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Background: The phase III KEYNOTE-913 study was conducted to evaluate the efficacy and safety of pembrolizumab as first-line therapy in patients with advanced Merkel cell carcinoma (MCC). Objective: The aim was to report results from the primary analysis of KEYNOTE-913. Patients and Methods: Patients with recurrent locally advanced or metastatic MCC received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 treatments (~ 2 years). The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary end points were duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 by BICR, overall survival (OS), and safety and tolerability. Results: Fifty-five patients were treated with pembrolizumab. The median time from first dose to data cutoff (February 15, 2024) was 50.3 months (range 38.7–59.4). The ORR was 49% (95% confidence interval [CI] 35–63), with 12 complete responses and 15 partial responses. The median DOR was 39.8 months (range 4.8–52.5+), and the 24-month DOR rate was 69%. The median PFS was 9.3 months (95% CI 3–26), and the 24-month PFS rate was 39%. The median OS was 24.3 months (95% CI 12.4 to not reached), and the 24-month OS rate was 51%. Any-grade treatment-related adverse events (AEs) occurred in 38 patients (69%); 13 patients (24%) experienced grade 3–5 AEs. The most common treatment-related AEs were fatigue (n = 12 [22%]), pruritus (n = 12 [22%]), and lipase increase (n = 10 [18%]). One patient died of treatment-related Guillain-Barré syndrome. Conclusions: Pembrolizumab provided durable antitumor activity and promising survival and had a manageable safety profile in patients with recurrent locally advanced or metastatic MCC, supporting its use in this population. Trial Registration: Clinicaltrials.gov, NCT03783078. [ABSTRACT FROM AUTHOR]

The quest for efficient green hydrogen production through Alkaline Water Electrolysis (AWE) is a critical aspect of the clean energy transition. The hydrogen evolution reaction (HER) in alkaline media is central to this process, with the performance of electrocatalysts being a determining factor for overall efficiency. Theoretical studies using energy-based descriptors are essential for designing high-performance alkaline HER electrocatalysts. This review summarizes various descriptors, including water adsorption energy, water dissociation barrier, and Gibbs free energy changes of hydrogen and hydroxyl adsorption. Examples of how to apply these descriptors to identify the active site of materials and better design high-performance alkaline HER electrocatalysts are provided, highlighting the previously underappreciated role of hydroxyl adsorption-free energy changes. As research progresses, integrating these descriptors with experimental data will be paramount in advancing AWE technology for sustainable hydrogen production. [ABSTRACT FROM AUTHOR]

The Goodwin–Keen model was introduced to study the structural instability of debt-financed economies. Despite its theoretical appeal, no empirical study has focused on this model to date. Using u.s. data for non-financial firms over the period 1959–2019, this paper tests the empirical validity of a Goodwin–Keen model accounting for dividends. We propose a two-step procedure to simultaneously estimate parameters and quantify their uncertainty. The model satisfactorily captures the historical cycles in the wage share and employment rate, while reflecting the trend growth in the debt-to-output ratio. The estimation provides meaningful parameters, although their large uncertainty suggests that the model fails to fully account for the private debt dynamics. The estimated model assigns a probability of at most 11% to the occurrence of a private-debt overhang over the 21st century. However, it would have failed to foretell the Global Financial Crisis. Further work is therefore needed to improve its prospective capacity. • A new estimation strategy is used to estimate the parameters of a Goodwin–Keen model for the United-States (1959-2019). • The model captures the historical wage-share, employment rate and corporate debt-to-output ratio trajectories. • The model's behavior is discussed based on prospective simulations and a backtesting over the 2008 crisis period. [ABSTRACT FROM AUTHOR]

This work focuses on the analysis of the mean longitudinal magnetic field as a stellar activity tracer in the context of small exoplanet detection and characterization in radial-velocity (RV) surveys. We use Solar Dynamics Observatory/Helioseismic and Magnetic Imager filtergrams to derive Sun-as-a-star magnetic field measurements, and show that the mean longitudinal magnetic field is an excellent rotational period detector and a useful tracer of the solar magnetic cycle. To put these results into context, we compare the mean longitudinal magnetic field to three common activity proxies derived from HARPS-N Sun-as-a-star data: the full width at half-maximum, the bisector span, and the S-index. The mean longitudinal magnetic field does not correlate with the RVs and therefore cannot be used as a one-to-one proxy. However, with high cadence and a long baseline, the mean longitudinal magnetic field outperforms all other considered proxies as a solar rotational period detector, and can be used to inform our understanding of the physical processes happening on the surface of the Sun. We also test the mean longitudinal magnetic field as a 'stellar proxy' on a reduced solar data set to simulate stellar-like observational sampling. With a Gaussian Process regression analysis, we confirm that the solar mean longitudinal magnetic field is the most effective of the considered indicators, and is the most efficient rotational period indicator over different levels of stellar activity. This work highlights the need for polarimetric time series observations of stars. [ABSTRACT FROM AUTHOR]

Background: Resource scarcity in health professions education (HPE) demands rigorous consideration of costs. Yet, thus far, we have been unable to completely and consistently identify the costs of HPE. To address this knowledge gap and enable use of economic evidence in decision making, a detailed overview of all existing costs and approaches to cost identification in HPE is needed. Objectives: This review summarises the diversity of costs, cost perspectives and cost identification methods used in economic research of HPE to answer the following questions: which educational topics, costs, cost perspectives and cost identification methods are being investigated in HPE literature? Methods: This investigation followed the Joanna Briggs Institute guidelines for scoping reviews. PubMed, ERIC, CINAHL and PsycINFO were iteratively searched for English language publications between 2012 and 2022 that reported costs of HPE. Data was extracted for study characteristics, educational context and economic methodology. Results: A total of 136 articles of original research on the costs of educating all major licence healthcare professionals were included. A diffuse interest in costs is reflected in publications from 93 distinct journals and by the diversity of educational topics and cost types explored. However, the majority of investigations failed to define the cost perspective (86, 63%) and cost identification methods (117, 86%) and did not demonstrate common reporting structure or cost terminology, all of which contribute to persistent inconsistencies in cost identification. Conclusion: The source of disharmonious cost identification in HPE is fuelled by diverse interests and divergent concepts of costs and costing methodology. Left in its current state, disharmonious cost identification will continue to limit transparency, comparison and synthesis of evidence, hamper objectivity in implementation and policy decisions and impede the efficient and sustainable allocation of resources. A research agenda must be developed, prioritised, and validated by the broader community to develop a theoretical framework for HPE cost research, define stakeholders, elicit values and preferences and chart a path toward harmonised costing. To enable better use of economic evidence in health professional education decision‐making, a detailed overview of all existing costs and approaches to cost identification in health professional education is provided [ABSTRACT FROM AUTHOR]

Representatives of Schizomida, known as short-tailed whip scorpions, are an understudied group within Megoperculata. They are found subterraneanly in tropical and sub-tropical regions. They lack eyes, have superior mobility, and possess a flagellum which is relevant to their mating, but in general little is known about their general biology. Fossil representatives of Schizomida from a variety of time periods are available for study. Using 23 fossil specimens (14 of which are described here for the first time) and 86 extant individuals from the literature, changes in both body size and flagella shape in Schizomida were compared over time. Measurements of prosoma length and leg length were used as a proxy for body size, and a comparative size analysis was carried out. Individuals from the Cretaceous period were found to be significantly smaller than extant individuals, contrary to our expectations. For flagellum shape, images were used to create reconstructions, which were then analysed using an elliptic Fourier analysis followed by a principal component analysis. The morphological diversity of the male flagellum shape was found to have decreased between the Cretaceous and modern fauna. We discuss potential explanations for our findings, although a greater understanding of the general biology of Schizomida is required to properly interpret our results. [ABSTRACT FROM AUTHOR]

Background: Although regular health screening is recommended, long‐term follow‐up data in healthy aged cats are lacking. Objectives: Determine the most common conditions in a large group of apparently healthy older cats and which diseases are manifested within 2 years in cats confirmed to be healthy based on extensive health screening. Animals: Client‐owned cats. Methods: Prospective study. Thorough history, physical examination, blood tests, and urinalysis were performed in 259 apparently healthy mature adult (7‐10 years) and senior (>10 years) cats. Semi‐annual follow‐up examinations were performed in 201 confirmed healthy cats. Results: At baseline, 21% of apparently healthy cats were not considered healthy but were diagnosed with International Renal Interest Society (IRIS) ≥ stage 2 chronic kidney disease (CKD; 7.7%) or hyperthyroidism (4.6%), among other disorders. Disease occurred significantly more frequently in senior cats compared with mature adult cats. In addition, 40% cats were overweight, 35% had moderate to severe dental disease, and 22% had abnormal cardiac auscultation findings. Within 2 years, 28% of mature adult and 54% of senior cats that were confirmed healthy at inclusion developed new diseases, most commonly IRIS ≥ stage 2 CKD (cumulative incidence, 13.4%), hyperthyroidism (8.5%), chronic enteropathy, hepatopathy or pancreatitis (7.5%), or neoplasia (7%). Conclusions and Clinical Importance: The high prevalence and 2‐year incidence of physical examination abnormalities and systemic diseases in apparently healthy older cats argue for regular health screening in cats ≥7 years of age. Although more common in senior cats, occult disease also occurs in mature adult cats, and owners should be informed accordingly. [ABSTRACT FROM AUTHOR]

Representatives of Schizomida, known as short-tailed whip scorpions, are an understudied group within Megoperculata. They are found subterraneanly in tropical and sub-tropical regions. They lack eyes, have superior mobility, and possess a flagellum which is relevant to their mating, but in general little is known about their general biology. Fossil representatives of Schizomida from a variety of time periods are available for study. Using 23 fossil specimens (14 of which are described here for the first time) and 86 extant individuals from the literature, changes in both body size and flagella shape in Schizomida were compared over time. Measurements of prosoma length and leg length were used as a proxy for body size, and a comparative size analysis was carried out. Individuals from the Cretaceous period were found to be significantly smaller than extant individuals, contrary to our expectations. For flagellum shape, images were used to create reconstructions, which were then analysed using an elliptic Fourier analysis followed by a principal component analysis. The morphological diversity of the male flagellum shape was found to have decreased significantly between the Cretaceous and modern fauna. We discuss potential explanations for our findings, although a greater understanding of the general biology of Schizomida is required to properly interpret our results. [ABSTRACT FROM AUTHOR]

Summary: The understanding of tree growth processes is crucial for promoting sustainable forest management strategies. This is a challenging task in highly biodiverse ecosystems where many tree species are observed on very few individuals and the small sample sizes hinder a good fit of species‐specific models. We propose the use of finite mixture of random coefficient regression models with multilevel nested random effects to infer guild specific fixed and random effects while evaluating the relative importance of the nested sources of variability on goodness‐of‐fit. This approach extends finite mixture of linear mixed model used for longitudinal or single group structured data contexts. A dedicated expectation–maximisation algorithm is introduced for parameter estimation. Simulations are performed for the evaluation of the misspecification of nested‐grouping structures. This work has been motivated by data collected biennially in Central African rainforests from 1986 to 2010. We show the accuracy of the proposed approach in successfully reproducing individual growth processes and classifying tree species into well‐differentiated clusters with clear ecological interpretations. Moreover, results confirm that interindividual variability appears as the most important factor to explain tropical tree species growth process variability from Central Africa forests. [ABSTRACT FROM AUTHOR]

Polyploidy, resulting from whole‐genome duplication (WGD), is ubiquitous in nature and reportedly associated with extreme environments and biological invasions. However, WGD usually comes with great costs, raising questions about the establishment chance of newly formed polyploids. The surprisingly high number of polyploid and mixed‐ploidy species observed in nature may be a consequence of their continuous emergence or may reflect stable polyploid persistence and even coexistence with the ancestral ploidy under certain circumstances. However, empirical studies on contemporary polyploid establishment often neglect the cost–benefit balances of polyploid characteristics, tradeoffs between phenotypic characteristics, intercytotype interactions, recurrent polyploid formation, and stochastic processes. Here, we advocate for considering population‐level success, combining the aforementioned factors that affect polyploid establishment and long‐term coexistence with their ancestors. We approach the paradox of polyploid establishment despite high costs from a modern coexistence theory perspective and give an overview of the diversity of mechanisms and their timing that may potentially enable stable rather than transient persistence. [ABSTRACT FROM AUTHOR]

Over the past few years, the scale of sensor networks has greatly expanded. This generates extended spatiotemporal datasets, which form a crucial information resource in numerous fields, ranging from sports and healthcare to environmental science and surveillance. Unfortunately, these datasets often contain missing values due to systematic or inadvertent sensor misoperation. This incompleteness hampers the subsequent data analysis, yet addressing these missing observations forms a challenging problem. This is especially the case when both the temporal correlation of timestamps within a single sensor and the spatial correlation between sensors are important. Here, we apply and evaluate 12 imputation methods to complete the missing values in a dataset originating from large-scale environmental monitoring. As part of a large citizen science project, IoT-based microclimate sensors were deployed for six months in 4400 gardens across the region of Flanders, generating 15-min recordings of temperature and soil moisture. Methods based on spatial recovery as well as time-based imputation were evaluated, including Spline Interpolation, MissForest, MICE, MCMC, M-RNN, BRITS, and others. The performance of these imputation methods was evaluated for different proportions of missing data (ranging from 10% to 50%), as well as a realistic missing value scenario. Techniques leveraging the spatial features of the data tend to outperform the time-based methods, with matrix completion techniques providing the best performance. Our results therefore provide a tool to maximize the benefit from costly, large-scale environmental monitoring efforts. [ABSTRACT FROM AUTHOR]

Background: Self-harm presents a significant public health challenge. Emergency departments (EDs) are crucial healthcare settings in managing self-harm, but clinician uncertainty in risk assessment may contribute to ineffective care. Clinical Decision Support Systems (CDSSs) show promise in enhancing care processes, but their effective implementation in self-harm management remains unexplored. Methods: PERMANENS comprises a combination of methodologies and study designs aimed at developing a CDSS prototype that assists clinicians in the personalized assessment and management of ED patients presenting with self-harm. Ensemble prediction models will be constructed by applying machine learning techniques on electronic registry data from four sites, i.e., Catalonia (Spain), Ireland, Norway, and Sweden. These models will predict key adverse outcomes including self-harm repetition, suicide, premature death, and lack of post-discharge care. Available registry data include routinely collected electronic health record data, mortality data, and administrative data, and will be harmonized using the OMOP Common Data Model, ensuring consistency in terminologies, vocabularies and coding schemes. A clinical knowledge base of effective suicide prevention interventions will be developed rooted in a systematic review of clinical practice guidelines, including quality assessment of guidelines using the AGREE II tool. The CDSS software prototype will include a backend that integrates the prediction models and the clinical knowledge base to enable accurate patient risk stratification and subsequent intervention allocation. The CDSS frontend will enable personalized risk assessment and will provide tailored treatment plans, following a tiered evidence-based approach. Implementation research will ensure the CDSS' practical functionality and feasibility, and will include periodic meetings with user-advisory groups, mixed-methods research to identify currently unmet needs in self-harm risk assessment, and small-scale usability testing of the CDSS prototype software. Discussion: Through the development of the proposed CDSS software prototype, PERMANENS aims to standardize care, enhance clinician confidence, improve patient satisfaction, and increase treatment compliance. The routine integration of CDSS for self-harm risk assessment within healthcare systems holds significant potential in effectively reducing suicide mortality rates by facilitating personalized and timely delivery of effective interventions on a large scale for individuals at risk of suicide. [ABSTRACT FROM AUTHOR]

Motivation Automatic cell type annotation methods assign cell type labels to new datasets by extracting relationships from a reference RNA-seq dataset. However, due to the limited resolution of gene expression features, there is always uncertainty present in the label assignment. To enhance the reliability and robustness of annotation, most machine learning methods address this uncertainty by providing a full reject option, i.e. when the predicted confidence score of a cell type label falls below a user-defined threshold, no label is assigned and no prediction is made. As a better alternative, some methods deploy hierarchical models and consider a so-called partial rejection by returning internal nodes of the hierarchy as label assignment. However, because a detailed experimental analysis of various rejection approaches is missing in the literature, there is currently no consensus on best practices. Results We evaluate three annotation approaches (i) full rejection, (ii) partial rejection, and (iii) no rejection for both flat and hierarchical probabilistic classifiers. Our findings indicate that hierarchical classifiers are superior when rejection is applied, with partial rejection being the preferred rejection approach, as it preserves a significant amount of label information. For optimal rejection implementation, the rejection threshold should be determined through careful examination of a method's rejection behavior. Without rejection, flat and hierarchical annotation perform equally well, as long as the cell type hierarchy accurately captures transcriptomic relationships. Availability and implementation Code is freely available at https://github.com/Latheuni/Hierarchical%5freject and https://doi.org/10.5281/zenodo.10697468. [ABSTRACT FROM AUTHOR]

A new saprotrophic species was discovered during our fungal inventory at the Boston Harbor Islands National Recreation Area (Massachusetts), which consists of 34 islands and peninsulas. Simocybe ramosa sp. nov. (Agaricales, Crepidotaceae) is described based on morphology and molecular phylogenetic data. The holotype collection was found in a Quercus (oak)–Carya (hickory) forest under bark of a dead oak tree on World's End peninsula, the largest land mass of the archipelago. Phylogenetic reconstruction of a dataset of the internal transcribed spacer region (ITS) resolved S. ramosa and S. rhabarbarina as sister species. Simocybe rhabarbarina is here redescribed based on the holotype and newly reported material from the Netherlands, and its presence on the island of Jersey, off the coast of northern France, is confirmed based on an ITS sequence. Finally, we compare morphological features of S. ramosa with S. rhabarbarina and the 20 species in the genus that have thus far been recorded in Canada, the US, and Mexico. [ABSTRACT FROM AUTHOR]

Background and Objectives: Most research studies on the effects of repeated plasma donation are observational with different study limitations, resulting in high uncertainty on the link between repeated plasma donation and health consequences. Here, we prospectively investigated the safety of intensive or less intensive plasma donation protocols. Materials and Methods: Sixty‐three male subjects participated in this randomized controlled trial and were divided into low‐frequency (LF, once/month, n = 16), high‐frequency (HF, three times/month, n = 16), very high‐frequency (VHF, two times/week, n = 16) and a placebo (P, once/month, n = 15) groups. Biochemical, haematological, clinical, physiological and exercise‐related data were collected before (D0), after 1½ months (D42) and after 3 months (D84) of donation. Results: In VHF, red blood cells, haemoglobin and haematocrit levels decreased while reticulocyte levels increased from D0 to D84. In both HF and VHF, plasma ferritin levels were lower at D42 and D84 compared to D0. In VHF, plasma levels of albumin, immunoglobulin G (IgG), immunoglobulin A (IgA) and immunoglobulin M (IgM) dropped from D0 to D42 and remained lower at D84 than at D0. In HF, plasma IgG, IgA and IgM were lower at D42, and IgG and IgM were lower at D84, compared to D0. Few adverse events were reported in HF and VHF. Repeated plasma donation had no effect on blood pressure, body composition or exercise performance. Conclusion: VHF plasmapheresis may result in a large reduction in ferritin and IgG levels. HF and VHF plasmapheresis may result in little to no difference in other biochemical, haematological, clinical, physiological and exercise‐related parameters. [ABSTRACT FROM AUTHOR]

This paper takes a look at the morphological structure of the two dominant diagrams (the triangle and the tripod) used in semiotic literature to represent the irreducible triadic sign of C. S. Peirce in order to evaluate their diagrammatic aptitude, i.e. allowing of deductive discoveries. Concluding that neither fully translates the properties attributed to the irreducible triadic sign on a visual level, an alternative diagram is proposed. This is a visual representation of the irreducible triadic sign that is directly connected with other fields of research, such as mathematics, but also with the work of Floyd Merrell and Paul Ryan and, most importantly, has the ability to bring both the pattern of a sign and the process of semiosis into one easily drawn diagram, the triquetra. [ABSTRACT FROM AUTHOR]

Within the broader context of improving interactions between artificial intelligence and humans, the question has arisen regarding whether auditory and rhythmic support could increase attention for visual stimuli that do not stand out clearly from an information stream. To this end, we designed an experiment inspired by pip-and-pop but more appropriate for eliciting attention and P3a-event-related potentials (ERPs). In this study, the aim was to distinguish between targets and distractors based on the subject's electroencephalography (EEG) data. We achieved this objective by employing different machine learning (ML) methods for both individual-subject (IS) and cross-subject (CS) models. Finally, we investigated which EEG channels and time points were used by the model to make its predictions using saliency maps. We were able to successfully perform the aforementioned classification task for both the IS and CS scenarios, reaching classification accuracies up to 76%. In accordance with the literature, the model primarily used the parietal–occipital electrodes between 200 ms and 300 ms after the stimulus to make its prediction. The findings from this research contribute to the development of more effective P300-based brain–computer interfaces. Furthermore, they validate the EEG data collected in our experiment. [ABSTRACT FROM AUTHOR]

Mechanisms underlying deviant cell size fluctuations among clonal bacterial siblings are generally considered to be cryptic and stochastic in nature. However, by scrutinizing heat-stressed populations of the model bacterium Escherichia coli, we uncovered the existence of a deterministic asymmetry in cell division that is caused by the presence of intracellular protein aggregates (PAs). While these structures typically locate at the cell pole and segregate asymmetrically among daughter cells, we now show that the presence of a polar PA consistently causes a more distal off-center positioning of the FtsZ division septum. The resulting increased length of PA-inheriting siblings persists over multiple generations and could be observed in both E. coli and Bacillus subtilis populations. Closer investigation suggests that a PA can physically perturb the nucleoid structure, which subsequently leads to asymmetric septation. [ABSTRACT FROM AUTHOR]

Objective: Patients with spondyloarthritis (SpA) often present with microscopic signs of gut inflammation, a risk factor for progressive disease. We investigated whether mucosal innate‐like T cells are involved in dysregulated interleukin‐23 (IL‐23)/IL‐17 responses in the gut‐joint axis in SpA. Methods: Ileal and colonic intraepithelial lymphocytes (IELs), lamina propria lymphocytes (LPLs), and paired peripheral blood mononuclear cells (PBMCs) were isolated from treatment‐naive patients with nonradiographic axial SpA with (n = 11) and without (n = 14) microscopic gut inflammation and healthy controls (n = 15) undergoing ileocolonoscopy. The presence of gut inflammation was assessed histopathologically. Immunophenotyping of innate‐like T cells and conventional T cells was performed using intracellular flow cytometry. Unsupervised clustering analysis was done by FlowSOM technology. Serum IL‐17A levels were measured via Luminex. Results: Microscopic gut inflammation in nonradiographic axial SpA was characterized by increased ileal intraepithelial γδ‐hi T cells, a γδ‐T cell subset with elevated γδ‐T cell receptor expression. γδ‐hi T cells were also increased in PBMCs of patients with nonradiographic axial SpA versus healthy controls and were strongly associated with Ankylosing Spondylitis Disease Activity Score. The abundance of mucosal‐associated invariant T cells and invariant natural killer T cells was unaltered. Innate‐like T cells in the inflamed gut showed increased RORγt, IL‐17A, and IL‐22 levels with loss of T‐bet, a signature that was less pronounced in conventional T cells. Presence of gut inflammation was associated with higher serum IL‐17A levels. In patients treated with tumor necrosis factor blockade, the proportion of γδ‐hi cells and RORγt expression in blood was completely restored. Conclusion: Intestinal innate‐like T cells display marked type 17 skewing in the inflamed gut mucosa of patients with nonradiographic axial SpA. γδ‐hi T cells are linked to intestinal inflammation and disease activity in SpA. [ABSTRACT FROM AUTHOR]

Background: Laboratory results are influenced by presence and severity of disease, as well as preanalytical factors, analytical variation, and biological variation. Biological variation data for urinary protein: creatinine ratio (UPC) and urine specific gravity (USG) in cats are lacking. Objectives: Determine the biological variation of UPC and USG in cats. Animals: Eighty healthy client‐owned cats. Methods: Prospective study. Urine was collected on days 0, 14, and 56 from all 80 cats to investigate the persistence of borderline or overt proteinuria or suboptimal urine concentration. In 15 of these cats, urine was collected weekly from day 0 to 42 to calculate the index of individuality (II) and reference change value (RCV), and on days 56 and 57 to evaluate day‐to‐day variability of UPC and USG. Results: Borderline or overt proteinuria (UPC ≥0.2) was present in 18/80 (23%) cats at baseline and persisted on 3 occasions in 2 months in 8/18 (44%) cats. Urine concentration was suboptimal at inclusion (USG <1.035) in 8/80 (10%) cats and at all 3 time points during 2 months in 3/8 (38%) cats. The II of UPC and USG indicated intermediate individuality. The 1‐sided RCV was 82% for UPC and 36% for USG. Proteinuria substage was identical on 2 consecutive days in 13/15 (87%) cats, and urine concentrating ability remained the same in all 15 cats. Conclusions and Clinical Importance: A >82% increase in UPC in a healthy cat is not solely attributable to physiological and analytical variation. For USG, a decrease of >36% is considered clinically relevant. [ABSTRACT FROM AUTHOR]

Objective Divergent therapeutic outcomes on different disease domains have been noted with IL-23 and IL-17A-blockade in PsA. Therefore, elucidating the role of RORγt, the master regulator of type 17 immune responses, is of potential therapeutic interest. To this end, RORγt inhibition was assessed in combined skin, joint and gut inflammation in vivo , using a PsA model. Methods We tested the efficacy of a RORγt antagonist in B10.RIII mice challenged with systemic overexpression of IL-23 by hydrodynamic injection of IL-23 enhanced episomal vector (IL-23 EEV). Clinical outcomes were evaluated by histopathology. Bone density and surface erosions were examined using micro-computed tomography. Cytokine production was measured in serum and by intracellular flow cytometry. Gene expression in PsA-related tissues was analysed by qPCR. Results RORγt-blockade significantly ameliorated psoriasis, peripheral arthritis and colitis development in IL-23 EEV mice (improvement of clinical scores and weight loss respectively by 91.8%, 58.2% and 7.0%, P  < 0.001), in line with profound suppression of an enhanced type IL-17 immune signature in PsA-affected tissues. Moreover, inflammation-induced bone loss and bone erosions were reduced (P  < 0.05 in calcaneus, P  < 0.01 in tibia). Sustained IL-23 overexpression resulted in only mild signs of sacroiliitis. Gamma-delta (γδ)-T cells, the dominant source of T cell-derived IL-17A and IL-22, were expanded during IL-23 overexpression, and together with Th17 cells, clearly countered by RORγt inhibition (P  < 0.001). Conclusion RORγt-blockade shows therapeutic efficacy in a preclinical PsA model with protection towards extra-musculoskeletal manifestations, reflected by a clear attenuation of type 17 cytokine responses by γδ-T cells and Th17 cells. [ABSTRACT FROM AUTHOR]

The photospheric unsigned magnetic flux has been shown to be highly correlated with radial velocity (RV) variations caused by solar surface activity. This activity indicator is therefore a prime candidate to unlock the potential of RV surveys to discover Earth twins orbiting Sun-like stars. We show for the first time how a precise proxy of the unsigned magnetic flux (Δα B 2) can be obtained from Sun-as-a-star intensity spectra by harnessing the magnetic information contained in over 4000 absorption lines in the wavelength range from 380 to 690 nm. This novel activity proxy can thus be obtained from the same spectra from which RVs are routinely extracted. We derived  Δα B 2 from 500 randomly selected spectra from the HARPS-N public solar data set, which spans from 2015 to 2018. We compared our estimates with the unsigned magnetic flux values from the Solar Dynamics Observatory (SDO) finding excellent agreement (median absolute deviation: 4.9 per cent). The extracted indicator  Δα B 2 correlates with SDO's unsigned magnetic flux estimates on the solar rotational time-scale (Pearson correlation coefficient 0.67) and on the 3-yr time-scale of our data set (correlation coefficient 0.91). We find correlations of  Δα B 2 with the HARPS-N solar RV variations of 0.49 on the rotational time-scale and 0.78 on the 3-yr time-scale. The Pearson correlation of  Δα B 2 with the RVs is found to be greater than the correlation of the classical activity indicators with the RVs. For solar-type stars,  Δα B 2 therefore represents the best simultaneous activity proxy known to date. [ABSTRACT FROM AUTHOR]

Background: Urinalysis is necessary for the diagnostic evaluation of chronic kidney disease in cats. Performing cystocentesis is not always feasible, but data comparing urine obtained by cystocentesis in the clinic with voided samples collected at home are lacking in cats. Objectives: To compare urinary protein:creatinine ratio (UPC) and urine specific gravity (USG) and to detect clinically relevant changes in proteinuria substage or urine concentration between urine collected at home and in‐clinic by cystocentesis in cats. Animals: Ninety‐two healthy and diseased client‐owned cats. Methods: Prospective study. Owners collected voided urine at home and within 1 to 15 hours, cystocentesis was performed in the clinic. Results: In a subset of motivated owners, 55% succeeded in collecting urine at home. Overall, UPC was higher (mean ±SD difference = 0.09 ±0.22; P <.001) and USG was lower (mean ±SD difference = −0.006 ±0.009; P <.001) in cystocentesis samples than in voided urine. Substantial agreement existed between sampling methods for UPC (weighted к = 0.68) and USG (к = 0.64) categories. A different proteinuria substage (UPC < 0.2, 0.2‐0.4, >0.4) was present in paired urine samples from 28% of cats. In 18% of cats, urine concentrating ability (USG < or ≥1.035) differed between both samples. Conclusions and Clinical Importance: Home sampling of urine is a valid alternative to cystocentesis in cats. However, because clinically relevant differences in UPC and USG were present in 28% and 18% of cats, respectively, by the same collection method for monitoring each cat is advised. [ABSTRACT FROM AUTHOR]

In a context where hospital capacities and emergency services are saturated, the day hospital can offer a space for multi-professional hospital care likely to meet the needs of city doctors, particularly in areas of medical desert. Located within the Max Fourestier hospital in Nanterre (92,000) and called the Vi'Tal center to mark the link between the city and the hospital, this care offer aims to simplify the links between city doctors and those of the hospital in order to allow patients to benefit quickly, at the request of their doctor, from hospital expertise. [ABSTRACT FROM AUTHOR]

Background: Treatment of nasal tumors in dogs is associated with high morbidity and reliable prognostic factors are lacking. Dynamic contrast‐enhanced computed tomography (DCECT) can be used to assess tumor perfusion. Objectives: To assess perfusion parameters of nasal tumors (correlating with tumor type) before and during radiotherapy (RT) and find potential correlation with survival. Animals: Twenty‐four client‐owned dogs with nasal tumors, including 16 epithelial tumors and 8 sarcomas. Methods: Prospective cross‐sectional study. All dogs had baseline DCECT to assess fractional vascular volume (BV), blood flow (BF), and transit time (TT). Thirteen dogs had repeat DCECT after 12 Gy of megavoltage RT. Survival times were calculated. Results: Median BV was 17.83 mL/100 g (range, 3.63‐66.02), median BF was 122.63 mL/100 g/minute (range, 23.65‐279.99), and median TT was 8.91 seconds (range, 4.57‐14.23). Sarcomas had a significantly lower BF than adenocarcinomas (P =.002), carcinomas (P =.01), and other carcinomas (P =.001), and significantly lower BV than adenocarcinomas (P =.03) and other carcinomas (P =.004). Significant associations were found between epithelial tumors and sarcoma for change in tumor volume (P =.01), width (P =.004), and length (P =.02) in that epithelial tumors decreased in volume whereas sarcomas increased in volume. Perfusion parameters were not correlated with survival. Conclusions and Clinical Importance: Nasal sarcomas have lower BV and BF than nasal carcinomas, and sarcomas have a lower size reduction than carcinomas early on during RT. Baseline results and changes in perfusion parameters may not be correlated with survival. [ABSTRACT FROM AUTHOR]

Background: Urinary protein:creatinine ratio (UPC) results affect the diagnosis, prognosis, and therapy of chronic kidney disease in cats. Objectives: To investigate the interlaboratory and intralaboratory variability and the effect of storage on UPC and International Renal Interest Society (IRIS) proteinuria substaging in cats. Animals: Healthy and diseased client‐owned cats. Methods: Prospective study. Urine of 60 cats was randomly sent to 4 (of 9) participating laboratories (to assess interlaboratory variability) and per cat, 2 laboratories each received 2 aliquots (to determine intralaboratory variability). Samples of 23 cats were analyzed in the same laboratory the day of collection, after preservation at 22°C for 1 day and at 4°C during 1‐7 days (short‐term storage) and at −24°C and −80°C for 6‐12 months (long‐term storage). Storage conditions were compared by equivalence testing. Results: UPCs showed good interclass correlation (ICC‐inter, 0.90) and excellent intraclass correlation (ICC‐intra, 0.99). However, in 30/60 (50%) cats at least 1 of 4 laboratories assigned a different IRIS proteinuria substage. Urinary protein:creatinine ratio remained stable with short‐term storage, but not after 6 months storage at −24°C and after 12 months storage at −24°C or −80°C. Long‐term storage caused a change in IRIS proteinuria substage in 27% of cats, whereas a shift occurred only in 4% of cats during short‐term storage. Conclusions and Clinical Importance: Laboratory choice for UPC measurement can result in different IRIS substaging for the same cat, whereas urine storage at room temperature for 1 day or in the refrigerator for up to 7 days does not clinically affect UPC. [ABSTRACT FROM AUTHOR]

OBJECTIVE Treatment of orofacial tumors in dogs is associated with high morbidity and reliable prognostic factors are lacking. Dynamic contrast-enhanced computed tomography (DCECT) can be used to assess tumor perfusion. The objectives of this study were to describe the perfusion parameters of different types of orofacial tumors and to describe the changes in perfusion parameters during radiotherapy (RT) in a subset of them. ANIMALS 11 dogs with orofacial tumors prospectively recruited. CLINICAL PRESENTATION AND PROCEDURES All dogs had baseline DCECT to assess blood volume (BV), blood flow (BF), and transit time (TT). Five dogs had repeat DCECT during megavoltage RT. RESULTS 5 squamous cell carcinomas, 3 sarcomas, 1 melanoma, 1 histiocytic sarcoma, and 1 acanthomatous ameloblastoma were included. Blood volume and BF were higher in squamous cell carcinomas than in sarcomas, although no statistical analysis was performed. At repeat DCECT, 4 dogs showed a reduction in the size of their tumor during RT. Among these dogs, 3 showed an increase in BV and BF and 1 a decrease in these parameters between the baseline and the follow-up DCECT. The only dog whose tumor increased in size between the first and the second DCECT showed a decrease in BV and BF. CLINICAL RELEVANCE Perfusion parameters derived from DCECT were described in a series of dogs with various types of orofacial tumors. The results suggest that epithelial tumors could have higher BV and BF than mesenchymal tumors, although larger sample sizes are needed to support these preliminary findings. [ABSTRACT FROM AUTHOR]

With a rapidly increasing number of Latinx students in a special education system that requires parent advocacy, it is imperative to study the perspectives Latinx families have on how to improve family-school partnerships. In this research, semi-structured interviews with 10 Latinx mothers who have children with disabilities led to insights about stressors and barriers, how families can be empowered, and how trusting partnerships can be facilitated. Implications for the field of special education are discussed. [ABSTRACT FROM AUTHOR]

Polyploidy, i.e. the occurrence of multiple sets of chromosomes, is regarded as an important phenomenon in plant ecology and evolution, with all flowering plants likely having a polyploid ancestry. Owing to genome shock, minority cytotype exclusion and reduced fertility, polyploids emerging in diploid populations are expected to face significant challenges to successful establishment. Their establishment and persistence are often explained by possible fitness or niche differences that would relieve the competitive pressure with diploid progenitors. Experimental evidence for such advantages is, however, not unambiguous, and considerable niche overlap exists among most polyploid species and their diploid counterparts. Here, we develop a neutral spatially explicit eco-evolutionary model to understand whether neutral processes can explain the eco-evolutionary patterns of polyploids. We present a general mechanism for polyploid establishment by showing that sexually reproducing organisms assemble in space in an iterative manner, reducing frequency-dependent mating disadvantages and overcoming potential reduced fertility issues. Moreover, we construct a mechanistic theoretical framework that allows us to understand the long-term evolution of mixed-ploidy populations and show that our model is remarkably consistent with recent phylogenomic estimates of species extinctions in the Brassicaceae family. [ABSTRACT FROM AUTHOR]

Purpose: Microtia describes a spectrum of auricular malformations ranging from mild dysplasia to anotia. A vast majority of microtia patients demonstrate congenital aural atresia (CAA). Isolated microtia has a right ear predominance (58–61%) and is more common in the male sex. Isolated microtia is a multifactorial condition involving genetic and environmental causes. The aim of this study is to describe the phenotype of children with unilateral isolated microtia and CAA, and to search for a common genetic cause trough DNA analysis. Methods: Phenotyping included a complete clinical examination. Description on the degree of auricular malformation (Weerda classification—Weerda 1988), assessment for hemifacial microsomia and age-appropriate audiometric testing were documented. Computerized tomography of the temporal bone with 3-D rendering provided a histopathological classification (HEAR classification—Declau et al. 1999). Genetic testing was carried out by single nucleotide polymorphism (SNP) microarray. Results: Complete data are available for 44 children (50% was younger than 33 days at presentation; 59.1% boys; 72.7% right ear). Type III microtia was present in 28 patients. Type 2b CAA existed in 32 patients. All patients had a normal hearing at the non-affected side. Genome wide deletion duplication analysis using microarray did not reveal any pathological copy number variant (CNV) that could explain the phenotype. Conclusions: Type III microtia (peanut-shell type) in combination with a type 2b CAA was the most common phenotype, present in 23 of 44 (52.3%) patients with isolated unilateral microtia. No abnormalities could be found by copy number variant (CNV) analysis. Whole exome sequencing in a larger sample with a similar phenotype may represent a future diagnostic approach. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreas cancer will become the second deadliest cancer in 2030. One-third of patients with pancreatic cancer are treated with surgery followed by intravenous chemotherapy. This aggressive treatment has to be delivered to people fit enough to receive it. Many variables are used to define this status, such as performance status, albuminemia or sarcopenia. In our study, we calculated the sarcopenia status by measuring via computer tomography the area of the psoas; if it is low in terms of sex and BMI, the patient is considered sarcopenic. We found out that sarcopenic patients with operated pancreatic cancer have a lower overall survival no matter the type of chemotherapy used. Background: Despite its toxicity, modified FOLFIRINOX is the main chemotherapy for localized, operable pancreatic adenocarcinomas. Sarcopenia is known as a factor in lower overall survival (OS). The purpose of this study was to assess the impact of sarcopenia on OS in patients with localized pancreatic ductal adenocarcinoma (PDAC) who received modified FOLFIRINOX or gemcitabine as adjuvant chemotherapy. Methods: Patients with operated PDAC who received gemcitabine-based (GEM group) or oxaliplatin-based (OXA group) adjuvant chemotherapy between 2008 and 2021 were retrospectively included. Sarcopenia was estimated on a baseline computed tomography (CT) examination using the skeletal muscular index (SMI). The primary evaluation criterion was OS. Secondary evaluation criteria were disease-free survival (DFS) and toxicity. Results: Seventy patients treated with gemcitabine-based (n = 49) and oxaliplatin-based (n = 21) chemotherapy were included, with a total of fifteen sarcopenic patients (eight in the GEM group and seven in the OXA group). The median OS was shorter in sarcopenic patients (25 months) compared to non-sarcopenic patients (158 months) (p = 0.01). A longer OS was observed in GEM non-sarcopenic patients (158 months) compared to OXA sarcopenic patients (14.4 months) (p < 0.01). The median OS was 157.7 months in the GEM group vs. 34.1 months in the OXA group (p = 0.13). No differences in median DFS were found between the GEM group and OXA group. More toxicity events were observed in the OXA group (50%) than in the GEM group (10%), including vomiting (p = 0.02), mucositis (p = 0.01) and neuropathy (p = 0.01). Conclusion: Sarcopenia is associated with a worse prognosis in patients with localized operated PDAC whatever the delivered adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Avelumab has been approved worldwide for treatment of metastatic Merkel cell carcinoma (mMCC), a rare and aggressive skin cancer. This study evaluated outcomes in patients with mMCC in France who received avelumab as second-line or later (2L+) treatment in routine clinical practice. This retrospective, noninterventional study evaluated all patients diagnosed with mMCC using two databases: CARADERM (French national database of rare dermatological cancers) and SNDS (national healthcare database), identified via probabilistic linkage. Eligible patients initiated avelumab as 2L+ treatment between August 2016 and December 2019 and were followed for 24 months. The primary endpoint was overall survival (OS) at 24 months. Overall, 180 patients who received 2L+ avelumab were identified (112 from CARADERM, 68 after SNDS linkage). Median age at diagnosis was 74.0 years and 177 (98.3 %) had received chemotherapy alone as first-line treatment. Median follow-up was 13.1 months. Median OS from start of avelumab was 14.6 months (95 % CI, 9.9–21.3) in the overall population, 15.9 months (95 % CI, 8.6–28.3) in CARADERM patients, and 13.3 months (95 % CI, 6.7–19.1) in non-CARADERM patients. OS rates at 12 and 24 months were 53.8 % (95 % CI, 46.2 %−60.8 %) and 40.5 % (95 % CI, 33.2 %−47.6 %), respectively. In evaluable patients (CARADERM database), median progression-free survival was 3.6 months (95 % CI, 2.7–7.5) and the objective response rate was 55.3 % (95 % CI, 45.3–65.4), including complete response in 31.9 %. Real-world outcomes with 2L+ avelumab treatment for mMCC are consistent with clinical trial findings, supporting the recommendation of avelumab as a standard of care. • This study examined patients with metastatic Merkel cell carcinoma in France. • 180 patients who received second-line or later avelumab treatment were identified. • Median overall survival was 14.6 months and 24-month overall survival was 40.5 %. • Objective response rate was 55.3 % including complete response in 31.9 %. • Findings support the use of avelumab treatment for patients with this disease. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the associations of childhood adversities (CAs) with lifetime onset and transitions across suicidal thoughts and behaviors (STB) among incoming college students. Methods: Web-based self-report surveys administered to 20,842 incoming college students from nine countries (response rate 45.6%) assessed lifetime suicidal ideation, plans and attempts along with seven CAs: parental psychopathology, three types of abuse (emotional, physical, sexual), neglect, bully victimization, and dating violence. Logistic regression estimated individual- and population-level associations using CA operationalizations for type, number, severity, and frequency. Results: Associations of CAs with lifetime ideation and the transition from ideation to plan were best explained by the exact number of CA types (OR range 1.32–52.30 for exactly two to seven CAs). Associations of CAs with a transition to attempts were best explained by the frequency of specific CA types (scaled 0–4). Attempts among ideators with a plan were significantly associated with all seven CAs (OR range 1.16–1.59) and associations remained significant in adjusted analyses with the frequency of sexual abuse (OR = 1.42), dating violence (OR = 1.29), physical abuse (OR = 1.17) and bully victimization (OR = 1.17). Attempts among ideators without plan were significantly associated with frequency of emotional abuse (OR = 1.29) and bully victimization (OR = 1.36), in both unadjusted and adjusted analyses. Population attributable risk simulations found 63% of ideation and 30–47% of STB transitions associated with CAs. Conclusion: Early-life adversities represent a potentially important driver in explaining lifetime STB among incoming college students. Comprehensive intervention strategies that prevent or reduce the negative effects of CAs may reduce subsequent onset of STB. [ABSTRACT FROM AUTHOR]

To push the radial velocity (RV) exoplanet detection threshold, it is crucial to find more reliable RV extraction methods. The least-squares deconvolution (LSD) technique has been used to infer the stellar magnetic flux from spectropolarimetric data for the past two decades. It relies on the assumption that stellar absorption lines are similar in shape. Although this assumption is simplistic, LSD provides a good model for intensity spectra and likewise an estimate for their Doppler shift. We present the multi-mask least-squares deconvolution (MM-LSD) RV extraction pipeline that extracts the RV from two-dimensional echelle-order spectra using LSD with multiple tailored masks after continuum normalization and telluric absorption line correction. The flexibility of LSD allows to exclude spectral lines or pixels at will, providing a means to exclude variable lines or pixels affected by instrumental problems. The MM-LSD pipeline was tested on HARPS-N data for the Sun and selected well-observed stars with 5.7 < V mag < 12.6. For FGK-type stars with median signal-to-noise ratio above 100, the pipeline delivered RV time series with on average 12 per cent lower scatter as compared to the HARPS-N RV extraction pipeline based on the cross-correlation function technique. The MM-LSD pipeline may be used as a standalone RV code, or modified and extended to extract a proxy for the magnetic field strength. [ABSTRACT FROM AUTHOR]

Background To assess the prevalence and evolution of transmitted drug resistance (TDR) in Belgium, a total of 3708 baseline human immunodeficiency virus (HIV)-1 polymerase sequences from patients diagnosed between 2013 and 2019 were analyzed. Methods Protease and reverse-transcriptase HIV-1 sequences were collected from the 7 national Aids Reference Laboratories. Subtype determination and drug resistance scoring were performed using the Stanford HIV Drug Resistance Database. Trends over time were assessed using linear regression, and the maximum likelihood approach was used for phylogenetic analysis. Results A total of 17.9% of the patients showed evidence of TDR resulting in at least low-level resistance to 1 drug (Stanford score  ≥15). If only the high-level mutations (Stanford score ≥60) were considered, TDR prevalence dropped to 6.3%. The majority of observed resistance mutations impacted the sensitivity for nonnucleoside reverse-transcriptase inhibitors (NNRTIs) (11.4%), followed by nucleoside reverse-transcriptase inhibitors (6.2%) and protease inhibitors (2.4%). Multiclass resistance was observed in 2.4%. Clustered onward transmission was evidenced for 257 of 635 patients (40.5%), spread over 25 phylogenetic clusters. Conclusions The TDR prevalence remained stable between 2013 and 2019 and is comparable to the prevalence in other Western European countries. The high frequency of NNRTI mutations requires special attention and follow-up. Phylogenetic analysis provided evidence for local clustered onward transmission of some frequently detected mutations. [ABSTRACT FROM AUTHOR]

The first year of college may carry especially high risk for onset of alcohol use disorders. We assessed the one-year incidence of alcohol use disorders (AUD) among incoming first-year students, predictors of AUD-incidence, prediction accuracy and population impact. A prospective cohort study of first-year college students (baseline: N = 5843; response rate = 51.8%; 1-year follow-up: n = 1959; conditional response rate = 41.6%) at a large university in Belgium was conducted. AUD were evaluated with the AUDIT and baseline predictors with the Composite International Diagnostic Interview Screening Scales (CIDI-SC). The one-year incidence of AUD was 3.9% (SE = 0.4). The most important individual-level baseline predictors of AUD incidence were being male (OR = 1.53; 95% CI = 1.12–2.10), a break-up with a romantic partner (OR = 1.67; 95% CI = 1.08–2.59), hazardous drinking (OR = 3.36; 95% CI = 1.31–8.63), and alcohol use characteristics at baseline (ORs between 1.29 and 1.38). Multivariate cross-validated prediction (cross-validated AUC = 0.887) shows that 55.5% of incident AUD cases occurred among the 10% of students at highest predicted risk (20.1% predicted incidence in this highest-risk subgroup). Four out of five students with incident AUD would hypothetically be preventable if baseline hazardous drinking was to be eliminated along with a reduction of one standard deviation in alcohol use characteristics scores, and another 15.0% would potentially be preventable if all 12-month stressful events were eliminated. Screening at college entrance is a promising strategy to identify students at risk of transitioning to more problematic drinking and AUD, thus improving the development and deployment of targeted preventive interventions. [ABSTRACT FROM AUTHOR]

Recently, asymptotic‐preserving Monte Carlo simulation methods have been developed to simulate the Boltzmann‐BGK equation with advective–diffusive limiting behaviour over a broad range of regimes. These simulation methods hybridize a particle tracing Monte Carlo scheme for the kinetic equation and a random walk (RW) Monte Carlo simulation for the advection–diffusion limit, combining the precision of the former with the efficiency of the latter. In the RW part of the simulation, details of the travelled path are absent. This complicates the extraction of integral quantities of interest such as mass, momentum, and energy sources. Here, we present a new estimation strategy that couples the RW parts of the particle trajectories with a deterministic simulation of the corresponding fluid model. The contributions of the RW parts to quantities of interest are then computed from a single time step of this fluid model in a post‐processing step. We illustrate this new estimation strategy for a fusion‐relevant test‐case and focus on the bias and variance present when using this estimator. [ABSTRACT FROM AUTHOR]

Reproductive parasites such as Wolbachia spread within host populations by inducing cytoplasmic incompatibility (CI). CI occurs when parasite‐modified sperm fertilizes uninfected eggs and is typified by great variation in strength across biological systems. In haplodiploid hosts, CI has different phenotypic outcomes depending on whether the fertilized eggs die or develop into males. Genetic conflict theories predict the evolution of host modulation of CI, which in turn influences the stability of reproductive parasitism. However, despite the ubiquity of CI‐inducing parasites in nature, there is scarce evidence for intraspecific host modulation of CI strength and phenotype. Here, we tested for intraspecific host modulation of Wolbachia‐induced CI in haplodiploid Tetranychus urticae mites. Using a single CI‐inducing Wolbachia variant and mitochondrion, a nuclear panel was created that consisted of infected and cured near‐isogenic lines. We performed a highly replicated age‐synchronized full diallel cross composed of incompatible and compatible control crosses. We uncovered host modifier systems that cause striking variation in CI strength when carried by infected T. urticae males. We observed a continuum of CI phenotypes in our crosses and identified strong intraspecific female modulation of the CI phenotype. Crosses established a recessive genetic basis for the maternal effect and were consistent with polygenic Mendelian inheritance. Both male and female modulation interacted with the genotype of the mating partner. Our findings identify spermatogenesis as an important target of selection for host modulation of CI strength and underscore the importance of maternal genetic effects for the CI phenotype. Our findings reveal that intraspecific host modulation of CI is underpinned by complex genetic architectures and confirm that the evolution of reproductive parasitism is contingent on host genetics. [ABSTRACT FROM AUTHOR]

Healthcare workers (HCW) are at high risk for suicide, yet little is known about the onset of suicidal thoughts and behaviors (STB) in this important segment of the population in conjunction with the COVID-19 pandemic. We conducted a multicenter, prospective cohort study of Spanish HCW active during the COVID-9 pandemic. A total of n = 4809 HCW participated at baseline (May–September 2020; i.e., just after the first wave of the pandemic) and at a four-month follow-up assessment (October–December 2020) using web-based surveys. Logistic regression assessed the individual- and population-level associations of separate proximal (pandemic) risk factors with four-month STB incidence (i.e., 30-day STB among HCW negative for 30-day STB at baseline), each time adjusting for distal (pre-pandemic) factors. STB incidence was estimated at 4.2% (SE = 0.5; n = 1 suicide attempt). Adjusted for distal factors, proximal risk factors most strongly associated with STB incidence were various sources of interpersonal stress (scaled 0–4; odds ratio [OR] range = 1.23–1.57) followed by personal health-related stress and stress related to the health of loved ones (scaled 0–4; OR range 1.30–1.32), and the perceived lack of healthcare center preparedness (scaled 0–4; OR = 1.34). Population-attributable risk proportions for these proximal risk factors were in the range 45.3–57.6%. Other significant risk factors were financial stressors (OR range 1.26–1.81), isolation/quarantine due to COVID-19 (OR = 1.53) and having changed to a specific COVID-19 related work location (OR = 1.72). Among other interventions, our findings call for healthcare systems to implement adequate conflict communication and resolution strategies and to improve family-work balance embedded in organizational justice strategies. [ABSTRACT FROM AUTHOR]

Background: In foreign language syndrome, patients switch from their native language and fixate for a period of time on a second language. There have been few reported cases. The language switch typically occurs postoperatively and spontaneously resolves after a short period of time. The primary cause of this switching remains unclear. There is speculation about the involvement of anesthesia, but its specific influence remains unclear.Case Presentation: A 17-year-old Dutch Caucasian male lost the ability to understand and speak Dutch for 24 hours after an orthopedic surgery, combined with a brief confused state including disorientation of place and the inability to recognize his parents. During the period, he communicated in English, which he had learned during school classes but had never spoken outside of school. Further follow-up, including neuropsychological examination, revealed no indication of cognitive impairment.Conclusions: The exact pathophysiology of foreign language syndrome remains unclear, most specifically whether it is a syndrome of its own or a phenotype of emergence delirium. There is still much to be learned, and further research is needed. [ABSTRACT FROM AUTHOR]

Background: Stereotactic approaches to diffuse intrinsic pontine gliomas (DIPGs) remain essential due to advances in molecular biology and management, necessitating tissue sampling. Here we present an effective technique with a biopsy by robot-assisted transcerebellar approach. Method: Our procedure was performed using the ROSA robotic system and the OARM CT scan, which provided stereotactic conditions for this transcerebellar approach to brainstem lesions. Conclusion: The robot-assisted transcerebellar stereotactic approach remains essential to provide complications for biopsy of brainstem lesions. [ABSTRACT FROM AUTHOR]

The COVID‐19 pandemic has had an immense and worldwide impact. In light of future pandemics or subsequent waves of COVID‐19 it is crucial to focus on the ethical issues that were and still are raised in this COVID‐19 crisis. In this paper, we look at issues that are raised in the testing and tracing of patients with COVID‐19. We do this by highlighting and expanding on an approach suggested by Fineberg that could serve as a public health approach. In this way, we highlight several ethical issues. As regards testing, questions are raised such as whether it is ethical to use less reliable tests in order to increase testing capacity or minimize harm for patients. Another issue is how wide testing should be and whether selective testing is in accordance with principles of social justice. Patients who have recovered from COVID‐19 might have some degree of immunity but attributing certain 'immunopriviliges' raises ethical questions. The use of various tracing methodologies (mobile apps or databases and trained tracers) raised evident questions of social justice and privacy. We argue why it is key to always uphold a test of proportionality where a fair balance must be sought. [ABSTRACT FROM AUTHOR]

Population spread from a limited pool of founding propagules is at the basis of biological invasions. The size and genetic variation of these propagules eventually affect whether the invasion is successful or not. The inevitable bottleneck at introduction decreases genetic diversity, and therefore should affect population growth and spread. However, many heavily bottlenecked invasive populations have been successful in nature. Negative effects of a genetic bottleneck are typically considered to be relaxed in benign environments because of a release from stress. Despite its relevance to understand and predict invasions, empirical evidence on the role of genetic diversity in relation to habitat quality is largely lacking. We use the mite Tetranychus urticae Koch as a model to experimentally assess spread rate and size of genetically depleted inbred populations vs. enriched mixed populations. This was assessed in replicated linear patch systems consisting of benign (bean), challenging (tomato), or a gradient (bean to tomato) habitat. As expected, we found no effect of genetic diversity on population size in benign habitat but found that it increased population size in challenging habitat. However, we found that population spread rates were increased due to genetic diversity in the benign but not in the challenging habitat. Additionally, variance in spread was consistently higher in genetically poor populations and highest in the challenging habitat. Our experiment challenges the general view that a bottleneck in genetic variation decreases invasion success in challenging but not benign environments. [ABSTRACT FROM AUTHOR]

[Display omitted] • Particle size reduction into nanoscale improved solubility properties of model poorly soluble API Indomethacin. • Rheometer aids in the development and quality control of semisolid extrusion 3D printing inks containing nanocrystals. • Rheological behavior suggested that polymer/water ratio and nanocrystal load were critical material attributes. • A strong correlation between the printing ink viscosity and printing pressure was established. The importance of ink rheology to the outcome of 3D printing is well recognized. However, rheological properties of printing inks containing drug nanocrystals have not been widely investigated. Therefore, the objective of this study was to establish a correlation between the composition of nanocrystal printing ink, the ink rheology, and the entire printing process. Indomethacin was used as a model poorly soluble drug to produce nanosuspensions with improved solubility properties through particle size reduction. The nanosuspensions were further developed into semisolid extrusion 3D printing inks with varying nanocrystal and poloxamer 407 concentrations. Nanocrystals were found to affect the rheological properties of the printing inks both by being less self-supporting and having higher yielding resistances. During printing, nozzle blockages occurred. Nevertheless, all inks were found to be printable. Finally, the rheological properties of the inks were successfully correlated with various printing and product properties. Overall, these experiments shed new light on the rheological properties of printing inks containing nanocrystals. [ABSTRACT FROM AUTHOR]

• healthcare workers experienced adverse mental health during the COVID-19 pandemic. • treatment use for mental disorders in this population is increasing, but remains low. • barriers include being too ashamed, waiting lists, and no available treatment. • one third of spanish healthcare workers use benzodiazepines for mental health issues. • more resources are needed for mental health surveillance among healthcare workers. Little is known about healthcare workers' (HCW) use of healthcare services for mental disorders. This study presents data from a 16-month prospective cohort study of Spanish HCW (n = 4,809), recruited shortly after the COVID-19 pandemic onset, and assessed at four timepoints using web-based surveys. Use of health services among HCW with mental health conditions (i.e., those having a positive screen for mental disorders and/or suicidal thoughts and behaviours [STB]) was initially low (i.e., 18.2 %) but increased to 29.6 % at 16-month follow-up. Service use was positively associated with pre-pandemic mental health treatment (OR=1.99), a positive screen for major depressive disorder (OR=1.50), panic attacks (OR=1.74), suicidal thoughts and behaviours (OR=1.22), and experiencing severe role impairment (OR=1.33), and negatively associated with being female (OR = 0.69) and a higher daily number of work hours (OR=0.95). Around 30 % of HCW with mental health conditions used anxiolytics (benzodiazepines), especially medical doctors. Four out of ten HCW (39.0 %) with mental health conditions indicated a need for (additional) help, with most important barriers for service use being too ashamed, long waiting lists, and professional treatment not being available. Our findings delineate a clear mental health treatment gap among Spanish HCW. [ABSTRACT FROM AUTHOR]

Background: Ipilimumab has shown long-term overall survival (OS) in patients with advanced melanoma in clinical trials, but robust real-world evidence is lacking. We present long-term outcomes from the IMAGE study (NCT01511913) in patients receiving ipilimumab and/or non-ipilimumab (any approved treatment other than ipilimumab) systemic therapies.Methods: IMAGE was a multinational, prospective, observational study assessing adult patients with advanced melanoma treated with ipilimumab or non-ipilimumab systemic therapies between June 2012 and March 2015 with ≥3 years of follow-up. Adjusted OS curves based on multivariate Cox regression models included covariate effects. Safety and patient-reported outcomes were assessed.Results: Among 1356 patients, 1094 (81%) received ipilimumab and 262 (19%) received non-ipilimumab index therapy (systemic therapy [chemotherapy, anti-programmed death 1 antibodies, or BRAF ± MEK inhibitors], radiotherapy, and radiosurgery). In the overall population, median age was 64 years, 60% were male, 78% were from Europe, and 78% had received previous treatment for advanced melanoma. In the ipilimumab-treated cohort, 780 (71%) patients did not receive subsequent therapy (IPI-noOther) and 314 (29%) received subsequent non-ipilimumab therapy (IPI-Other) on study. In the non-ipilimumab-treated cohort, 205 (78%) patients remained on or received other subsequent non-ipilimumab therapy (Other-Other) and 57 (22%) received subsequent ipilimumab therapy (Other-IPI) on study. Among 1151 patients who received ipilimumab at any time during the study (IPI-noOther, IPI-Other, and Other-IPI), 296 (26%) reported CTCAE grade ≥ 3 treatment-related adverse events, most occurring in year 1. Ipilimumab-treated and non-ipilimumab-treated patients who switched therapy (IPI-Other and Other-IPI) had longer OS than those who did not switch (IPI-noOther and Other-Other). Patients with prior therapy who did not switch therapy (IPI-noOther and Other-Other) showed similar OS. In treatment-naive patients, those in the IPI-noOther group tended to have longer OS than those in the Other-Other group. Patient-reported outcomes were similar between treatment cohorts.Conclusions: With long-term follow-up (≥ 3 years), safety and OS in this real-world population of patients treated with ipilimumab 3 mg/kg were consistent with those reported in clinical trials. Patient-reported quality of life was maintained over the study period. OS analysis across both pretreated and treatment-naive patients suggested a beneficial role of ipilimumab early in treatment.Trial Registration: ClinicalTrials.gov , NCT01511913. Registered January 19, 2012 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01511913. [ABSTRACT FROM AUTHOR]

Background: Healthcare workers are a key occupational group at risk for suicidal thoughts and behaviors (STB). We investigated the prevalence and correlates of STB among hospital workers during the first wave of the Spain COVID‐19 outbreak (March–July 2020). Methods: Data come from the baseline assessment of a cohort of Spanish hospital workers (n = 5450), recruited from 10 hospitals just after the height of the coronavirus disease 2019 (COVID‐19) outbreak (May 5–July 23, 2020). Web‐based self‐report surveys assessed 30‐day STB, individual characteristics, and potentially modifiable contextual factors related to hospital workers' work and financial situation. Results: Thirty‐day STB prevalence was estimated at 8.4% (4.9% passive ideation only, 3.5% active ideation with or without a plan or attempt). A total of n = 6 professionals attempted suicide in the past 30 days. In adjusted models, 30‐day STB remained significantly associated with pre‐pandemic lifetime mood (odds ratio [OR] = 2.92) and anxiety disorder (OR = 1.90). Significant modifiable factors included a perceived lack of coordination, communication, personnel, or supervision at work (population‐attributable risk proportion [PARP] = 50.5%), and financial stress (PARP = 44.1%). Conclusions and Relevance: Thirty‐day STB among hospital workers during the first wave of the Spain COVID‐19 outbreak was high. Hospital preparedness for virus outbreaks should be increased, and strong governmental policy response is needed to increase financial security among hospital workers. [ABSTRACT FROM AUTHOR]