to identify the pooled estimates. Analyses were stratified by country and region. Results: Approximately 80% of both younger and older adolescents reported ≥60 min of MVPA ≥1 days per week. This prevalence was ≥94% in Europe and Central Asia and North America, while the estimates for the other regions were 14y = 1.09 (95%CI: 1.08‒1.10)). Conclusion: Approximately 8 out of 10 adolescents reported accumulating ≥60 min of MVPA ≥1 days per week, with notable differences between regions. Gender differences were observed in several countries, especially among the oldest adolescents. Priorities for physical activity promotion among adolescents should include increasing access/opportunities for physical activity among those who do not achieve ≥60 min of MVPA ≥1 days per week and reducing gender inequalities.

Background Despite improvement in devices, in‐stent restenosis remains a frequent and challenging complication of percutaneous coronary interventions. Methods and Results The RESTO (Morphological Parameters of In‐Stent Restenosis Assessed and Identified by OCT [Optical Coherence Tomography]; study NCT04268875) was a prospective multicenter registry including patients presenting with coronary syndromes related to in‐stent restenosis. All patients underwent preintervention OCT analysis, which led to analysis of in‐stent restenosis phenotype, number of strut layers, and presence of stent underexpansion. The primary end point was the in‐stent restenosis type according to the OCT morphological classification. The 1‐year incidence of target vessel failure (a composite of death from cardiac causes, target‐vessel myocardial infarction, or ischemia‐driven target‐vessel revascularization) was assessed. The study included 297 patients. The culprit stent was a drug‐eluting stent in 74.2% of cases. OCT analysis revealed the presence of neoatherosclerosis in 57% (52% calcified), neointimal hyperplasia in 43% (58% homogeneous), stent underexpansion (minimal stent area

Summary: Background: Surgical care holds significant importance in healthcare, especially in low and middle-income countries, as at least 50% of the 4.2 million deaths within the initial 30 days following surgery take place in these countries. The Lancet Commission on Global Surgery proposed six indicators to enhance surgical care. In Colombia, studies have been made using secondary data. However, strategies to reduce perioperative mortality have not been implemented. This study aims to describe the fourth indicator, perioperative mortality rate (POMR), with primary data in Colombia. Methods: A multicentre prospective cohort study was conducted across 54 centres (hospitals) in Colombia. Each centre selected a 7-day recruitment period between 05/2022 and 01/2023. Inclusion criteria involved patients over 18 years of age undergoing surgical procedures in operating rooms. Data quality was ensured through a verification guideline and statistical analysis using mixed-effects multilevel modelling with a case mix analysis of mortality by procedure-related, patient-related, and hospital-related conditions. Findings: 3807 patients were included with a median age of 48 (IQR 32–64), 80.3% were classified as ASA I or II, and 27% of the procedures had a low-surgical complexity. Leading procedures were Orthopedics (19.2%) and Gynaecology/Obstetrics (17.7%). According to the Clavien–Dindo scale, postoperative complications were distributed in major complications (11.7%, 10.68–12.76) and any complication (31.6%, 30.09–33.07). POMR stood at 1.9% (1.48–2.37), with elective and emergency surgery mortalities at 0.7% (0.40–1.23) and 3% (2.3–3.89) respectively. Interpretation: The POMR was higher than the ratio reported in previous national studies, even when patients had a low–risk profile and low-complexity procedures. The present research represents significant public health progress with valuable insights for national decision-makers to improve the quality of surgical care. Funding: This work was supported by Universidad del Rosario and Fundación Cardioinfantil-Instituto de Cardiología grant number CTO-057-2021, project-ID IV-FGV017.

Abstract Yersinia pestis has been infecting humans since the Late Neolithic (LN). Whether those early infections were isolated zoonoses or initiators of a pandemic remains unclear. We report Y. pestis infections in two individuals (of 133) from the LN necropolis at Warburg (Germany, 5300–4900 cal BP). Our analyses show that the two genomes belong to distinct strains and reflect independent infection events. All LN genomes known today (n = 4) are basal in the phylogeny and represent separate lineages that probably originated in different animal hosts. In the LN, an opening of the landscape resulted in the introduction of new rodent species, which may have acted as Y. pestis reservoirs. Coincidentally, the number of dogs increased, possibly leading to Y. pestis infections in canines. Indeed, we detect Y. pestis in an LN dog. Collectively, our data suggest that Y. pestis frequently entered human settlements at the time without causing significant outbreaks.

Abstract The quest for targeted therapies is critical in the battle against cancer. The RAS/MAP kinase pathway is frequently implicated in neoplasia, with ERK playing a crucial role as the most distal kinase in the RAS signaling cascade. Our previous research demonstrated that the interaction between ERK and MYD88, an adaptor protein in innate immunity, is crucial for RAS-dependent transformation and cancer cell survival. In this study, we examine the biological consequences of disrupting the ERK-MYD88 interaction through the ERK D-recruitment site (DRS), while preserving ERK’s kinase activity. Our results indicate that EI-52, a small-molecule benzimidazole targeting ERK-MYD88 interaction induces an HRI-mediated integrated stress response (ISR), resulting in immunogenic apoptosis specific to cancer cells. Additionally, EI-52 exhibits anti-tumor efficacy in patient-derived tumors and induces an anti-tumor T cell response in mice in vivo. These findings suggest that inhibiting the ERK-MYD88 interaction may be a promising therapeutic approach in cancer treatment.

Abstract Epigenetic clocks are age predictors that use machine-learning models trained on DNA CpG methylation values to predict chronological or biological age. Increases in predicted epigenetic age relative to chronological age (epigenetic age acceleration) are connected to aging-associated pathologies, and changes in epigenetic age are linked to canonical aging hallmarks. However, epigenetic clocks rely on training data from bulk tissues whose cellular composition changes with age. Here, we found that human naive CD8+ T cells, which decrease in frequency during aging, exhibit an epigenetic age 15–20 years younger than effector memory CD8+ T cells from the same individual. Importantly, homogenous naive T cells isolated from individuals of different ages show a progressive increase in epigenetic age, indicating that current epigenetic clocks measure two independent variables, aging and immune cell composition. To isolate the age-associated cell intrinsic changes, we created an epigenetic clock, the IntrinClock, that did not change among 10 immune cell types tested. IntrinClock shows a robust predicted epigenetic age increase in a model of replicative senescence in vitro and age reversal during OSKM-mediated reprogramming.

New tuberculosis (TB) drugs with little existing antimicrobial resistance enable a pan-TB treatment regimen, intended for universal use without prior drug-susceptibility testing. However, widespread use of such a regimen could contribute to an increasing prevalence of antimicrobial resistance, potentially rendering the pan-TB regimen ineffective or driving clinically problematic patterns of resistance. We developed a model of multiple sequential TB patient cohorts to compare treatment outcomes between continued use of current standards of care (guided by rifampin-susceptibility testing) and a hypothetical pan-TB approach. A pan-TB regimen that met current target profiles was likely to initially outperform the standard of care; however, a rising prevalence of transmitted resistance to component drugs could make underperformance likely among subsequent cohorts. Although the pan-TB approach led to an increased prevalence of resistance to novel drugs, it was unlikely to cause accumulation of concurrent resistance to novel drugs and current first-line drugs.

Abstract This paper presents a dataset of 3D sagittal left otolith meshes from 339 individual red mullet (Mullus barbatus). These immature specimens were collected from 17 geographical areas covering the entire Mediterranean Sea. Measured biological parameters were: fish total length (TL ± 1 mm, range from 125 to 238 mm), total weight (W ± 0.1 g, range from 14.9 to 168.0 g), sex (S), sexual maturity staging (Mat). The 3D otolith dataset comprises high-resolution meshes of otoliths obtained using microtomography (29.2 μm voxel size). The data offer valuable insights into the morphological variability and population structure of red mullet populations in the Mediterranean Sea. Potential applications of the dataset include age determination, stock identification, and population connectivity analysis. These applications aim to enhance the understanding of red mullet populations and contribute to the sustainable management of marine resources in the Mediterranean Sea.

Abstract Background Exploring the value of baseline and early 18F-FDG PET/CT evaluations in prediction PFS in ER+/HER2- metastatic breast cancer patients treated with a cyclin-dependent kinase inhibitor in combination with an endocrine therapy. Methods Sixty-six consecutive breast cancer patients who underwent a pre-therapeutic 18F-FDG PET/CT and a second PET/CT within the first 6 months of treatment were retrospectively included. Metabolic tumour volume (MTV) and total lesion glycolysis (TLG) and Dmax, which represents tumour dissemination and is defined as the distance between the two most distant lesions, were computed. The variation in these parameters between baseline and early evaluation PET as well as therapeutic evaluation using PERCIST were assessed as prognosticators of PFS at 18 months. Results The median follow-up was equal to 22.5 months. Thirty progressions occurred (45.4%). The average time to event was 17.8 ± 10.4 months. At baseline, Dmax was the only predictive metabolic parameter. Patients with a baseline Dmax ≤ 18.10 cm had a significantly better 18 m-PFS survival than the others: 69.2% (7.7%) versus 36.7% (8.8%), p = 0.017. There was no association between PERCIST evaluation and 18 m-PFS status (p = 0.149) and there was no difference in 18 m-PFS status between patients classified as complete, partial metabolic responders or having stable metabolic disease. Conclusion Disease spread at baseline PET, as assessed by Dmax, is predictive of an event occurring within 18 months. In the absence of early metabolic progression, which occurs in 15% of patients, treatment should be continued regardless of the quality of the initial response to treatment.

Abstract The variability of proteins at the sequence level creates an enormous potential for proteome complexity. Exploring the depths and limits of this complexity is an ongoing goal in biology. Here, we systematically survey human and plant high-throughput bottom-up native proteomics data for protein truncation variants, where substantial regions of the full-length protein are missing from an observed protein product. In humans, Arabidopsis, and the green alga Chlamydomonas, approximately one percent of observed proteins show a short form, which we can assign by comparison to RNA isoforms as either likely deriving from transcript-directed processes or limited proteolysis. While some detected protein fragments align with known splice forms and protein cleavage events, multiple examples are previously undescribed, such as our observation of fibrocystin proteolysis and nuclear translocation in a green alga. We find that truncations occur almost entirely between structured protein domains, even when short forms are derived from transcript variants. Intriguingly, multiple endogenous protein truncations of phase-separating translational proteins resemble cleaved proteoforms produced by enteroviruses during infection. Some truncated proteins are also observed in both humans and plants, suggesting that they date to the last eukaryotic common ancestor. Finally, we describe novel proteoform-specific protein complexes, where the loss of a domain may accompany complex formation.

Abstract The far-from-equilibrium solidification during additive manufacturing often creates large residual stresses that induce solid-state cracking. Here we present a strategy to suppress solid-state cracking in an additively manufactured AlCrFe2Ni2 high-entropy alloy via engineering phase transformation pathway. We investigate the solidification microstructures formed during laser powder-bed fusion and directed energy deposition, encompassing a broad range of cooling rates. At high cooling rates (104−106 K/s), we observe a single-phase BCC/B2 microstructure that is susceptible to solid-state cracking. At low cooling rates (102−104 K/s), FCC phase precipitates out from the BCC/B2 matrix, resulting in enhanced ductility (~10 %) and resistance to solid-state cracking. Site-specific residual stress/strain analysis reveals that the ductile FCC phase can largely accommodate residual stresses, a feature which helps relieve residual strains within the BCC/B2 phase to prevent cracking. Our work underscores the value of exploiting the toolbox of phase transformation pathway engineering for material design during additive manufacturing.

Abstract Background Generating synthetic patient data is crucial for medical research, but common approaches build up on black-box models which do not allow for expert verification or intervention. We propose a highly available method which enables synthetic data generation from real patient records in a privacy preserving and compliant fashion, is interpretable and allows for expert intervention. Methods Our approach ties together two established tools in medical informatics, namely OMOP as a data standard for electronic health records and Synthea as a data synthetization method. For this study, data pipelines were built which extract data from OMOP, convert them into time series format, learn temporal rules by 2 statistical algorithms (Markov chain, TARM) and 3 algorithms of causal discovery (DYNOTEARS, J-PCMCI+, LiNGAM) and map the outputs into Synthea graphs. The graphs are evaluated quantitatively by their individual and relative complexity and qualitatively by medical experts. Results The algorithms were found to learn qualitatively and quantitatively different graph representations. Whereas the Markov chain results in extremely large graphs, TARM, DYNOTEARS, and J-PCMCI+ were found to reduce the data dimension during learning. The MultiGroupDirect LiNGAM algorithm was found to not be applicable to the problem statement at hand. Conclusion Only TARM and DYNOTEARS are practical algorithms for real-world data in this use case. As causal discovery is a method to debias purely statistical relationships, the gradient-based causal discovery algorithm DYNOTEARS was found to be most suitable.

Novel copper-nickel matrix composites reinforced with silicon carbide (SiC) micro particles for metal contact applications were manufactured by powder metallurgy technology and were experimentally characterized. Cu and Cu alloys are commonly used as metal contact for either vacuum, oil, or SF6 in low-voltage circuit breaker devices, but their application in environments with the presence of oxygen is limited due to their tendency to form high-resistance copper oxides. Thus, the addition of Ni as an alloying element provides resistance to both humidity and several corrosive environments and increases the composites' hardness, mechanical strength, and wear resistance. Moreover, SiC was chosen due to its contribution to mechanical strength, mouldability, low production cost, and non-reactive nature at ordinary temperatures. Here, three SiC particle size distributions were considered, and it was found that the composites' physical properties are also dependent on the ceramic loading. After evaluating these properties, two specific SiC concentrations were potentially considered for electrode applications: 10 wt% and 20 wt%. The obtained hardness values are in the range of 55–65 HR30T which guarantees the necessary strength without detriment of the contact area whereas the welding is minimized. In addition to a homogeneous particle distribution in the solid material, specific wear resistance of ∼10−5 mm3N−1m−1 and electrical conductivities of ∼20 %IACS were obtained. Considering these parameters, Cu-Ni/SiC composites' performance is not compromised compared to commercial Ag/WC materials commonly used in metal contact applications.

La revolución de la tecnología y las telecomunicaciones ha permitido la innovación en modelos de negocios mediante el uso de plataformas, en particular las de domicilios, que han generado un ecosistema de gestión por algoritmos que en muchos casos somete a los trabajadores a condiciones de control y precarización de sus actividades. El caso de Rappi es un ejemplo de uso de la innovación para la precarización de los trabajadores incluso con la negación misma de su carácter de trabajador, mas aun en contextos como el colombiano con una estructura laboral precaria y una clase empresarial rentista. Este trabajo analiza el caso Rappi en Colombia por medio del uso de entrevistas y encuestas realizadas entre el 2021 y el 2024.

Background and objectivesRobotic approach in colorectal surgery is rapidly gaining interest, particularly in the context of rectal cancer resection. Despite economic barriers, substantial proliferation of robotic colorectal procedures has been observed throughout Latin America. However, there is a lack of data regarding intraoperative and early postoperative outcomes, as well as oncological and long-term results. This systematic review aims to provide an overview of the surgical outcomes of robotic-assisted colorectal approaches across Latin America.Material and methodsA systematic literature search of electronic databases, including PubMed, LILACS, Scopus, Cochrane Library and Scielo, was performed and reported in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The main target of the literature search was studies that reported outcomes of colorectal robotic surgery in Latin America.ResultsA total of 9,694 published articles were identified from the initial search. Nine thousand six hundred thirty-six publications were excluded after title and abstract review and removal of duplicates. Fifty-eight articles were thoroughly reviewed, and 11 studies met the inclusion criteria. The critical appraisal of study quality (biases risk assessment) was performed according to the Joanna Briggs Institute (JBI) Manual for Evidence Synthesis. In general, the overall study quality was poor. Of the 11 studies included in the analysis, ten addressed intraoperative and early postoperative outcomes, seven addressed oncological/pathological outcomes, and just one addressed long-term outcomes. Ten studies evaluated intraoperative and early postoperative outcomes, encompassing a total of 425 patients, the majority of whom were diagnosed with colorectal cancer. Morbidity rates exhibited a range between 0% and 45.9%, while mortality ranged from 0% to 2.5%.ConclusionFew studies have been published addressing intraoperative, postoperative, pathological, and oncological outcomes of robotic colorectal surgery in this region. Undoubtedly, there are unique challenges not encountered by developed countries, including economic obstacles in establishing structured training programmes and high-quality centres for the development of robotic surgery. Further studies are needed to assess the real extent of robotic surgery in the region and its results.Systematic Review Registrationhttps://www.crd.york.ac.uk/, PROSPERO (CRD42023494112).

Abstract Understanding the mechanisms underlying amyloid‐β (Aβ) aggregation is pivotal in the context of Alzheimer's disease. This study aims to elucidate the secondary nucleation process of Aβ42 peptides by combining experimental and computational methods. Using a newly developed nanopipette‐based amyloid seeding and translocation assay, confocal fluorescence spectroscopy, and molecular dynamics simulations, the influence of the seed properties on Aβ aggregation is investigated. Both fragmented and unfragmented seeds played distinct roles in the formation of oligomers, with fragmented seeds facilitating the formation of larger aggregates early in the incubation phase. The results show that secondary nucleation leads to the formation of oligomers of various sizes and structures as well as larger fibrils structured in β‐sheets. From these findings a mechanism of secondary nucleation involving two types of aggregate populations, one released and one growing on the mother fiber is proposed.

IntroductionGenerative Artificial Intelligence (Gen AI) is rapidly transforming education holds immense potential for enhancing learning experiences and fostering innovation skills crucial for success in today’s rapidly changing job market. However, successful integration depends on student adoption. This study investigates factors influencing business students’ intention to use Gen AI in Innovation courses, focusing on the role of Perceived Enjoyment.MethodA cross-sectional predictive analysis was conducted using data from 92 business undergraduate students in a Peruvian higher education institution. A survey questionnaire, adapted from Teo and Noyes, was used to measure perceived enjoyment, usefulness, ease of use, attitude toward, and intention to use Gen AI tools.ResultsThe study found a strong positive relationship between Perceived Enjoyment and the intention to use Gen AI in Innovation courses. Furthermore, Perceived Enjoyment was positively associated with perceived ease of use. Interestingly, perceived usefulness did not show a significant effect on the intention to use Gen AI.ConclusionOur finding challenges the traditional emphasis on perceived usefulness as the primary driver of technology acceptance. Instead, our results suggest that prioritizing user enjoyment and ease of use in the design and implementation of Gen AI tools may be a more effective strategy for promoting their adoption in educational settings. This shift in focus from utility to experience could be crucial in unlocking the full potential of Gen AI to transform education.

يتناول هذا المقال استخدام تعبير «بلا كيف» في علم الكلام الإسلامي التقليدي، وخاصة في سياق المصطلحات المتشابهة التي تُستخدم لوصف الله. يُستخدم تعبير «بلا كيف» بشكل متكرر في النصوص الكلامية لرفض أي محاولة لإسناد شكل أو هيئة مادية لله، مما يتجنب أي تفسير مجسّم. يستعرض المقال ثلاثة مواقف تاريخية تتعلق بالآيات المتشابهة: التأويل، التجسيم الحرفي، وموقف «بلا كيف». كما يناقش الاختلافات بين الغزالي، الذي يؤيد التأويل، وابن تيمية، المدافع عن «بلا كيف». ويخلص المقال إلى أن الحدود بين هذه المواقف تبقى غامضة، وأن مفهوم «بلا كيف» يختلف بين الأشاعرة وابن تيمية.

ObjectiveBipolar Disorder (BD) is a severe mental illness associated with high rates of general medical comorbidity, reduced life expectancy, and premature mortality. Although BD has been associated with high medical hospitalization, the factors that contribute to this risk remain largely unexplored. We used baseline medical and psychiatric records to develop a supervised machine learning model to predict general medical admissions after discharge from psychiatric hospitalization.MethodsIn this retrospective three-year cohort study of 71 patients diagnosed with BD (mean age=52.19 years, females=56.33%), lasso regression models combining medical and psychiatric records, as well as those using them separately, were fitted and their predictive power was estimated using a leave-one-out cross-validation procedure.ResultsThe proportion of medical admissions in patients with BD was higher compared with age- and sex-matched hospitalizations in the same region (25.4% vs. 8.48%). The lasso model fairly accurately predicted the outcome (area under the curve [AUC]=69.5%, 95%C.I.=55–84.1; sensitivity=61.1%, specificity=75.5%, balanced accuracy=68.3%). Notably, pre-existing cardiovascular, neurological, or osteomuscular diseases collectively accounted for more than 90% of the influence on the model. The accuracy of the model based on medical records was slightly inferior (AUC=68.7%, 95%C.I. = 54.6-82.9), while that of the model based on psychiatric records only was below chance (AUC=61.8%, 95%C.I.=46.2–77.4).ConclusionOur findings support the need to monitor medical comorbidities during clinical decision-making to tailor and implement effective preventive measures in people with BD. Further research with larger sample sizes and prospective cohorts is warranted to replicate these findings and validate the predictive model.

Introduction: Lung cancer is the leading cause of cancer death among American Indian and Alaska Native (AI/AN) people, and AI/AN people have the highest rate of smoking of any racial or ethnic group in the US. There is limited research to inform culturally-relevant strategies for lung cancer prevention inclusive of lung cancer screening (LCS). The objective of this study was to understand determinants of LCS and tobacco cessation care in at-risk urban-dwelling AI/ANs. Materials and Methods: This was a mixed-methods community-based participatory research study including complimentary qualitative discussions and surveys conducted in Seattle, Washington, USA from 2022 to 2023. The study measures and analytic approach integrated the Consolidated Framework for Implementation Research and Tribal Critical Race Theory and qualitative transcripts were analyzed using thematic analysis. Participants were self-identified AI/AN people who were age ≥ 40 and had ≥ 10-year history of commercial cigarette smoking. Results: Forty-five participants completed surveys and participated in discussions, 48% were female, the median age was 58 and median smoking history was 24 pack-years of commercial cigarette use. Themes revealed prominent barriers to LCS care including access, costs, awareness, and fear. Many reported previous negative and discriminatory encounters within and outside the health system which may also serve as barriers. Most participants endorsed cancer screening and increased education, recommending Indigenous-centered, delivered, and tailored programs, as well barrier-directed support. Conclusions: In a broad sample of at-risk urban-dwelling AI/AN people, our findings suggest enthusiasm for preventive care but several complex barriers. Participants endorsed culturally-tailored programs which could provide relevant education and address barriers.

We read with great interest the recent paper by Lo et al., who argue that there is an urgent need to ensure the quality of modelling evidence used to support international and national guideline development. Here we outline efforts by the Tuberculosis Modelling and Analysis Consortium, together with the World Health Organization Global Task Force on Tuberculosis Impact Measurement, to develop material to improve the quality and transparency of country-level tuberculosis modelling to inform decision-making.

Abstract Introduction Tuberculosis (TB) causes over 1 million deaths annually. Providing effective treatment is a key strategy for reducing TB deaths. In this study, we identified factors associated with unsuccessful treatment outcomes among individuals treated for TB in Brazil. Methods We obtained data on individuals treated for TB between 2015 and 2018 from Brazil’s National Disease Notification System (SINAN). We excluded patients with a history of prior TB disease or with diagnosed TB drug resistance. We extracted information on patient-level factors potentially associated with unsuccessful treatment, including demographic and social factors, comorbid health conditions, health-related behaviors, health system level at which care was provided, use of directly observed therapy (DOT), and clinical examination results. We categorized treatment outcomes as successful (cure, completed) or unsuccessful (death, regimen failure, loss to follow-up). We fit multivariate logistic regression models to identify factors associated with unsuccessful treatment. Results Among 259,484 individuals treated for drug susceptible TB, 19.7% experienced an unsuccessful treatment outcome (death during treatment 7.8%, regimen failure 0.1%, loss to follow-up 11.9%). The odds of unsuccessful treatment were higher with older age (adjusted odds ratio (aOR) 2.90 [95% confidence interval: 2.62–3.21] for 85-100-year-olds vs. 25-34-year-olds), male sex (aOR 1.28 [1.25–1.32], vs. female sex), Black race (aOR 1.23 [1.19–1.28], vs. White race), no education (aOR 2.03 [1.91–2.17], vs. complete high school education), HIV infection (aOR 2.72 [2.63–2.81], vs. no HIV infection), illicit drug use (aOR 1.95 [1.88–2.01], vs. no illicit drug use), alcohol consumption (aOR 1.46 [1.41–1.50], vs. no alcohol consumption), smoking (aOR 1.20 [1.16–1.23], vs. non-smoking), homelessness (aOR 3.12 [2.95–3.31], vs. no homelessness), and immigrant status (aOR 1.27 [1.11–1.45], vs. non-immigrants). Treatment was more likely to be unsuccessful for individuals treated in tertiary care (aOR 2.20 [2.14–2.27], vs. primary care), and for patients not receiving DOT (aOR 2.35 [2.29–2.41], vs. receiving DOT). Conclusion The risk of unsuccessful TB treatment varied systematically according to individual and service-related factors. Concentrating clinical attention on individuals with a high risk of poor treatment outcomes could improve the overall effectiveness of TB treatment in Brazil.

Abstract The aim of this work is to quantitatively assess the wavefront phase of keratoconic eyes measured by the ocular aberrometer t·eyede (based on WaveFront Phase Imaging Sensor), characterized by a lateral resolution of 8.6 µm without requiring any optical element to sample the wavefront information. We evaluated the parameters: root mean square error, Peak-to-Valley, and amplitude of the predominant frequency (Fourier Transform analysis) of a section of the High-Pass filter map in keratoconic and healthy cohorts. Furthermore, we have analyzed keratoconic eyes that presented dark–light bands in this map to assess their period and orientation with the Fourier Transform. There are significant statistical differences (p value

Abstract Backgroud Modelling discrete-time cause-specific hazards in the presence of competing events and non-proportional hazards is a challenging task in many domains. Survival analysis in longitudinal cohorts often requires such models; notably when the data is gathered at discrete points in time and the predicted events display complex dynamics. Current models often rely on strong assumptions of proportional hazards, that is rarely verified in practice; or do not handle sequential data in a meaningful way. This study proposes a Transformer architecture for the prediction of cause-specific hazards in discrete-time competing risks. Contrary to Multilayer perceptrons that were already used for this task (DeepHit), the Transformer architecture is especially suited for handling complex relationships in sequential data, having displayed state-of-the-art performance in numerous tasks with few underlying assumptions on the task at hand. Results Using synthetic datasets of 2000–50,000 patients, we showed that our Transformer model surpassed the CoxPH, PyDTS, and DeepHit models for the prediction of cause-specific hazard, especially when the proportional assumption did not hold. The error along simulated time outlined the ability of our model to anticipate the evolution of cause-specific hazards at later time steps where few events are observed. It was also superior to current models for prediction of dementia and other psychiatric conditions in the English longitudinal study of ageing cohort using the integrated brier score and the time-dependent concordance index. We also displayed the explainability of our model’s prediction using the integrated gradients method. Conclusions Our model provided state-of-the-art prediction of cause-specific hazards, without adopting prior parametric assumptions on the hazard rates. It outperformed other models in non-proportional hazards settings for both the synthetic dataset and the longitudinal cohort study. We also observed that basic models such as CoxPH were more suited to extremely simple settings than deep learning models. Our model is therefore especially suited for survival analysis on longitudinal cohorts with complex dynamics of the covariate-to-outcome relationship, which are common in clinical practice. The integrated gradients provided the importance scores of input variables, which indicated variables guiding the model in its prediction. This model is ready to be utilized for time-to-event prediction in longitudinal cohorts.

Abstract Witnessing another’s pain can heighten pain in the observer. However, research has focused on the observer’s intrapersonal experience. Here, a social transmission-chain explored the spread of socially-acquired nocebo hyperalgesia. Dyads of genuine participants were randomised to ‘Generations’ (G1–G3). G1-Demonstrators, observed by G2-Observers, experienced high/low thermal pain contingent on supposed activity/inactivity of a sham-treatment. G2 became Demonstrators, witnessed by G3-Observers. They experienced fixed low-temperature stimuli irrespective of sham-treatment ‘activity’. G3 then Demonstrated for G4-Observers (a confederate), also experiencing low-temperature stimuli only. Pain ratings, electrodermal activity, and facial action units were measured. G1’s treatment-related pain propagated throughout the chain. G2 and G3 participants showed heightened subjective and physiological response to sham-treatment, despite equivalent stimulus temperatures, and G3 never witnessing the initial pain-event. Dyadic interpersonal physiological synchrony (electrodermal activity) and psychological synchrony (Observer’s ability to predict the Demonstrator’s pain), predicted subsequent socially-acquired pain. Implications relate to the interpersonal spread of maladaptive pain experiences.

Abstract Background Antenatal balanced energy and protein (BEP) supplements have well-documented benefits for pregnancy outcomes. However, considerable practical gaps remain in the effective and cost-effective delivery of antenatal BEP supplements at scale in low- and middle-income countries. Methods A randomized effectiveness study will be conducted in two sub-cities of Addis Ababa, Ethiopia, to evaluate the effectiveness, cost-effectiveness, and implementation of different targeting strategies of antenatal BEP supplements. Pregnant women aged 18 to 49, with a gestational age of 24 weeks or less, and attending antenatal visits in one of the nine study health facilities are eligible for enrollment. In six of the health facilities, participants will be randomized to one of three study arms: control (Arm 1), targeted BEP provision based on baseline nutritional status (Arm 2), and targeted BEP supplementation based on baseline nutritional status and monthly gestational weight gain (GWG) monitoring (Arm 3). In the remaining three facilities, participants will be assigned to universal BEP provision (Arm 4). Participants in Arms 2 and 3 will receive BEP supplements if they have undernutrition at enrollment, as defined by a baseline body mass index less than 18.5 kg/m2 or mid-upper arm circumference less than 23 cm. In Arm 3, in addition to targeting based on baseline undernutrition, regular weight measurements will be used to identify insufficient GWG and inform the initiation of additional BEP supplements. Participants in Arm 4 will receive BEP supplements until the end of pregnancy, regardless of baseline nutritional status or GWG. All participants will receive standard antenatal care, including iron and folic acid supplementation. A total of 5400 pregnant women will be enrolled, with 1350 participants in each arm. Participants will be followed up monthly during their visits to the antenatal facilities until delivery. Maternal and infant health status will be evaluated within 72 h after delivery and at 6 weeks postpartum. The effectiveness and cost-effectiveness of the different BEP targeting strategies in preventing adverse pregnancy outcomes will be compared across arms. Qualitative data will be analyzed to assess the feasibility, acceptability, and implementation of different supplementation strategies. Discussion This study will inform global recommendations and operational guidelines for the effective and cost-effective delivery of antenatal BEP supplements. The targeted approaches have the potential for broader scale-up in Ethiopia and other low-resource settings with a high burden of undernutrition among pregnant women. Trial registration ClinicalTrials.gov registration number: NCT06125860. Registered November 9, 2023.

Abstract Translational research requires data at multiple scales of biological organization. Advancements in sequencing and multi-omics technologies have increased the availability of these data, but researchers face significant integration challenges. Knowledge graphs (KGs) are used to model complex phenomena, and methods exist to construct them automatically. However, tackling complex biomedical integration problems requires flexibility in the way knowledge is modeled. Moreover, existing KG construction methods provide robust tooling at the cost of fixed or limited choices among knowledge representation models. PheKnowLator (Phenotype Knowledge Translator) is a semantic ecosystem for automating the FAIR (Findable, Accessible, Interoperable, and Reusable) construction of ontologically grounded KGs with fully customizable knowledge representation. The ecosystem includes KG construction resources (e.g., data preparation APIs), analysis tools (e.g., SPARQL endpoint resources and abstraction algorithms), and benchmarks (e.g., prebuilt KGs). We evaluated the ecosystem by systematically comparing it to existing open-source KG construction methods and by analyzing its computational performance when used to construct 12 different large-scale KGs. With flexible knowledge representation, PheKnowLator enables fully customizable KGs without compromising performance or usability.

Abstract Background Reduced clearance of cerebrospinal fluid (CSF) has been suggested as a pathological feature of Alzheimer’s disease (AD). With extensive documentation in non-human mammals and contradictory human neuroimaging data it remains unknown whether the nasal mucosa is a CSF drainage site in humans. Here, we used dynamic PET with [1-11C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid. Methods 24 cognitively normal subjects (≥ 65 years) were dynamically PET imaged for 60 min. using [1-11C]-Butanol. Imaging with either [11C]-PiB or [18F]-FBB identified 8 amyloid PET positive (Aβ+) and 16 Aβ- subjects. MRI-determined regions of interest (ROI) included: the carotid artery, the lateral orbitofrontal (LOF) brain, the cribriform plate, and an All-turbinate region comprised of the superior, middle, and inferior turbinates. The bilateral temporalis muscle and jugular veins served as control regions. Regional time-activity were used to model tracer influx, egress, and AUC. Results LOF and All-turbinate 60 min AUC were positively associated, thus suggesting a connection between the brain and the nose. Further, the Aβ+ subgroup demonstrated impaired tracer kinetics, marked by reduced tracer influx and slower egress. Conclusion The data show that tracer kinetics for brain and nasal turbinates are related to each other and both reflect the amyloid status of the brain. As such, these data add to evidence that the nasal pathway is a potential CSF drainage site in humans. These data warrant further investigation of brain and nasal contributions to protein clearance in neurodegenerative disease.

Abstract Background B-type lamins are critical nuclear envelope proteins that interact with the three-dimensional genomic architecture. However, identifying the direct roles of B-lamins on dynamic genome organization has been challenging as their joint depletion severely impacts cell viability. To overcome this, we engineered mammalian cells to rapidly and completely degrade endogenous B-type lamins using Auxin-inducible degron technology. Results Using live-cell Dual Partial Wave Spectroscopic (Dual-PWS) microscopy, Stochastic Optical Reconstruction Microscopy (STORM), in situ Hi-C, CRISPR-Sirius, and fluorescence in situ hybridization (FISH), we demonstrate that lamin B1 and lamin B2 are critical structural components of the nuclear periphery that create a repressive compartment for peripheral-associated genes. Lamin B1 and lamin B2 depletion minimally alters higher-order chromatin folding but disrupts cell morphology, significantly increases chromatin mobility, redistributes both constitutive and facultative heterochromatin, and induces differential gene expression both within and near lamin-associated domain (LAD) boundaries. Critically, we demonstrate that chromatin territories expand as upregulated genes within LADs radially shift inwards. Our results indicate that the mechanism of action of B-type lamins comes from their role in constraining chromatin motion and spatial positioning of gene-specific loci, heterochromatin, and chromatin domains. Conclusions Our findings suggest that, while B-type lamin degradation does not significantly change genome topology, it has major implications for three-dimensional chromatin conformation at the single-cell level both at the lamina-associated periphery and the non-LAD-associated nuclear interior with concomitant genome-wide transcriptional changes. This raises intriguing questions about the individual and overlapping roles of lamin B1 and lamin B2 in cellular function and disease.

Abstract Background In many countries, nitrous oxide is used in a gas mixture (EMONO) for short-term analgesia. Cases of addiction, with significant misuse, have been reported in hospitalized patients. Patients suffering from sickle cell disease (SCD) could represent a high-risk population for substance use disorder (SUD) due to their significant pain crisis and repeated use of EMONO. The objective of the PHEDRE study was to assess the prevalence of SUD for EMONO in French SCD patients. Results A total of 993 patients were included. Among 339 EMONO consumers, only 38 (11%) had a SUD, with very few criteria, corresponding mainly to a mild SUD due to a use higher than expected (in quantity or duration) and relational tensions with the care teams. Almost all patients (99.7%) were looking for an analgesic effect, but 68% of patients were also looking for other effects. The independent risks factors associated with at least one SUD criterion were: the feeling of effects different from the expected therapeutic effects of EMONO, at least one hospitalization for vaso occlusive crisis in the past 12 months and the presence of a SUD for at least one other analgesic drug. Conclusions The use of EMONO was not problematic for the majority of patients. Manifestations of SUD that led to tensions with healthcare teams should alert and lead to an evaluation, to distinguish a true addiction from a pseudoaddiction which may be linked to an insufficient analgesic treatment related to an underestimation of pain in SCD patients. Trial registration : Clinical Trials, NCT02580565. Registered 16 October 2015, https://clinicaltrials.gov/

Abstract Type VI CRISPR enzymes have been developed as programmable RNA-guided Cas proteins for eukaryotic RNA editing. Notably, Cas13 has been utilized for site-targeted single base edits, demethylation, RNA cleavage or knockdown and alternative splicing. However, the ability to edit large stretches of mRNA transcripts remains a significant challenge. Here, we demonstrate that CRISPR-Cas13 systems can be repurposed to assist trans-splicing of exogenous RNA fragments into an endogenous pre-mRNA transcript, a method termed CRISPR Assisted mRNA Fragment Trans-splicing (CRAFT). Using split reporter-based assays, we evaluate orthogonal Cas13 systems, optimize guide RNA length and screen for optimal trans-splicing site(s) across a range of intronic targets. We achieve markedly improved editing of large 5’ and 3’ segments in different endogenous mRNAs across various mammalian cell types compared to other spliceosome-mediated trans-splicing methods. CRAFT can serve as a versatile platform for attachment of protein tags, studying the impact of multiple mutations/single nucleotide polymorphisms, modification of untranslated regions (UTRs) or replacing large segments of mRNA transcripts.

CD4+CD25+Foxp3+ regulatory T cells (Treg) have been implicated in pain modulation in various inflammatory conditions. However, whether Treg cells hamper pain at steady state and by which mechanism is still unclear. From a meta-analysis of the transcriptomes of murine Treg and conventional T cells (Tconv), we observe that the proenkephalin gene (Penk), encoding the precursor of analgesic opioid peptides, ranks among the top 25 genes most enriched in Treg cells. We then present various evidence suggesting that Penk is regulated in part by members of the Tumor Necrosis Factor Receptor (TNFR) family and the transcription factor Basic leucine zipper transcription faatf-like (BATF). Using mice in which the promoter activity of Penk can be tracked with a fluorescent reporter, we also show that Penk expression is mostly detected in Treg and activated Tconv in non-inflammatory conditions in the colon and skin. Functionally, Treg cells proficient or deficient for Penk suppress equally well the proliferation of effector T cells in vitro and autoimmune colitis in vivo. In contrast, inducible ablation of Penk in Treg leads to heat hyperalgesia in both male and female mice. Overall, our results indicate that Treg might play a key role at modulating basal somatic sensitivity in mice through the production of analgesic opioid peptides.

BackgroundChronic pain affects approximately 30% of the general population, severely degrades quality of life and professional life, and leads to additional health care costs. Moreover, the medical follow-up of patients with chronic pain remains complex and provides only fragmentary data on painful daily experiences. This situation makes the management of patients with chronic pain less than optimal and may partly explain the lack of effectiveness of current therapies. Real-life monitoring of subjective and objective markers of chronic pain using mobile health (mHealth) programs could better characterize patients, chronic pain, pain medications, and daily impact to help medical management. ObjectiveThis cohort study aimed to assess the ability of our mHealth tool (eDOL) to collect extensive real-life medical data from chronic pain patients after 1 year of use. The data collected in this way would provide new epidemiological and pathophysiological data on chronic pain. MethodsA French national cohort of patients with chronic pain treated at 18 pain clinics has been established and followed up using mHealth tools. This cohort makes it possible to collect the determinants and repercussions of chronic pain and their evolutions in a real-life context, taking into account all environmental events likely to influence chronic pain. The patients were asked to complete several questionnaires, body schemes, and weekly meters, and were able to interact with a chatbot and use educational modules on chronic pain. Physicians could monitor their patients’ progress in real time via an online platform. ResultsThe cohort study included 1427 patients and analyzed 1178 patients. The eDOL tool was able to collect various sociodemographic data; specific data for characterizing pain disorders, including body scheme; data on comorbidities related to chronic pain and its psychological and overall impact on patients’ quality of life; data on drug and nondrug therapeutics and their benefit-to-risk ratio; and medical or treatment history. Among the patients completing weekly meters, 49.4% (497/1007) continued to complete them after 3 months of follow-up, and the proportion stabilized at 39.3% (108/275) after 12 months of follow-up. Overall, despite a fairly high attrition rate over the follow-up period, the eDOL tool collected extensive data. This amount of data will increase over time and provide a significant volume of health data of interest for future research involving the epidemiology, care pathways, trajectories, medical management, sociodemographic characteristics, and other aspects of patients with chronic pain. ConclusionsThis work demonstrates that the mHealth tool eDOL is able to generate a considerable volume of data concerning the determinants and repercussions of chronic pain and their evolutions in a real-life context. The eDOL tool can incorporate numerous parameters to ensure the detailed characterization of patients with chronic pain for future research and pain management. Trial RegistrationClinicalTrials.gov NCT04880096; https://clinicaltrials.gov/ct2/show/NCT04880096

Abstract Background Robotic spinal surgery may result in better pedicle screw placement accuracy, and reduction in radiation exposure and length of stay, compared to freehand surgery. The purpose of this randomized controlled trial (RCT) is to compare screw placement accuracy of robot-assisted surgery with integrated 3D computer-assisted navigation versus freehand surgery with 2D fluoroscopy for arthrodesis of the thoraco-lumbar spine. Methods This is a single-centre evaluator-blinded RCT with a 1:1 allocation ratio. Participants (n = 300) will be randomized into two groups, robot-assisted (Mazor X Stealth Edition) versus freehand, after stratification based on the planned number of pedicle screws needed for surgery. The primary outcome is the proportion of pedicle screws placed with grade A accuracy (Gertzbein-Robbins classification) on postoperative computed tomography images. The secondary outcomes are intervention time, operation room occupancy time, length of stay, estimated blood loss, surgeon’s radiation exposure, screw fracture/loosening, superior-level facet joint violation, complication rate, reoperation rate on the same level or one level above, functional and clinical outcomes (Oswestry Disability Index, pain, Hospital Anxiety and Depression Scale, sensory and motor status) and cost-utility analysis. Discussion This RCT will provide insight into whether robot-assisted surgery with the newest generation spinal robot yields better pedicle screw placement accuracy than freehand surgery. Potential benefits of robot-assisted surgery include lower complication and revision rates, shorter length of stay, lower radiation exposure and reduction of economic cost of the overall care. Trial registration ClinicalTrials.gov NCT05553028. Registered on September 23, 2022

Creating floor plan layouts for houses, offices, hotels, or videogame levels is time-consuming. In several applications, the process starts with a bubble diagram or graph derived from a client’s requirements, which is then used as a basis for drawing a blueprint to continue the design process. That process requires a tool to preserve consistency between design models and diminish the design time. Hence, we have developed a Unity plugin to graphically represent a building layout using nodes and edges for rooms and doors that also allow defining the size and aspect ratio of spaces. This abstract representation is then automatically converted into a blueprint and optimized for explicit constraints (doors, size, and ratio) and implicit ones (tightness, convexity) by applying stochastic hill-climbing or steepest ascent hill-climbing algorithms. Then, the user can edit that blueprint further. As a final result, the tool generates a navigable 3D representation of the floor plan for the user to explore and go back to edit it if necessary. Results show that both algorithms are computing efficient enough to apply them interactively in the tool while providing functional building layouts. This work can assist established designers or enable building layout tools to be used by non-experts, such as potential homebuyers wishing to communicate a desired layout to an architect or hobbyist game designers working on their first videogame.

Abstract A partial loss of effectiveness of deep brain stimulation of the ventral intermediate nucleus of the thalamus (VIM) has been reported in some patients with essential tremor (ET), possibly due to habituation to permanent stimulation. This study focused on the evolution of VIM local-field potentials (LFPs) data over time to assess the long-term feasibility of closed-loop therapy based on thalamic activity. We performed recordings of thalamic LFPs in 10 patients with severe ET using the ACTIVA™ PC + S (Medtronic plc.) allowing both recordings and stimulation in the same region. Particular attention was paid to describing the evolution of LFPs over time from 3 to 24 months after surgery when the stimulation was Off. We demonstrated a significant decrease in high-beta LFPs amplitude during movements inducing tremor in comparison to the rest condition 3 months after surgery (1.91 ± 0.89 at rest vs. 1.27 ± 1.37 µV2/Hz during posture/action for N = 8/10 patients; p = 0.010), 12 months after surgery (2.92 ± 1.75 at rest vs. 2.12 ± 1.78 µV2/Hz during posture/action for N = 7/10 patients; p = 0.014) and 24 months after surgery (2.32 ± 0.35 at rest vs 0.75 ± 0.78 µV2/Hz during posture/action for 4/6 patients; p = 0.017). Among the patients who exhibited a significant decrease of high-beta LFP amplitude when stimulation was Off, this phenomenon was observed at least twice during the follow-up. Although the extent of this decrease in high-beta LFPs amplitude during movements inducing tremor may vary over time, this thalamic biomarker of movement could potentially be usable for closed-loop therapy in the long term.

Background Percutaneous left atrial appendage closure (LAAC) has been suggested as an alternative to long‐term oral anticoagulation for nonvalvular atrial fibrillation, but comparative data remain scarce. We aimed to assess ischemic and bleeding outcomes of LAAC compared with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) for the prevention of cardioembolic events in patients with atrial fibrillation. Methods and Results Embase and MEDLINE were searched for randomized trials comparing LAAC, VKAs, and DOACs. The primary efficacy end point was any stroke or systemic embolism. Treatment effects were calculated from a network meta‐analysis and ranked according to the surface under the cumulative ranking curve. Seven trials and 73 199 patients were included. The risk of the primary end point was not statistically different between LAAC versus VKAs (odds ratio [OR], 0.92 [95% CI, 0.62–1.50]) and LAAC versus DOACs (OR, 1.11 [95% CI, 0.71–1.73]). LAAC and DOACs resulted in similar risk of major or minor (OR, 0.93 [95% CI, 0.61–1.42]) and major bleeding (OR, 0.92 [95% CI, 0.58–1.46]); however, after exclusion of procedural bleeding, bleeding risk was significantly lower in those undergoing LAAC. Both LAAC and DOACs reduced the risk of all‐cause death compared with VKAs (LAAC versus VKAs: OR, 0.70 [95% CI, 0.53–0.91]; DOACs versus VKAs: OR, 0.90 [95% CI, 0.85–0.95], respectively). DOACs ranked as the best treatment for stroke or systemic embolism prevention (66.9%) and LAAC for reducing major bleeding (63.9%) and death (96.4%). Conclusions As a nonpharmacological alternative to oral anticoagulation for atrial fibrillation, LAAC showed similar efficacy and safety compared with VKAs or DOACs. Prospective confirmation from larger studies is warranted.

Abstract Animals occupying higher trophic levels can have disproportionately large influence on ecosystem structure and functioning, owning to intricate behavioral responses to their environment, but the effects of behavioral adaptations on aquatic ecosystem dynamics are underrepresented, especially in model studies. Here, we explore how adaptive behavior of fish can affect the dynamics of aquatics ecosystems. We frame fish behavior in the context of the central trade‐off between feeding and predation, calculating the optimal level of feeding determined by ambient food availability and predation risk. To explore whole‐ecosystem consequences of fish behavior, we embed our behavioral model within the Water Ecosystems Tool (WET), a contemporary end‐to‐end aquatic ecosystem model. The principle of optimality provides a robust and mechanistic framework for representing animal behavior that is relevant for complex models, and can provide a stabilizing effect on model dynamics. The model predicts an emergent functional response similar to Holling type III, but with richer dynamics and a more rigorous theoretical foundation. We show how adaptive fish behavior works to stabilize food web dynamics compared to a control model with no optimal behavior, and how changing the strength of the underlying trade‐off has profound effects on trophic control and food web structure. Furthermore, we demonstrate how including fish behavior allows for an overall more realistic response of the model system to environmental perturbation in the form of nutrient enhancement. We discuss the structuring effects of behavioral adaptations in real ecosystems, and how approaches like this one may benefit aquatic ecological modeling. Our study further highlights how a mechanistic approach based on concepts from theoretical ecology can be successfully implemented in complex operational models resulting in improved dynamics and descriptive power.