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Abstract Fluoroquinolone resistance in E. coli isolates from livestock in Europe remains high despite EMA restrictions on fluoroquinolone use in animals. However, flumequine, a quinolone not classified as a fluoroquinolone by various regulatory bodies, is still used in livestock in the Netherlands, Belgium, Greece and France. We investigated whether flumequine selects for the same resistance mechanisms in E. coli. Resistant and non-resistant E. coli isolates were obtained from caecal fermentation assays and broilers exposed to concentrations of flumequine and enrofloxacin. Flumequine usage leads to an approximately 3-fold increase in resistant E. coli in the caecal fermentation, similar to enrofloxacin. In vitro exposure to both flumequine and enrofloxacin revealed the same amino acid substitutions (S83L, D87G) in GyrA. Additionally, the same resistance-causing substitutions were found in phenotypically resistant E. coli isolates from broilers treated with either enrofloxacin or flumequine. Flumequine induces similar resistance mechanisms as enrofloxacin, warranting equivalent restrictions on its use.

Abstract The H1 Collaboration reports the first measurement of the 1-jettiness event shape observable $$\tau _1^b$$ τ 1 b in neutral-current deep-inelastic electron-proton scattering (DIS). The observable $$\tau _1^b$$ τ 1 b is equivalent to a thrust observable defined in the Breit frame. The data sample was collected at the HERA ep collider in the years 2003–2007 with center-of-mass energy of $$\sqrt{s}=319\,\textrm{GeV} $$ s = 319 GeV , corresponding to an integrated luminosity of 351.1 $$\textrm{pb}^{-1}$$ pb - 1 . Triple differential cross sections are provided as a function of $$\tau _1^b$$ τ 1 b , event virtuality $$Q^{2}$$ Q 2 , and inelasticity y, in the kinematic region $$Q^{2} >150\,\textrm{GeV}^2 $$ Q 2 > 150 GeV 2 . Single differential cross sections are provided as a function of $$\tau _1^b$$ τ 1 b in a limited kinematic range. Double differential cross sections are measured, in contrast, integrated over $$\tau _1^b$$ τ 1 b and represent the inclusive neutral-current DIS cross section measured as a function of $$Q^{2}$$ Q 2 and y. The data are compared to a variety of predictions and include long-standing and more recent Monte Carlo event generators, predictions in fixed-order perturbative QCD where calculations up to $$\mathcal {O}(\alpha _\textrm{s} ^3)$$ O ( α s 3 ) are available for $$\tau _1^b$$ τ 1 b or inclusive DIS, and resummed predictions at next-to-leading logarithmic accuracy matched to fixed order predictions at $$\mathcal {O}(\alpha _\textrm{s} ^2)$$ O ( α s 2 ) . These comparisons reveal sensitivity of the 1-jettiness observable to QCD parton shower and resummation effects, as well as the modeling of hadronization and fragmentation. Within their range of validity, the fixed-order predictions provide a good description of the data. Monte Carlo event generators are predictive over the full measured range and hence their underlying models and parameters can be constrained by comparing to the presented data.

Abstract The Breit frame provides a natural frame to analyze lepton–proton scattering events. In this reference frame, the parton model hard interactions between a quark and an exchanged boson defines the coordinate system such that the struck quark is back-scattered along the virtual photon momentum direction. In Quantum Chromodynamics (QCD), higher order perturbative or non-perturbative effects can change this picture drastically. As Bjorken-x decreases below one half, a rather peculiar event signature is predicted with increasing probability, where no radiation is present in one of the two Breit-frame hemispheres and all emissions are to be found in the other hemisphere. At higher orders in $$\alpha _{s}$$ α s or in the presence of soft QCD effects, predictions of the rate of these events are far from trivial, and that motivates measurements with real data. We report on the first observation of the empty current hemisphere events in electron–proton collisions at the HERA collider using data recorded with the H1 detector at a center-of-mass energy of 319 GeV. The fraction of inclusive neutral-current DIS events with an empty hemisphere is found to be $$0.0112 \pm 3.9\%_\text {stat} \pm 4.5\%_{\text {syst}} \pm 1.6\%_{\text {mod}}$$ 0.0112 ± 3.9 % stat ± 4.5 % syst ± 1.6 % mod in the selected kinematic region of $$150

Aim: To assess the effectiveness of Clinical Decision Support Tools (CDSTs) in enhancing the quality of care outcomes in primary cardiovascular disease (CVD) prevention. Methods: A systematic review was undertaken in accordance with PRISMA guidelines, and included searches in Ovid Medline, Ovid Embase, CINAHL, and Scopus. Eligible studies were randomized controlled trials of CDSTs comprising digital notifications in electronic health systems (EHS/EHR) in various primary healthcare settings, published post-2013, in patients with CVD risks and without established CVD. Two reviewers independently assessed risk of bias using the Cochrane RoB-2 tool. Attainment of clinical targets was analysed using a Restricted Maximum Likelihood random effects meta-analysis. Other relevant outcomes were narratively synthesised due to heterogeneity of studies and outcome metrics. Results: Meta-analysis revealed CDSTs showed improvement in systolic (Mean Standardised Difference (MSD)=0.39, 95 %CI=-0.31, -1.10) and diastolic blood pressure target achievement (MSD=0.34, 95 %CI=-0.24, -0.92), but had no significant impact on lipid (MSD=0.01; 95 %CI=-0.10, 0.11) or glucose target attainment (MSD=-0.19, 95 %CI=-0.66, 0.28). The CDSTs with active prompts increased statin initiation and improved patients’ adherence to clinical appointments but had minimal effect on other medications and on enhancing adherence to medication. Conclusion: CDSTs were found to be effective in improving blood pressure clinical target attainments. However, the presence of multi-layered barriers affecting the uptake, longer-term use and active engagement from both clinicians and patients may hinder the full potential for achieving other quality of care outcomes. Lay Summary: The study aimed to evaluate how Clinical Decision Support Tools (CDSTs) impact the quality of care for primary cardiovascular disease (CVD) management. CDSTs are tools designed to support healthcare professionals in delivering the best possible care to patients by providing timely and relevant information at the point of care (ie. digital notifications in electronic health systems). Although CDST are designed to improve the quality of healthcare outcomes, the current evidence of their effectiveness is inconsistent. Therefore, we conducted a systematic review with meta-analysis, to quantify the effectiveness of CDSTs. The eligibility criteria targeted patients with CVD risk factors, but without diagnosed CVD. The meta-analysis found that CDSTs showed improvement in systolic and diastolic blood pressure target achievement but did not significantly impact lipid or glucose target attainment. Specifically, CDSTs showed effectiveness in increasing statin prescribing but not antihypertensives or antidiabetics prescribing. Interventions with CDSTs aimed at increasing screening programmes were effective for patients with kidney diseases and high-risk patients, but not for patients with diabetes or teenage patients with hypertension. Alerts were effective in improving patients' adherence to clinical appointments but not in medication adherence. This study suggests CDSTs are effective in enhancing a limited number of quality of care outcomes in primary CVD prevention, but there is need for future research to explore the mechanisms and context of multiple barriers that may hinder the full potential for cardiovascular health outcomes to be achieved.

ABSTRACT In the global efforts to combat antimicrobial resistance and reduce antimicrobial use in pig production, there is a continuous search for methods to prevent and/or treat infections. Within this scope, we explored the relationship between the developing piglet nasal microbiome and (zoonotic) bacterial pathogens from birth until 10 weeks of life. The nasal microbiome of 54 pigs was longitudinally studied over 16 timepoints on 9 farms in 3 European countries (Germany, Ireland, and the Netherlands) using amplicon sequencing targeting the V3-V4 16S rRNA region as well as the tuf gene for its staphylococcal discrimination power. The piglets’ age, the farm, and the litter affected the nasal microbiome, with piglets’ age explaining 19% of the variation in microbial composition between samples. Stabilization of the microbiome occurred around 2 weeks post-weaning. Notably, while opportunistic pathogens were ubiquitously present, they did not cause disease. The piglet nasal microbiome often carried species associated with gut, skin, or vagina, which suggests that contact with the vaginal and fecal microbiomes shapes the piglet nasal microbiome. We identified bacterial co-abundance groups of species that were present in the nasal microbiomes in all three countries over time. Anti-correlation between these species and known bacterial pathogens identified species that might be exploited for pathogen reduction. Further experimental evidence is required to confirm these findings. Overall, this study advances our understanding of the piglet nasal microbiome, the factors influencing it, and its longitudinal development, providing insights into its role in health and disease.IMPORTANCEOur study on the nasal microbiota development in piglets across farms in three European countries found that the microbiomes developed similarly in all locations. Additionally, we observed that the colonization of porcine pathogens was either positively or negatively associated with the presence of other bacterial species. These findings enhance our knowledge of co-colonizing species in the nasal cavity and the identified microbial interactions that can be explored for the development of interventions to control pathogens in porcine husbandry.

ABSTRACT Antimicrobial resistance (AMR) is an emerging worldwide problem and a health threat for humans and animals. Antimicrobial usage in human and animal medicine or in agriculture results in selection for AMR. The selective concentration of antimicrobial compounds can be lower than the minimum inhibitory concentration and differs between environments, which can be a reason for bacterial resistance. Therefore, knowledge of the minimal selective concentration (MSC), under natural conditions, is essential to understand the selective window of bacteria when exposed to residual antimicrobials. In this study, we estimated the MSCs of three antimicrobials, amoxicillin, doxycycline, and enrofloxacin in a complex microbial community by conducting fermentation assays with cecal material derived from broilers. We examined the phenotypic resistance of Escherichia coli, resistome, and microbiome after 6 and 30 hours of fermenting in the presence of the antimicrobials of interest. The concentrations were estimated to be 10–100 times lower than the epidemiological cut-off values in E. coli for the respective antimicrobials as determined by EUCAST, resulting in an MSC between 0.08 and 0.8 mg/L for amoxicillin, 0.4 and 4 mg/L for doxycycline, and 0.0125 and 0.125 mg/L for enrofloxacin. Additionally, resistome analysis provided an MSC for doxycycline between 0.4 and 4 mg/L, but amoxicillin and enrofloxacin exposure did not induce a significant difference. Our findings indicate at which concentrations there is still selection for antimicrobial-resistant bacteria. This knowledge can be used to manage the risk of the emergence of antimicrobial-resistant bacteria.IMPORTANCEAntimicrobial resistance possibly affects human and animal health, as well as economic prosperity in the future. The rise of antimicrobial-resistant bacteria is a consequence of using antimicrobial compounds in humans and animals selecting for antimicrobial-resistant bacteria. Concentrations reached during treatment are known to be selective for resistant bacteria. However, at which concentrations residues are still selective is important, especially for antimicrobial compounds that remain in the environment at low concentrations. The data in this paper might inform decisions regarding guidelines and regulations for the use of specific antimicrobials. In this study, we are providing these minimal selective concentrations for amoxicillin, doxycycline, and enrofloxacin in complex environments.

ABSTRACT Bacterial vaginosis (BV) is a polymicrobial infection of the female reproductive tract. BV is characterized by replacement of health-associated Lactobacillus species by diverse anerobic bacteria, including the well-known Gardnerella vaginalis. Prevotella timonensis, and Prevotella bivia are anerobes that are found in a significant number of BV patients, but their contributions to the disease process remain to be determined. Defining characteristics of anerobic overgrowth in BV are adherence to the mucosal surface and the increased activity of mucin-degrading enzymes such as sialidases in vaginal secretions. We demonstrate that P. timonensis, but not P. bivia, strongly adheres to vaginal and endocervical cells to a similar level as G. vaginalis but did not elicit a comparable proinflammatory epithelial response. The P. timonensis genome uniquely encodes a large set of mucus-degrading enzymes, including four putative fucosidases and two putative sialidases, PtNanH1 and PtNanH2. Enzyme assays demonstrated that fucosidase and sialidase activities in P. timonensis cell-bound and secreted fractions were significantly higher than for other vaginal anerobes. In infection assays, P. timonensis efficiently removed fucose and α2,3- and α2,6-linked sialic acid moieties from the epithelial glycocalyx. Recombinantly expressed P. timonensis NanH1 and NanH2 cleaved α2,3 and α2,6-linked sialic acids from the epithelial surface, and sialic acid removal by P. timonensis could be blocked using inhibitors. This study demonstrates that P. timonensis has distinct virulence-related properties that include initial adhesion and a high capacity for mucin degradation at the vaginal epithelial mucosal surface. Our results underline the importance of understanding the role of different anerobic bacteria in BV.IMPORTANCEBacterial vaginosis (BV) is a common vaginal infection that affects a significant proportion of women and is associated with reduced fertility and increased risk of secondary infections. Gardnerella vaginalis is the most well-known BV-associated bacterium, but Prevotella species including P. timonensis and P. bivia may also play an important role. We showed that, similar to G. vaginalis, P. timonensis adhered well to the vaginal epithelium, suggesting that both bacteria could be important in the first stage of infection. Compared to the other bacteria, P. timonensis was unique in efficiently removing the protective mucin sugars that cover the vaginal epithelium. These results underscore that vaginal bacteria play different roles in the initiation and development of BV.

Abstract In rivers worldwide, multiple scales of dunes coexist. It is unknown how the larger, primary dunes interact with secondary bedforms that are superimposed. We test the hypothesis that streamwise variability in the sediment flux inferred from the downstream migration of secondary bedforms explains migration of the host dune, based on bathymetric data from a lowland, sand‐bedded river. Results indicate that transport estimated from secondary bedform migration increases along the host dune stoss, eroding the stoss slope. When the superimposed bedforms disintegrate at the primary lee slopes, results indicate that all sediment transport associated to secondary bedform migration is arrested in the lee of the host dune, explaining migration of the host dune. When secondary dunes persist however, only part of the sediments transport linked to secondary dunes contributes to the migration of the host dune. This study gives novel insight into the fundamental mechanisms controlling the kinematics of compound dunes.

Most Campylobacter jejuni isolates carry the fucose utilization cluster (Cj0480c-Cj0489) that supports the metabolism of l-fucose and d-arabinose. In this study we quantified l-fucose and d-arabinose metabolism and metabolite production, and the impact on Caco-2 cell interaction and binding to fibronectin, using C. jejuni NCTC11168 and the closely related human isolate C. jejuni strain 286. When cultured with l-fucose and d-arabinose, both isolates showed increased survival and production of acetate, pyruvate and succinate, and the respective signature metabolites lactate and glycolic acid, in line with an overall upregulation of l-fucose cluster proteins. In vitro Caco-2 cell studies and fibronectin-binding experiments showed a trend towards higher invasion and a significantly higher fibronectin binding efficacy of C. jejuni NCTC11168 cells grown with l-fucose and d-arabinose, while no significant differences were found with C. jejuni 286. Both fibronectin binding proteins, CadF and FlpA, were detected in the two isolates, but were not significantly differentially expressed in l-fucose or d-arabinose grown cells. Comparative proteomics analysis linked the C. jejuni NCTC11168 phenotypes uniquely to the more than 135-fold upregulated protein Cj0608, putative TolC-like component MacC, which, together with the detected Cj0606 and Cj0607 proteins, forms the tripartite secretion system MacABC with putative functions in antibiotic resistance, cell envelope stress response and virulence in Gram negative pathogenic bacteria. Further studies are required to elucidate the role of the MacABC system in C. jejuni cell surface structure modulation and virulence.

Abstract To inform future Dutch COVID-19 testing policies we did an experimental vignette study to investigate whether inclusion of the less reliable lateral flow tests (self-tests) would change test-uptake sufficiently to improve population-level test sensitivity. A representative sample (n = 3,270) participated in a 2-by-2 online experiment to evaluate the effects of test-guidelines including self-testing advice (IV1), and the effects of self-test availability (IV2) on expected test uptake (PCR test, self-test or no test) and sensitivity of the overall test strategy (primary outcome). Across four scenarios, changing test advice did not affect expected testing behaviour. Self-test availability, however, increased the timeliness of testing, the number of people testing, and overall test strategy sensitivity. Based on these findings, we recommend that (national) policy facilitates a supply of self-tests at home, for example through free and pro-active distribution of test-kits during a pandemic. This could substantially enhance the chances of timely detecting and isolating patients.

Abstract Male germ cell development requires precise regulation of gene activity in a cell-type and stage-specific manner, with perturbations in gene expression during spermatogenesis associated with infertility. Here, we use steady-state, nascent and single-cell RNA sequencing strategies to comprehensively characterize gene expression across male germ cell populations, to dissect the mechanisms of gene control and provide new insights towards therapy. We discover a requirement for pausing of RNA Polymerase II (Pol II) at the earliest stages of sperm differentiation to establish the landscape of gene activity across development. Accordingly, genetic knockout of the Pol II pause-inducing factor NELF in immature germ cells blocks differentiation to spermatids. Further, we uncover unanticipated roles for Pol II pausing in the regulation of meiosis during spermatogenesis, with the presence of paused Pol II associated with double-strand break (DSB) formation, and disruption of meiotic gene expression and DSB repair in germ cells lacking NELF.

Abstract Background Although the paracrine effects of mesenchymal stem/stromal cells (MSCs) have been recognized as crucial mediators of their regenerative effects on tissue repair, the potential of MSC secretomes as effective substitutes for cellular therapies remains underexplored. Methods In this study, we compared MSCs from the human dermis (DSCs) and adipose tissue (ASCs) with their secretomes regarding their efficacy for skin wound healing using a translationally relevant murine model. Results Proteomic analysis revealed that while there was a substantial overlap in protein composition between DSC and ASC secretomes, specific proteins associated with wound healing and angiogenesis were differentially expressed. Despite a similar angiogenic potential in vivo, DSC and ASC secretomes were found to be less effective than cells in accelerating wound closure and promoting tissue remodeling. Conclusions Overall, secretome-treated groups showed intermediary results between cells- and control-treated (empty scaffold) groups. These findings highlight that although secretomes possess therapeutic potential, their efficacy might be limited compared to cellular therapies. This study contributes to the growing understanding of MSC secretomes, emphasizes the need for further protocol optimization, and offers insights into their potential applications in regenerative medicine.

In this commentary paper, I will introduce the concept of engagement data. I define engagement data as the digital metrics, calculations and visualisations that are deemed to give an insight into students’ on-task behaviour, their participation, their perceived capacity to pay attention, or their (technical) interactions with an educational platform. These kinds of data are common in Learning Management Systems and learning content platforms on which schools increasingly rely. The categories of engagement data discussed in this paper include time spent on-task, task completion, contribution, and biometric data. Besides conceptualising engagement data, this paper invites both scholars and educators to reflect critically on the datafication of engagement. I will argue that engagement data only offer a limited, quantified idea of student engagement and that this has far-reaching implications for children's digital rights. Children's behavioural data is harvested without their explicit consent or knowledge. These engagement data then become prescriptive constructs used for monitoring and accountability purposes, ignoring children's voice in relation to their own (dis)engagement.

Ubiquitous datafication of children and families in educational and everyday settings is both a result of and catalyst for power asymmetries between digital platforms and their users. These platforms seek to know their users by extracting and analysing various streams of personal information, often discreetly. However, the users are rarely equipped to do the same to the platforms as information about these platforms is often obscured, convoluted, or simply unavailable. This article explores the possibilities of reversing such power imbalance via the design intervention of an Australia-focused educational technology (EdTech) database developed by the authors of this article. Employing a design intervention method, the database is a collection of publicly available information about EdTech companies and products that target young children and their parents or educators in Australia. This alternate commentary article presents and discusses the ongoing processes of developing the database to reflect on what it says about the power relations between EdTech providers and their users. It demonstrates how the database works as a pedagogical space where people learn how to critically unpack and think about contemporary EdTech platforms. The database is positioned as a point of convergence for different actors involved in children's digital learning to collectively understand what needs to be done to enact and protect children's digital rights in education.

Background: The “September epidemic” is a well-described phenomenon of increased pediatric asthma-related health care utilization from August to September each year. The coronavirus disease 2019 (COVID-19) pandemic has brought about significant changes in health care utilization, warranting an investigation into its impact on the September epidemic. Objective: Our aim was to identify the impact of COVID-19 in asthma-related health care utilization, specifically in the September epidemic. Methods: Our study involved a retrospective analysis of data from a Children's Hospital in New York City. We compared the change in asthma-related health care utilization during August and September 2020 with the average change in utilization during the same period in 2017-2019 and 2021-2022. Stratified analyses based on age and sex were conducted by using chi-square tests to determine variations in health care utilization. Results: During September 2020, there was a marked reduction in emergency department (ED) visits related to asthma, with only a 6% rise from the preceding month. This stands in contrast to the observed increases from 89% to 193% in the other years studied (P < .05 for all). This pattern was seen in both sexes and in children under 13 years old (P < .05). No significant variation was found for those older than 13 years (P > .05). Conclusions: Despite an overall reduction in health care utilization over the first year of the COVID-19 pandemic, the decline in ED visits related to asthma during the September epidemic was significantly more pronounced. These results suggest that there may be remediable risk factors contributing to the September epidemic that can be used to guide future interventions for managing pediatric asthma.

A secondary scale of bedforms, superimposed on larger, primary dunes, has been observed in fluvial systems worldwide. This notwithstanding, very little is known about the morphological behavior and characteristics of this secondary scale. This study aims to better characterize and understand how two dune scales coexist in fluvial systems and how both scales adapt over time and space, considering their interdependence. The study is based on analysis of a large biweekly multibeam echo sounding dataset from the river Waal, a lowland sand-bedded river. Results reveal that the secondary dune scale is ubiquitous across space and time and not limited to specific flow or transport conditions. Whereas primary dunes lengthen during low flows, secondary dune height, lee slope angle, and length correlate with discharge. Secondary dune size and migration strongly depend on the primary dune lee slope angle and height. Secondary dunes can migrate over the lee slope of low-angled primary dunes, and their height is inversely correlated to the upstream primary dune height and lee slope angle. In the Waal river, a lateral variation in bed grain size, attributed to shipping, largely affects dune morphology. Primary dunes are lower and less often present in the southern lane, where grain sizes are smaller. Here, secondary bedforms are more developed. At peak discharge, secondary bedforms even become the dominant scale, whereas primary dunes entirely disappear but are re-established during lower flows.

Abstract Background Clostridium botulinum is an anaerobic, Gram-positive, rod-shaped bacterium that forms spores and the neurotoxin botulinum. It is best known for its toxin-induced flaccid paralytic disease, which is deadly without correct treatment. In this report, we show a completely different clinical course with fatal outcome. Case presentation A 37-year-old African man born in Sierra Leone was admitted. After admission, his condition rapidly worsened due to severe septic shock and progressive multiorgan failure. No neurological signs were seen. Despite treatment with antibiotics, fluid resuscitation, and norepinephrine, the multiorgan failure deteriorated further and he died as a result. Blood and synovial fluid cultures showed Clostridium botulinum. No botulinum toxins were found. Conclusion This is a rare case of fatal septic shock due to Clostridium botulinum-induced septic arthritis without any sign of the classic clinical syndrome of botulism.

Abstract Objective Emerging variants and sublineages of SARS‐CoV‐2 have differing disease severity, transmissibility, and immune evasion. The neurological conditions associated with the original strain of SARS‐CoV‐2 are well established. Our study assessed the neurological presentations specific to hospitalized patients during the B.1.1.529 (Omicron) variant surge in New York City. Methods A total of 178 cases with positive RT‐PCR result within 6 weeks before admission, and subsequent development of select neurological conditions during the SARS‐CoV‐2 B.1.1.529 (Omicron) surge between December 1, 2021 and February 28, 2022, were included from 12,800 SARS‐CoV‐2‐positive hospital admissions. Clinical data from acute hospitalizations were compared to findings of inpatient neurological cases with COVID‐19 infections from the initial surge in NYC in the same hospital system. Results Compared to SARS‐CoV‐2 infections of the original strain, COVID‐19 cases hospitalized during the Omicron surge (B.1.1.529) were associated with incidental and/or asymptomatic COVID‐19 cases (96, 53.9%) and an increased incidence of pre‐existing neurological and immunocompromising conditions. Encephalopathy, seizures, and stroke remained the most prevalent neurological conditions identified in hospitalized COVID‐19 cases during the study period, reflecting a similar distribution of neurological presentations associated with the original strain. Interpretation In our cohort of 178 admitted SARS‐CoV‐2‐positive patients with select neurological conditions during the Omicron B.1.1.529 surge, 54% of COVID‐19 cases were considered incidental and/or asymptomatic, and the identified neurological conditions resembled those associated with the original SARS‐CoV‐2 strain. Further studies characterizing neurological presentation in Omicron sublineages and other variants are warranted in an ongoing COVID‐19 pandemic.