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Abstract Understanding how Legionella spp. proliferate in multispecies biofilms is essential to develop strategies to control their presence in building plumbing. Here, we analyzed biofilm formation and Legionella spp. colonization on new plumbing material during 8 weeks. Biofilm formation was characterized by an initial increase in intact cell concentrations up to 9.5 × 105 cells/cm2, followed by a steady decrease. We identified Comamonas, Caulobacter, Schlegella, Blastomonas and Methyloversatilis as pioneer genera in the biofilm formation process. Importantly, L. pneumophila was the dominant Legionella spp. and rapidly colonized the biofilms, with culturable cell concentrations peaking at 3.1 × 104 MPN/cm2 after 4 weeks already. Moreover, several Legionella species co-occurred and had distinct dynamics of biofilm colonization. Vermamoeba vermiformis (V. vermiformis) was the dominant protist identified with 18S rRNA gene amplicon sequencing. Together our results highlight that biofilm formation upon introduction of new building plumbing material is a dynamic process where pathogenic Legionella species can be part of the earliest colonizers.

Abstract Augmenting the portfolio of therapeutics for type 2-driven diseases is crucial to address unmet clinical needs and to design personalized treatment schemes. An attractive therapy for such diseases would consist in targeting the recruitment of T helper 2 (Th2) lymphocytes to inflammatory sites. Herein, we show the degradation of filamins (FLN) a and b by the ASB2α E3 ubiquitin ligase as a mechanism sustaining Th2 lymphocyte functions. Low levels of FLNa and FLNb confer an elongated shape to Th2 lymphocytes associated with efficient αVβ3 integrin-dependent cell migration. Genes encoding the αVβ3 integrin and ASB2α belong to the core of Th2-specific genes. Using genetically modified mice, we find that increasing the levels of FLNa and FLNb in Th2 lymphocytes reduces airway inflammation through diminished Th2 lymphocyte recruitment in inflamed lungs. Collectively, our results highlight ASB2α and its substrates FLNa and FLNb to alter Th2 lymphocyte-mediated responses.

Abstract Background Paediatric critical care nurses face challenges in promptly detecting patient deterioration and delivering high-quality care, especially in low-resource settings (LRS). Patient monitors equipped with data-driven algorithms that monitor and integrate clinical data can optimise scarce resources (e.g. trained staff) offering solutions to these challenges. Poor algorithm output design and workflow integration, however, are important factors hindering successful implementation. This study aims to explore nurses’ perspectives to inform the development of a data-driven algorithm and user-friendly interface for future integration into a continuous vital signs monitoring system for critical care in LRS. Methods Human-centred design methods, including contextual inquiry, semi-structured interviews, prototyping and co-design sessions, were carried out at the high-dependency units of Queen Elizabeth Central Hospital and Zomba Central Hospital in Malawi between March and July 2023. Triangulating these methods, we identified what algorithm could assist nurses and used co-creation methods to design a user interface prototype. Data were analysed using qualitative content analysis. Results Workflow observations demonstrated the effects of personnel shortages and limited monitor equipment for vital signs monitoring. Interviews identified four themes: workload and workflow, patient prioritisation, interaction with guardians, and perspectives on data-driven algorithms. The interviews emphasised the advantages of predictive algorithms in anticipating patient deterioration, underlining the need to integrate the algorithm’s output, the (constant) monitoring data, and the patient’s present clinical condition. Nurses preferred a scoring system represented with familiar scales and colour codes. During co-design sessions, trust, usability and context specificity were emphasised as requirements for these algorithms. Four prototype components were examined, with nurses favouring scores represented by colour codes and visual representations of score changes. Conclusions Nurses in the LRS studied, perceived that data-driven algorithms, especially for predicting patient deterioration, could improve the provision of critical care. This can be achieved by translating nurses’ perspectives into design strategies, as has been carried out in this study. The lessons learned were summarised as actionable pre-implementation recommendations for the development and implementation of data-driven algorithms in LRS.

Abstract Introduction UVA-UVB increases skin matrix metalloproteinases and breaks down extracellular proteins and fibrillar type 1 collagen, leading to photodamage. Topical application of nicotinamide prevents UV-induced immunosuppression. Several studies have demonstrated the importance of protection against UV. This study aims to determine the biological effect of a high broad-spectrum UVB-UVA sunscreen containing nicotinamide and panthenol (SSNP) on photodamaged skin using linear confocal optical coherence tomography (LC-OCT), immunohistochemistry, and RNA profiling. Methods Two areas of severely photodamaged forearm skin (L01 and L02) and one less sun-damaged (naturally protected) area on the inner part of the forearm (L03) were identified in 14 subjects. These areas were imaged using LC-OCT and L01 and L03 were biopsied at baseline. After 4 weeks of treatment with SSNP, L02 was reimaged using LC-OCT, and biopsied. Histology, immunostaining with p21, p53, PCNA, and CPD, and RNA sequencing were performed in all samples. Results LC-OCT analysis showed that epidermis thickness and the number of keratinocytes is higher in the sun-exposed areas than in the non-exposed areas. Comparing before and after treatment, even though there is a trend towards normalization, the differences were not statistically significant. The expression of p21, PCNA, p53, and CPD increased in severely photodamaged skin compared to less-damaged skin. When comparing before and after treatment, only p21 showed a trend to decrease expression. RNA sequencing analysis identified 1552 significant genes correlating with the progression from non-visibly photodamaged skin to post-treatment and pre-treatment samples; in the analysis comparing pre- and post-treatment samples, 5429 genes were found to be significantly associated. A total of 1115 genes are common in these two analyses. Additionally, nine significant genes from the first analysis and eight from the second are related to collagen. Six of these collagen genes are common in the two analyses. MAPK and cGMP-PKG signalling pathways are upregulated in the progression to photodamage analysis. In the pre- and post-treatment analysis, 32 pathways are downregulated after treatment, the most statistically significant being the ErbB, Hippo, NOD-like receptor, TNF, and NF-kB signalling pathways. Conclusion This study demonstrates the role of SSNP in collagen generation, highlights the relevance of the cGMP-PKG and MAPK signalling pathways in photodamage, and shows the ability of SSNP to downregulate pathways activated by UV exposure. Additionally, it deepens our understanding of the effect of SSNP on immune-related pathways.

Abstract Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy affecting the elderly, for which therapeutic options are limited. DNA hypomethylating agents (HMAs) provide transient responses, failing to eradicate the malignant clone. Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization, evidenced by alterations in histone marks H3K9me2 and H3K9me3. These repressive marks together with DNA methylation are essential for suppressing transposable elements (TEs). In solid cancers, the antitumor efficacy of HMAs involves the derepression of TEs, mimicking a state of viral infection. In this study, we demonstrate a significant disorganization of heterochromatin in CMML HSCs and progenitors (HSPCs) characterized by an increase in the repressive mark H3K9me2, mainly at the level of TEs, and a repression of immune and age-associated transcripts. Combining HMAs with G9A/GLP H3K9me2 methyltransferase inhibitors reactivates these pathways, selectively targeting mutated cells while preserving wild-type HSCs, thus offering new therapeutic avenues for this severe myeloid malignancy.

Abstract Human respiratory syncytial virus (RSV) is a major cause of acute respiratory infection. In 2020, RSV was eliminated from New Zealand due to non-pharmaceutical interventions (NPI) used to control the spread of SARS-CoV-2. However, in 2021, following a brief quarantine-free travel agreement with Australia, there was a large-scale nationwide outbreak of RSV that led to reported cases more than five-times higher than typical seasonal patterns. We generated 1470 viral genomes of both RSV-A and RSV-B sampled between 2015–2022 from across New Zealand. Using a phylodynamics approach, we used these data to better understand RSV transmission patterns in New Zealand prior to 2020, and how RSV became re-established in the community following the relaxation of COVID-19 restrictions. We found that in 2021, there was a large epidemic of RSV due to an increase in importations, leading to several large genomic clusters of both RSV-A ON1 and RSV-B BA9 genotypes. However, while a number of viral importations were detected, there was also a major reduction in RSV genetic diversity compared to pre-pandemic years. These data reveal the impact of NPI used during the COVID-19 pandemic on other respiratory infections and highlight the important insights that can be gained from viral genomes.

Abstract Background In recent years, sustainable employability, rooted in the capability approach, has received substantial attention due to its associations with work and health-related outcomes. While previous studies have indicated that being able and enabled to achieve important work values (i.e., work capabilities) is positively associated with desirable work outcomes, most of these studies have primarily employed a cross-sectional design to explore these associations. This study aimed to examine the long-term relationships between work capabilities and work and wellbeing-related outcomes, including work ability, work engagement, task and creative performance, organizational citizenship behavior, organizational commitment, job and life satisfaction, turnover intention, and burnout symptoms. Methods Data were collected from 251 randomly selected Dutch employees through a two-wave survey conducted in 2021 and 2023 via the Longitudinal Internet Studies for the Social Sciences panel. Multiple linear regression analyses were performed to assess these associations while controlling for potential covariates. Results The results revealed that participants valued a diverse range of work capabilities but encountered challenges in realizing these valued capabilities. The capability set positively predicted desirable outcomes and was associated with reduced burnout over a two-year period. Conclusions Supporting and enabling employees to realize their capabilities is essential for improving favorable work outcomes and diminishing burnout in today’s volatile work environment. These findings further emphasize the importance of organizations improving conversion factors to bridge the gap between valued capabilities and their actualization.

Abstract Background The aim of this study was to compare genetic gain and rate of inbreeding for different mass selection breeding programs with the aim of increasing larval body weight (LBW) in black soldier flies. The breeding programs differed in: (1) sampling of individuals for phenotyping (either random over the whole population or a fixed number per full sib family), (2) selection of adult flies for breeding (based on an adult individual’s phenotype for LBW or random from larvae preselected based on LBW), and (3) mating strategy (mating in a group with unequal male contributions or controlled between two females and one male). In addition, the numbers of phenotyped and preselected larvae were varied. The sex of an individual was unknown during preselection and females had higher LBW, resulting in more females being preselected. Results Selecting adult flies based on their phenotype for LBW increased genetic gain by 0.06 genetic standard deviation units compared to randomly selecting from the preselected larvae. Fixing the number of phenotyped larvae per family increased the rate of inbreeding by 0.15 to 0.20% per generation. Controlled mating compared to group mating decreased the rate of inbreeding by 0.02 to 0.03% per generation. Phenotyping more than 4000 larvae resulted in a lack of preselected males due to the sexual dimorphism. Preselecting both too few and too many larvae could negatively impact genetic gain, depending on the breeding program. Conclusions A mass selection breeding programs in which the adult fly is selected based on their larval phenotype, breeding animals mate in a group and sampling larvae for phenotyping at random over the whole population is recommended for black soldier flies, considering the positive effect on rates of genetic gain and inbreeding. The number of phenotyped and preselected larvae should be calculated based on the expected female weight deviation to ensure sufficient male and female candidates are selected.

Abstract Most published prediction models for Coronavirus Disease 2019 (COVID-19) were poorly reported, at high risk of bias, and heterogeneous in model performance. To tackle methodological challenges faced in previous prediction studies, we investigated whether model updating and extending improves mortality prediction, using the Intensive Care Unit (ICU) as a proxy. All COVID-19 patients admitted to seven ICUs in the Euregio-Meuse Rhine during the first pandemic wave were included. The 4C Mortality and SEIMC scores were selected as promising prognostic models from an external validation study. Five predictors could be estimated based on cohort size. TRIPOD guidelines were followed and logistic regression analyses with the linear predictor, APACHE II score, and country were performed. Bootstrapping with backward selection was applied to select variables for the final model. Additionally, shrinkage was performed. Model discrimination was displayed as optimism-corrected areas under the ROC curve and calibration by calibration slopes and plots. The mortality rate of the 551 included patients was 36%. Discrimination of the 4C Mortality and SEIMC scores increased from 0.70 to 0.74 and 0.70 to 0.73 and calibration plots improved compared to the original models after updating and extending. Mortality prediction can be improved after updating and extending of promising models.

Abstract Background Compared to the general population, people living in prison are at an increased risk to experience negative (mental) health outcomes. Moreover, delinquency and drug use have many risk factors in common. A need exists for increasing the knowledge about health needs, drug use patterns and the coverage of drug-related interventions in prison within Europe. The current protocol describes the design of a study about wellbeing, drug use and related care in prison. Methods/design A multicentre mixed method design is implemented in five European countries (Belgium, Cyprus, Greece, Lithuania and Luxembourg). Qualitative and quantitative data collection tools are combined in order to generate complementary and comprehensive results. First, a cross-sectional survey among people living in prison is conducted. This survey is based on a model questionnaire, the European Questionnaire on Drug use among people living in Prison, developed by the European Monitoring Centre for Drug and Drugs Addiction. Second, people living in prison and people who have been recently released from prison are involved in qualitative semi-structured face-to-face interviews. The main topics of interest are the use of drugs and other health related topics such as loneliness, anxiety, depression, infectious diseases, suicide and treatment. Third, data regarding health and social reintegration measures in prison is collected through a quantitative survey addressed to the prison authorities. Discussion This study protocol presentes a European study which aims to assess drug use among people living in prison and recently released people who use drugs as well as the existing care services in prisons. Hereby, factors related to the prison environment and their needs, both inside and outside prison are taken into account. Importantly, this study protocol describes a methodology which is developed to be executed in different prison settings within different countries simultaneously. Accordingly, for each country the protocol is adjustable to specific national legal requirements, regional differences and distinct local regulations of prison administrations. However, extensive modularity inevitably comes with significant limitations of comparability and generalizability of the results.

Abstract Several multivariate prognostic models have been published to predict outcomes in patients with first episode psychosis (FEP), but it remains unclear whether those predictions generalize to independent populations. Using a subset of demographic and clinical baseline predictors, we aimed to develop and externally validate different models predicting functional outcome after a FEP in the context of a schizophrenia-spectrum disorder (FES), based on a previously published cross-validation and machine learning pipeline. A crossover validation approach was adopted in two large, international cohorts (EUFEST, n = 338, and the PSYSCAN FES cohort, n = 226). Scores on the Global Assessment of Functioning scale (GAF) at 12 month follow-up were dichotomized to differentiate between poor (GAF current

Abstract Endothelial cells are key players in the cardiovascular system. Among other things, they are responsible for sprouting angiogenesis, the process of new blood vessel formation essential for both health and disease. Endothelial cells are strongly regulated by the juxtacrine signaling pathway Notch. Recent studies have shown that both Notch and angiogenesis are influenced by extracellular matrix stiffness; however, the underlying mechanisms are poorly understood. Here, we addressed this challenge by combining computational models of Notch signaling and YAP/TAZ, stiffness- and cytoskeleton-regulated mechanotransducers whose activity inhibits both Dll4 (Notch ligand) and LFng (Notch-Dll4 binding modulator). Our simulations successfully mimicked previous experiments, indicating that this YAP/TAZ-Notch crosstalk elucidates the Notch and angiogenesis mechanoresponse to stiffness. Additional simulations also identified possible strategies to control Notch activity and sprouting angiogenesis via cytoskeletal manipulations or spatial patterns of alternating stiffnesses. Our study thus inspires new experimental avenues and provides a promising modeling framework for further investigations into the role of Notch, YAP/TAZ, and mechanics in determining endothelial cell behavior during angiogenesis and similar processes.

Abstract Introduction LMNB1-related autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurodegenerative disorder caused by overexpression of LMNB1. We retrospectively reviewed charts of all ADLD patients seen at Mayo Clinic. Methods All available data from molecularly confirmed ADLD patients was reviewed. Results Of eight patients identified, three were male. Age at symptom onset ranged from 33 to 64 years. In males, the first symptom was erectile dysfunction (2/3) or neurogenic bladder (1/3) and, in females, weakness (3/5), bladder dysfunction (2/5), or depression (1/5). Diagnostic delay from symptom onset was a median of 6 (IQR 2.3–10) years. Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8). Family history was positive in 6. All eight patients had LMNB1 duplication. Eighteen brain MRIs were reviewed from 7 patients. All showed symmetric confluent T2W deep cerebral and periventricular white matter hyperintensities with involvement of the posterior limb of the internal capsule, corpus callosum, corticospinal tract in brain stem, and superior and middle cerebellar peduncles. Seven spine MRIs from six patients showed moderate diffuse atrophy of the spinal cord. Conclusion Typical clinical symptoms and characteristic MRI changes should prompt genetic testing for ADLD.

Summary: Background & Aims: Sarcopenia and myosteatosis are proving to be major factors to predict mortality in intensive care patients. Few studies are currently focusing on evaluating the functional impact after intensive care discharge and none has considered sarcopenia and myosteatosis as prognostic factors.The aim of our study was to determine whether sarcopenia and myosteatosis are reliable prognostic factors for mid-term functional impact in critical patients a few months after intensive care discharge. Methods: We carried out a retrospective monocentric study using computed-tomography scanner performed on intensive care admission and/or three months after discharge to assess sarcopenia and myosteatosis in 43 patients with critical illnesses who underwent a multidisciplinary evaluation on a multidisciplinary consultation's day hospital.We used L3 and/or T4 computed-tomography-scan levels to assess sarcopenia with the skeletal muscle index and myosteatosis with skeletal muscle density. These data were compared with main patient characteristics on intensive care admission and during intensive care stay and with functional assessments at the post intensive care multidisciplinary consultations, based on hand grip strength test, 6-minute walking test, and peak inspiratory pressure. Results: We found a good correlation of both skeletal muscle index and skeletal muscle density for T4 and L3 levels. Skeletal muscle index was correlated with hand grip strength test, and skeletal muscle density with 6-minute walking test, which are both functional tests recommended in the algorithm of the European Working Group on Sarcopenia in Older People to diagnose sarcopenia. Peak inspiratory pressure was correlated with both skeletal muscle index and skeletal muscle density and also with other functional tests. Conclusions: We confirmed the reliability of thoracic computed-tomography-scan to assess sarcopenia and myosteatosis. We found that skeletal muscle index and skeletal muscle density are independent but complementary predictive factors for functional impact at mid-term in intensive care patients. Peak inspiratory pressure could be a useful tool for the assessment and management of sarcopenia.

Osteoarthritis (OA) is a condition that affects the quality of life of millions of patients worldwide. Current clinical treatments, in most cases, lead to cartilage repair with deposition of fibrocartilage tissue, which is mechanically inferior and not as durable as hyaline cartilage tissue. We designed an mRNA delivery strategy to enhance the natural healing potential of autologous bone marrow aspirate concentrate (BMAC) for articular cartilage repair. We used mineral-coated microparticles to deliver TGF-β1 mRNA to autologous BMAC. mRNA-activated BMAC was suspended in peripheral blood to generate therapeutic BMAC clots, which were then implanted in rabbit osteochondral defects. Tracking studies revealed that the clots were reliably maintained in the defects for at least 2 weeks. TGF-β1 mRNA delivery significantly increased TGF-β1 production in BMAC clots and increased early expression of articular chondrocyte markers within osteochondral defects. At 9 weeks post-surgery, the mRNA-treated defects had a superior macroscopic cartilage appearance, decreased type I collagen deposition, increased stain intensity for type II collagen and increased glycosaminoglycan deposition area when compared to the controls. Despite the transient expression of therapeutic mRNA we have detected lasting effects, such as a decrease in fibrocartilage formation demonstrated by the decrease in type I collagen deposition and the improvement in macroscopic appearance in the treatment group.

Abstract Over 700,000 people die by suicide annually. Collecting longitudinal fine-grained data about at-risk individuals, as they occur in the real world, can enhance our understanding of the temporal dynamics of suicide risk, leading to better identification of those in need of immediate intervention. Self-assessment questionnaires were collected over time from 89 at-risk individuals using the EMMA smartphone application. An artificial intelligence (AI) model was trained to assess current level of suicidal ideation (SI), an early indicator of the suicide risk, and to predict its progression in the following days. A key challenge was the unevenly spaced and incomplete nature of the time series data. To address this, the AI was built on a missing value imputation algorithm. The AI successfully distinguished high SI levels from low SI levels both on the current day (AUC = 0.804, F1 = 0.625, MCC = 0.459) and three days in advance (AUC = 0.769, F1 = 0.576, MCC = 0.386). Besides past SI levels, the most significant questions were related to psychological pain, well-being, agitation, emotional tension, and protective factors such as contacts with relatives and leisure activities. This represents a promising step towards early AI-based suicide risk prediction using a smartphone application.

Abstract Background Acne vulgaris is a chronic inflammatory skin condition with a multifactorial pathogenesis. The clinical appearance of acne and its sequelae may differ according to phototypes. Data regarding the potential benefit of dermocosmetics (DC) regardless of phototype are lacking and assessing acne improvement can be difficult, given the lack of visual support in people with skin of colour. A DC regimen, combining a cleanser and a cream, both containing thermal spring water, has been developed for the management of mild‐to‐moderate acne, for all skin phototypes studied. Objectives To assess the efficacy and local tolerance of a DC routine in mild‐to‐moderate acne and to visualize the clinical improvement in all skin phototypes. Methods In an open‐labelled, multicentre clinical study, subjects of any phototype aged above 11 years and above with mild (N = 48, 55.2%) or moderate (N = 39, 44.8%) facial acne applied the DC twice daily for 56 days. No other acne care was allowed. Acne severity, as well as inflammatory and noninflammatory lesion counts, were assessed at baseline, Days 28 and 56. Photographs were taken using a novel imaging tool based on multimodal acquisition, to show clinical improvement over time. Results Eighty‐seven subjects, 41 adults and 46 adolescents, were included; 59.8% were female and were aged between 11 and 44 years. The total acne lesion count decreased by 34%, the noninflammatory lesion count by 28%, and the inflammatory lesion count by 52% at Day 56. All % changes were statistically significant (p

Digital pathology (DP) transforms practice by replacing traditional glass slide review with digital whole slide images and workflows. Although digitization may improve accuracy and efficiency, transitioning to digital practice requires staff to learn new skills and adopt new ways of working and collaborating. In this study, we aimed to evaluate the experiences and perceptions of individuals involved in the day-to-day work of implementing DP in a tertiary academic medical center using Normalization Process Theory, a social theory that explains the processes by which innovations are operationalized and sustained in practice. Between September 2021 and June 2022, dermatopathologists, referring clinicians, and support staff at Mayo Clinic (Minnesota, Florida, and Arizona) participated in interviews (n=22) and completed surveys (n=34) concerning the transition. Normalization Process Theory informed the selection of validated survey items (Normalization Measure Development Questionnaire) and guided qualitative analysis. Participants reported high agreement with statements related to shared understanding and potential value of DP for workflow integration and working relationships. Qualitative themes reflecting the way organization and social context enable these processes were mapped onto implementation stages and related key activities. We found that earlier processes of implementation (understanding and working out participation) were better supported than later stages (doing it and reflecting on it). Our analysis helps identify targets for further intervention to hasten and help sustain implementation, including additional support in software and technological integration, workflows and work redesign, and regular monitoring and feedback systems. The use of implementation theory, such as Normalization Process Theory, may provide useful pointers to enable other similar digital system transition efforts.

Abstract The Bcl2-associated athanogene-3 (BAG3) protein, a critical regulator of cellular survival, has been identified as a potential therapeutic target in various malignancies. This study investigates the role of BAG3 within stromal fibroblasts and its interaction with B-cell chronic lymphocytic leukemia (B-CLL) cells. Previous research demonstrated that BAG3 maintains the active state of pancreatic stellate cells (PSCs) and aids pancreatic ductal adenocarcinoma (PDAC) spread via cytokine release. To explore BAG3’s role in bone marrow-derived stromal fibroblasts, BAG3 was silenced in HS-5 cells using siRNA. In co-culture experiments with PBMCs from B-CLL patients, BAG3 silencing in HS-5 cells increased apoptosis and decreased phosphorylation of BTK, AKT, and ERK in B-CLL cells, thus disrupting their pro-survival key signaling pathways. The observation of fibroblast-activated protein (FAP) positive cells in infiltrated bone marrow specimens co-expressing BAG3 further support the involvement of the protein in fibroblast-mediated tumor survival. Additionally, BAG3 appears to support B-CLL survival by modulating cytokine networks, including IL-10 and CXCL12, which are essential for leukemic cell survival and proliferation. A robust correlation between BAG3 expression and the levels of CXCL12 and IL-10 was observed in both co-cultures and patient specimens. These findings point out the need for a more in-depth comprehension of the intricate network of interactions within the tumor microenvironment and provide valuable insights for the selection of new potential therapeutic targets in the medical treatment of CLL.

The 2020 COVID-19 pandemic caused a huge displacement for people globally. This displacement resulted in a shift in notions of personal reality and affective relationships. Creativity is a sensitive process that is impacted by one’s physical, social, and cultural reality. In this paper, I understand creativity to encompass the process, experience, and feelings associated with the creation of new products and ideas, that are both novel and appropriate to a given situation or time-period (Amabile et al. 2005). This ethnography explores the impact of the pandemic on the creative processes of six Toronto-based artists. I explore the effects of decreased collaboration, decreased social interaction, and greater isolation, on the motivation for art creation, the content of art created and the overall affectual states of the artists. I consider how these changes were linked to the different layers of Hennessey and Amabile (2010)’s structural model of creativity and I posit why artists had different creative outcomes. Preference for alone time when creating art versus creating through collaboration impacted people’s motivation for creativity during COVID-19 and the subsequent amount of art created. Preference for alone time was also linked to the affective results of different artists during the COVID-19 pandemic—those who previously collaborated during their artistic process suffered more than those who mostly created in solitude. The mediums different artists engaged with also impacted motivation and their ability to continue creating.

Abstract piRNAs are crucial for transposon silencing, germ cell maturation, and fertility in male mice. Here, we report on the genetic landscape of piRNA dysfunction in humans and present 39 infertile men carrying biallelic variants in 14 different piRNA pathway genes, including PIWIL1, GTSF1, GPAT2, MAEL, TDRD1, and DDX4. In some affected men, the testicular phenotypes differ from those of the respective knockout mice and range from complete germ cell loss to the production of a few morphologically abnormal sperm. A reduced number of pachytene piRNAs was detected in the testicular tissue of variant carriers, demonstrating impaired piRNA biogenesis. Furthermore, LINE1 expression in spermatogonia links impaired piRNA biogenesis to transposon de-silencing and serves to classify variants as functionally relevant. These results establish the disrupted piRNA pathway as a major cause of human spermatogenic failure and provide insights into transposon silencing in human male germ cells.

Abstract Background The COVID-19 pandemic has demanded crisis management at all governance levels. While most research has focused on responses of national governments, city-level governance had significant potential to develop tailored approaches. This study explored how the local COVID-19 response was organised and adapted to the specific city population and context in the City of Antwerp, Belgium. Methods A case study using semi-structured interviews was set up with 20 key informants with a central role in the coordination and implementation of the city-level COVID-19 response in Antwerp. Thematic analysis of transcripts was guided by an adapted version of the OECD risk management cycle. Results Respondents’ accounts provide a granular understanding of pandemic preparedness, crisis management, and response and adaptation to the COVID-19 crisis in a mid-size European city. Its size was large enough to have a strong capacity within its government bodies, to utilise the expertise of strong partners in the area and to mobilise a critical mass for action, yet small enough to quickly establish connections and trust. In addition to a universal approach, they developed tailored responses to specific neighbourhoods and groups. Well-established community and organisational ties enhanced the effectiveness of grassroots initiatives. The perceived feeling of joint action contributed to a strong collective agency, but respondents noted the need for a system for monitoring and learning. Conclusions Local governments are important to develop tailored strategies and organise a locally relevant crisis response in cities. They need expertise and agency, with enough flexibility to experiment. To harness promising practices and avoid repeating errors in future crises, it is crucial to develop a system that better evaluates and monitors local responses, before, during and after crises.

Background: Noise is omnipresent in the operating room. The average noise in the operating room generally ranges between 60 and 65 dB and can sometimes exceed 100 dB, despite the ARS (Agence Régionale de Santé) and WHO (World Health Organization) recommending levels of 35 dB(A). This study aimed to evaluate the effect of different kinds of background auditory stimuli on the performance of surgeons during an arthroscopic simulation task. Methods: Forty-seven surgeons with varying experience in arthroscopic surgery undertook different exercises under four different conditions: quiet, classical music, hard rock, and sustained chatter. All background auditory stimuli were set at 65 dB(A). Each participant underwent double randomization for the four sound stimuli and the four exercises to be performed. A musical questionnaire was also completed by each participant. Data related to each exercise included operating time in seconds, distance from the camera or instruments in centimeters, and an overall score automatically calculated by the simulator based on safety, economy of movement, and speed (scale: 0–20 points). Results: Operative time in an environment with classical music was significantly lower than in an environment with hard rock (95.9 s vs. 128.7 s, p = 0.0003). The overall rating in an environment with chatter was significantly lower than in a silent environment (11.7 vs. 15.7, p

Crop disease often leads to field epidemics with serious threats to yield. Early symptoms are sometimes difficult to identify, so the origin of primary inoculum is a critical focal point in the study of plant diseases, as it can help design management strategies to reduce crop losses. Here, we investigated whether anthracnose of water yams (Dioscorea alata L.) caused by the species complex Colletotrichum gloeosporioides can start from infected seed tubers from the previous harvest. Over two years, we collected tubers with varying pathogen prevalence in the field directly from producers and conducted fungal isolations in the lab to sample C. gloeosporioides. We also proceeded to artificially inoculate tubers before planting and monitored disease development. Finally, we genotyped isolates from leaves in the fields and assessed fixation indices between plots based on plot ownership (plots with a common seed tuber origin from a single farmer) vs. samples in plots from unrelated producers in Guadeloupe, Martinique, and Barbados. We were unable to isolate the fungus from harvested tubers in either sampling survey nor did any plants grown from inoculated tubers develop any disease symptoms during growth. Also, the genetic structure of samples within each plot was independent of plot ownership, though this occurred with varying levels in the different islands. These results suggest that contaminated planting material from seed tubers is not the primary source of the disease, which is in contrast to the common perception of yam anthracnose prevalence in the Antilles.

Abstract Background Isoprostanes and prostaglandins are biomarkers for oxidative stress and inflammation. Their role in Alzheimer's disease (AD) pathophysiology is yet unknown. In the current study, we aim to identify the association of isoprostanes and prostaglandins with the Amyloid, Tau, Neurodegeneration (ATN) biomarkers (Aβ-42, p-tau, and t-tau) of AD pathophysiology in mild cognitive impairment (MCI) subjects. Methods Targeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LCMS) in 147 paired plasma-CSF samples from the Ace Alzheimer Center Barcelona and 58 CSF samples of MCI patients from the Mannheim/Heidelberg cohort. Linear regression was used to evaluate the association of metabolites with CSF levels of ATN biomarkers in the overall sample and stratified by Aβ-42 pathology and APOE genotype. We further evaluated the role of metabolites in MCI to AD dementia progression. Results Increased CSF levels of PGF2α, 8,12-iso-iPF2α VI, and 5-iPF2α VI were significantly associated (False discovery rate (FDR)

This study examined how employees experience humanness in organizations related to leadership behavior. More specifically, it was aimed to define what experienced humanness is from the perspective of employees, and which leadership behaviors employees perceive to contribute to these experiences of organizational humanness. To fulfill this aim, an exploratory grounded theory study was conducted, in which 13 employees were interviewed until saturation was attained, investigating their experiences in organizations that relate to humanness and examples of leadership behavior that influence it. Three overarching categories of experienced humanness were identified in organizations i.e., bounded space, attentive care, and human connection. Furthermore, eight specific sets of leadership behaviors appear to contribute to the experience of humanness. The findings were compared to the scientific literature and led to the conclusion that the findings yield unique elements, (e.g., fostering human connection within a team) that have not been covered in previous conceptualizations.

Abstract Reading requires the transformation of a complex array of visual features into sounds and meaning. For deaf signers who experience changes in visual attention and have little or no access to the sounds of the language they read, understanding the visual constraints underlying reading is crucial. This study aims to explore a fundamental aspect of visual perception intertwined with reading: the crowding effect. This effect manifests as the struggle to distinguish a target letter when surrounded by flanker letters. Through a two-alternative forced choice task, we assessed the recognition of letters and symbols presented in isolation or flanked by two or four characters, positioned either to the left or right of fixation. Our findings reveal that while deaf individuals exhibit higher accuracy in processing letters compared to symbols, their performance falls short of that of their hearing counterparts. Interestingly, despite their proficiency with letters, deaf individuals didn’t demonstrate quicker letter identification, particularly in the most challenging scenario where letters were flanked by four characters. These outcomes imply the development of a specialized letter processing system among deaf individuals, albeit one that may subtly diverge from that of their hearing counterparts.

Abstract Background Post-intensive care syndrome (PICS), defined as physical, cognitive, and mental-health symptoms persisting long after intensive-care-unit (ICU) discharge, is increasingly recognised as a healthcare priority. Data on screening for PICS are sparse. Our objective here was to describe post-ICU screening in France, with special attention to visit availability and evaluations done during visits. Methods We conducted an online multicentre survey by emailing an anonymous 43-item questionnaire to French ICUs. For each ICU, a single survey was sent to either the head or the intensivist in charge of follow-up visits. Results Of 252 ICUs invited to participate, 161 (63.9%) returned the completed survey. Among them, 46 (28.6%) offered follow-up visits. Usually, a single visit led by an intensivist was scheduled 3 to 6 months after ICU discharge. Approximately 50 patients/year/ICU, that is, about 5% of admitted patients, attended post-ICU visits. The main criteria used to select patients for follow-up were ICU stay and/or invasive mechanical ventilation duration longer than 48 h, cardiac arrest, septic shock, and acute respiratory distress syndrome. Among ICUs offering visits, 80% used validated instruments to screen for PICS. Of the 115 ICUs not offering follow-up, 50 (43.5%) indicated an intention to start follow-up within the next year. The main barriers to offering follow-up were lack of available staff and equipment or not viewing PICS screening as a priority. Half the ICUs offering visits worked with an established network of post-ICU care professionals, and another 17% were setting up such a network. Obstacles to network creation were lack of interest among healthcare professionals and lack of specific training in PICS. Conclusion Only a small minority of ICU survivors received follow-up designed to detect PICS. Less than a third of ICUs offered follow-up visits but nearly another third planned to set up such visits within the next year. Recommendations issued by French health authorities in 2023 can be expected to improve the availability and standardisation of post-ICU follow-up.

Abstract Background Since late 2019, fortification of ‘regular’ cannabis plant material with synthetic cannabinoid receptor agonists (SCRAs) has become a notable phenomenon on the drug market. As many SCRAs pose a higher health risk than genuine cannabis, recognizing SCRA-adulterated cannabis is important from a harm reduction perspective. However, this is not always an easy task as adulterated cannabis may only be distinguished from genuine cannabis by dedicated, often expensive and time-consuming analytical techniques. In addition, the dynamic nature of the SCRA market renders identification of fortified samples a challenging task. Therefore, we established and applied an in vitro cannabinoid receptor 1 (CB1) activity-based procedure to screen plant material for the presence of SCRAs. Methods The assay principle relies on the functional complementation of a split-nanoluciferase following recruitment of β-arrestin 2 to activated CB1. A straightforward sample preparation, encompassing methanolic extraction and dilution, was optimized for plant matrices, including cannabis, spiked with 5 µg/mg of the SCRA CP55,940. Results The bioassay successfully detected all samples of a set (n = 24) of analytically confirmed authentic Spice products, additionally providing relevant information on the ‘strength’ of a preparation and whether different samples may have originated from separate batches or possibly the same production batch. Finally, the methodology was applied to assess the occurrence of SCRA adulteration in a large set (n = 252) of herbal materials collected at an international dance festival. This did not reveal any positives, i.e. there were no samples that yielded a relevant CB1 activation. Conclusion In summary, we established SCRA screening of herbal materials as a new application for the activity-based CB1 bioassay. The simplicity of the sample preparation, the rapid results and the universal character of the bioassay render it an effective and future-proof tool for evaluating herbal materials for the presence of SCRAs, which is relevant in the context of harm reduction.

Abstract Seaweed farming is widely promoted as an approach to mitigating climate change despite limited data on carbon removal pathways and uncertainty around benefits and risks at operational scales. We explored the feasibility of climate change mitigation from seaweed farming by constructing five scenarios spanning a range of industry development in coastal British Columbia, Canada, a temperate region identified as highly suitable for seaweed farming. Depending on growth rates and the fate of farmed seaweed, our scenarios sequestered or avoided between 0.20 and 8.2 Tg CO2e year−1, equivalent to 0.3% and 13% of annual greenhouse gas emissions in BC, respectively. Realisation of climate benefits required seaweed-based products to replace existing, more emissions-intensive products, as marine sequestration was relatively inefficient. Such products were also key to reducing the monetary cost of climate benefits, with product values exceeding production costs in only one of the scenarios we examined. However, model estimates have large uncertainties dominated by seaweed production and emissions avoided, making these key priorities for future research. Our results show that seaweed farming could make an economically feasible contribute to Canada’s climate goals if markets for value-added seaweed based products are developed. Moreover, our model demonstrates the possibility for farmers, regulators, and researchers to accurately quantify the climate benefits of seaweed farming in their regional contexts.

Abstract Background Previous studies have produced conflicting results concerning the extent of magnitude representation deficit and its relationship with arithmetic achievement in children with 22q11.2 deletion syndrome. More specifically, it remains unclear whether deficits are restricted to visuospatial content or are more general and whether they could explain arithmetical impairment. Methods Fifteen 5- to 12-year-old children with 22q11.2 deletion syndrome and 23 age-matched healthy controls performed a non-symbolic magnitude comparison task. Depending on the trial, participants had to compare stimuli with high or low visuospatial load (visuospatial stimuli or temporal sequence of visual stimuli). The participants also completed a battery of arithmetic skills (ZAREKI-R) and a battery of global cognitive functioning (WISC-V or WPPSI-IV), from which working memory and visuospatial indices were derived. Results Children with 22q11.2DS responded as fast as healthy controls did but received fewer correct responses, irrespective of visuospatial load. In addition, their performance in the non-symbolic magnitude comparison task did not correlate with the ZAREKI total score, while the working memory index did. Conclusion Children with 22q11.2DS might suffer from a global magnitude representation deficit rather than a specific deficit due to visuospatial load. However, this deficit alone does not seem to be related to arithmetic achievement. Working memory might be a better concern of interest in favoring arithmetic skills in patients with 22q11.2 deletion syndrome. Trial registration Clinicaltrials, NCT04373226 . Registered 16 September 2020.

OBJECTIVES: Etiological factors of testicular germ cell tumors (TGCT) remain largely unknown, but a causal role of occupational exposures to solvents has been suggested. Previous studies analyzing these exposures reported discordant results, potentially related to exposure assessment methods. The aim of this study was to investigate the role of occupational exposure to solvents on the risk of developing TGCT among young men. METHODS: This study examined occupational exposures to solvents and TGCT risk based on the lifetime work histories of 454 cases and 670 controls, aged 18–45 years, of the French national TESTIS case–control study. Solvent exposure was estimated using: (i) exposure assignment by job-exposure matrix (JEM) and (ii) JEM combined with self-reported exposure data from specific questionnaires (SQ) and expert assessment (EA). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression models. RESULTS: Both approaches (JEM and JEM+SQ+EA) showed a consistent association between TGCT and trichloroethylene exposure (exposed versus not exposed; JEM=OR 1.80 [95% confidence interval (CI) 1.12–2.90] and JEM+SQ+EA= OR 2.59 (95% CI 1.42–4.72). Both approaches also observed positive associations with ketone esters and fuels & petroleum-based solvents. CONCLUSION: The results suggest that some organic solvents might be involved in the pathogenesis of TGCT among occupationally exposed men. The combined use of JEM+SQ+EA seemed to limit misclassification by considering individual exposure variability and is, therefore, an appealing approach to assess occupational exposures in epidemiological studies.

Cet article propose une analyse des Notes d’une voyageuse en Turquie (1910) de Marcelle Tinayre afin de montrer comment ce récit de voyage participe au discours féministe français du début du vingtième siècle. En mettant en valeur les capacités des Françaises, favorisées par les privilèges de l’impérialisme, Tinayre souligne ce dont elles sont capables. Grâce à ce récit de voyage, Tinayre acquiert aussi une plus grande légitimité dans sa carrière de femme de lettres.

While cities are attractive places, brimming with opportunities and possibilities for their inhabitants, they have also been found to have negative consequences, especially on physical and mental health. In a world of ever-growing urban populations, it is important to understand how to make cities healthier and more pleasant places to live. In the present study, we investigated the impact of art as an urban intervention and compared it to the well-known effects of greenery (i.e., plants and vegetation) in an identically framed intervention. Specifically, we looked at how people engage with a Graetzloase (a type of parklet) and its embedding urban environment in terms of visual and spatial attraction as well as wellbeing. The Graetzloase displayed either abstract art or greenery and was placed on two distinct streets that, among other elements, also contained art and greenery. Our field study captured the ongoing experiences during people’s exploration of the urban environment by employing mobile eye-trackers and physiological devices. While our findings demonstrated a certain level of visual and spatial attraction towards the Graetzloases, it was not as pronounced as initially anticipated. Nevertheless, our analyses still inform on What decorating element should be placed in a Graetzloase, as well as Where to implement the Graetzloase. Our results suggest that artistic elements are more visually attractive (i.e., they were looked at for longer times) than the greenery, and that both visual and spatial attraction towards the Graetzloases are greatly impacted by the street context. We found that the Art Graetzloase when displayed in a wide street containing greenery elements, is visually more present in the participant’s visual field than all the other experimental combinations. The more precise analyses of the participant viewing behavior confirm this trend. Regarding wellbeing, we found no evidence for the impact of street context or the types of decorations in the Graetzloases. Our results establish an initial empirical foundation for the design and placement of not only future parklets but also urban art interventions in general.

Wie sähe die (Literatur-)Geschichte des Surrealismus und der historischen Avantgarden insgesamt aus, schriebe man diese konsequent aus einer Genderperspektive? Dies ist die Frage, die die vorliegenden Überlegungen motiviert. In ihnen wird der Surrealismus der Jahre 1924/1925 in den Blick genommen, in denen Breton mit der Publikation des ersten Manifeste du surréalisme (1924) seine Version des Begriffs Surrealismus gegen konkurrierende Akteure durchsetzt und im kulturellen Feld seiner Zeit positioniert. In der bisherigen Forschung zur Selbstpositionierung des Surrealismus in den Gründungsjahren wurde die Funktion ‚weiblicher‘ Vor- und Feindbilder zumeist nur am Rande behandelt oder ins Anekdotische abgedrängt. Demgegenüber soll hier am Beispiel dreier politisch und/oder künstlerisch aktiver Frauen – der Anarchistin Germaine Berton sowie der Schriftstellerinnen Aurel und Rachilde – gezeigt werden, wie sich die zunächst noch vage Bewegung durch die symbolische Aneignung oder Delegitimierung der politischen und kulturellen Leistungen von Aktivistinnen und Künstlerinnen ihre spezifischen Konturen als Surrealismus verlieh.

Summary: Here, we provide a protocol for the identification of E3 ubiquitin ligases that are functional when implemented as biodegraders using a cell-based screening assay. We describe steps for establishing a stable cell line expressing a GFP-tagged protein of interest (POI), preparing a sub-library of E3 ligases to screen, and performing the cell-based screening. This protocol can be broadly applied to identify any functional E3 ligase in a biodegrader setting.For complete details on the use and execution of this protocol, please refer to Cornebois et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

We investigated the role of ChiA and its associated polymorphisms in the interaction between Crohn’s disease (CD)-associated adherent-invasive Escherichia coli (AIEC) and intestinal mucosa. We observed a higher abundance of chiA among the metagenome of CD patients compared to healthy subjects. In dextran sulfate sodium-induced colitis mice model, AIEC-LF82∆chiA colonization was reduced in ileal, colonic and fecal samples compared to wild-type LF82. The binding of ChiA to recombinant human CHI3L1 or mucus was higher with the pathogenic polymorphism. The strength of ChiA-mucin interaction was 300-fold stronger than ChiA-rhCHI3L1. ChiA was able to degrade mucin to promote its growth and enabled LF82 to get closer to epithelial cells. The pathogenic polymorphism of ChiA had a stronger impact on mucus degradation than on the binding capability of AIEC to adhere to the intestinal epithelium. We observed that ChiA could favor an efficient bacterial invasion of intestinal crypts, and that ChiA, especially its pathogenic polymorphism, gives LF82 an advantage to uptake within Peyer’s patches, macrophages and mesenteric lymph nodes. All together, these data support the role of ChiA in the virulence of AIEC and show that it could be a promising target to reduce AIEC colonization in patients with CD.

ABSTRACT: Background: Traumatic thoracolumbar fracture fixation without neurological injury can be performed using the traditional open, mini-open Wiltse, and percutaneous approaches. This systematic review and meta-analysis aims to compare perioperative outcomes between these approaches. Methods: PubMed, Web of Science, Scopus, Embase, and the Cochrane Library were searched for all relevant observational comparative studies. Results: 5 randomized trials and 22 comparative cohort studies were included. Compared to the traditional open approach (n=959), the Wiltse approach (n=410) was associated with significantly lower operative time, intraoperative estimated blood loss (EBL), and length of stay (LOS). There was no significant difference between the two in terms of postoperative visual analog scale (VAS) and Cobb angle. Compared to the percutaneous approach (n=980), the Wiltse approach was associated with shorter operative and fluoroscopy time, as well as significantly improved Cobb and vertebral body angles. The percutaneous approach was associated with improved vertebral body height. There was no significant difference between the two for blood loss, postoperative VAS, or LOS. Compared to the traditional open approach, the percutaneous approach was associated with shorter operative time, lower EBL, shorter LOS and better postoperative VAS and Oswestry Disability Index. There was no difference between the two in postoperative Cobb angle, vertebral angle, or vertebral body height. Overall study heterogeneity was high. Conclusions: Utilization of minimally invasive surgical approaches holds great promise for lowering patient morbidity and optimizing care. A prospective trial is needed to assess outcomes and guide surgical decision making.

Promoting urban well-being is a significant societal task in the context of rapid urbanization. Past research has highlighted that interaction with urban green spaces, such as parks and forests, is key in promoting urban well-being. However, there is limited knowledge regarding the potential in promoting well-being from non-nature elements. In the present study, we explored whether interacting with art could enhance well-being in urban street contexts. In our field experiment, we built two interventions on urban streets, decorating them with either laminated art prints or green elements. We measured subjective and physiological well-being before and after the interaction with the interventions. With this paradigm, we assessed if, not only green, but also artistic interventions can improve well-being. Our results showed that, after interacting with the artistic intervention in an urban environment, the participants reported reduced feelings of anxiety, stress, and negative mood as they did with the green intervention. Further, our results indicate that improvements in well-being were linked to participants’ evaluations of the testing location (restorativeness), of aesthetic quality of the intervention (e.g., beauty, meaningfulness), and of their overall experience (e.g., enjoyment). These findings have significant implications in promoting urban well-being and city planning, as they highlight the potential of art as a novel tool for enhancing urban well-being.

ABSTRACTVaccination coverage against hepatitis A virus (HAV), hepatitis B virus (HBV), and human papillomaviruses (HPV) is insufficient among men who have sex with men (MSM), partly because of their high prevalence of vaccine hesitancy (VH) specific to these vaccines. This study aimed to investigate determinants of specific VH in MSM, focusing on characteristics of their sexual activity, propensity to use prevention tools and medical care, disclosure of sexual orientation to health care professionals (HCPs), and perceived stigmatization. A cross-sectional electronic survey (February – August 2022) collected perceptions of HBV, HAV, and HPV, and of their respective vaccines among 3,730 French MSM and enabled the construction of a specific VH variable. Using agglomerative hierarchical cluster analysis, we constructed a typology of MSM sexual and prevention practices. We identified three MSM clusters (low- (C1, 24%), moderate- (C2, 41%), and high- (C3, 35%) “sexual activity/medical engagement”) that showed an increasing gradient in the use of medical prevention with regular medical care and exposure to high-risk sexual practices. A multiple ordinal logistic regression showed that overall specific VH was higher in the C1 cluster and in men who had not informed their physician of their sexual orientation. This typology could usefully help to adapt vaccination communication strategies for MSM prevention program according to patients’ profiles. HCPs should be encouraged and trained to ask men about their sexual practices and to provide appropriate vaccination recommendations nonjudgmentally.

ABSTRACTGovernments and intergovernmental organizations support scientific research to produce the knowledge and tools needed to monitor and mitigate global environmental changes (GEC). However, GEC-related policy decisions are often not based on scientific evidence, and GEC research is often not based on policy-relevant questions, resulting in a science-policy gap. Assessing the GEC policy priorities of researchers and policymakers is an essential step towards closing this gap. This task was undertaken by the Inter-American Institute for Global Change Research (IAI), an intergovernmental organization pursuing science and capacity building to reach the vision of a sustainable Americas. The assessment included survey consultations, listening sessions, and an analysis of policy documents for 17 countries of the Americas. Three key findings emerged from this assessment. First, the top current priority for policymakers was Climate action, and Biodiversity and ecosystem services for researchers, with a poor alignment between the priorities of these social actors at the country level. Second, clusters of non-neighboring countries had a profile of GEC priorities more similar than clusters of neighboring countries, although there were some sub-regional clusters around particular GEC goals. Third, researchers and policymakers agreed that the lack of cross-sectoral collaboration and communication between technical and non-technical actors are important barriers. A key opportunity for policymakers was the growing funding and international cooperation for GEC, while for researchers, the growing body of evidence to inform GEC decision-making. These findings have implications for the design of research and capacity-building actions targeted to the priorities and needs of the region.

For diversity to exist in the medical graduate workforce, students from all backgrounds should have equitable opportunities of employment. Specialties have utilized a minimal threshold for USMLE Step 1 score when screening applicants for residency interviews. The OHSU SOM class of 2021 completed a 14-question voluntary survey on their Step 1 score and the following non-modifiable risk factors: Adverse Childhood Experience score (ACEs), sex, gender, Underrepresented in Medicine status (URiM), family income during adolescence, highest degree held by a guardian, discrimination experience during medical school, federal/state assistance use, and rural versus urban primary home. Descriptive statistics and unadjusted risk ratios were applied to study the relation between Step 1 score and non-modifiable risk factors as well as certain non-modifiable risk factors and ACEs ≥ 3. The mean Step 1 score was 230 (213, 247). Of the students, 28.2% identified ACEs ≥ 3, 13.6% were considered URiM, and 65.4% were female. URiM were 2.34 (1.30, 4.23), females were 2.77 (1.06–7.29), and those who experienced discrimination in medical school were 4.25 (1.85, 9.77) times more likely to have ACEs ≥ 3. Students who had ACEs ≥ 3 were 3.58 (1.75, 7.29) times less likely to meet a minimal threshold for residency interviews of 220. These are the first results to demonstrate a relationship between Step 1 score and ACEs. Those who identified as URiM, females, and those who experienced discrimination in medical school were at a higher risk of ACEs of ≥ 3. Step 1 transitioned to pass/fail in January 2022. However, the first application cycle that residencies will see pass/fail scoring is 2023–2024, and fellowships will continue to see scored Step 1 until, at the earliest, the 2026–2027 application cycle. These data contribute to a foundation of research that could apply to Step 2CK testing scores, and help to inform decisions about the diversity and equity of the residency interview process.

Despite the progress of anti-cancer treatment, the prognosis of many patients with solid tumors is still dismal. Reliable noninvasive biomarkers are needed to predict patient survival and therapy response. Here, we propose a Humoral Complementomics approach: a work-up of assays to comprehensively evaluate complement proteins, activation fragments, and autoantibodies targeting complement proteins in plasma, which we correlated with the intratumoral complement activation, and/or local production, focusing on localized and metastatic clear cell renal cell carcinoma (ccRCC). In two prospective ccRCC cohorts, plasma C2, C5, Factor D and properdin were elevated compared to healthy controls, reflecting an inflammatory phenotype that correlated with plasma calprotectin levels but did not associate with CRP or with patient prognosis. Conversely, autoantibodies against the complement C3 and the reduced form of FH (a tumor neo-epitope reported in lung cancer) correlated with a favorable outcome. Our findings pointed to a specific group of patients with elevated plasma C4d and C1s-C1INH complexes, indicating the initiation of the classical pathway, along with elevated Ba and Bb, indicating alternative pathway activation. Boostrapped Lasso regularized Cox regression revealed that the most predictive complement biomarkers were elevated plasma C4d and Bb levels at the time of surgery, which correlated with poor prognosis. In conclusion, we propose Humoral Complementomics as an unbiased approach to study the global state of the complement system in any pathological plasma sample and disease context. Its implementation for ccRCC revealed that elevated C4d and Bb in plasma are promising prognostic biomarkers, correlating with shorter progression-free survival.

Background The zoonotic infection caused by tapeworms Echinococcus is a neglected tropical disease in poor regions with limited access to suitable sanitary conditions. Hydatid cysts produced by Echinococcus granulosus use fatty-acid-binding proteins (FABP) to obtain the fatty acids and cholesterol necessary for their survival from the host. In this work, we analyzed the behaviour of saturated, monounsaturated, and polyunsaturated fatty acids against EgFABP1. Methods We used computational biology and chemistry techniques and binding free energy estimations by molecular mechanics generalized Born surface area (MM/GBSA). Results This research has enabled us to clarify the EgFABP1 isoforms identified in the database, suggesting their potential involvement in diverse cellular activities of Echinococcus granulosus. Conversely, examining the global and local chemical reactivity of 14 fatty acids revealed that liposolubility is contingent upon the degree of unsaturation in the FAs. Additionally, FAs exhibited acceptable levels of oral absorption and bioavailability. The binding of EgFABP1 with FAs analyzed by molecular dynamics simulation showed us that these are highly stable, where the best affinity was with docosahexaenoic acid. Conclusions Our results suggest that the action of fatty acids could play an interesting role in detecting early Echinococcus granulosus.

Background Although the COVID-19 pandemic has diminished in intensity, the virus continues to circulate globally. The SARS-CoV-2 main protease (Mpro) is a key enzyme in the life cycle of the virus, making it important for the development of treatments against future variants of the virus. In this work, Peruvian natural compounds were evaluated against different mutations of the SARS-CoV-2 Mpro. Methods In silico techniques such as virtual screening, all-atom molecular dynamics simulations, and energy estimation analysis were applied. Results Of the tested compounds by virtual screening, rutin was identified as the best binding agent against the different proposed Mpro mutations. In addition, computational simulations and energy estimation analysis demonstrated the high structural and energetic stability between the Mpro-rutin systems. Conclusions Overall, our study identified rutin as the most promising compound with a strong affinity for various Mpro mutations, potentially playing a key role in the development of new treatments for emerging viral variants.

The mechanisms of initiation of spreading depolarization (SD) are understudied due to a paucity of disease models with spontaneously occurring events. We here present a novel mouse model of familial hemiplegic migraine type 2 (FHM2), expressing the missense T345A-mutated α2 subunit of the Na+/K+ adenosine triphosphatase pump (Atp1a2T345A). Homozygous Atp1a2T345A mice showed regular spontaneous SDs that exhibit a diurnal rhythm and typically originate from the hippocampus. Heterozygous Atp1a2T345A mice rarely exhibited spontaneous SDs and, for electrically induced SDs, only showed an increased propagation speed, whereas homozygotes showed both increased propagation and decreased threshold. Remarkably, despite hippocampal hyperexcitability, spontaneous SDs in Atp1a2T345A mice were only rarely associated with epileptic behavior, and seizure expression during kindling was decreased. Spontaneous SDs could be prevented by modulation of persistent sodium currents. Hippocampal SDs occurred in the presence of an NMDA-receptor antagonist, but these events did not reach the cortex, suggesting that initiation and propagation of SD depend on different mechanisms in this model.