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Background: In septic shock, the classic fluid resuscitation strategy can lead to a potentially harmful positive fluid balance. This multicenter, randomized, single-blind, parallel, controlled pilot study assessed the effectiveness of a restrictive fluid strategy aiming to limit daily volume., Methods: Patients 18-85 years' old admitted to the ICU department of three French hospitals were eligible for inclusion if they had septic shock and were in the first 24 h of vasopressor infusion. Exclusion criteria were acute kidney injury requiring renal replacement therapy, end stage chronic kidney disease, and severe malnutrition. Patients were electronically randomized 1:1 to either an optimized fluid restriction (reducing fluid intake as much as possible in terms of maintenance fluids and fluids for drug dilution during the first 7 days) or standard fluid strategy. The primary outcome was cumulative fluid balance (ml/kg) in the first 5 days. Patients and statisticians were blinded to group arm, but not clinicians., Results: Between September 2021 and February 2023, 1201 patients were screened and 50 included, with two in the control group withdrawing, thus 48 patients were analyzed (24 in each group). In the first 5 days, the optimized restrictive strategy and control groups received 89.7 (IQR 35; 128.9) and 114.3 (IQR 78.8; 168.5) ml/kg of fluid, respectively (mean difference: 35.9 ml/kg [0.0; 71.8], p = 0.0506). After 5 days, the median cumulative fluid balance was 6.9 (IQR - 13.7; 52.1) and 35.0 (IQR - 7.9; 40.2) ml/kg in the optimized restrictive strategy and control groups, respectively (absolute difference 13.2 [95%CI - 15.2; 41.6], p = 0.42). After 28 days, mortality and the numbers of days alive without life support were similar between groups. The main adverse events were severe hypernatremia in 1 and 2 patients in the fluid restriction strategy and control groups, respectively, and acute kidney injury KDIGO 3 in 4 and 7 patients in the fluid restriction strategy and control groups, respectively., Conclusions: In ICU patients with septic shock, an optimized restrictive fluid strategy targeting hidden fluid intakes did not reduce the overall fluid balance at day 5. Trial registration ClinicalTrials.gov identifier NCT04947904, registered on 1 July 2021., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Comité de Protection des Personnes Sud-Méditerranée II (Number 2020-A01952-37). Written informed consent was obtained from patients or their legal surrogates. Consent for publication: Written informed consent was obtained from patients or their legal surrogates either before randomization or as soon as possible thereafter. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The 2014 chikungunya outbreak in the Dominican Republic resulted in intense local transmission, with high postoutbreak seroprevalence. The resulting population immunity will likely minimize risk for another large outbreak through 2035, but changes in population behavior or environmental conditions or emergence of different virus strains could lead to increased transmission.

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics., Competing Interests: Competing interests: S.L.Z. has acted as a consultant for Health Lumen. A.H. and R.T.L. have received funding from Pfizer Inc. R.T.L. has performed paid consultancy for Health Lumen and Fitfile Ltd. J.S.W. has acted as a consultant for MyoKardia, Pfizer, Foresite Labs and Health Lumen and received institutional support from Bristol Myers Squibb and Pfizer Inc. P.C. has received personal fees for consultancies, outside the present work, for Amicus, Pfizer Inc., Owkin and Bristol Myers Squibb. M.-P.D. declares holding equity in Dalcor Pharmaceuticals, unrelated to this work. The authors who are affiliated with deCODE genetics/Amgen Inc. and Regeneron Pharmaceuticals declare competing financial interests as employees. The other authors declare no competing interests., (© 2024. The Author(s).)

Dilated cardiomyopathy (DCM) is a heart muscle disease that represents an important cause of morbidity and mortality, yet causal mechanisms remain largely elusive. Here, we perform a large-scale genome-wide association study and multitrait analysis for DCM using 9,365 cases and 946,368 controls. We identify 70 genome-wide significant loci, which show broad replication in independent samples and map to 63 prioritized genes. Tissue, cell type and pathway enrichment analyses highlight the central role of the cardiomyocyte and contractile apparatus in DCM pathogenesis. Polygenic risk scores constructed from our genome-wide association study predict DCM across different ancestry groups, show differing contributions to DCM depending on rare pathogenic variant status and associate with systolic heart failure across various clinical settings. Mendelian randomization analyses reveal actionable potential causes of DCM, including higher bodyweight and higher systolic blood pressure. Our findings provide insights into the genetic architecture and mechanisms underlying DCM and myocardial function more broadly., Competing Interests: Competing interests: P.T.E. has received sponsored research support from Bayer AG, IBM Health, Bristol Myers Squibb and Pfizer; he has consulted for Bayer AG, Novartis and MyoKardia. K.G.A. has received sponsored research support from Sarepta Therapeutics and Bayer AG, and reports a research collaboration with Novartis. Y.M.P. is involved in the development of therapies for DCM as an advisor to Forbion and Medical Director at ARMGO pharma and CMO at Phlox Therapeutics. P.C. reports personal fees for consultancies, outside the present work, for Amicus, OWKIN, Pfizer and SANOFI. J.S.W. has received research support from Bristol Myers Squibb, and has acted as a consultant for MyoKardia, Pfizer, Foresite Labs, Health Lumen and Tenaya Therapeutics. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Despite almost a century of research on energetics in biological systems, we still cannot explain energy regulation in social groups, like ant colonies. How do individuals regulate their collective activity without a centralized control system? What is the role of social interactions in distributing the workload amongst group members? And how does the group save energy by avoiding being constantly active? We offer new insight into these questions by studying an intuitive compartmental model, calibrated with and compared to data on ant colonies. The model describes a previously unexplored balance between positive and negative social feedback driven by individual activity: when activity levels are low, the presence of active individuals stimulates inactive individuals to start working; when activity levels are high, however, active individuals inhibit each other, effectively capping the proportion of active individuals at any one time. Through the analysis of the system's stability, we demonstrate that this balance results in energetic spending at the group level growing proportionally slower than the group size. Our finding is reminiscent of Kleiber's law of metabolic scaling in unitary organisms and highlights the critical role of social interactions in driving the collective energetic efficiency of group-living organisms., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Porfiri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Individual immune responses to SARS-CoV-2 are well-studied, while the combined effect of these responses on population-level immune dynamics remains poorly understood. Given the key role of population immunity on pathogen transmission, delineation of the factors that drive population immune evolution has critical public health implications., Methods: We enrolled individuals 5 years and older selected using a multistage cluster survey approach in the Northwest and Southeast of the Dominican Republic. Paired blood samples were collected mid-pandemic (Aug 2021) and late pandemic (Nov 2022). We measured serum pan-immunoglobulin antibodies against the SARS-CoV-2 spike protein. Generalized Additive Models (GAMs) and random forest models were used to analyze the relationship between changes in antibody levels and various predictor variables. Principal component analysis and partial dependence plots further explored the relationships between predictors and antibody changes., Findings: We found a transformation in the distribution of antibody levels from an irregular to a normalized single peak Gaussian distribution that was driven by titre-dependent boosting. This led to the convergence of antibody levels around a common immune setpoint, irrespective of baseline titres and vaccination profile., Interpretation: Our results suggest that titre-dependent kinetics driven by widespread transmission direct the evolution of population immunity in a consistent manner. These findings have implications for targeted vaccination strategies and improved modeling of future transmission, providing a preliminary blueprint for understanding population immune dynamics that could guide public health and vaccine policy for SARS-CoV-2 and potentially other pathogens., Funding: The study was primarily funded by the Centers for Disease Control and Prevention grant U01GH002238 (EN). Salary support was provided by Wellcome Trust grant 206250/Z/17/Z (AK) and the Australian National Health and Medical Research Council Investigator grant APP1158469 (CLL)., Competing Interests: Declaration of interests EJN is the PI on a US Centers for Disease Control and Prevention (CDC) funded U01 award that funded the study. AK and CLL are co-investigators on the same award. DD, MdSA, SG, MCE, WD, GA, MB, and KWR have received salary support, consultancy fees, or travel paid through this award. BL is an employee of the US CDC. CTP, LC, IMS and RSR are employees of the Ministry of Ministry of Health and Social Assistance, Dominican Republic, that was subcontracted with funds from the US CDC award. AK is supported by the Wellcome Trust, UK. CLL is supported by the Australian National Health and Medical Research Council. CDC staff supported the design and manuscript editing. We declare no other competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Animal groups need to achieve and maintain consensus to minimize conflict among individuals and prevent group fragmentation. An excellent example of a consensus challenge is cooperative transport, where multiple individuals cooperate to move a large item together. This behaviour, regularly displayed by ants and humans only, requires individuals to agree on which direction to move in. Unlike humans, ants cannot use verbal communication but most likely rely on private information and/or mechanical forces sensed through the carried item to coordinate their behaviour. Here, we investigated how groups of weaver ants achieve consensus during cooperative transport using a tethered-object protocol, where ants had to transport a prey item that was tethered in place with a thin string. This protocol allows the decoupling of the movement of informed ants from that of uninformed individuals. We showed that weaver ants pool together the opinions of all group members to increase their navigational accuracy. We confirmed this result using a symmetry-breaking task, in which we challenged ants with navigating an open-ended corridor. Weaver ants are the first reported ant species to use a 'wisdom-of-the-crowd' strategy for cooperative transport, demonstrating that consensus mechanisms may differ according to the ecology of each species.

There is limited information on the compared performances of biological, serological. and molecular assays with high-throughput sequencing (HTS) for viral indexing in temperate fruit crops. Here, using a range of samples of predetermined virological status, we compared two performance criteria (inclusivity and analytical sensitivity) of enzyme-linked immunosorbent assay (ELISA), molecular hybridization, reverse transcription (RT)-PCR, and double-stranded RNA (dsRNA) HTS for the detection of a total of 14 viruses (10 genera) and four viroids (three genera). When undiluted samples from individual plants were used, ELISA had the lowest performance, with an overall detection rate of 68.7%, followed by RT-PCR (82.5%) and HTS (90.7%; 100% if considering only viruses). The lower performance of RT-PCR reflected the inability to amplify some isolates as a consequence of point mutations affecting primer-binding sites. In addition, HTS identified viruses that had not been identified by other assays in nearly two-thirds of the samples. Analysis of serial dilutions of fruit tree samples allowed comparison of analytical sensitivities for various viruses. ELISA showed the lowest analytical sensitivity, but RT-PCR showed higher analytical sensitivity than HTS for most of the samples. Overall, these results confirm the superiority of HTS over biological indexing in terms of speed and inclusivity and show that while the absolute analytical sensitivity of RT-PCR tends to be higher than that of HTS, PCR inclusivity is affected by viral genetic diversity. Taken together, these results make a strong case for the implementation of HTS-based approaches in fruit tree viral testing protocols supporting quarantine and certification programs., Competing Interests: The author(s) declare no conflict of interest.

Mass behavior is the rapid adoption of similar conduct by all group members, with potentially catastrophic outcomes such as mass panic. Yet, these negative consequences are rare in integrated social systems such as social insect colonies, thanks to mechanisms of social regulation. Here, we test the hypothesis that behavioral deactivation between active individuals is a powerful social regulator that reduces energetic spending in groups. Borrowing from scaling theories for human settlements and using behavioral data on harvester ants, we derive ties between the hypermetric scaling of the interaction network and the hypometric scaling of activity levels, both relative to the colony size. We use elements of economics theory and metabolic measurements collected with the behavioral data to link activity and metabolic scalings with group size. Our results support the idea that metabolic scaling across social systems is the product of different balances between their social regulation mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Objective: This study investigates the role of trust in shaping COVID-19 vaccine acceptance in the Dominican Republic (DR) during the COVID-19 pandemic., Design: Cross-sectional household survey., Setting: Randomly selected households across 134 clusters in the DR, from 30 June 2021 to 12 October 2021., Participants: 5999 participants ≥16 years of age were enrolled., Outcome Measures: COVID-19 vaccine hesitancy (CVH) data were collected from participants ≥16 years of age and analysed as both an ordinal and binary variable., Results: Overall, CVH was low (5.2% (95% CI 4.6% to 5.8%)), but more common among younger individuals, women and individuals of Mestizo ethnicity. Higher trust in local government, national government, scientists and local doctors (considered official sources) was associated with lower odds of CVH (OR 0.89 (95% CI 0.72 to 0.88), 0.89 (95% CI 0.81 to 0.98), 0.87 (95% CI 0.80 to 0.94) and 0.70 (95% CI 0.62 to 0.80), respectively). Higher trust in religious leaders, social media and traditional media (considered unofficial sources) was associated with higher odds of CVH, with respective ORs of 1.32 (95% CI 1.18 to 1.47), 1.30 (95% CI 1.19 to 1.41) and 1.08 (95% CI 0.97 to 1.22)., Conclusion: We report findings on CVH from a national household survey in the DR and identify overall low rates of CVH but marked heterogeneity by age, gender and ethnicity. Trust in unofficial versus official sources of information is associated with increased CVH. These findings highlight and quantify the importance of trust as a key parameter when considering public health communication strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Tick-borne bacteria of the genera Ehrlichia and Anaplasma cause several emerging human infectious diseases worldwide. In this study, we conduct an extensive survey for Ehrlichia and Anaplasma infections in the rainforests of the Amazon biome of French Guiana. Through molecular genetics and metagenomics reconstruction, we observe a high indigenous biodiversity of infections circulating among humans, wildlife, and ticks inhabiting these ecosystems. Molecular typing identifies these infections as highly endemic, with a majority of new strains and putative species specific to French Guiana. They are detected in unusual rainforest wild animals, suggesting they have distinctive sylvatic transmission cycles. They also present potential health hazards, as revealed by the detection of Candidatus Anaplasma sparouinense in human red blood cells and that of a new close relative of the human pathogen Ehrlichia ewingii, Candidatus Ehrlichia cajennense, in the tick species that most frequently bite humans in South America. The genome assembly of three new putative species obtained from human, sloth, and tick metagenomes further reveals the presence of major homologs of Ehrlichia and Anaplasma virulence factors. These observations converge to classify health hazards associated with Ehrlichia and Anaplasma infections in the Amazon biome as distinct from those in the Northern Hemisphere., (© 2024. The Author(s).)

Introduction: South Africa has one of the highest rates of internal migration on the continent, largely comprised of men seeking labour in urban centres. South African men who move within the country (internal migrants) are at higher risk than non-migrant men of acquiring HIV yet are less likely to test or use pre-exposure prophylaxis (PrEP). However, little is known about the mechanisms that link internal migration and challenges engaging in HIV services., Methods: We recruited 30 internal migrant men (born outside Gauteng Province) during August 2022 for in-depth qualitative interviews at two sites in Johannesburg (Gauteng) where migrants may gather, a factories workplace and a homeless shelter. Interviewers used open-ended questions, based in the Theory of Triadic Influence, to explore experiences and challenges with HIV testing and/or PrEP. A mixed deductive inductive content analytic approach was used to review data and explain why participants may or may not use these services., Results: Migrant men come to Johannesburg to find work, but unreliable income, daily stress and time constraints limit their availability to seek health services. While awareness of HIV testing is high, the fear of a positive diagnosis often overshadows the benefits. In addition, many men lack knowledge about the opportunity for PrEP should they test negative, though they express interest in the medication after learning about it. Additionally, these men struggle with adjusting to urban life, lack of social support and fear of potential stigma. Finally, the necessity to prioritize work combined with long wait times at clinics further restricts their access to HIV services. Despite these challenges, Johannesburg also presents opportunities for HIV services for migrant men, such as greater anonymity and availability of HIV information and services in the city as compared to their rural homes of origin., Conclusions: Bringing HIV services to migrant men at community sites may ease the burden of accessing these services. Including PrEP counselling and services alongside HIV testing may further encourage men to test, particularly if integrated into counselling for livelihood and coping strategies, as well as support for navigating health services in Johannesburg., (© 2024 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Tick-borne Apicomplexa encompass a group of parasites responsible for significant medical and veterinary diseases, including babesiosis, theileriosis, and hepatozoonosis. In this study, we investigated the presence and diversity of tick-borne Apicomplexa in wildlife and ticks inhabiting the Amazon rainforests of French Guiana. To this end, we conducted molecular screening and typing using 18S rRNA sequences on a collection of 1161 specimens belonging to 71 species, including 44 species of wild mammals, five species of passerines, and 22 species of ticks. We characterized eight genovariants of Babesia, Theileria, Hemolivia, and Hepatozoon parasites, some matching known species, while others suggested potential novel species. These parasites were detected in wild mammals, including opossums, sloths, armadillos, porcupines, margays, greater grisons, and ticks, but not in passerines. Finally, similarities with surveys conducted in Brazil highlight the specific sylvatic transmission cycles of South American tick-borne Apicomplexa., (© R. Koual et al., published by EDP Sciences, 2024.)

Fundamental knowledge gaps exist about the plasticity of cells from adult soma and the potential diversity of body shape and behavior in living constructs derived from genetically wild-type cells. Here anthrobots are introduced, a spheroid-shaped multicellular biological robot (biobot) platform with diameters ranging from 30 to 500 microns and cilia-powered locomotive abilities. Each Anthrobot begins as a single cell, derived from the adult human lung, and self-constructs into a multicellular motile biobot after being cultured in extra cellular matrix for 2 weeks and transferred into a minimally viscous habitat. Anthrobots exhibit diverse behaviors with motility patterns ranging from tight loops to straight lines and speeds ranging from 5-50 microns s -1 . The anatomical investigations reveal that this behavioral diversity is significantly correlated with their morphological diversity. Anthrobots can assume morphologies with fully polarized or wholly ciliated bodies and spherical or ellipsoidal shapes, each related to a distinct movement type. Anthrobots are found to be capable of traversing, and inducing rapid repair of scratches in, cultured human neural cell sheets in vitro. By controlling microenvironmental cues in bulk, novel structures, with new and unexpected behavior and biomedically-relevant capabilities, can be discovered in morphogenetic processes without direct genetic editing or manual sculpting., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Incidence of COVID-19 has been associated with sociodemographic factors. We investigated variations in SARS-CoV-2 seroprevalence at sub-national levels in the Dominican Republic and assessed potential factors influencing variation in regional-level seroprevalence. Data were collected in a three-stage cross-sectional national serosurvey from June to October 2021. Seroprevalence of antibodies against the SARS-CoV-2 spike protein (anti-S) was estimated and adjusted for selection probability, age, and sex. Multilevel logistic regression was used to estimate the effect of covariates on seropositivity for anti-S and correlates of 80% protection (PT 80 ) against symptomatic infection for the ancestral and Delta strains. A total of 6683 participants from 134 clusters in all 10 regions were enrolled. Anti-S, PT80 for the ancestral and Delta strains odds ratio varied across regions, Enriquillo presented significant higher odds for all outcomes compared with Yuma. Compared to being unvaccinated, receiving ≥2 doses of COVID-19 vaccine was associated with a significantly higher odds of anti-S positivity (OR 85.94, [10.95-674.33]) and PT 80 for the ancestral (OR 4.78, [2.15-10.62]) and Delta strains (OR 3.08, [1.57-9.65]) nationally and also for each region. Our results can help inform regional-level public health response, such as strategies to increase vaccination coverage in areas with low population immunity against currently circulating strains.

In connectivity models, land cover types are assigned cost values characterizing their resistance to species movements. Landscape genetic methods infer these values from the relationship between genetic differentiation and cost distances. The spatial heterogeneity of population sizes, and consequently genetic drift, is rarely included in this inference although it influences genetic differentiation. Similarly, migration rates and population spatial distributions potentially influence this inference. Here, we assessed the reliability of cost value inference under several migration rates, population spatial patterns and degrees of population size heterogeneity. Additionally, we assessed whether considering intra-population variables, here using gravity models, improved the inference when drift is spatially heterogeneous. We simulated several gene flow intensities between populations with varying local sizes and spatial distributions. We then fit gravity models of genetic distances as a function of (i) the 'true' cost distances driving simulations or alternative cost distances, and (ii) intra-population variables (population sizes, patch areas). We determined the conditions making the identification of the 'true' costs possible and assessed the contribution of intra-population variables to this objective. Overall, the inference ranked cost scenarios reliably in terms of similarity with the 'true' scenario (cost distance Mantel correlations), but this 'true' scenario rarely provided the best model goodness of fit. Ranking inaccuracies and failures to identify the 'true' scenario were more pronounced when migration was very restricted (<4 dispersal events/generation), population sizes were most heterogeneous and some populations were spatially aggregated. In these situations, considering intra-population variables helps identify cost scenarios reliably, thereby improving cost value inference from genetic data., (© 2023 John Wiley & Sons Ltd.)

Introduction: Childhood chronic diseases affect family functioning and well-being. The aim of this study was to measure the impact of caring for a child with PUV, and the factors that most impact the burden of care., Patients and Method: We gave a questionnaire on the familial impact of having a child with posterior urethral valves to all parents of a child included in the CIRCUP trial from 2015 onwards. The questionnaire included questions about the parents' demographics, health, professional, financial and marital status and how these evolved since the child's birth as well as the "impact on family scale" (IOFS), which gives a total score ranging from 15 (no impact) to 60 (maximum impact). We then analyzed both the results of the specific demographic questions as well as the factors which influenced the IOFS score., Results: We retrieved answers for 38/51 families (74.5% response rate). The average IOFS score was 23.7 (15-51). We observed that the child's creatinine level had an effect on the IOFS score ( p  = 0.02), as did the parent's gender ( p  = 0.008), health status ( p  = 0.015), being limited in activity since the birth of the child ( p  = 0.020), being penalized in one's job ( p  = 0.009), being supported in one's job ( p  = 0.002), and decreased income ( p  = 0.004). Out of 38 mother/father binomials, 8/33 (24.2%) declared that they were no longer in the same relationship afterwards., Conclusion: In conclusion, having a boy with PUV significantly impacts families. The risk of parental separation and decrease in revenue is significant. Strategies aiming to decrease these factors should be put in place as soon as possible., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Harper, Botto, Peycelon, Michel, Leclair, Garnier, Clermidi, Arnaud, Dariel, Dobremez, Faure, Fourcade, Boudaoud, Chaussy, Huiart, Bocquet, Ferdynus and Sauvat.)

Animals are often faced with time-critical decisions without prior information about their actions' outcomes. In such scenarios, individuals budget their investment into the task to cut their losses in case of an adverse outcome. In animal groups, this may be challenging because group members can only access local information, and consensus can only be achieved through distributed interactions among individuals. Here, we combined experimental analyses with theoretical modeling to investigate how groups modulate their investment into tasks in uncertain conditions. Workers of the arboreal weaver ant Oecophylla smaragdina form three-dimensional chains using their own bodies to bridge vertical gaps between existing trails and new areas to explore. The cost of a chain increases with its length because ants participating in the structure are prevented from performing other tasks. The payoffs of chain formation, however, remain unknown to the ants until the chain is complete and they can explore the new area. We demonstrate that weaver ants cap their investment into chains, and do not form complete chains when the gap is taller than 90 mm. We show that individual ants budget the time they spend in chains depending on their distance to the ground, and propose a distance-based model of chain formation that explains the emergence of this tradeoff without the need to invoke complex cognition. Our study provides insights into the proximate mechanisms that lead individuals to engage (or not) in collective actions and furthers our knowledge of how decentralized groups make adaptive decisions in uncertain conditions.

Habitat connectivity is a key objective of current conservation policies and is commonly modeled by landscape graphs (i.e., sets of habitat patches [nodes] connected by potential dispersal paths [links]). These graphs are often built based on expert opinion or species distribution models (SDMs) and therefore lack empirical validation from data more closely reflecting functional connectivity. Accordingly, we tested whether landscape graphs reflect how habitat connectivity influences gene flow, which is one of the main ecoevolutionary processes. To that purpose, we modeled the habitat network of a forest bird (plumbeous warbler [Setophaga plumbea]) on Guadeloupe with graphs based on expert opinion, Jacobs' specialization indices, and an SDM. We used genetic data (712 birds from 27 populations) to compute local genetic indices and pairwise genetic distances. Finally, we assessed the relationships between genetic distances or indices and cost distances or connectivity metrics with maximum-likelihood population-effects distance models and Spearman correlations between metrics. Overall, the landscape graphs reliably reflected the influence of connectivity on population genetic structure; validation R 2 was up to 0.30 and correlation coefficients were up to 0.71. Yet, the relationship among graph ecological relevance, data requirements, and construction and analysis methods was not straightforward because the graph based on the most complex construction method (species distribution modeling) sometimes had less ecological relevance than the others. Cross-validation methods and sensitivity analyzes allowed us to make the advantages and limitations of each construction method spatially explicit. We confirmed the relevance of landscape graphs for conservation modeling but recommend a case-specific consideration of the cost-effectiveness of their construction methods. We hope the replication of independent validation approaches across species and landscapes will strengthen the ecological relevance of connectivity models., (© 2023 The Authors. Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)

During their lifetime, superorganisms, like unitary organisms, undergo transformations that change the machinery of their collective behaviour. Here, we suggest that these transformations are largely understudied and propose that more systematic research into the ontogeny of collective behaviours is needed if we hope to better understand the link between proximate behavioural mechanisms and the development of collective adaptive functions. In particular, certain social insects engage in self-assemblage, forming dynamic and physically connected architectures with striking similarities to developing multicellular organisms, making them good model systems for ontogenetic studies of collective behaviour. However, exhaustive time series and three-dimensional data are required to thoroughly characterize the different life stages of the collective structures and the transitions between these stages. The well-established fields of embryology and developmental biology offer practical tools and theoretical frameworks that could speed up the acquisition of new knowledge about the formation, development, maturity and dissolution of social insect self-assemblages and, by extension, other superorganismal behaviours. We hope that this review will encourage an expansion of the ontogenetic perspective in the field of collective behaviour and, in particular, in self-assemblage research, which has far-reaching applications in robotics, computer science and regenerative medicine. This article is part of a discussion meeting issue 'Collective behaviour through time'.

Most studies of collective animal behaviour rely on short-term observations, and comparisons of collective behaviour across different species and contexts are rare. We therefore have a limited understanding of intra- and interspecific variation in collective behaviour over time, which is crucial if we are to understand the ecological and evolutionary processes that shape collective behaviour. Here, we study the collective motion of four species: shoals of stickleback fish ( Gasterosteus aculeatus ), flocks of homing pigeons ( Columba livia ), a herd of goats ( Capra aegagrus hircus ) and a troop of chacma baboons ( Papio ursinus ). First, we describe how local patterns (inter-neighbour distances and positions), and group patterns (group shape, speed and polarization) during collective motion differ across each system. Based on these, we place data from each species within a 'swarm space', affording comparisons and generating predictions about the collective motion across species and contexts. We encourage researchers to add their own data to update the 'swarm space' for future comparative work. Second, we investigate intraspecific variation in collective motion over time and provide guidance for researchers on when observations made over different time scales can result in confident inferences regarding species collective motion. This article is part of a discussion meeting issue 'Collective behaviour through time'.

To assess changes in SARS-CoV-2 spike binding antibody prevalence in the Dominican Republic and implications for immunologic protection against variants of concern, we prospectively enrolled 2,300 patients with undifferentiated febrile illnesses in a study during March 2021-August 2022. We tested serum samples for spike antibodies and tested nasopharyngeal samples for acute SARS-CoV-2 infection using a reverse transcription PCR nucleic acid amplification test. Geometric mean spike antibody titers increased from 6.6 (95% CI 5.1-8.7) binding antibody units (BAU)/mL during March-June 2021 to 1,332 (95% CI 1,055-1,682) BAU/mL during May-August 2022. Multivariable binomial odds ratios for acute infection were 0.55 (95% CI 0.40-0.74), 0.38 (95% CI 0.27-0.55), and 0.27 (95% CI 0.18-0.40) for the second, third, and fourth versus the first anti-spike quartile; findings were similar by viral strain. Combining serologic and virologic screening might enable monitoring of discrete population immunologic markers and their implications for emergent variant transmission.

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction., (© 2023. The Author(s).)

Self-organisation is the spontaneous emergence of spatio-temporal structures and patterns from the interaction of smaller individual units. Examples are found across many scales in very different systems and scientific disciplines, from physics, materials science and robotics to biology, geophysics and astronomy. Recent research has highlighted how self-organisation can be both mediated and controlled by confinement. Confinement is an action over a system that limits its units' translational and rotational degrees of freedom, thus also influencing the system's phase space probability density; it can function as either a catalyst or inhibitor of self-organisation. Confinement can then become a means to actively steer the emergence or suppression of collective phenomena in space and time. Here, to provide a common framework and perspective for future research, we examine the role of confinement in the self-organisation of soft-matter systems and identify overarching scientific challenges that need to be addressed to harness its full scientific and technological potential in soft matter and related fields. By drawing analogies with other disciplines, this framework will accelerate a common deeper understanding of self-organisation and trigger the development of innovative strategies to steer it using confinement, with impact on, e.g. , the design of smarter materials, tissue engineering for biomedicine and in guiding active matter.

Rationale and Objectives: Evaluate the implementation of an MRI scanner dedicated to emergencies on the management of patients admitted in the emergency department (ED) for binocular diplopia (BD)., Material and Methods: This was a prospective non-interventional single-center study from February 2018 to February 2020. A total of 110 patients were included: 52 patients during the first stage (29 women; 23 men; mean age 65.2 years); 58 during the second stage (29 women; 29 men; mean age 51.4 years). Patients underwent an enhanced-CT examination in the first stage and an MRI examination in the second stage. Criteria used to evaluate the new management of patients were: proportion of patients with an imaging diagnosis explaining BD, turnaround time (TT), ED length of stay (EDLOS), hospital admission rate, hospital length of stay (HLOS), number of MRI examinations requested as a second procedure for the same indication and radiation doses. Descriptive statistics were used to present results with Student's test for quantitative variables and chi-square test for qualitative variables., Results: Respectively 1 (1.92%) and 17 (29.31%) patients had definitive diagnosis in stages 1 and 2, with a significant difference in examination modalities (p=0.0001). The TT, EDLOS, hospital admission rate, and HLOS were not significantly different between the two stages. Radiation dose was significantly different between the two groups (p<0.05)., Conclusion: Implementation of an MRI scanner dedicated to emergencies can improve the etiological diagnostic performance of binocular diplopia and reduce patient's exposure to ionizing radiation without increasing the average turnaround time or emergency department length of stay., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

While ecologists agree that habitat loss has a substantial negative effect on biodiversity it is still very much a matter of debate whether habitat fragmentation has a lesser effect and whether this effect is positive or negative for biodiversity. Here, we assess the relative influence of tropical forest loss and fragmentation on the prevalence of vector-borne blood parasites of the genera Plasmodium and Haemoproteus in six forest bird species. We also determine whether habitat loss and fragmentation are associated with a rise or fall in prevalence. We sample more than 4000 individual birds from 58 forest sites in Guadeloupe and Martinique. Considering 34 host-parasite combinations independently and a fine characterization of the amount and spatial configuration of habitat, we use partial least square regressions to disentangle the relative effects of forest loss, forest fragmentation, landscape heterogeneity, and local weather conditions on spatial variability of parasite prevalence. Then we test for the magnitude and the sign of the effect of each environmental descriptor. Strikingly, we show that forest fragmentation explains twice as much of the variance in prevalence as habitat loss or landscape heterogeneity. In addition, habitat fragmentation leads to an overall rise in prevalence in Guadeloupe, but its effect is variable in Martinique. Both habitat loss and landscape heterogeneity exhibit taxon-specific effects. Our results suggest that habitat loss and fragmentation may have contrasting effects between tropical and temperate regions and that inter-specific interactions may not respond in the same way as more commonly used biodiversity metrics such as abundance and diversity., (© 2022 John Wiley & Sons Ltd.)

Background: Population-level SARS-CoV-2 immunological protection is poorly understood but can guide vaccination and non-pharmaceutical intervention priorities. Our objective was to characterise cumulative infections and immunological protection in the Dominican Republic., Methods: Household members ≥5 years were enrolled in a three-stage national household cluster serosurvey in the Dominican Republic. We measured pan-immunoglobulin antibodies against the SARS-CoV-2 spike (anti-S) and nucleocapsid glycoproteins, and pseudovirus neutralising activity against the ancestral and B.1.617.2 (Delta) strains. Seroprevalence and cumulative prior infections were weighted and adjusted for assay performance and seroreversion. Binary classification machine learning methods and pseudovirus neutralising correlates of protection were used to estimate 50% and 80% protection against symptomatic infection., Findings: Between 30 Jun and 12 Oct 2021 we enrolled 6683 individuals from 3832 households. We estimate that 85.0% (CI 82.1-88.0) of the ≥5 years population had been immunologically exposed and 77.5% (CI 71.3-83) had been previously infected. Protective immunity sufficient to provide at least 50% protection against symptomatic SARS-CoV-2 infection was estimated in 78.1% (CI 74.3-82) and 66.3% (CI 62.8-70) of the population for the ancestral and Delta strains respectively. Younger (5-14 years, OR 0.47 [CI 0.36-0.61]) and older (≥75-years, 0.40 [CI 0.28-0.56]) age, working outdoors (0.53 [0.39-0.73]), smoking (0.66 [0.52-0.84]), urban setting (1.30 [1.14-1.49]), and three vs no vaccine doses (18.41 [10.69-35.04]) were associated with 50% protection against the ancestral strain., Interpretation: Cumulative infections substantially exceeded prior estimates and overall immunological exposure was high. After controlling for confounders, markedly lower immunological protection was observed to the ancestral and Delta strains across certain subgroups, findings that can guide public health interventions and may be generalisable to other settings and viral strains., Funding: This study was funded by the US CDC., Competing Interests: E.J.N. is the PI on a US CDC funded U01 award that funded the study, and C.L.L., A.K., D.D., M.d.S.A., A.C.R., H.M., S.G., M.C.E., W.D., N.I., G.A., B.H., K.D., M.B., E.F., and L.I. have received salaries, consultancy fees, or travel paid through this award. E.Z.G., B.L., and A.E.-B. are employees of the US CDC. B.H., C.T., L.C., F.P., and R.S.-R. are employees of the Ministry of Ministry of Health and Social Assistance, Dominican Republic, that was subcontracted with funds from the US CDC award. A.K. and E.F. are supported by the Welcome Trust, UK. D.B. had a patent for COVID-19 vaccine licensed to Janssen. We declare no other competing interests., (© 2022 The Author(s).)

Objective: Boys with posterior urethral valves (PUV) present an increased risk of febrile urinary tract infection (fUTI). Identifying specific risk factors could allow for tailoring UTI prevention. The aim of this study was to use the data from the CIRCUP randomized controlled trial data to identify patient characteristics associated with a higher risk of fUTI., Patients and Methods: We performed a secondary analysis of the data from the CIRCUP randomized trial which included boys with PUV, randomized to circumcision and antibiotic prophylaxis vs. antibiotic prophylaxis alone and followed for 2 years. There was only 1 episode of fUTI in the circumcision group vs. 17 in the uncircumcised group. We therefore only studied the antibiotic prophylaxis alone group and compared age at prenatal diagnosis, size and weight at birth, presence of dilating VUR at diagnosis, abnormal DMSA scan at 2 months, and nadir creatinine between children who presented a fUTI and those who did not, as well as age at first episode of fUTI., Results: The study group consisted of 42 patients of which 17 presented at least on fUTI. Presence of dilating VUR was significantly associated with risk of fUTI ( p = 0.03), OR: 6 [CI 95% = (1.13-27.52)]. None of the other parameters were associated with increased risk of fUTI. We observed three distinct time periods for presenting a fUTI with a decrease in infection rate after the first 40 days of life, then at 240 days of life., Conclusion: In boys with PUV, presence of high-grade VUR is associated with a higher risk of presenting a fUTI. The rate of febrile UTIs seems to decrease after 9 months., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Harper, Botto, Peycelon, Michel, Leclair, Garnier, Clermidi, Arnaud, Dariel, Dobremez, Faure, Fourcade, Boudaoud, Chaussy, Collin, Huiart, Ferdynus, Bocquet and Sauvat.)

Introduction: The poor prognosis of ovarian carcinoma (OvC) is due to the advanced stage at diagnosis, a high risk of relapse after first-line therapies, and the lack of efficient treatments in the recurrence setting. Circulating tumor DNA (ctDNA) analysis is a promising tool to assess treatment-resistant OvC and may avoid iterative tissue biopsies. We aimed to evaluate the genomic profile of recurrent heavily pre-treated OvC., Methods: We performed tumor panel-based sequencing as well as low-coverage whole-genome sequencing (LC-WGS) of tumor and plasma collected in patients with ovarian cancer included in the PERMED-01 trial. Whole-exome sequencing (WES) data of plasma samples were also analyzed and compared to mutation and copy number alteration (CNA) tumor profiles. The prognostic value [progression-free survival (PFS)] of these alterations was assessed in an exploratory analysis., Results: Tumor and plasma genomic analyses were done for 24 patients with heavily pretreated OvC [67% high-grade serous carcinoma (HGSC)]. Tumor mutation burden was low (median 2.04 mutations/Mb) and the most frequent mutated gene was TP53 (94% of HGSC). Tumor CNAs were frequent with a median of 50% of genome altered fraction. Plasma LC-WGS and WES detected ctDNA in 21/24 cases (88%) with a median tumor fraction of 12.7%. We observed a low correlation between plasma and tumor CNA profiles. However, this correlation was significant in cases with the highest circulating tumor fraction. Plasma genome altered fraction and plasma mutation burden ( p  = 0.011 and p = 0.041, respectively, log-rank tests) were associated with PFS., Conclusions: Combination of LC-WGS and WES can detect ctDNA in most pre-treated OvCs. Some ctDNA characteristics, such as genome altered fraction and plasma mutation burden, showed prognostic value. ctDNA assessment with LC-WGS may be a promising and non-expansive tool to evaluate disease evolution in this disease with high genomic instability., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02342158, identifier NCT02342158., Competing Interests: AnG declares nonfinancial support from Novartis (travel, accommodation, and meeting registration fees). RS declares research grants from EISAI and AstraZeneca; advisory board for Roche, GSK, and Novartis; non-financial support (travel, accommodation, and meeting registration fees) from Pfizer, Roche, GSK, BMS, and AstraZeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sabatier, Garnier, Guille, Carbuccia, Pakradouni, Adelaide, Provansal, Cappiello, Rousseau, Chaffanet, Birnbaum, Mamessier, Gonçalves and Bertucci.)

Antibody-drug conjugates (ADC) represent a fast-growing drug class in oncology. However, ADCs are associated with resistance, and therapies able to overcome it are of utmost importance. Recently, enfortumab vedotin-ejfv (EV) was approved in nectin-4+ metastatic urothelial cancer. We previously described PVRL4/nectin-4 as a new therapeutic target in breast cancer and produced an efficient EV-like ADC comprising a human anti-nectin-4 mAb conjugated to monomethyl auristatin-E (MMAE) named N41mab-vcMMAE. To study the consequence of the long-term treatment with this ADC, we developed a preclinical breast cancer model in mice, and report a mechanism of resistance to N41mab-vcMMAE after 9-month treatment and a way to reverse it. RNA-sequencing pointed to an upregulation in resistant tumors of ABCB1 expression, encoding the multidrug resistance protein MDR-1/P-glycoprotein (P-gp), associated with focal gene amplification and high protein expression. Sensitivity to N41mab-vcMMAE of the resistant model was restored in vitro by P-gp pharmacologic inhibitors, like tariquidar. P-gp is expressed in a variety of normal tissues. By delivering the drug to the tumor more specifically than classical chemotherapy, we hypothesized that the combined use of ADC with P-gp inhibitors might reverse resistance in vivo without toxicity. Indeed, we showed that the tariquidar/N41mab-vcMMAE combination was well tolerated and induced a rapid regression of ADC-resistant tumors in mice. In contrast, the tariquidar/docetaxel combination was toxic and poorly efficient. These results show that ABC transporter inhibitors can be safely used with ADC to reverse ADC-induced resistance and open new opportunities in the fight against multidrug resistance., (©2022 American Association for Cancer Research.)

Introduction: The prognosis of advanced urological cancers (AUC) remains unfavorable, and few data are available regarding precision medicine., Methods: the PERMED-01 prospective clinical trial assessed the impact of molecular profiling in adults with refractory advanced solid cancer, in terms of number of patients with tumor actionable genetic alterations (AGA), feasibility, description of molecular alterations, treatment, and clinical outcome. We present here those results in the 64 patients enrolled with AUC. DNA extracted from a new tumor biopsy was profiled in real-time (targeted NGS, whole-genome array-comparative genomic hybridization), and the results were discussed during a weekly molecular tumor board meeting., Results: a complete molecular profile was obtained in 49 patients (77%). Thirty-eight (59%) had at least one AGA. Twelve (19%) received a matched therapy on progression, of which 42% had a PFS2/PFS1 ratio ≥ 1.3 versus 5% in the "non-matched therapy group" ( n = 25). The objective response and disease control rates were higher in the "matched therapy group" (33% and 58%, respectively) than in the "non-matched therapy group" (13% and 22%), as was the 6-month OS (75% vs. 42%)., Conclusion: the profiling of a newly biopsied tumor sample identified AGA in 59% of patients with AUC, led to "matched therapy" in 19%, and provided clinical benefit in 8%.

The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently activated in HER2-negative breast cancer and may play a role in taxane resistance. The phase IB/II TAKTIC trial (NCT01980277) has shown that combining a dual AKT and p70 ribosomal protein S6 kinase (p70S6K) inhibitor (LY2780301) taken orally with weekly paclitaxel in HER2-negative advanced breast cancer is feasible, with preliminary evidence of efficacy. We wanted to explore whether circulating tumor DNA (ctDNA) may be a surrogate marker of treatment efficacy in this setting. Serial plasma samples were collected and cell-free DNA was sequenced using low-coverage whole-genome sequencing, and analysis was completed with droplet digital polymerase chain reaction (PCR) for some patients with driver mutations. Baseline tumor fraction (TF) and TF after 7 weeks on treatment were compared to progression-free survival (PFS) and the overall response rate. We also explored circulating copy number alterations associated with treatment failure. Of the 51 patients enrolled in the TAKTIC trial, at least one plasma sample was available for 44 cases (96 timepoints). All patients with tumor TP53, PI3KCA, or AKT1 mutations harbored at least one of these alterations in plasma. TF at inclusion was correlated with PFS (6m-PFS was 92% for ctDNAneg patients vs 68% for ctDNApos cases; hazard ratio [HR] = 3.45, 95% confidence interval [CI] [1.34-8.90], P = 0.007). ctDNA status at week 7 was not correlated with prognosis. Even though most circulating copy number alterations were conserved at disease progression, some genomic regions of interest were altered in post-progression samples. In conclusion, ctDNA detection at baseline was associated with shorter PFS in patients included in the TAKTIC trial. Plasma-based copy number analysis may help to identify alterations involved in resistance to treatment., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background and Aims: Coronavirus disease 2019 (COVID-19) is a serious public health issue that became rapidly pandemic. Liver injury and comorbidities, including metabolic syndrome, are associated with severe forms of the disease. This study sought to investigate liver injury, clinical features, and risk factors in patients with mild, moderate, and severe COVID-19., Methods: We retrospectively included all consecutive patients hospitalized with laboratory-confirmed COVID-19 between February, 22 and May 15, 2020 at the emergency rooms of a French tertiary hospital. Medical history, symptoms, biological and imaging data were collected., Results: Among the 1381 hospitalizations for COVID-19, 719 patients underwent liver tests on admission and 496 (68.9%) patients displayed abnormal liver tests. Aspartate aminotransferase was most commonly abnormal in 57% of cases, followed by gamma-glutamyl transferase, alanine aminotransferase, albumin, alkaline phosphatase, and total bilirubin in 56.5%, 35.9%, 18.4%, 11.4%, and 5.8%. The presence of hepatocellular type more than 2xULN was associated with a higher risk of hospitalization and a worse course of severe disease (odd ratio [OR] 5.599; 95%CI: 1.27-23.86; p = 0.021; OR 3.404; 95% CI: 2.12-5.47; p < 0.001, respectively). A higher NAFLD fibrosis score was associated with a higher risk of hospitalization (OR 1.754; 95%CI: 1.27-2.43, p < 0.001). In multivariate analyses, patients with high fibrosis-4 index had a 3-fold greater risk of severe disease (p < 0.001)., Conclusion: Abnormal liver tests are common in patients with COVID-19 and could predict the outcome. Patients with non-alcoholic fatty liver disease and liver fibrosis are at higher risk of progressing to severe COVID-19., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Biological systems must adjust to changing external conditions, and their resilience depends on their control mechanisms. How is dynamic control implemented in noisy, decentralized systems? Army ants' self-assembled bridges are built on unstable features, like leaves, which frequently move. Using field experiments and simulations, we characterize the bridges' response as the gaps they span change in size, identify the control mechanism, and explore how this emerges from individuals' decisions. For a given gap size, bridges were larger after the gap increased rather than decreased. This hysteresis was best explained by an accumulator model, in which individual decisions to join or leave a bridge depend on the difference between its current and equilibrium state. This produces robust collective structures that adjust to lasting perturbations while ignoring small, momentary shifts. Our field data support separate joining and leaving cues; joining is prompted by high bridge performance and leaving by an excess of ants. This leads to stabilizing hysteresis, an important feature of many biological and engineered systems., (© 2022. The Author(s).)

Rationale/objectives: SARS-CoV-2 is the cause of worldwide COVID-19, which severity has been linked to the immune and inflammatory response. Here, we investigate Torquetenovirus (TTV) DNA load - a marker reflecting the intensity of the overall immune response - as well as SARS-CoV-2 RNAemia and IgM/IgG antibodies in COVID-19-positive patients., Methods: Two hundred and fifteen COVID-19-positive patients were enrolled, including 87 severe cases and 128 mild-moderate cases. SARS-CoV-2 RNAemia and IgM/IgG antibodies, as well as TTV DNA loads, were measured on longitudinal plasma samples., Results: The rate of severe cases was higher in patients with low TTV DNA load in plasma considering a threshold of 700 copies/mL. In severe patients, SARS-CoV-2 RNAemia positivity rates were higher than those in mild-moderate cases at any timepoint. When combined, TTV DNA load and SARS-CoV-2 RNAemia allowed to predict the outcome of COVID-19 infection, with a higher risk (HR=12.4) of ICU admission in patients with low TTV DNA load and positive SARS-CoV-2 RNAemia., Conclusions: TTV DNA load and SARS-CoV-2 RNAemia may be effective, non-invasive markers reflecting disease severity and poor outcome that could be conveniently measured in a clinical laboratory setting, as soon as COVID-19 diagnosis is made., (Copyright © 2022. Published by Elsevier B.V.)

Circulating tumor cells have a strong potential as a quasi-non-invasive tool for setting up a precision medicine strategy for cancer patients. Using a second-generation "filtration-based" technology to isolate CTCs, the Screencell™ technology (Sarcelles, France), we performed a large and simultaneous analysis of all atypical circulating tumor cells ( aCTCs ) isolated from the blood of metastatic breast cancer (mBC) patients. We correlated their presence with clinicopathological and survival data. We included 91 mBC patients from the PERMED-01 study. The median number of aCTCs was 8.3 per mL of blood. Three subsets of aCTCs , absent from controls, were observed in patients: single ( s-aCTCs ), circulating tumor micro-emboli ( CTM ), and giant-aCTCs ( g-aCTCs ). The presence of g-aCTCs was associated with shorter progression free survival and overall survival. This study highlights the heterogeneity of aCTCs in mBC patients both at the cytomorphological and molecular levels. In addition, it suggests the usefulness of the g-aCTC subset as a prognostic factor and a potential stratification tool to treat late-stage mBC patients and improve their chances of benefiting from early clinical trials.

Genetic structure, i.e. intra-population genetic diversity and inter-population genetic differentiation, is influenced by the amount and spatial configuration of habitat. Measuring the amount of reachable habitat (ARH) makes it possible to describe habitat patterns by considering intra-patch and inter-patch connectivity, dispersal capacities and matrix resistance. Complementary ARH metrics computed under various resistance scenarios are expected to reflect both drift and gene flow influence on genetic structure. Using an empirical genetic dataset concerning the large marsh grasshopper (Stethophyma grossum), we tested whether ARH metrics are good predictors of genetic structure. We further investigated (i) how the components of the ARH influence genetic structure and (ii) which resistance scenario best explains these relationships. We computed local genetic diversity and genetic differentiation indices in genetic graphs, and ARH metrics in the unified and flexible framework offered by landscape graphs, and we tested the relationships between these variables. ARH metrics were relevant predictors of the two components of genetic structure, providing an advantage over commonly used habitat metrics. Although allelic richness was significantly explained by three complementary ARH metrics in the best PLS regression model, private allelic richness and MIW indices were essentially related with the ARH measured outside the focal patch. Considering several matrix resistance scenarios was also key for explaining the different genetic responses. We thus call for further use of ARH metrics in landscape genetics to explain the influence of habitat patterns on the different components of genetic structure., (© 2021. The Author(s), under exclusive licence to The Genetics Society.)

Selective harvest, such as poaching, impacts group-living animals directly through mortality of individuals with desirable traits, and indirectly by altering the structure of their social networks. Understanding the relationship between disturbance-induced, structural network changes and group performance in wild animals remains an outstanding problem. To address this problem, we evaluated the immediate effect of disturbance on group sociality in African savanna elephants-an example, group-living species threatened by poaching. Drawing on static association data from ten free-ranging groups, we constructed one empirically based, population-wide network and 100 virtual networks; performed a series of experiments 'poaching' the oldest, socially central or random individuals; and quantified the immediate change in the theoretical indices of network connectivity and efficiency of social diffusion. Although the social networks never broke down, targeted elimination of the socially central conspecifics, regardless of age, decreased network connectivity and efficiency. These findings hint at the need to further study resilience by modeling network reorganization and interaction-mediated socioecological learning, empirical data permitting. The main contribution of our work is in quantifying connectivity together with global efficiency in multiple social networks that feature the sociodemographic diversity likely found in wild elephant populations. The basic design of our simulation makes it adaptable for hypothesis testing about the consequences of anthropogenic disturbance or lethal management on social interactions in a variety of group-living species with limited, real-world data., Competing Interests: The authors have declared that no competing interests exist.

Background: Boys with posterior urethral valves (PUVs) have an increased risk of febrile urinary tract infections (fUTIs). Circumcision is believed to reduce the risk of fUTIs in boys, although there are no randomized trials demonstrating this., Objective: To determine the effect of circumcision on the risk of fUTIs in boys with PUVs., Design, Setting, and Participants: A clinical randomized trial that ran between August 2012 and July 2017 was conducted. The trial was multicentric, including 13 referral centers for pediatric urology. Male boys, aged 1-28 d, diagnosed with posterior urethral valves, confirmed by voiding cystogram, were included. The exclusion criteria included presence of a genital malformation contraindicating performing a circumcision., Intervention: Participants were randomized to neonatal circumcision + antibiotic prophylaxis (CATB) or antibiotic prophylaxis alone (ATB), and followed for 2 yr., Outcome Measurements and Statistical Analysis: The primary outcome was a risk of presenting fUTIs in each group. An fUTI was defined as fever (>38.5 °C) with evidence of pyuria and culture-proven infection on urinalysis, obtained by urethral catheterization or suprapubic aspiration. A bivariate analysis of the primary outcome was performed using the Kaplan-Meier method., Results and Limitations: In total, 91 patients were included: 49 in group CATB and 42 in group ATB. The probability of presenting an fUTI was 20% in group ATB versus 3% in group CATB. The hazard ratio of presenting an fUTI within 2 yr in the ATB group compared with that in the CATB group was 10.3 (95% confidence interval: 1.3-82.5). Sixty-four children (70.3%) had a complete follow-up at 2 yr of age., Conclusions: Circumcision significantly decreases the risk of presenting an fUTI in boys with PUVs., Patient Summary: In this report, we compared, in a multicentric trial, the number of febrile urinary tract infections (UTIs) in boys with posterior urethral valves who had either antibiotic prophylaxis alone or antibiotic prophylaxis and circumcision. We found that those who had a circumcision had a significantly lower risk of febrile UTIs., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Hormone-resistant HER2-negative or triple-negative advanced breast cancers (ABC) are routinely treated with paclitaxel chemotherapy. LY2780301 is a dual inhibitor of p70 ribosomal protein S6 kinase and AKT. The TAKTIC study aimed at exploring the combination of paclitaxel and LY2780301 in this population., Methods: In this multicentric phase Ib/II trial, we enrolled patients with HER2-negative ABC, with (phase IB) or without (phase II) prior to cytotoxic treatment for advanced disease. Oral LY2780301 was administered once daily in combination with intravenous weekly paclitaxel. Primary endpoints were to determine the recommended phase II dose (RP2D) of the combination of LY2780301 with weekly paclitaxel (phase Ib), and to estimate a 6 months objective response rate (ORR) (phase II) in patients with HER2-negative ABC, both in the overall patient population and in cases with activation of the PI3K/AKT pathway (PI3KAKT+)., Results: A total of 51 patients were enrolled; RP2D was LY2780301 500 mg QD+ paclitaxel 80 mg/m 2 . Main drug-related adverse events noted in phase Ib included neuropathy (75% of patients, grade 3-4 in 8%), asthenia (58% of patients, no grade 3-4), and ungual toxicity (50% of patients, grade 3-4 in 25%). They were similar in the phase II part, except that 14% of patients experienced pneumonia (grade 3-4 in 6%). In the phase II part, 6-month ORR in the overall population and in PI3KAKT+ subgroup were, respectively, 63.9% [48.8-76.8] and 55% [35-73.7]., Conclusion: Combining LY2780301 and weekly paclitaxel in patients with HER2-negative ABC was feasible with preliminary evidence of efficacy in both the overall population and the PI3KAKT+ subgroup., Trial Registration Id: NCT01980277., Competing Interests: Conflict of interest statement CV received research a grant from BMS, participated in the advisory board for Pfizer and Novartis. AG received non-financial support from Roche, Novartis, AstraZeneca and Pfizer. RS received research grants from EISAI and AstraZeneca, participated in the advisory board for GSK, Pfizer, Roche and Novartis and received non-financial support from Pfizer, Roche, GSK, Novartis, and AstraZeneca. All remaining authors have declared no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Seedling recruitment is a bottleneck for population dynamics and range shift. The vital rates linked to recruitment by seed are impacted by amplified drought induced by climate change. In the Mediterranean region, autumn and winter seedling emergence and mortality may have strong impact on the overall seedling recruitment. However, studies focusing on the temporal dynamic of recruitment during these seasons are rare. This study was performed in a deciduous Mediterranean oak forest located in southern France and quantifies the impact of amplified drought conditions on autumn and winter seedling emergence and seedling mortality rates of two herbaceous plant species with meso-Mediterranean and supra-Mediterranean distribution (respectively, Silene italica and Silene nutans ). Seedlings were followed from October 2019 to May 2020 in both undisturbed and disturbed plots where the litter and the aboveground biomass have been removed to create open microsites. Amplified drought conditions reduced seedling emergence and increased seedling mortality for both Silene species but these negative effects were dependent on soil disturbance conditions. Emergence of S. italica decreased only in undisturbed plots (-7%) whereas emergence of S .  nutans decreased only in disturbed plots (-10%) under amplified drought conditions. The seedling mortality rate of S .  italica was 51% higher under amplified drought conditions in undisturbed plots while that of S .  nutans was 38% higher in disturbed plots. Aridification due to lower precipitation in the Mediterranean region will negatively impact the seedling recruitment of these two Silene species. Climate change effects on early vital rates may likely have major negative impacts on the overall population dynamic., (© 2021 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Objective: To determine which patients should benefit from the interposition of a well-vascularized flap between the neourethra and the penile skin and if it should be performed even in mild hypospadias., Patients and Methods: A retrospective study on patients with a primary hypospadias repair was performed (2003-2017). Only patients undergoing urethroplasty based on the principle of a tubularization were selected to ensure comparable groups. Patients were assigned in two groups according to the use or not of a cover flap. Univariate analysis and adjusted logistic regression were used to evaluate the relation between postoperative complications, the severity of hypospadias, the use of flap and patients' characteristics., Results: Three-hundred and seventy-six patients were included with anterior (59.3%), midshaft (27.4%) and posterior hypospadias (13.3%). The median follow-up was 54 months (24 months-17 years). The overall rate of fistula was 11.7% (n = 44). Comparing the outcome in children with flap (n = 217) to controls (n = 159) showed that the use of a flap reduces the rate of fistula (6.5 vs 18.9%, p < 0.001). Stratification of the study according to the phenotype reveals that the more severe the hypospadias, the more protective was the flap (OR = 2.6 for anterior, 5.5 for midpenile, 7.1 for posterior hypospadias). The flap remains nevertheless significantly effective whatever the phenotype (p < 0.05 for anterior, p = 0.01 for midpenile, p = 0.02 for posterior hypospadias)., Conclusions: The more severe the hypospadias, the more effective is the cover flap to avoid fistula. It remains nevertheless suitable even in anterior hypospadias and the use of a cover flap should not be limited to the surgery of severe phenotypes., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure., Methods and Results: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene., Conclusion: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: The benefit of precision medicine based on relatively limited gene sets and often-archived samples remains unproven. PERMED-01 (NCT02342158) was a prospective monocentric clinical trial assessing, in adults with advanced solid cancer, the feasibility and impact of extensive molecular profiling applied to newly biopsied tumor sample and based on targeted NGS (t-NGS) of the largest gene panel to date and whole-genome array-comparative genomic hybridization (aCGH) with assessment of single-gene alterations and clinically relevant genomic scores., Methods: Eligible patients with refractory cancer had one tumor lesion accessible to biopsy. Extracted tumor DNA was profiled by t-NGS and aCGH. We assessed alterations of 802 "candidate cancer" genes and global genomic scores, such as homologous recombination deficiency (HRD) score and tumor mutational burden. The primary endpoint was the number of patients with actionable genetic alterations (AGAs). Secondary endpoints herein reported included a description of patients with AGA who received a "matched therapy" and their clinical outcome, and a comparison of AGA identification with t-NGS and aCGH versus whole-exome sequencing (WES)., Results: Between November 2014 and September 2019, we enrolled 550 patients heavily pretreated. An exploitable complete molecular profile was obtained in 441/550 patients (80%). At least one AGA, defined in real time by our molecular tumor board, was found in 393/550 patients (71%, two-sided 90%CI 68-75%). Only 94/550 patients (17%, 95%CI 14-21) received an "AGA-matched therapy" on progression. The most frequent AGAs leading to "matched therapy" included PIK3CA mutations, KRAS mutations/amplifications, PTEN deletions/mutations, ERBB2 amplifications/mutations, and BRCA1/2 mutations. Such "matched therapy" improved by at least 1.3-fold the progression-free survival on matched therapy (PFS2) compared to PFS on prior therapy (PFS1) in 36% of cases, representing 6% of the enrolled patients. Within patients with AGA treated on progression, the use of "matched therapy" was the sole variable associated with an improved PFS2/PFS1 ratio. Objective responses were observed in 19% of patients treated with "matched therapy," and 6-month overall survival (OS) was 62% (95%CI 52-73). In a subset of 112 metastatic breast cancers, WES did not provide benefit in term of AGA identification when compared with t-NGS/aCGH., Conclusions: Extensive molecular profiling of a newly biopsied tumor sample identified AGA in most of cases, leading to delivery of a "matched therapy" in 17% of screened patients, of which 36% derived clinical benefit. WES did not seem to improve these results., Trial Registration: ID-RCB identifier: 2014-A00966-41; ClinicalTrials.gov identifier: NCT02342158 .

Graph-theoretic approaches have relevant applications in landscape genetic analyses. When species form populations in discrete habitat patches, genetic graphs can be used (a) to identify direct dispersal paths followed by propagules or (b) to quantify landscape effects on multi-generational gene flow. However, the influence of their construction parameters remains to be explored. Using a simulation approach, we constructed genetic graphs using several pruning methods (geographical distance thresholds, topological constraints, statistical inference) and genetic distances to weight graph links (F ST , D PS , Euclidean genetic distances). We then compared the capacity of these different graphs to (a) identify the precise topology of the dispersal network and (b) to infer landscape resistance to gene flow from the relationship between cost-distances and genetic distances. Although not always clear-cut, our results showed that methods based on geographical distance thresholds seem to better identify dispersal networks in most cases. More interestingly, our study demonstrates that a sub-selection of pairwise distances through graph pruning (thereby reducing the number of data points) can counter-intuitively lead to improved inferences of landscape effects on dispersal. Finally, we showed that genetic distances such as the D PS or Euclidean genetic distances should be preferred over the F ST for landscape effect inference as they respond faster to landscape changes., (© 2021 John Wiley & Sons Ltd.)

An inherent strength of evolved collective systems is their ability to rapidly adapt to dynamic environmental conditions, offering resilience in the face of disruption. This is thought to arise when individual sensory inputs are filtered through local interactions, producing an adaptive response at the group level. To understand how simple rules encoded at the individual level can lead to the emergence of robust group-level (or distributed) control, we examined structures we call "scaffolds," self-assembled by Eciton burchellii army ants on inclined surfaces that aid travel during foraging and migration. We conducted field experiments with wild E. burchellii colonies, manipulating the slope over which ants traversed, to examine the formation of scaffolds and their effects on foraging traffic. Our results show that scaffolds regularly form on inclined surfaces and that they reduce losses of foragers and prey, by reducing slipping and/or falling of ants, thus facilitating traffic flow. We describe the relative effects of environmental geometry and traffic on their growth and present a theoretical model to examine how the individual behaviors underlying scaffold formation drive group-level effects. Our model describes scaffold growth as a control response at the collective level that can emerge from individual error correction, requiring no complex communication among ants. We show that this model captures the dynamics observed in our experiments and is able to predict the growth-and final size-of scaffolds, and we show how the analytical solution allows for estimation of these dynamics., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Smooth Muscle Cells (SMC) are unique amongst all muscle cells in their capacity to modulate their phenotype. Indeed, SMCs do not terminally differentiate but instead harbour a remarkable capacity to dedifferentiate, switching between a quiescent contractile state and a highly proliferative and migratory phenotype, a quality often associated to SMC dysfunction. However, phenotypic plasticity remains poorly examined in the field of gastroenterology in particular in pathologies in which gut motor activity is impaired. Here, we assessed SMC status in biopsies of infants with chronic intestinal pseudo-obstruction (CIPO) syndrome, a life-threatening intestinal motility disorder. We showed that CIPO-SMCs harbour a decreased level of contractile markers. This phenotype is accompanied by an increase in Platelet-Derived Growth Factor Receptor-alpha (PDGFRA) expression. We showed that this modulation occurs without origin-related differences in CIPO circular and longitudinal-derived SMCs. As we characterized PDGFRA as a marker of digestive mesenchymal progenitors during embryogenesis, our results suggest a phenotypic switch of the CIPO-SMC towards an undifferentiated stage. The development of CIPO-SMC culture and the characterization of SMC phenotypic switch should enable us to design therapeutic approaches to promote SMC differentiation in CIPO., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Robot swarms have, to date, been constructed from artificial materials. Motile biological constructs have been created from muscle cells grown on precisely shaped scaffolds. However, the exploitation of emergent self-organization and functional plasticity into a self-directed living machine has remained a major challenge. We report here a method for generation of in vitro biological robots from frog ( Xenopus laevis ) cells. These xenobots exhibit coordinated locomotion via cilia present on their surface. These cilia arise through normal tissue patterning and do not require complicated construction methods or genomic editing, making production amenable to high-throughput projects. The biological robots arise by cellular self-organization and do not require scaffolds or microprinting; the amphibian cells are highly amenable to surgical, genetic, chemical, and optical stimulation during the self-assembly process. We show that the xenobots can navigate aqueous environments in diverse ways, heal after damage, and show emergent group behaviors. We constructed a computational model to predict useful collective behaviors that can be elicited from a xenobot swarm. In addition, we provide proof of principle for a writable molecular memory using a photoconvertible protein that can record exposure to a specific wavelength of light. Together, these results introduce a platform that can be used to study many aspects of self-assembly, swarm behavior, and synthetic bioengineering, as well as provide versatile, soft-body living machines for numerous practical applications in biomedicine and the environment., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)