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Topology optimization is currently enjoying renewed interest thanks to the recent development of 3D printing techniques, which offer the possibility of producing these new complex designs. One of the difficulties encountered in manufacturing topologically optimized magnetostatic structures is that they are not necessarily mechanically stable. In order to take this mechanical constraint into account, we have developed a SIMP-based topology optimization algorithm which relies on numerical simulations of both the mechanical deformation and the magnetostatic behavior of the structure. Two variants are described in this paper, respectively taking into account the compliance or the von Mises constraint. By comparing the designs obtained with those from magnetostatic optimization alone, our approach proves effective in obtaining efficient and robust designs.

Background: As educational digital technologies are increasingly being used in schools, past research left unanswered the question of these technologies' impact on the socioeconomic achievement gap even when equal access is guaranteed. Objectives: The objectives of the present study are to examine whether and how the socioeconomic achievement gap can be reduced through the use of computer-assisted instruction (CAI). Methods: We addressed this issue experimentally by comparing CAI to conventional teacher-led classroom instruction with more than 800 middle and high school students from disadvantaged and highly privileged socioeconomic backgrounds in a range of topics. Results and Conclusions: Both disadvantaged and highly privileged students taught with CAI outperformed those taught with conventional instruction, thus maintaining the socioeconomic achievement gap constant. However, we also found that disadvantaged students receiving CAI performed as well as highly privileged students receiving conventional teacher-led instruction. Takeaways: The positive effects associated with CAI may therefore help compensate the difficulties of students with a disadvantaged background, a still neglected possibility.

The microbial community composition in subsoils remains understudied, and it is largely unknown whether subsoil microorganisms show a similar response to global warming as microorganisms at the soil surface do. Since microorganisms are the key drivers of soil organic carbon decomposition, this knowledge gap causes uncertainty in the predictions of future carbon cycling in the subsoil carbon pool (>g50g% of the soil organic carbon stocks are below 30gcm soil depth). In the Blodgett Forest field warming experiment (California, USA) we investigated how +4ggC warming in the whole-soil profile to 100gcm soil depth for 4.5 years has affected the abundance and community structure of microorganisms. We used proxies for bulk microbial biomass carbon (MBC) and functional microbial groups based on lipid biomarkers, such as phospholipid fatty acids (PLFAs) and branched glycerol dialkyl glycerol tetraethers (brGDGTs). With depth, the microbial biomass decreased and the community composition changed. Our results show that the concentration of PLFAs decreased with warming in the subsoil (below 30gcm) by 28g% but was not affected in the topsoil. Phospholipid fatty acid concentrations changed in concert with soil organic carbon. The microbial community response to warming was depth dependent. The relative abundance of Actinobacteria increased in warmed subsoil, and Gram+ bacteria in subsoils adapted their cell membrane structure to warming-induced stress, as indicated by the ratio of anteiso to iso branched PLFAs. Our results show for the first time that subsoil microorganisms can be more affected by warming compared to topsoil microorganisms. These microbial responses could be explained by the observed decrease in subsoil organic carbon concentrations in the warmed plots. A decrease in microbial abundance in warmed subsoils might reduce the magnitude of the respiration response over time. The shift in the subsoil microbial community towards more Actinobacteria might disproportionately enhance the degradation of previously stable subsoil carbon, as this group is able to metabolize complex carbon sources.

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen's d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions.

Few have studied the COVID-19 pandemic's impact on tobacco use status assessment and cessation counseling. Electronic health record data from 217 primary care clinics were examined from January 1, 2019 to July 31, 2021. Data included telehealth and in-person visits for 759,138 adult patients (aged >18 years). Monthly rates of tobacco assessment per 1,000 patients were calculated. From March 2020 to May 2020, tobacco assessment monthly rates declined by 50% and increased from June 2020 to May 2021 but remained 33.5% lower than pre-pandemic levels. Rates of tobacco cessation assistance changed less, but remain low. These findings are significant given the relevance of tobacco use to increased severity of COVID-19. Key words: community health center; COVID-19; primary care; smoking status assessment; tobacco https://doi.org/10.1370/afm.2948, INTRODUCTION The COVID-19 pandemic dramatically altered patterns of primary health care-seeking and delivery. This was reflected in a dramatic increase in telehealth visits (ie, video and telephone visits) (1,2) and [...]

Tourism plays an important part in soft power as a public diplomacy tool that, alongside destination branding, aims to reinforce the image of a place to attract visitors, with the ensuing multiplier effect on its economy. Both destination branding and public diplomacy seek the common goal of generating a positive reputation and image of the place, although they pursue different interests. On the one hand, destination branding aims at attracting tourists with an eminently economic objective in mind; while, on the other hand, public diplomacy seeks to promote national interests (economic, social, political), and advance foreign policy goals. Destination branding and public diplomacy can be regarded as two faces of the same coin, as together they leverage a country’s equity in soft power. Japan has furthered its economic, social, and political goals by projecting the image of a technologically advanced country boasting a rich cultural tradition through skillful management of its soft power and its public diplomacy, that in recent times has revolved around cultural diplomacy with the “Cool Japan” strategy for the promotion of cultural industries, as well as around sports diplomacy, with the celebration of the Tokyo 2020 Olympic Games, which owing to the COVID pandemic became an example of failed destination branding, that nevertheless did not obscure their success in terms of sports diplomacy.

Para la economía cubana el turismo representa un sector estratégico; por ello, ha aprobado un conjunto de medidas para su incentivo, entre las que se destaca la reparación de habitaciones e instalaciones hoteleras a través de las inversiones lo que garantiza el incremento de la satisfacción de los visitantes a la Isla. En este sentido, se ha comprobado que una de las deficiencias que afectan este bienestar radica en la falta de integración entre los procesos de Ama de Llaves (limpieza de habitaciones) y de Servicios Técnicos. Por tanto, el objetivo de este trabajo es diseñar un procedimiento para la integración de ambos procesos en un hotel cubano. El modelo escogido está basado en el Análisis Modal de Fallos y Efectos (AMFE), que tiene en cuenta la gestión de riesgos, sus efectos y sus causas; para determinar los índices de severidad, ocurrencia y detección. Calcular, así, el número de prioridad de riesgo y, con este valor, establecer un orden en la gestión de sus riesgos. La aplicación estableció un orden a las causas de uno de sus modos de fallos (riesgos), según el número de prioridad de riesgo y severidad.

Abstract Artificial intelligence (AI) is transforming the field of medical imaging and has the potential to bring medicine from the era of ‘sick-care’ to the era of healthcare and prevention. The development of AI requires access to large, complete, and harmonized real-world datasets, representative of the population, and disease diversity. However, to date, efforts are fragmented, based on single–institution, size-limited, and annotation-limited datasets. Available public datasets (e.g., The Cancer Imaging Archive, TCIA, USA) are limited in scope, making model generalizability really difficult. In this direction, five European Union projects are currently working on the development of big data infrastructures that will enable European, ethically and General Data Protection Regulation-compliant, quality-controlled, cancer-related, medical imaging platforms, in which both large-scale data and AI algorithms will coexist. The vision is to create sustainable AI cloud-based platforms for the development, implementation, verification, and validation of trustable, usable, and reliable AI models for addressing specific unmet needs regarding cancer care provision. In this paper, we present an overview of the development efforts highlighting challenges and approaches selected providing valuable feedback to future attempts in the area. Key points • Artificial intelligence models for health imaging require access to large amounts of harmonized imaging data and metadata. • Main infrastructures adopted either collect centrally anonymized data or enable access to pseudonymized distributed data. • Developing a common data model for storing all relevant information is a challenge. • Trust of data providers in data sharing initiatives is essential. • An online European Union meta-tool-repository is a necessity minimizing effort duplication for the various projects in the area.

Abstract Due to commonalities in pathophysiology, age-related macular degeneration (AMD) represents a uniquely accessible model to investigate therapies for neurodegenerative diseases, leading us to examine whether pathways of disease progression are shared across neurodegenerative conditions. Here we use single-nucleus RNA sequencing to profile lesions from 11 postmortem human retinas with age-related macular degeneration and 6 control retinas with no history of retinal disease. We create a machine-learning pipeline based on recent advances in data geometry and topology and identify activated glial populations enriched in the early phase of disease. Examining single-cell data from Alzheimer’s disease and progressive multiple sclerosis with our pipeline, we find a similar glial activation profile enriched in the early phase of these neurodegenerative diseases. In late-stage age-related macular degeneration, we identify a microglia-to-astrocyte signaling axis mediated by interleukin-1β which drives angiogenesis characteristic of disease pathogenesis. We validated this mechanism using in vitro and in vivo assays in mouse, identifying a possible new therapeutic target for AMD and possibly other neurodegenerative conditions. Thus, due to shared glial states, the retina provides a potential system for investigating therapeutic approaches in neurodegenerative diseases.

Homologous recombination deficiency is linked with platinum-based chemotherapy response in triple-negative breast cancer (TNBC) but methods to clinically identify these patients are lacking. Here, using patient-derived xenografts of TNBC the authors demonstrate that shallow HRD is predictive of response to platinum-based chemotherapy.

Previous reviews of strategies to increase cervical cancer screening are more than 10 years old, the U.S. continues to fall short of the Healthy People 2030 cervical cancer screening goal, and guidelines were revised in 2018, therefore an updated review of the existing literature is needed. We conducted a scoping review using electronic databases PubMed, Scopus, and Ovid Medline that included publication dates between 2012 and 2021 to answer the question, “Which strategies implemented in U.S. primary care settings have been most successful in increasing rates of cervical cancer screening since the 2012 US Preventative Services Task Force cervical cancer screening guidelines were published?” We mapped findings to pre-specified implementation strategy categories. After initially identifying 399 articles, we excluded 350 due to duplicates or not meeting review criteria, leaving 49 articles for full review. We excluded 37 of these during full-text review and identified 2 additional articles from the manual search of reference lists for a total of 14 studies for abstraction. Eleven articles reported on strategies resulting in increased cervical cancer screening, and 3 did not. Clinic workflow re-design strategies showed the greatest promise in improving cervical cancer screening rates, education strategies for patients had mixed results, and quality management strategies were not effective. These findings suggest clinical workflow re-structures and patient education strategies can increase cervical cancer screening in primary care settings. Results are particularly important in settings that care for underserved populations, as these settings may need additional implementation strategies to decrease cervical cancer screening disparities.

Abstract Solidification of the cores of small planets and moons is thought to occur in the “iron snow” regime, in which iron crystals form near the core‐mantle boundary and fall until re‐melting at greater depth. The resulting buoyancy flux may sustain convection and dynamo action. This regime of crystallization is poorly understood. Here we present the first laboratory experiments designed to model iron snow. We find that solidification happens in a cyclic pattern, with intense solidification bursts separated by crystal‐free periods. This is explained by the necessity of reaching a finite amount of supercooling to re‐initiate crystallization once the crystals formed earlier have migrated away. When scaled to planetary cores, our results suggest that crystallization and the associated buoyancy flux would be strongly heterogeneous in time and space, which eventually impacts the time variability and geometry of the magnetic field.

Antimicrobial resistance is a critical public health issue that requires a thorough understanding of the factors that influence the selection and spread of antibiotic-resistant bacteria. Biocides, which are widely used in cleaning and disinfection procedures in a variety of settings, may contribute to this resistance by inducing similar defense mechanisms in bacteria against both biocides and antibiotics. However, the strategies used by bacteria to adapt and develop cross-resistance remain poorly understood, particularly within biofilms –a widespread bacterial habitat that significantly influences bacterial tolerance and adaptive strategies. Using a combination of adaptive laboratory evolution experiments, genomic and RT-qPCR analyses, and biofilm structural characterization using confocal microscopy, we investigated in this study how Escherichia coli biofilms adapted after 28 days of exposure to three biocidal active substances and the effects on cross-resistance to antibiotics. Interestingly, polyhexamethylene biguanide (PHMB) exposure led to an increase of gentamicin resistance (GenR) phenotypes in biofilms formed by most of the seven E. coli strains tested. Nevertheless, most variants that emerged under biocidal conditions did not retain the GenR phenotype after removal of antimicrobial stress, suggesting a transient adaptation (adaptive resistance). The whole genome sequencing of variants with stable GenR phenotypes revealed recurrent mutations in genes associated with cellular respiration, including cytochrome oxidase (cydA, cyoC) and ATP synthase (atpG). RT-qPCR analysis revealed an induction of gene expression associated with biofilm matrix production (especially curli synthesis), stress responses, active and passive transport and cell respiration during PHMB exposure, providing insight into potential physiological responses associated with adaptive crossresistance. In addition, confocal laser scanning microscopy (CLSM) observations demonstrated a global effect of PHMB on biofilm architectures and compositions formed by most E. coli strains, with the appearance of dense cellular clusters after a 24h-exposure. In conclusion, our results showed that the PHMB exposure stimulated the emergence of an adaptive cross-resistance to gentamicin in biofilms, likely induced through the activation of physiological responses and biofilm structural modulations altering gradients and microenvironmental conditions in the biological edifice.

Arming oncolytic viruses with transgenes encoding immunomodulators improves their therapeutic efficacy by enhancing and/or sustaining the innate and adaptive anti-tumoral immune responses. We report here the isolation, selection, and vectorization of a blocking anti-human PDL1 single-domain antibody (sdAb) isolated from PDL1-immunized alpacas. Several formats of this sdAb were vectorized into the vaccinia virus (VV) and evaluated for their programmed cell death protein 1 (PD1)/PD1 ligand (PDL1) blocking activity in the culture medium of tumor cells infected in vitro. In those conditions, VV-encoded homodimeric sdAb generated superior PDL1 blocking activity compared to a benchmark virus encoding full-length avelumab. The sdAb was further used to design simple, secreted, and small tumor necrosis factor superfamily (TNFSF) fusions with the ability to engage their cognate receptors (TNFRSF) only in the presence of PDL1-positive cells. Finally, PDL1-independent alternatives of TNFRSF agonists were also constructed by fusing different variants of surfactant protein-D (SP-D) oligomerization domains with TNFSF ectodomains. An optimal SP-D–CD40L fusion with an SP-D collagen domain reduced by 80% was identified by screening with a transfection/infection method where poxvirus transfer plasmids and vaccinia virus were successively introduced into the same cell. However, once vectorized in VV, this construct had a much lower CD40 agonist activity compared to the SP-D–CD40L construct, which is completely devoid of the collagen domain that was finally selected. This latest result highlights the importance of working with recombinant viruses early in the payload selection process. Altogether, these results bring several complementary solutions to arm oncolytic vectors with powerful immunomodulators to improve their immune-based anti-tumoral activity.

IntroductionContact tracing and treatment of latent tuberculosis infection (LTBI) is a key element of tuberculosis (TB) control in low TB incidence countries. A TB control and prevention program has been active in the Basque Country since 2003, including the development of the nurse case manager role and a unified electronic record. Three World Health Organization-approved LTBI regimens have been used: isoniazid for 6 months (6H), rifampicin for 4 months (4R), and isoniazid and rifampicin for 3 months (3HR). Centralized follow-up by a TB nurse case manager started in January 2016, with regular telephone follow-up, telemonitoring of blood test results, and monitoring of adherence by electronic review of drugs dispensed in pharmacies.ObjectiveTo estimate LTBI treatment completion and toxicity of different preventive treatment regimens in a real-world setting. Secondary objective: to investigate the adherence to different approaches to preventive treatment monitoring.MethodsA multicentre retrospective cohort study was conducted using data collected prospectively on contacts of patients with TB in five hospitals in Biscay from 2003 to 2022.ResultsA total of 3,066 contacts with LTBI were included. The overall completion rate was 66.8%; 86.5% of patients on 3HR (n = 699) completed treatment vs. 68.3% (n = 1,260) of those on 6H (p