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Analysis of male and female mice exposed to a high fat diet reveals that the male mouse brain is more susceptible to resultant metabolic changes.

Abstract This study explored the informational variables guiding steering behaviour in a locomotor interception task with targets moving along circular trajectories. Using a new method of analysis focussing on the temporal co-evolution of steering behaviour and the potential information sources driving it, we set out to invalidate reliance on plausible informational candidates. Applied to individual trials rather than ensemble averages, this Qualitative Inconsistency Detection (QuID) method revealed that steering behaviour was not compatible with reliance on information grounded in any type of change in the agent-centred target-heading angle. First-order changes in the environment-centred target’s bearing angle could also not adequately account for the variations in behaviour observed under the different experimental conditions. Capturing the observed timing of unfolding steering behaviour ultimately required a combination of (velocity-based) first-order and (acceleration-based) second-order changes in bearing angle. While this result may point to reliance on fractional-order based changes in bearing angle, the overall importance of the present findings resides in the demonstration of the necessity to break away from the existing practice of trying to fit behaviour into a priori postulated functional strategies based on categorical differences between operative heuristic rules or control laws.

Abstract A targeted injury to the mouse intervertebral disc (IVD) is often used to recapitulate the degenerative cascade of the human pathology. Since injuries can vary in magnitude and localization, it is critical to examine the effects of different injuries on IVD degeneration. We thus evaluated the degenerative progression resulting from either a partial- or full-width injury to the mouse lumbar IVD using contrast-enhanced micro-computed tomography and histological analyses. A lateral-retroperitoneal surgical approach was used to access the lumbar IVD, and the injuries to the IVD were produced by either incising one side of the annulus fibrosus or puncturing both sides of the annulus fibrosus. Female C57BL/6J mice of 3–4 months age were used in this study. They were divided into three groups to undergo partial-width, full-width, or sham injuries. The L5/6 and L6/S1 lumbar IVDs were surgically exposed, and then the L6/S1 IVDs were injured using either a surgical scalpel (partial-width) or a 33G needle (full-width), with the L5/6 serving as an internal control. These animals recovered and then euthanized at either 2-, 4-, or 8-weeks after surgery for evaluation. The IVDs were assessed for degeneration using contrast-enhanced microCT (CEµCT) and histological analysis. The high-resolution 3D CEµCT evaluation of the IVD confirmed that the respective injuries were localized within one side of the annulus fibrosus or spanned the full width of the IVD. The full-width injury caused significant deteriorations in the nucleus pulposus, annulus fibrous and at the interfaces after 2 weeks, which was sustained through the 8 weeks, while the partial width injury caused localized disruptions that remained limited to the annulus fibrosus. The use of CEµCT revealed distinct IVD degeneration profiles resulting from partial- and full-width injuries. The partial width injury may serve as an alternative model for IVD degeneration resulting from localized annulus fibrosus injuries.

Abstract Background Advances in our understanding of the tumor microenvironment have radically changed the cancer field, highlighting the emerging need for biomarkers of an active, favorable tumor immune phenotype to aid treatment stratification and clinical prognostication. Numerous immune-related gene signatures have been defined; however, their prognostic value is often limited to one or few cancer types. Moreover, the area of non-coding RNA as biomarkers remains largely unexplored although their number and biological roles are rapidly expanding. Methods We developed a multi-step process to identify immune-related long non-coding RNA signatures with prognostic connotation in multiple TCGA solid cancer datasets. Results Using the breast cancer dataset as a discovery cohort we found 2988 differentially expressed lncRNAs between immune favorable and unfavorable tumors, as defined by the immunologic constant of rejection (ICR) gene signature. Mapping of the lncRNAs to a coding-non-coding network identified 127 proxy protein-coding genes that are enriched in immune-related diseases and functions. Next, we defined two distinct 20-lncRNA prognostic signatures that show a stronger effect on overall survival than the ICR signature in multiple solid cancers. Furthermore, we found a 3 lncRNA signature that demonstrated prognostic significance across 5 solid cancer types with a stronger association with clinical outcome than ICR. Moreover, this 3 lncRNA signature showed additional prognostic significance in uterine corpus endometrial carcinoma and cervical squamous cell carcinoma and endocervical adenocarcinoma as compared to ICR. Conclusion We identified an immune-related 3-lncRNA signature with prognostic connotation in multiple solid cancer types which performed equally well and in some cases better than the 20-gene ICR signature, indicating that it could be used as a minimal informative signature for clinical implementation.

Monte-Carlo diffusion simulations are a powerful tool for validating tissue microstructure models by generating synthetic diffusion-weighted magnetic resonance images (DW-MRI) in controlled environments. This is fundamental for understanding the link between micrometre-scale tissue properties and DW-MRI signals measured at the millimetre-scale, optimizing acquisition protocols to target microstructure properties of interest, and exploring the robustness and accuracy of estimation methods. However, accurate simulations require substrates that reflect the main microstructural features of the studied tissue. To address this challenge, we introduce a novel computational workflow, CACTUS (Computational Axonal Configurator for Tailored and Ultradense Substrates), for generating synthetic white matter substrates. Our approach allows constructing substrates with higher packing density than existing methods, up to 95% intra-axonal volume fraction, and larger voxel sizes of up to 500μm3 with rich fibre complexity. CACTUS generates bundles with angular dispersion, bundle crossings, and variations along the fibres of their inner and outer radii and g-ratio. We achieve this by introducing a novel global cost function and a fibre radial growth approach that allows substrates to match predefined targeted characteristics and mirror those reported in histological studies. CACTUS improves the development of complex synthetic substrates, paving the way for future applications in microstructure imaging.

Introduction: Pulmonary embolism (PE) is a frequent complication in COVID-19. However, the influence of PE on the prognosis of COVID-19 remains unclear as previous studies were affected by misclassification bias. Therefore, we evaluated a cohort of COVID-19 patients whom all underwent systematic screening for PE (thereby avoiding misclassification) and compared clinical outcomes between patients with and without PE. Materials and methods: We included all COVID-19 patients who were admitted through the ED between April 2020 and February 2021. All patients underwent systematic work-up for PE in the ED using the YEARS-algorithm. The primary outcome was a composite of in-hospital mortality and ICU admission. We also evaluated long-term outcomes including PE occurrence within 90 days after discharge and one-year all-cause mortality. Results: 637 ED patients were included in the analysis. PE was diagnosed in 46 of them (7.2%). The occurrence of the primary outcome did not differ between patients with PE and those without (28.3% vs. 26.9%, p = 0.68). The overall rate of PE diagnosed in-hospital (after an initial negative PE screening in the ED) and in the first 90 days after discharge was 3.9% and 1.2% respectively. One-year all-cause mortality was similar between patients with and without PE (26.1% vs. 24.4%, p = 0.83). Conclusions: In a cohort of COVID-19 patients who underwent systematic PE screening in the ED, we found no differences in mortality rate and ICU admissions between patients with and without PE. This may indicate that proactive PE screening, and thus timely diagnosis and treatment of PE, may limit further clinical deterioration and associated mortality in COVID-19 patients.

Sulforaphane is a naturally occurring, potent antioxidant, found in Brassicaceae plants such as broccoli, and is being considered for use in the treatment of fibrosis, cancer and preeclampsia. As sulforaphane is orally administered and has been shown to demonstrate antimicrobial properties in aerobic conditions, there is also the potential for impact on the gut microbiome under anaerobic conditions. Here, we have determined the effect of sulforaphane on the growth of 43 common human gastrointestinal microbiota, representing common commensals and pathogens. The enteropathogenic Escherichia coli strain EPEC E2348/69 showed the most significant increases in growth in the presence of sulforaphane. Proteomic analysis of this isolate showed that sulforaphane increased anaerobic respiration, whilst metabolomics identified differentially produced metabolites that can decrease inflammation in human cells. Therefore, sulforaphane can increase growth of specific gastrointestinal microbiota, correlating with increased production of anti-inflammatory metabolites. Thus, providing a novel mechanism for modulating inflammatory states in patients.

Introdução: Com o aumento do uso de dispositivos tecnológicos e auxiliares na reabilitação, tem-se observado um crescente interesse na exergaming e gamificação para melhorar a motivação e o envolvimento dos indivíduos em processo de reabilitação (Willwacher & Korn, 2021). No entanto, embora o exergaming e a gamificação tenham já sido amplamente estudados em vários contextos, há uma falta de compreensão sobre o que a literatura indica relativamente à experiência, perceção e expectativas dos indivíduos acerca do recurso ao exergaming e à gamificação para reabilitação. Objetivo: Sintetizar a literatura qualitativa disponível para fornecer uma compreensão abrangente das experiências, perceções, e expectativas utilização de exergaming e/ou gamificação por parte dos indivíduos em processo de reabilitação. Material e métodos: Foi desenvolvida uma revisão sistemática da literatura de evidência qualitativa com recurso às recomendações do JBI e a extensão PRISMA (JBI, 2020). Foi utilizada uma estratégia de pesquisa em três fases. Os critérios de inclusão incluíram estudos com indivíduos com idade superior a 18 anos em processo de reabilitação com recurso a exergaming e/ou gamificação, que visassem a compreensão das suas experiências, perceções e expectativas no uso destas tecnologias. Foram considerados todos os contextos de reabilitação. Estudos qualitativos e mixed-methods publicados em inglês ou português de natureza qualitativa foram incluídos, sem limite temporal. A estratégia de busca incluiu as seguintes bases de dados: MEDLINE (PubMed), CINAHL (EBSCOhost), SportDiscus(EBSCOHost), PEDro, Scopus, Dart-Europe e RCAAP. Para efeitos deste trabalho, foi realizada uma análise preliminar dos resultados obtidos na MEDLINE (PubMed). Resultados: Num total de 310 artigos, foram analisados 63 artigos após aplicação dos critérios de inclusão. Pela análise dos artigos, verificou-se que as categorias consideradas facilitadoras mais mencionadas se relacionavam aspetos de motivação associada ao divertimento, benefícios percecionados, e o impacto psicossocial. As categorias consideradas como dificultadoras mais mencionadas relacionavam-se com a monotonia/tédio a médio longo-prazo, frustração pela dificuldade no jogo, e perceção de não existir recuperação. Conclusões: Os resultados sugerem que a gamificação/exergaming podem ser ferramentas percecionadas como eficazes no processo de reabilitação. No entanto, desafios como a monotonia/tédio e a frustração devem ser abordados para garantir um engajamento sustentado.

Introduction: Surgeons are frequently faced with challenging clinical dilemmas evaluating whether the benefits of surgery outweigh the substantial risks routinely encountered with spinal tumor surgery. The Clinical Risk Analysis Index (RAI-C) is a robust frailty tool administered via a patient-friendly questionnaire that strives to augment preoperative risk stratification. The objective of the study was to prospectively measure frailty with RAI-C and track postoperative outcomes after spinal tumor surgery. Methods: Patients surgically treated for spinal tumors were followed prospectively from 7/2020–7/2022 at a single tertiary center. RAI-C was ascertained during preoperative visits and verified by the provider. The RAI-C scores were assessed in relation to postoperative functional status (measured by modified Rankin Scale score [mRS]) at the last follow-up visit. Results: Of 39 patients, 47% were robust (RAI 0–20), 26% normal (21–30), 16% frail (31–40), and 11% severely frail (RAI 41+).). Pathology included primary (59%) and metastatic (41%) tumors with corresponding mRS>2 rates of 17% and 38%, respectively. Tumors were classified as extradural (49%), intradural extramedullary (46%), or intradural intramedullary (5.4%) with mRS>2 rates of 28%, 24%, and 50%, respectively. RAI-C had a positive association with mRS>2 ​at follow-up: 16% for robust, 20% for normal, 43% for frail, and 67% for severely frail. The two deaths in the series had the highest RAI-C scores (45 and 46) and were patients with metastatic cancer. The RAI-C was a robust and diagnostically accurate predictor of mRS>2 in receiver operating characteristic curve analysis (C-statistic: 0.70, 95 CI: 0.49–0.90). Conclusions: The findings exemplify the clinical utility of RAI-C frailty scoring for prediction of outcomes after spinal tumor surgery and it has potential to help in the surgical decision-making process as well as surgical consent. As a preliminary case series, the authors intend to provide additional data with a larger sample size and longer follow-up duration in a future study.

Introdução: Pessoas acamadas correm o risco de múltiplos problemas causados pela imobilidade prolongada. Assim, existe a necessidade de desenvolver soluções que garantam a implementação de programas de reabilitação física de forma interativa, evitando o desenvolvimento da síndrome da imobilidade. Neste contexto, surgiu o projeto ABLEFIT – visa desenvolver um sistema avançado de reabilitação física para pessoas acamadas com imobilidade prolongada. Objetivos: Criar um dispositivo médico (Ablefit) para a reabilitação física de pessoas acamadas com imobilidade prolongada, considerando aspetos de funcionalidade, ergonomia e segurança. Material e Métodos: Um consórcio foi criado entre a Escola Superior de Enfermagem de Coimbra, o sector industrial e a faculdade de engenharia para criar o protótipo. Etapa1 – Scoping review para mapear programas de reabilitação física para pessoas acamadas com imobilidade prolongada. Etapa2 – Criação do protótipo de acordo com a evidência obtida na scoping review. Etapa3 – Estudo pré-clínico, abordagem multi-método centrado no utilizador (User and Human-Centered Design) avaliou a funcionalidade, ergonomia e segurança do dispositivo. Etapa4 – O protótipo foi aprimorado considerando os aspetos identificados no estudo pré-clínico. Etapa5 – Novo estudo pré-clínico realizado para garantir a viabilidade das melhorias realizadas e garantir a segurança do novo modelo. Resultados: Os resultados da scoping review (Cardoso et al., 2022) sustentaram o desenvolvimento e versatilidade do protótipo, oferecendo resposta ao nível dos domínios motor e cardiorrespiratório, contemplando movimentos lineares e circulares, passivos e ativos. A primeira etapa pré-clínica foi desenvolvida com uma amostra de 11 enfermeiros e 1 fisioterapeuta (manipularam o aparelho) e 8 end-users idosos (usaram o aparelho). Observou-se a necessidade de incorporar estabilizadores articulares e integrar gamificação para promover a motivação e conscientização do processo de recuperação. Com esta informação, desenvolveu-se uma nova versão do Ablefit para dar resposta ao objetivo proposto, tendo sido desenvolvido um segundo estudo pré-clínico para garantir a sua funcionalidade, ergonomia e segurança. Conclusões: O desenvolvimento do sistema Ablefit permite monitorizar um conjunto de variáveis e condições inerentes à imobilidade. Ao mesmo tempo permite ser uma solução dinâmica, utilizando tecnologias de gamificação, através da criação de planos de reabilitação personalizados.

Introdução: Doentes acamados com imobilidade prolongada desenvolvem frequentemente complicações como pneumonia, úlceras de pressão, atrofia muscular e trombose venosa profunda (TVP), aumentando as taxas de mortalidade durante o internamento e após alta, e com um impacto relevante em termos económicos. Atualmente, o desenvolvimento de dispositivos médicos inovadores, principalmente na tecnologia de reabilitação, é uma tendência da área da saúde que visa aumentar e manter a independência e a autonomia de pessoas com deficiência física. Para responder a esta realidade e, assim, contribuir para a resolução dos problemas mencionados, o projeto “Ablefit” propõe o desenvolvimento de um sistema avançado de reabilitação. Objetivos: Avaliar a funcionalidade, ergonomia e segurança do protótipo Ablefit desenvolvido. Material e Métodos: Um estudo pré-clínico foi realizado através de um design centrado no usuário e uma abordagem de método misto com usuários finais. Recrutou-se uma amostra não randomizada de oito idosos (65 anos ou mais) em condição física saudável. Os participantes realizaram exercícios passivos e ativos nos membros superiores e inferiores utilizando o Ablefit. Vários parâmetros foram avaliados e registados antes, durante e após os exercícios. Entrevistas semiestruturadas foram realizadas ao final dos testes. Os dados quantitativos foram analisados através do SPSS, nomeadamente estatística descritiva e os dados qualitativos, através da análise de conteúdo. Resultados: Os participantes tinham entre 69 e 89 anos (M= 78,60; DP=6,98), e sete (70,0%) eram do sexo feminino. As diferenças não foram significativas na pressão arterial, frequência cardíaca e saturação de oxigênio. A análise de conteúdo revelou cinco categorias: segurança, facilidade de uso/aprendizagem, conforto, movimentos e benefícios. Conclusão: Este estudo contribuiu para desenvolver um novo protótipo atualizado e otimizado, com inclusão de mudanças nas categorias identificadas, com reforço de um sistema de feedback ao usuário final, demonstrando a necessidade de desenvolver soluções centradas na pessoa.

Zinc is a trace mineral of interest for optimizing growth in feedlot cattle due to its roles in many physiological functions, including growth. Twenty-four Angus-cross steers (467 ± 13 kg) were used to assess the effects of supplemental Zn and ractopamine hydrochloride (RAC) on trace mineral concentrations and muscle gene expression. Four GrowSafe-equipped pens were randomly assigned to treatments (1 pen of six steers/treatment): 0 (CON), 60 (LOW), 120 (MED) or 180 (HI) mg supplemental Zn/kg DM (Availa-Zn, Zinpro). Dietary Zn treatments were initiated on d 0 and RAC supplementation (300 mg·steer·-1·d-1; Actogain45, Zoetis) began on d 53. Blood, liver and muscle (longissimus thoracis) samples were collected from all steers on d -4, 48, and 67. The LOW treatment was removed from gene expression analyses due to < 3 steers being represented for 14 of 22 genes. Data were analyzed using ProcMixed of SAS with the fixed effect of treatment and steer as the experimental unit; orthogonal linear and quadratic contrast statements were used to compare treatments. On d 48 and 67, there were linear and quadratic trends for plasma Zn to be greater in Zn-supplemented steers than CON (P ≤ 0.10). On d 48, there was a tendency for a quadratic decrease on the expression of SLC30A4 (P ≤ 0.07) but no other differences due to treatment. On d 67, several genes involved in Zn transport and storage (MTA1, SLC39A7, SLC39A8, SLC39A9, SLC39A10, SLC39A13) were decreased (P ≤ 0.08), suggesting increased growth influences intracellular Zn trafficking and demands.

COVID-19 has disproportionately impacted individuals depending on where they live and work, and based on their race, ethnicity, and socioeconomic status. Studies have documented catastrophic disparities at critical points throughout the pandemic, but have not yet systematically tracked their severity through time. Using anonymized hospitalization data from March 11, 2020 to June 1, 2021 and fine-grain infection hospitalization rates, we estimate the time-varying burden of COVID-19 by age group and ZIP code in Austin, Texas. During this 15-month period, we estimate an overall 23.7% (95% CrI: 22.5-24.8%) infection rate and 29.4% (95% CrI: 28.0-31.0%) case reporting rate. Individuals over 65 were less likely to be infected than younger age groups (11.2% [95% CrI: 10.3-12.0%] vs 25.1% [95% CrI: 23.7-26.4%]), but more likely to be hospitalized (1,965 per 100,000 vs 376 per 100,000) and have their infections reported (53% [95% CrI: 49-57%] vs 28% [95% CrI: 27-30%]). We used a mixed effect poisson regression model to estimate disparities in infection and reporting rates as a function of social vulnerability. We compared ZIP codes ranking in the 75th percentile of vulnerability to those in the 25th percentile, and found that the more vulnerable communities had 2.5 (95% CrI: 2.0-3.0) times the infection rate and only 70% (95% CrI: 60%-82%) the reporting rate compared to the less vulnerable communities. Inequality persisted but declined significantly over the 15-month study period. Our results suggest that further public health efforts are needed to mitigate local COVID-19 disparities and that the CDC's social vulnerability index may serve as a reliable predictor of risk on a local scale when surveillance data are limited.

Summary: Background: Systems biology leveraging multi-OMICs technologies, is rapidly advancing development of precision therapies and matching patients to targeted therapies, leading to improved responses. A new pillar of precision oncology lies in the power of chemogenomics to discover drugs that sensitizes malignant cells to other therapies. Here, we test a chemogenomic approach using epigenomic inhibitors (epidrugs) to reset patterns of gene expression driving the malignant behavior of pancreatic tumors. Methods: We tested a targeted library of ten epidrugs targeting regulators of enhancers and super-enhancers on reprogramming gene expression networks in seventeen patient-derived primary pancreatic cancer cell cultures (PDPCCs), of both basal and classical subtypes. We subsequently evaluated the ability of these epidrugs to sensitize pancreatic cancer cells to five chemotherapeutic drugs that are clinically used for this malignancy. Findings: To comprehend the impact of epidrug priming at the molecular level, we evaluated the effect of each epidrugs at the transcriptomic level of PDPCCs. The activating epidrugs showed a higher number of upregulated genes than the repressive epidrugs (χ2 test p-value

Coaxial wire-based laser metal deposition is a versatile and efficient additive process that can achieve a high deposition rate in the manufacturing of complex structures. In this paper, a three-beam coaxial wire system is studied, with particular attention to the effects of deposition height and laser defocusing on the resulting bead geometry. As the deposition standoff distance changes, so does the workpiece illumination proportion, which describes the ratio of energy going directly into the feedstock wire and into the substrate. Single titanium beads are deposited at varying defocus levels and deposition rates and the bead aspect ratio is measured and analyzed. Over the experimental settings, the defocusing level and deposition rate were found to have a significant effect on the resulting bead aspect ratio. As the defocusing level is increased away from the beam convergence plane, the spot size increases and the deposited track is wider and flatter. Process parameters can be used to tune the deposited material to a desired aspect ratio. In coaxial wire deposition, defocusing provides an adjustment mechanism to the distribution of heat between the wire and substrate and has an important impact on the resulting deposit.

Maintenance is a highly procedural activity requiring motor and cognitive engagement. The aim of this experimental study was to examine how expertise affects maintenance tasks, in particular, the use of procedural documents. A total of 22 aircraft maintenance technicians were divided into two groups according to their level of expertise. Helicopter maintenance was evaluated in a real work environment, using an eye tracker, a fixed camera, and NASA-TLX to measure workload. Both groups reported a high mental load. Novices showed elevated levels of effort and mental demand. Experts were faster at all levels of the task and spent less time consulting maintenance documentation. The acquisition of procedural information was greater at the start of the task, where the gap between groups was more pronounced. This may be related to the overall planning of the task, in addition, the task was atomized, with frequent back-and-forth between execution and information intake, for all participants. Novices had a longer document consultation duration, spread over a greater number of consultations, but did not have a higher average consultation time. The results indicate a higher mental load for novices, potentially linked to an increased atomization of the task, as shown by the frequency of consultations.

As the closest major galaxy merger and home to thousands of super star clusters (SSCs), the Antennae Galaxies (NGC 4038 and NGC 4039) are an important location to study the molecular clouds at sites of vigorous star formation. We cataloged giant molecular clouds (GMCs) in the region where the two galaxies overlap using high-resolution (∼0.″1–10 pc) Atacama Large Millimeter/submillimeter Array observations of the ^12 CO(2−1) and ^13 CO(2−1) emission lines. Of the 72 individual GMCs identified in the overlap region, 17 are within uncertainties of having the necessary mass, pressure, and size needed to form SSCs. Of those 17 GMCs, only one has significant ionizing radiation, indicating that the birth environments are likely still intact in the 16 other GMCs. We compared the physical properties calculated from ^12 CO(2−1) GMC data with observations of 10 other galaxies obtained using the same emission line and similar resolution. Compared to other sources in this sample, the GMCs from the Antennae, as well as in other starbursts and in the centers of galaxies, have the highest luminosities, surface densities, and turbulent pressures. The GMCs in starbursts and at the centers of galaxies also have large line widths, although the line widths in the Antennae are among the widest. These comparative results also indicate that the Antennae GMCs have the highest virial parameters despite their high densities.

We present a comparative study of the molecular gas in two galaxies from the Legacy ExtraGalactic UV Survey (LEGUS) sample: barred spiral NGC 1313 and flocculent spiral NGC 7793. These two galaxies have similar masses, metallicities, and star formation rates, but NGC 1313 is forming significantly more massive star clusters than NGC 7793, especially young massive clusters (10 ^4 M _⊙ ). Using Atacama Large Millimeter/submillimeter Array (ALMA) CO(2–1) observations of the two galaxies with the same sensitivity and resolution (13 pc), we directly compare the molecular gas in these two similar galaxies to determine the physical conditions responsible for their large disparity in cluster formation. By fitting size–line width relations for the clouds in each galaxy, we find that NGC 1313 has a higher intercept than NGC 7793, implying that its clouds have higher kinetic energies at a given size scale. NGC 1313 also has more clouds near virial equilibrium than NGC 7793, which may be connected to its higher rate of massive cluster formation. However, these virially bound clouds do not show a stronger correlation with young clusters than with the general cloud population. We find surprisingly small differences between the distributions of molecular cloud populations in the two galaxies, though the largest of those differences is that NGC 1313 has higher surface densities and lower freefall times.

We compare the molecular cloud properties in subgalactic regions of two galaxies, barred spiral NGC 1313, which is forming many massive clusters, and flocculent spiral NGC 7793, which is forming significantly fewer massive clusters despite having a similar star formation rate to NGC 1313. We find that there are larger variations in cloud properties between different regions within each galaxy than there are between the galaxies on a global scale, especially for NGC 1313. There are higher masses, line widths, pressures, and virial parameters in the arms of NGC 1313 and the center of NGC 7793 than in the interarm and outer regions of the galaxies. The massive cluster formation of NGC 1313 may be driven by its greater variation in environment, allowing more clouds with the necessary conditions to emerge, although no one parameter seems primarily responsible for the difference in star formation. Meanwhile NGC 7793 has clouds that are as massive and have as much kinetic energy as the clouds in the arms of NGC 1313, but have densities and pressures more similar to those in the interarm regions and so are less inclined to collapse and form stars. The cloud properties in NGC 1313 and NGC 7793 suggest that spiral arms, bars, interarm regions, and flocculent spirals each represent distinct environments with regard to molecular cloud populations. We see surprisingly little difference in surface density between the regions, suggesting that the differences in surface densities frequently seen between arm and interarm regions in lower-resolution studies are indicative of the sparsity of molecular clouds, rather than differences in their true surface density.

Abstract Pancreatic ductal adenocarcinoma (PDAC), has recently been found to be a heterogeneous disease, although the extension of its diversity remains to be fully understood. Here, we harmonize transcriptomic profiles derived from both PDAC epithelial and microenvironment cells to develop a Master Regulators (MR)-Gradient model that allows important inferences on transcriptional networks, epigenomic states, and metabolomics pathways that underlies this disease heterogeneity. This gradient model was generated by applying a blind source separation based on independent components analysis and robust principal component analyses (RPCA), following regulatory network inference. The result of these analyses reveals that PDAC prognosis strongly associates with the tumor epithelial cell phenotype and the immunological component. These studies were complemented by integration of methylome and metabolome datasets generated from patient-derived xenograft (PDX), together experimental measurements of metabolites, immunofluorescence microscopy, and western blot. At the metabolic level, PDAC favorable phenotype showed a positive correlation with enzymes implicated in complex lipid biosynthesis. In contrast, the unfavorable phenotype displayed an augmented OXPHOS independent metabolism centered on the Warburg effect and glutaminolysis. Epigenetically, we find that a global hypermethylation profile associates with the worst prognosis. Lastly, we report that, two antagonistic histone code writers, SUV39H1/SUV39H2 (H3K9Me3) and KAT2B (H3K9Ac) were identified key deregulated pathways in PDAC. Our analysis suggests that the PDAC phenotype, as it relates to prognosis, is determined by a complex interaction of transcriptomic, epigenomic, and metabolic features. Furthermore, we demonstrated that PDAC prognosis could be modulated through epigenetics.

Abstract Correlations between increasing concentrations of circulating tumor DNA (ctDNA) in plasma and disease progression have been shown. A nonlinear mixed effects model to describe the dynamics of epidermal growth factor receptor (EGFR) ctDNA data from patients with non‐small cell lung cancer (NSCLC) combined with a parametric survival model were developed to evaluate the ability of these modeling techniques to describe ctDNA data. Repeated ctDNA measurements on L858R, exon19del, and T790M mutants were available from 54 patients with EGFR mutated NSCLC treated with erlotinib or gefitinib. Different dynamic models were tested to describe the longitudinal ctDNA concentrations of the driver and resistance mutations. Subsequently, a parametric time‐to‐event model for progression‐free survival (PFS) was developed. Predicted L858R, exon19del, and T790M concentrations were used to evaluate their value as predictor for disease progression. The ctDNA dynamics were best described by a model consisting of a zero‐order increase and first‐order elimination (19.7/day, 95% confidence interval [CI] 14.9–23.6/day) of ctDNA concentrations. In addition, time‐dependent development of resistance (5.0 × 10−4, 95% CI 2.0 × 10−4–7.0 × 10−4/day) was included in the final model. Relative change in L858R and exon19del concentrations from baseline was identified as most significant predictor of disease progression (p = 0.001). The dynamic model for L858R, exon19del, and T790M concentrations in ctDNA and time‐to‐event model adequately described the observed concentrations and PFS data in our clinical cohort. In addition, it was shown that nonlinear mixed effects modeling is a valuable method for the analysis of longitudinal and heterogeneous biomarker datasets obtained from clinical practice.

Amyloidomas are focal solitary amyloid masses without systemic involvement that have been observed to occur in various body locations. When presenting intracranially, they pose a challenging diagnostic and therapeutic course given their location and rarity. We report a case of a 62-year-old man with a 4-year history of seizure and headaches. Magnetic resonance imaging was initially inconclusive but revealed an ill-defined right temporal lobe lesion. Biopsy later confirmed a cerebral amyloidoma. We also review the current literature on the pathogenesis, imaging findings, prognosis, and treatment of cerebral amyloidomas.

Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its different subtypes are linked to mutations in dozens of different genes. Mutations in ganglioside‐induced differentiation‐associated protein 1 (GDAP1) cause two types of CMT, demyelinating CMT4A and axonal CMT2K. The GDAP1‐linked CMT genotypes are mainly missense point mutations. Despite clinical profiling and in vivo studies on the mutations, the etiology of GDAP1‐linked CMT is poorly understood. Here, we describe the biochemical and structural properties of the Finnish founding CMT2K mutation H123R and CMT2K‐linked R120W, both of which are autosomal dominant mutations. The disease variant proteins retain close to normal structure and solution behavior, but both present a significant decrease in thermal stability. Using GDAP1 variant crystal structures, we identify a side‐chain interaction network between helices ⍺3, ⍺6, and ⍺7, which is affected by CMT mutations, as well as a hinge in the long helix ⍺6, which is linked to structural flexibility. Structural analysis of GDAP1 indicates that CMT may arise from disruption of specific intra‐ and intermolecular interaction networks, leading to alterations in GDAP1 structure and stability, and, eventually, insufficient motor and sensory neuron function.

Abstract Background An effective use of surgical antibiotic prophylaxis (SAP) appears essential to prevent the development of infections linked to surgery while inappropriate and excessive prescriptions of prophylactic antibiotics increase the risk of adverse effects, bacterial resistance and Clostridium difficile infections. In this study, we aimed to analyze SAP practices in an acute secondary hospital in Belgium during the years 2016–2021 in order to evaluate the impacts of combined stewardship interventions, implemented thanks to a physician-pharmacist collaboration. Methods A quasi-experimental study on SAP practices was conducted during 5 years (2016–2021) in a Belgian University Hospital. We first performed a retrospective observational transversal study on a baseline group (2016.1–2016.4). Then, we constituted a group of patients (2017.1–2017.4) to test a combined intervention strategy of stewardship which integrated the central role of a pharmacist in antibiotic stewardship team and in the pre-operative delivery of nominative kits of antibiotics adapted to patient factors. After this test, we collected patient data (2018.1–2018.4) to evaluate the sustained effects of stewardship interventions. Furthermore, we evaluated SAP practices (2019.1–2019.4) after the diffusion of a computerized decision support system. Finally, we analyzed SAP practices in the context of the COVID-19 pandemic (2020.1–2020.4 and 2021.1–2021.4). The groups were compared from year to year in terms of compliance to institutional guidelines, as evaluated from seven criteria (χ2 test). Results In total, 760 surgical interventions were recorded. The observational study within the baseline group showed that true penicillin allergy, certain types of surgery and certain practitioners were associated with non-compliance (p

BackgroundDiagnosing concomitant pulmonary embolism (PE) in COVID-19 patients remains challenging. As such, PE may be overlooked. We compared the diagnostic yield of systematic PE-screening based on the YEARS-algorithm to PE-screening based on clinical gestalt in emergency department (ED) patients with COVID-19.MethodsWe included all ED patients who were admitted because of COVID-19 between March 2020 and February 2021. Patients already receiving anticoagulant treatment were excluded. Up to April 7, 2020, the decision to perform CT-pulmonary angiography (CTPA) was based on physician's clinical gestalt (clinical gestalt cohort). From April 7 onwards, systematic PE-screening was performed by CTPA if D-dimer level was ≥1000 ug/L, or ≥500 ug/L in case of ≥1 YEARS-item (systematic screening cohort).Results1095 ED patients with COVID-19 were admitted. After applying exclusion criteria, 289 were included in the clinical gestalt and 574 in the systematic screening cohort. The number of PE diagnoses was significantly higher in the systematic screening cohort compared to the clinical gestalt cohort: 8.2% vs. 1.0% (3/289 vs. 47/574; p100 mg/L (OR 2.78, 95%CI 1.37-5.66, p = 0.005) were independently associated with PE.ConclusionIn ED patients with COVID-19, the number of PE diagnosis was significantly higher in the cohort that underwent systematic PE screening based on the YEARS-algorithm in comparison with the clinical gestalt cohort, with a number needed to test of 7.1 CTPAs to detect one PE.

Study objective: Data is scarce regarding which dialysis modality portends more severe cardiac valvular calcification (CVC). Our aim was to compare the degree of CVC in hemodialysis (HD) and peritoneal dialysis (PD) patient cohorts prior to open heart surgery (OHS) using a CT calcium score. Design, setting, and participants: Dialysis patients who underwent OHS at our institution from 2009 to 2019 and who had pre-surgical cardiac CT were included in our study. We obtained duration of dialysis modality prior to their surgical date. There were two study cohorts to evaluate outcomes of interest: mitral and aortic calcification. CVC was assessed using the Agatston score. Logistic regression was performed to test for the association of PD and HD cumulative dialysis duration with presence of CVC. Results: A total of 214 and 166 patients met inclusion for the mitral and aortic strata, respectively. Age, female sex, and BMI were associated with higher odds of presence of mitral calcification. Age and BMI were associated with higher odds of presence of aortic calcification, while female sex was associated with lower odds in the aortic strata. Cumulative years on PD and cumulative years on HD were not significantly associated with presence of CVC in either cohort. Conclusion: Presence of mitral and aortic calcification for patients undergoing OHS was not significantly associated with cumulative length of PD or HD after adjusting for age, gender, and BMI suggesting that there may be more factors at play in the progression of CVC in end stage renal disease patients than what was previously established.

Although the concept of connectivity is ubiquitous in ecology and evolution, its definition is often inconsistent, particularly in interdisciplinary research. In an ecological context, population connectivity refers to the movement of individuals or species across a landscape. It is measured by locating organisms and tracking their occurrence across space and time. In an evolutionary context, connectivity is typically used to describe levels of current and past gene flow, calculated from the degree of genetic similarity between populations. Both connectivity definitions are useful in their specific contexts, but rarely are these two perspectives combined. Different definitions of connectivity could result in misunderstandings across subdisciplines. Here, we unite ecological and evolutionary perspectives into a single unifying framework by advocating for connectivity to be conceptualized as a generational continuum. Within this framework, connectivity can be subdivided into three timescales: (1) within a generation (e.g., movement), (2) across one parent-offspring generation (e.g., dispersal), and (3) across two or more generations (e.g., gene flow), with each timescale determining the relevant context and dictating whether the connectivity has ecological or evolutionary consequences. Applying our framework to real-world connectivity questions can help to identify sampling limitations associated with a particular methodology, further develop research questions and hypotheses, and investigate eco-evolutionary feedback interactions that span the connectivity continuum. We hope this framework will serve as a foundation for conducting and communicating research across subdisciplines, resulting in a more holistic understanding of connectivity in natural systems.

The emergence of the rare syndrome called vaccine-induced immune thrombocytopenia and thrombosis (VITT) after adenoviral vector vaccines, including ChAdOx1 nCov-19, raises concern about one's predisposing risk factors. Here we report the case of a 56-year-old white man who developed VITT leading to death within 9 days of symptom onset. He presented with superior sagittal sinus thrombosis, right frontal intraparenchymal hematoma, frontoparietal subarachnoid and massive ventricular hemorrhage, and right lower extremity arterial and venous thrombosis. His laboratory results showed elevated D-dimer, C-reactive protein, tissue factor, P-selectin (CD62p), and positive anti-platelet factor 4. The patient's plasma promoted higher CD62p expression in healthy donors' platelets than the controls. Genetic investigation on coagulation, thrombophilia, inflammation, and type I interferon-related genes was performed. From rare variants in European or African genomic databases, 68 single-nucleotide polymorphisms (SNPs) in one allele and 11 in two alleles from common SNPs were found in the patient genome. This report highlights the possible relationship between VITT and genetic variants. Additional investigations regarding the genetic predisposition of VITT are needed.

Abstract Introduction: Theta burst stimulation (TBS) is a type of rTMS protocol which has the advantage of a shorter delivery time over traditional rTMS. When applied to motor cortex, intermittent TBS (iTBS) has been shown to yield excitatory aftereffects, whereas continuous TBS (cTBS) may lead to inhibitory aftereffects, both lasting from minutes to hours. The majority of TBS research has targeted motor, frontal, and parietal regions, and to date very few studies have examined its efficacy at visual areas. We designed a sham‐controlled study to investigate the immediate poststimulation and short‐term (1 h post‐stimulation) effects of iTBS and cTBS to V1. Methods: Using multiecho functional magnetic resonance imaging, we measured the direct and indirect effects of TBS by comparing resting state functional connectivity (FC) before and after stimulation in whole brain networks, and seeds from V1 (stimulation site) and neighboring occipital and parietal visual networks. In addition, we also measured pre‐ and post‐TBS phosphene thresholds (PTs) to examine the modulatory effects of TBS on cortical excitability. Results: We found no changes in FC for iTBS, cTBS or sham stimulation conditions from baseline to poststimulation timepoints. Additionally, cTBS and iTBS had no effect on visual cortical excitability. Conclusions: Our results indicate that unlike our previous low frequency rTMS to V1 study, which resulted in widespread FC changes up to at least 1 h after stimulation, TBS to V1 does not affect FC. Contrary to the studies showing comparable TBS and rTMS aftereffects in motor and frontal regions, our findings suggest that a single session of cTBS or iTBS to V1 at 80% PT using a standard protocol of 600 pulses may not be effective in targeting FC, especially in clinical settings where therapy for pathological networks is the goal.