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Abstract Background The global incidence of type 2 diabetes (T2D) is rapidly increasing, with retinopathy being its most common complication and a leading cause of preventable blindness. Although the precise mechanisms involved in the development of diabetic retinopathy (DR) are not fully understood, defective immunomodulation is a recognized key factor in its pathophysiology. Regulatory T cells (Treg) regulate inflammation and promote regeneration, and while they are known to have important anti-inflammatory and neuroprotective roles in other tissues, including central nervous system, their role in the diabetic retina remains largely unknown. The aim of the present study is to examine the effect of Treg expansion of retinal neurodegeneration, an early event in the pathogenesis of DR. Methods Treg expansion was achieved by co-injecting recombinant mouse IL-2 with anti-IL-2 monoclonal antibody or its isotype in db/db mice as an established model of T2D. Treg expansion was confirmed via flow cytometry in blood, spleen, and retina. Fundus angiography was performed in the days prior to animal sacrifice at 18 weeks. To study the effect of Tregs on retinal neurons, glia and vascular permeability, immunohistochemistry against Cone-Arrestin, PKCα, synaptophysin, ChAT, TH, GFAP, Iba-1, calbindin, Brn3a, RBPMS, isolectin B4, and albumin was used. Retinal VEGF levels were measured with a magnetic bead-based immunoassay, and NLRP3, Casp1, p20 and IL-18 were analyzed by Western Blot in retinal homogenates. Results There was a significant decrease in Treg in db/db mice blood. When this deficiency was corrected in db/db mice by systemic Treg expansion, there was an effective protection against retinal neurodegenerative, gliotic, inflammatory changes and vascular leakage associated with T2D. Importantly, Treg expansion did not impact the T2D phenotype in db/db mice as evaluated by blood glucose, HbA1c and circulating insulin. Conclusion Treg modulation in T2D offers a promising therapeutic approach to prevent early stages of DR. This strategy focuses on reducing neuroinflammation and mitigating the associated neuronal, glial, and vascular degenerative changes characteristic of DR.

Abstract Background Lateral Medullary Syndrome (LMS) is a posterior circulation stroke (PCS) that has a broad array of manifestations but most classically presents with Horner’s syndrome, ipsilateral ataxia, and ipsilateral hyperalgesia. Although dysphagia is also common, isolated and single presentation of this alone is rare and there are only a few case reports of this in the literature. This presentation can bias a clinician’s differential diagnosis and delay diagnosis. Case presentation A previously healthy 53-year-old-male presented with a complaint of dysphagia. He had no PCS symptoms, a National Institute of Health Stroke Scale (NIHSS) of zero, and an otherwise unremarkable neurological exam. Stroke imaging including non-contrast computed tomography (NCCT) scan of his head and computed tomography angiography (CTA) scan of his head and neck revealed no acute abnormalities. He was found to be positive for Influenza A, but otherwise all other etiologies for his dysphagia were worked up, including consultation with other specialty services, without resolve. Two days later, the patient subsequently developed new right sided sensory deficits and left sided Horner’s syndrome, in which a magnetic resonance imaging (MRI) scan of his head revealed an acute infarct of the left lateral medulla with likely thrombus in the left posterior inferior cerebellar artery (PICA). Conclusions PCS is frequently missed due to the often-vague symptoms and reassuring negative imaging. This case highlights the variability of presentations that ED physicians may encounter. Nonetheless, a high index of suspicion for PCS should be maintained even in young patients without risk factors. Lastly, dysphagia is never normal, and this case demonstrates the need to reconsider neurogenic origin when other causes have been ruled out.

En el siguiente artículo se comparten los resultados de una investigación[1] en la que se estudió sobre el Esquelazo de octubre de 1967, en Esquel, Chubut, Argentina. Esta pueblada se llevó a cabo en el marco de la dictadura de Onganía y del surgimiento de la nueva izquierda, siendo un primer antecedente antes del Cordobazo de 1969. El Esquelazo permite conocer las dinámicas de época que fueron la antesala de una serie de revueltas populares que, conocidas bajo el sufijo “azo”, posibilitan identificar el rol de los grupos subalternos. Este trabajo recupera fuentes documentales, aportes de los estudios sobre la memoria, y la perspectiva de género.

Abstract In many parts of the world, domestic and wild animal populations interact at the interface between natural and agricultural ecosystems. Introduced with the first inhabitants arriving from eastern Africa, the bushpig (Potamochoerus larvatus) is the largest living terrestrial mammal in Madagascar. Bushpigs are regularly reported close to human settlements where they damage crops and gardens. As domestic pigs are often raised in free-ranging conditions around the villages, bushpigs and domestic pigs can interact leading to the transmission and circulation of shared swine pathogens that impact both animal and human health. In this study, we characterized the socio-ecological context of bushpig–domestic pig interactions in two different regions of western Madagascar. We conducted participatory mapping sessions and focus group interviews with 65 hunters, 80 pig farmers and 96 crop farmers in 20 fokontany, the smallest administrative unit in Madagascar. After discussing with participants, we gathered information about the spatialization of interactions and their potential geographical drivers. We explored data by performing multiple correspondence analysis and hierarchical clustering on principal components. Based on the reported occurrence or absence of bushpig-domestic pig interactions we were able to classify areas with high or intermediate levels of interactions or no interactions at all. Interactions between the two pig species were reported in only 25% of the fokontany assessed. Even though both suid species were attracted to fruit trees, crops, and water sources, only indirect interactions in those spots were reported. Direct interactions were reported in 10% of cases and referred to interspecific sexual and/or agonistic behavior. The participatory methods used to acquire local knowledge about natural events were confirmed as valuable, low-cost exploratory methods to characterize areas with wild-domestic animal interactions. The results of this study will help plan future studies to characterize the interface between the two species from an ecological or epidemiological perspective using more sensitive and sophisticated ecological approaches.

Abstract Background KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions. Methods Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model. Results Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression. Conclusions We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.

Introduction: The effects of the rs822393 variant of ADIPOQ gene on metabolic parameters such as insulin resistance and adiponectin levels following weight loss through dietary intervention are still uncertain. The aim of this study was to evaluate the role of rs822393 of ADIPOQ gene on adiponectin levels and metabolic parameters after weight loss with a high-fat hypocaloric diet with Mediterranean pattern during 12 weeks. Methods: A population of 283 patients with obesity was allocated to a dietary intervention trial with a high-fat hypocaloric diet during 12 weeks. Adiposity and biochemical parameters were determined. rs822393 was assessed with a dominant model analysis (CC vs. CT + TT). Results: These patients had three different genotypes: CC (59.0%), CT (33.6%), and TT (7.4%). The allelic frequencies for C and T were 0.89 and 0.20, respectively. Basal and post-intervention HDL cholesterol, adiponectin levels, and adiponectin/leptin ratio were lower in T-allele than non-T-allele carriers. After dietary intervention, BMI, weight, fat mass, waist circumference, systolic blood pressure, insulin, HOMA-IR, leptin, total cholesterol, and LDL cholesterol levels improved significantly in both genotype groups. Moreover, HDL cholesterol (CC vs. CT + TT) (delta: 8.9 ± 1.1 mg/dL vs. 1.7 ± 0.8 mg/dL; p = 0.02), serum adiponectin in non-T-allele carriers (43.1 ± 5.9 ng/dL vs. 2.8 ± 3 0.0 ng/dL; p = 0.01), and adiponectin/leptin ratio (1.37 ± 0.1 units vs. 0.17 ± 0.08 units; p = 0.02) improved only in non-T-allele carriers after weight loss. Conclusion: Individuals with obesity and without the T allele of rs822393 experienced improvements in adiponectin levels, adiponectin/leptin ratio, and HDL cholesterol levels after following a high-fat hypocaloric diet with a Mediterranean pattern.

Summary: Abdominal and thoracic aortic aneurysms (AAAs, TAAs) remain a major cause of deaths worldwide, in part due to the lack of reliable prognostic markers or early warning signs. Sox6 has been found to regulate renin controlling blood pressure. We hypothesized that Sox6 may serve as an important regulator of the mechanisms contributing to hypertension-induced aortic aneurysms. Phenotype and laboratory-wide association scans in a clinical cohort found that SOX6 gene expression is associated with aortic aneurysm in subjects of European ancestry. Sox6 and tumor necrosis factor alpha (TNF-α) expression were upregulated in aortic tissues from patients affected by either AAA or TAA. In Sox6 knockout mice with angiotensin-II-induced AAA, we found that Sox6 plays critical role in the development and progression of AAA. Our data support a regulatory role of SOX6 in the development of hypertension-induced AAA, suggesting that Sox6 may be a therapeutic target for the treatment of aortic aneurysms.

Abstract Organic–inorganic hybrid thermoelectric (TE) materials have attracted tremendous interest for harvesting waste heat energy. Due to their mechanical flexibility, inorganic‐organic hybrid TE materials are considered to be promising candidates for flexible energy harvesting devices. In this work, enhanced TE properties of Tellurium (Te) nanowires (NWs)‐ poly (3‐hexylthiophene‐2, 5‐diyl) (P3HT) hybrid materials are reported by improving the charge transport at interfacial layer mediated via controlled oxidation. A power factor of ≈9.8 µW (mK2)−1 is obtained at room temperature for oxidized P3HT‐TeNWs hybrid materials, which increases to ≈64.8 µW (mK2)−1 upon control of TeNWs oxidation. This value is sevenfold higher compared to P3HT‐TeNWs‐based hybrid materials reported in the literature. MD simulation reveals that oxidation‐free TeNWs demonstrate better templating for P3HT polymer compared to oxidized TeNWs. The Kang–Snyder model is used to study the charge transport in these hybrid materials. A large σE0 value is obtained which is related to better templating of P3HT on oxygen‐free TeNWs. This work provides evidence that oxidation control of TeNWs is critical for better interface‐driven charge transport, which enhances the thermoelectric properties of TeNWs‐P3HT hybrid materials. This work provides a new avenue to improve the thermoelectric properties of a new class of hybrid thermoelectric materials.

Abstract The emergence of new structures can often be linked to the evolution of novel cell types that follows the rewiring of developmental gene regulatory subnetworks. Vertebrates are characterized by a complex body plan compared to the other chordate clades and the question remains of whether and how the emergence of vertebrate morphological innovations can be related to the appearance of new embryonic cell populations. We previously proposed, by studying mesoderm development in the cephalochordate amphioxus, a scenario for the evolution of the vertebrate head mesoderm. To further test this scenario at the cell population level, we used scRNA-seq to construct a cell atlas of the amphioxus neurula, stage at which the main mesodermal compartments are specified. Our data allowed us to validate the presence of a prechordal-plate like territory in amphioxus. Additionally, the transcriptomic profile of somite cell populations supports the homology between specific territories of amphioxus somites and vertebrate cranial/pharyngeal and lateral plate mesoderm. Finally, our work provides evidence that the appearance of the specific mesodermal structures of the vertebrate head was associated to both segregation of pre-existing cell populations, and co-option of new genes for the control of myogenesis.

Purpose – To understand how organizations, public or private, must increase their productivity perception (PP), independently of the sector. This article aims to analyze PP in the digital transformation (DT) process to determine how it is affected by technostress (TS) and work engagement (WE), two concepts that seem to be forces opposing PP. Design/methodology/approach – The authors use data from a questionnaire addressed to personnel in two organizations (public and private). The analysis applies partial least squares technique to the 505 valid responses obtained from these organizations. This analysis is based not on representativeness but on uniqueness. Findings – The results suggest a positive, significant relationship between DT and PP. This article integrates DT and its effects on aspects of people's health, PP and WE. The model thus includes interactions of technology with human elements. In both business and administrative environments, PP is key to optimizing resources and survival of organizations. Research limitations/implications – DT processes are different and complex because every organization is different. The authors recommend expanding this study to other sectors in both spheres, public and private. Aligning the objectives of the institutions for aid with DT is also quite complicated. Practical implications – This study contributes to improving participating organizations. It also provides government institutions with a clear foundation from which to encourage actions that promote the health and WE of their workforce without reducing productivity. In addition, this study adds novelty to the research line. Originality/value – The authors have deepened this line of research by developing fuller knowledge of the relationships among novel and necessary variables in organizations. The authors provide complementary, different and inspiring value in addressing this line of research.

Introduction Globally, transgender (‘trans’) women experience extreme social and economic marginalisation due to intersectional stigma, defined as the confluence of stigma that results from the intersection of social identities and positions among those who are oppressed multiple times. Among trans women, gender-based stigma intersects with social positions such as engagement in sex work and substance use, as well as race-based stigma to generate a social context of vulnerability and increased risk of HIV acquisition. In Brazil, trans women are the ‘most at-risk’ group for HIV, with 55 times higher estimated odds of HIV infection than the general population; further, uptake of HIV testing and pre-exposure prophylaxis (PrEP) among trans women is significantly lower than other at-risk groups. Through extensive formative work, we developed Manas por Manas, a multilevel intervention using HIV prevention strategies with demonstrated feasibility and acceptability by trans women in Brazil, to address intersectional stigma and increase engagement in the HIV prevention continuum.Methods and analysis We are conducting a two-arm randomised wait-list controlled trial of the intervention’s efficacy in São Paulo, Brazil, to improve uptake of HIV testing and PrEP among transgender women (N=400). The primary outcomes are changes in HIV testing (self-testing and clinic based), changes in PrEP uptake and changes in PrEP persistence at baseline and follow-up assessment for 12 months at 3-month intervals.Ethics and dissemination This study was approved by University of California, San Francisco Institutional Review Board (15-17910) and Comissão Nacional de Ética em Pesquisa (Research Ethics National Commission, CAAE: 25215219.8.0000.5479) in Brazil. Participants provided informed consent before enrolment. We are committed to collaboration with National Institutes of Health officials, other researchers, and health and social services communities for rapid dissemination of data and sharing of materials. The results will be published in peer-reviewed academic journals and scientific presentations.Trial registration number NCT03081559.

In the context of Industry 4.0, engineering education is evolving rapidly, requiring new approaches to continuing engineering education (CEE). Traditional methods struggle to meet the demands of professionals looking to update their skills. This study presents an experimental proposal using the Multisensory Virtual Decision Making Center (MVDC) to improve CEE training creation. The MVDC creates collaborative and immersive virtual environments, enabling real-time participation and decision-making with a greater sense of presence and complete data visualization. The proposed experiment compares the effectiveness of MVDC sessions with traditional video call sessions in developing CEE courses. The research aims to evaluate improvements in the quality of decisions, participation, and user satisfaction in this collaborative process by streamlining the training planning process for continuing education. This study anticipates significant insights into integrating cutting-edge technologies such as MVDC for CEE, proposing it as a crucial tool for upskilling and reskilling. Expected outcomes include practical guidelines for implementing multisensory environments in CEE curriculum development, highlighting their potential to revolutionize the planning process. The research underscores the need for innovative approaches to meet the changing demands of the engineering workforce in the era of Industry 4.0. It lays the foundation for future studies that validate and expand these findings, paving the way for more effective and engaging CEE programs.

Traditional manufacturing industries are currently immersed in an automation process, integrating new techniques and tools, driven by the demands from producers to improve the manufacturing process as well as the working conditions of employees. For the footwear industry, bonding is a key operation in the manufacturing process where the outsole is assembled onto the lasted shoe. However, in this operation, workers are often subjected to hazardous substances (i.e., organic solvents) and perform repetitive tasks with limited added value. Against this background, this paper describes the results of a research project, whose aim was to obtain the maximum benefit from different technologies analyzed, such as collaborative robotics, artificial vision and multirobot control, for the manipulation of flexible/deformable objects. The main result of this project is a robotic workcell for shoe bonding that has been introduced in the production line to fully automate the operation. This workcell integrates three collaborative robots, one for (hot melt) adhesive application and another two, with two-finger electric grippers, to carry out the bonding synchronously. Different vision systems have also been embedded to conduct the various processes involved. The entire operation is controlled and coordinated through ROS (Robot Operating System). The key findings of this research showcase the automation of a process traditionally undertaken by humans. In this novel approach, two robots collaborate to manipulate flexible objects, liberating the operator from engaging in repetitive, non-value-added tasks and the handling of hazardous substances.

Accurate simulation techniques are indispensable to efficiently propose new memory or architectural organizations. As implementing new hardware concepts in real systems is often not feasible, cycle-accurate simulators employed together with certain benchmarks are commonly used. However, detailed simulators may take too much time to execute these programs until completion. Therefore, several techniques aimed at reducing this time are usually employed. These schemes select fragments of the source code considered as representative of the entire application’s behaviour–mainly in terms of performance, but not plenty considering the behaviour of cache memory levels–and only these intervals are simulated. Our hypothesis is that the different simulation windows currently employed when evaluating microarchitectural proposals, especially those involving the last level cache (LLC), do not reproduce the overall cache behaviour during the entire execution, potentially leading to wrong conclusions on the real performance of the proposals assessed. In this work, we first demonstrate this hypothesis by evaluating different cache replacement policies using various typical simulation approaches. Consequently, we also propose a simulation strategy, based on the applications’ LLC activity, which mimics the overall behaviour of the cache much closer than conventional simulation intervals. Our proposal allows a fairer comparison between cache-related approaches as it reports, on average, a number of changes in the relative order among the policies assessed – with respect to the full simulation – more than 30% lower than that of conventional strategies, maintaining the simulation time largely unchanged and without losing accuracy on performance terms, especially for memory-intensive applications.

A compact antenna design is proposed to synthesize two-dimensional amplitude monopulse radiation patterns, with application to integrated sensing and communications in the ISM 2.4 GHz band. The antenna makes use of two air-filled leaky waveguides to generate four diagonally scanned beams without the need of complex feeding networks. The design demonstrates the generation of monopulse patterns in the two perpendicular planes of the antenna, covering an angular field of view of 40° X 60° where the Direction of Arrival can be estimated. The simple structure and compactness of this antenna makes it very suitable for low-cost multi-functional joint radar-communications using commercial wireless networks.

The efficient series connection of planar leaky-wave antennas (LWA) to obtain directive frequency beam scanning, is proposed in this paper. Conditions for the proper performance are here derived, showing that the distance between antennas must be minimized while optimizing the phase shift introduced by the interconnection. Consequently, the methodology to design the transition is presented by an example using SMA connectors and a meander coaxial cable. Such series arrangement is useful to overcome the restricted directivity of planar LWAs in the UHF band due to limited PCB standard manufacturing sizes, while optimizing the radiation efficiency. The presented theory is validated with practical design examples of microstrip LWA arrays operating in the 900 MHz UHF band. Also, the frequency-beam scanning behaviour of the series-fed LWA array is analysed, demonstrating good performance when the proposed design conditions are satisfied, compared to a non-optimized design which can lead to destructive interference in the desired scanning directions.

Abstract Question Severe asthma and COPD exacerbations requiring hospitalization are linked to increased disease morbidity and healthcare costs. We sought to identify Electronic Health Record (EHR) features of severe asthma and COPD exacerbations and evaluate the performance of four machine learning (ML) and one deep learning (DL) model in predicting readmissions using EHR data. Study design and methods Observational study between September 30, 2012, and December 31, 2017, of patients hospitalized with asthma and COPD exacerbations. Results This study included 5,794 patients, 1,893 with asthma and 3,901 with COPD. Patients with asthma were predominantly female (n = 1288 [68%]), 35% were Black (n = 669), and 25% (n = 479) were Hispanic. Black (44 vs. 33%, p = 0.01) and Hispanic patients (30 vs. 24%, p = 0.02) were more likely to be readmitted for asthma. Similarly, patients with COPD readmissions included a large percentage of Blacks (18 vs. 10%, p

Ultramafic ecosystems are renowned for high endemism and habitat specialization. However, most of our understanding of ultramafic plant ecology comes from Mediterranean and temperate climes, raising questions about the generalizability of plant responses to ultramafic soils. This is especially apparent in tropical ultramafic ecosystems which exhibit a wide range of endemism and differentiation between ultramafic and adjacent non-ultramafic soils. Our objectives were two-fold: 1) synthesize our understanding of tropical ultramafic plant ecology, paying particular attention to generalities that may explain variation in endemism and habitat specialization among tropical ultramafic ecosystems; and 2) define an interdisciplinary research agenda using tropical ultramafic ecosystems as a macroecological model. We demonstrate that tropical ultramafic floras are diverse and variable in plant form and function due to the interactive effects of biogeography, climate, and edaphic properties. The variable rates of endemism, specialization, and stress tolerance traits across tropical ultramafic ecosystems have implications for the management and conservation of these diverse systems. Los ecosistemas ultramaficos son reconocidos por su endemismo y especializacion del habitat. Sin embargo, la mayor parte de nuestra comprension de la ecologia vegetal ultramafica proviene de climas mediterraneos y templados, lo que plantea dudas sobre la generalizacion de las respuestas de las plantas a los suelos ultramaficos. Esto es especialmente evidente en los ecosistemas tropicales ultramaficos que exhiben una amplia gama de endemismo y diferenciacion entre suelos tropicales ultramaficos y no ultramaficos adyacentes. Nosotros teniamos dos objetivos: 1) sintetizar nuestra comprension actual de la ecologia de las plantas tropicales ultramaficas, prestando especial atencion a las generalidades que pueden explicar la variacion en el endemismo y la especializacion del habitat entre los ecosistemas tropicales ultramaficos; y 2) definir una agenda de investigacion interdisciplinaria utilizando ecosistemas ultramaficos tropicales como modelo macroecologico. Las floras tropicales ultramaficas son diversas y variables en la forma y funcion de las plantas debido a los efectos interactivos de la biogeografia, el clima y las propiedades edaficas. Las tasas variables de endemismo, especializacion y rasgos de tolerancia al estres en los ecosistemas tropicales ultramaficos tienen implicaciones para el manejo y conservacion de estos diversos sistemas. Keywords Edaphic * Endemism * Hyperaccumulator * Metallophyte * Serpentine * Unusual soil, Introduction Ultramafic (serpentine) soils have long attracted scientific attention due to their specialized flora and ecological and evolutionary implications. However, our understanding of ultramafic plant ecology remains dominated by research [...]

Abstract Background BAT1706 is a proposed biosimilar of bevacizumab (Avastin®). We aimed to compare the efficacy and safety of BAT1706 with that of EU‐sourced reference bevacizumab (EU‐bevacizumab) in patients with advanced nonsquamous non‐small cell lung cancer (NSCLC). Methods Patients were randomized 1:1 to BAT1706 plus paclitaxel and carboplatin (BAT1706 arm) or EU‐bevacizumab plus paclitaxel and carboplatin (EU‐bevacizumab arm) given every 3 weeks for six cycles, followed by maintenance therapy with BAT1706 or EU‐bevacizumab. The primary endpoint was overall response rate at week 18 (ORR18). Clinical equivalence was demonstrated if the 90% confidence interval (CI) of the BAT1706:EU‐bevacizumab ORR18 risk ratio was contained within the predefined equivalence margins of 0.75–1.33 (China National Medical Products Administration requirements), or 0.73–1.36 (US Food and Drug Administration), or if the 95% CI of the ORR18 risk difference between treatments was contained within the predefined equivalence margin of −0.12 to 0.15 (EMA requirements). Results In total, 649 randomized patients (BAT1706, n = 325; EU‐bevacizumab, n = 324) received at least one cycle of combination treatment. The ORR18 was comparable between the BAT1706 and EU‐bevacizumab arms (48.0% and 44.5%, respectively). The ORR18 risk ratio of 1.08 (90% CI: 0.94–1.24) and the ORR18 risk difference of 0.03 (95% CI: −0.04 to 0.11) were within the predefined equivalence margins, demonstrating the biosimilarity of BAT1706 and EU‐bevacizumab. The safety profile of BAT1706 was consistent with that of EU‐bevacizumab and no new safety signals were observed. Conclusion In patients with advanced nonsquamous NSCLC, BAT1706 demonstrated clinical equivalence to EU‐bevacizumab in terms of efficacy, safety, pharmacokinetics, and immunogenicity.

Abstract Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c‐Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c‐Jun expression in SCs has been associated with regenerative failure, it is unclear whether the inability to maintain a repair state is associated with the transition into an axonal growth inhibition phenotype. We here find that reparative SCs transition into a senescent phenotype, characterized by diminished c‐Jun expression and secretion of inhibitory factors for axonal regeneration in aging and chronic denervation. In both conditions, the elimination of senescent SCs by systemic senolytic drug treatment or genetic targeting improved nerve regeneration and functional recovery, increased c‐Jun expression and decreased nerve inflammation. This work provides the first characterization of senescent SCs and their influence on axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration and functional recovery after peripheral nerve injuries.

Abstract A muon collider would enable the big jump ahead in energy reach that is needed for a fruitful exploration of fundamental interactions. The challenges of producing muon collisions at high luminosity and 10 TeV centre of mass energy are being investigated by the recently-formed International Muon Collider Collaboration. This Review summarises the status and the recent advances on muon colliders design, physics and detector studies. The aim is to provide a global perspective of the field and to outline directions for future work.

Axonal degeneration is a central pathological feature of multiple sclerosis and is closely associated with irreversible clinical disability. Current noninvasive methods to detect axonal damage in vivo are limited in their specificity and clinical applicability, and by the lack of proper validation. We aimed to validate an MRI framework based on multicompartment modeling of the diffusion signal (AxCaliber) in rats in the presence of axonal pathology, achieved through injection of a neurotoxin damaging the neuronal terminal of axons. We then applied the same MRI protocol to map axonal integrity in the brain of multiple sclerosis relapsing-remitting patients and age-matched healthy controls. AxCaliber is sensitive to acute axonal damage in rats, as demonstrated by a significant increase in the mean axonal caliber along the targeted tract, which correlated with neurofilament staining. Electron microscopy confirmed that increased mean axonal diameter is associated with acute axonal pathology. In humans with multiple sclerosis, we uncovered a diffuse increase in mean axonal caliber in most areas of the normal-appearing white matter, preferentially affecting patients with short disease duration. Our results demonstrate that MRI-based axonal diameter mapping is a sensitive and specific imaging biomarker that links noninvasive imaging contrasts with the underlying biological substrate, uncovering generalized axonal damage in multiple sclerosis as an early event.