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Abstract Increased intracranial pressure (ICP) ≥15 mmHg is associated with adverse neurological outcomes, but needs invasive intracranial monitoring. Using the publicly available MIMIC-III Waveform Database (2000–2013) from Boston, we developed an artificial intelligence-derived biomarker for elevated ICP (aICP) for adult patients. aICP uses routinely collected extracranial waveform data as input, reducing the need for invasive monitoring. We externally validated aICP with an independent dataset from the Mount Sinai Hospital (2020–2022) in New York City. The AUROC, accuracy, sensitivity, and specificity on the external validation dataset were 0.80 (95% CI, 0.80–0.80), 73.8% (95% CI, 72.0–75.6%), 73.5% (95% CI 72.5–74.5%), and 73.0% (95% CI, 72.0–74.0%), respectively. We also present an exploratory analysis showing aICP predictions are associated with clinical phenotypes. A ten-percentile increment was associated with brain malignancy (OR = 1.68; 95% CI, 1.09-2.60), intracerebral hemorrhage (OR = 1.18; 95% CI, 1.07–1.32), and craniotomy (OR = 1.43; 95% CI, 1.12–1.84; P

ABSTRACTMucinous colorectal cancer (CRC) is a common histological subtype of colorectal adenocarcinoma, associated with a poor response to chemoradiotherapy. The commensal facultative anaerobes fusobacteria, have been associated with poor prognosis specifically in mesenchymal CRC. Interestingly, fusobacterial infection is especially prevalent in mucinous CRC. The objective of this study was therefore to increase our understanding of beneficial and detrimental effects of fusobacterial infection, by contrasting host cell signaling and immune responses in areas of high vs. low infection, using mucinous rectal cancer as a clinically relevant example. We employed spatial transcriptomic profiling of 106 regions of interest from 8 mucinous rectal cancer samples to study gene expression in the epithelial and immune segments across regions of high versus low fusobacterial infection. Fusobacteria high regions were associated with increased oxidative stress, DNA damage, and P53 signaling. Meanwhile regions of low fusobacterial prevalence were characterized by elevated JAK-STAT, Il-17, Il-1, chemokine and TNF signaling. Immune masks within fusobacterial high regions were characterized by elevated proportions of cytotoxic (CD8+) T cells (p = 0.037), natural killer (NK) cells (p

We evaluated whether naphthenic acid fraction compounds (NAFCs) extracted from oil sand tailings adversely affect fish survival and behaviour. Following a before–after-control-impact design, we housed wild-caught juvenile yellow perch (Perca flavescens) in outdoor mesocosms to assess survival and behaviour under baseline conditions, then exposed fish to one of three treatments: negative control, 2 mg/L NAFC, or 15 mg/L NAFC. We performed behavioural assays (no-stimulus activity, food stimulus, and predator stimulus using a model bird) and assessed a comprehensive suite of endpoints (equilibrium losses, activity, shoaling, burst swimming, freezing, and space use). We found that exposure to 15 mg/L NAFCs substantially reduced fish survival and impaired fish equilibrium in all three behavioural tests. Furthermore, exposure to NAFCs impaired anti-predator behaviour: while the activity of control fish increased by two-fold in response to a predator stimulus, fish exposed to 2 or 15 mg/L NAFC did not change their activity levels after stimulation. No significant changes were observed in other behavioural endpoints. Overall, our findings suggest that a week-long exposure to NAFCs at concentrations commonly found in tailings ponds, constructed wetlands, and other mining-impacted waters may affect multiple facets of fish behaviour that could ultimately lead to reduced fitness in fish populations.

Abstract Background High‐salt diets promote urine dilution and decrease urolithiasis risk. Objective Prospectively evaluate the safety of chronic high dietary salt intake (randomized controlled trial). Animals Twenty research colony neutered, healthy aged cats (11.5 years [10.0‐11.6], median [interquartile range]). Methods Healthy cats were randomized to control or high‐salt dry diets (sodium: 1.02 ± 0.16 [mean, SD] and 3.26 ± 0.30 g/Mcal metabolizable energy [ME], respectively; chloride: 2.26 ± 0.33 and 5.71 ± 0.28 g/Mcal ME, respectively), fed for up to 60 months. Assessments included CBC, plasma biochemistry, urinalysis, glomerular filtration rate (GFR), blood pressure, renal and cardiac (conventional Doppler and 2‐dimensional color tissue Doppler) imaging, annually. Cats that died or were euthanized underwent necropsy. Diet effects over time were evaluated with linear mixed models. Results Follow‐up duration (median [Interquartile range]) was similar between the control (38.7 months [28.6‐48.2]) and high‐salt group (51.4 months [45.7‐59.0]). Diet had no significant effect on changes in GFR, blood pressure, plasma creatinine concentration, end‐diastolic left ventricular (LV) wall thicknesses, LV internal diameters, LV systolic function, left atrial size, or systolic and diastolic Doppler variables. One control cat developed hypertension. One high‐salt group cat developed persistent azotemia. Serial plasma biochemistry and urine specific gravity suggested early chronic kidney disease in 4 nonazotemic cats (2 per group), consistent with necropsy findings. Conclusions and Clinical Importance In healthy aged cats, a commercial veterinary diet containing 3.26 ± 0.30 g/Mcal ME sodium was safe with regard to renal and cardiac function for up to 5 years.

Stellar and black hole feedback heat and disperse surrounding cold gas clouds, launching gas flows off circumnuclear and galactic disks, producing a dynamic interstellar medium. On large scales bordering the cosmic web, feedback drives enriched gas out of galaxies and groups, seeding the intergalactic medium with heavy elements. In this way, feedback shapes galaxy evolution by shutting down star formation and ultimately curtailing the growth of structure after the peak at redshift 2–3. To understand the complex interplay between gravity and feedback, we must resolve both the key physics within galaxies and map the impact of these processes over large scales, out into the cosmic web. The Advanced X-ray Imaging Satellite (AXIS) is a proposed X-ray probe mission for the 2030s with arcsecond spatial resolution, large effective area, and low background. AXIS will untangle the interactions of winds, radiation, jets, and supernovae with the surrounding interstellar medium across the wide range of mass scales and large volumes driving galaxy evolution and trace the establishment of feedback back to the main event at cosmic noon. This white paper is part of a series commissioned for the AXIS Probe mission concept; additional AXIS white papers can be found at the AXIS website.

Abstract Heartland virus was first isolated in 2009 from two patients in Missouri and is transmitted by the Lone Star tick, Amblyomma americanum. To understand disease transmission and pathogenesis, it is necessary to develop an animal model which utilizes the natural route of transmission and manifests in a manner similar to documented human cases. Herein we describe our investigations on identifying A129 mice as the most appropriate small animal model for HRTV pathogenesis that mimics human clinical outcomes. We further investigated the impact of tick saliva in enhancing pathogen transmission and clinical outcomes. Our investigations revealed an increase in viral load in the groups of mice that received both virus and tick salivary gland extract (SGE). Spleens of all infected mice showed extramedullary hematopoiesis (EH), depleted white pulp, and absence of germinal centers. This observation mimics the splenomegaly observed in natural human cases. In the group that received both HRTV and tick SGE, the clinical outcome of HRTV infection was exacerbated compared to HRTV only infection. EH scores and the presence of viral antigens in spleen were higher in mice that received both HRTV and tick SGE. In conclusion, we have developed a small animal model that mimics natural human infection and also demonstrated the impact of tick salivary factors in exacerbating the HRTV infection.

Tick-borne flaviviruses (TBFV) can cause severe neuroinvasive disease which may result in death or long-term neurological deficit in over 50% of survivors. Multiple mechanisms for invasion of the central nervous system (CNS) by flaviviruses have been proposed including axonal transport, transcytosis, endothelial infection, and Trojan horse routes. Flaviviruses may utilize different or multiple mechanisms of neuroinvasion depending on the specific virus, infection site, and host variability. In this work we have shown that the infection of BALB/cJ mice with either Powassan virus lineage I (Powassan virus) or lineage II (deer tick virus) results in distinct spatial tropism of infection in the CNS which correlates with unique clinical presentations for each lineage. Comparative transcriptomics of infected brains demonstrates the activation of different immune pathways and downstream host responses. Ultimately, the comparative pathology and transcriptomics are congruent with different clinical signs in a murine model. These results suggest that the different disease presentations occur in clinical cases due to the inherent differences in the two lineages of Powassan virus.

Abstract Ticks transmit several arthropod-borne pathogens in New York State. The primary human-biting ticks in this region are Ixodes scapularis, Amblyomma americanum, and Dermacentor variabilis. Body regions where tick bites human vary depending on the tick species and life stage, and clothing worn by the host. A community tick submission system was used to acquire information about bite-site location prior to pathogen testing to understand species and life stage-specific body-segment preferences. These data resulted in the identification of species-specific preferences for location, with D. variabilis preferentially biting the head and neck and A. americanum preferring the thighs, groin, and abdomen. Ixodes scapularis was found across the body, although it showed a significant life stage difference with adults preferring the head, midsection, and groin, while nymphs/larvae preferred the extremities. Infection with Borrelia burgdorferi resulted in a significant change in attachment site. This provides an assessment of which body region ticks of the most common species in New York are likely to be found.

Methane (CH4) is a potent greenhouse gas and plays a significant role in recent increasing global temperatures. The oceans are a natural source of methane contributing to atmospheric methane concentrations, yet our understanding of the oceanic methane cycle is poorly constrained. Accumulating evidence indicates that a significant part of oceanic CH4 is produced in oxygenated surface waters as a by-product of phytoplanktonic activity. This study focused on the subtropical North Atlantic Ocean (26∘ N, 80′ W and 26∘ N, 18′ W) where the distribution of dissolved CH4 concentrations and associated air–sea fluxes during winter 2020 were investigated. Water samples from 64 stations were collected from the upper water column up to depths of 400 m. The upper oxic mixed layer was oversaturated in dissolved CH4 with concentrations ranging 3–7 nmol L−1, with the highest concentrations of 7–10 nmol L−1 found to the east of the transect, consistent with other subtropical regions of the world's oceans. The high anomalies of dissolved CH4 were found to be associated with phosphate-depleted waters and regions where the abundance of the ubiquitous picocyanobacteria Synechococcus and Prochlorococcus were elevated. Although other phytoplanktonic phyla cannot be excluded, this suggests that cyanobacteria contribute to the release of CH4 in this region. The calculation of air–sea fluxes further confirmed the subtropical North Atlantic Ocean as a source of CH4. This study provides evidence to corroborate the key role that picocyanobacteria play in helping to explain the oversaturation of CH4 found in surface mixed layer of the open ocean, otherwise known as the “ocean methane paradox”.

A passive wireless high-temperature sensor for far-field applications was developed for stable temperature sensing up to 1000 °C. The goal is to leverage the properties of electroceramic materials, including adequate electrical conductivity, high-temperature resilience, and chemical stability in harsh environments. Initial sensors were fabricated using Ag for operation to 600 °C to achieve a baseline understanding of temperature sensing principles using patch antenna designs. Fabrication then followed with higher temperature sensors made from (In, Sn) O2 (ITO) for evaluation up to 1000 °C. A patch antenna was modeled in ANSYS HFSS to operate in a high-frequency region (2.5–3.5 GHz) within a 50 × 50 mm2 confined geometric area using characteristic material properties. The sensor was fabricated on Al2O3 using screen printing methods and then sintered at 700 °C for Ag and 1200 °C for ITO in an ambient atmosphere. Sensors were evaluated at 600 °C for Ag and 1000 °C for ITO and analyzed at set interrogating distances up to 0.75 m using ultra-wideband slot antennas to collect scattering parameters. The sensitivity (average change in resonant frequency with respect to temperature) from 50 to 1000 °C was between 22 and 62 kHz/°C which decreased as interrogating distances reached 0.75 m.

In 2021 JET exploited its unique capabilities to operate with T and D–T fuel with an ITER-like Be/W wall (JET-ILW). This second major JET D–T campaign (DTE2), after DTE1 in 1997, represented the culmination of a series of JET enhancements—new fusion diagnostics, new T injection capabilities, refurbishment of the T plant, increased auxiliary heating, in-vessel calibration of 14 MeV neutron yield monitors—as well as significant advances in plasma theory and modelling in the fusion community. DTE2 was complemented by a sequence of isotope physics campaigns encompassing operation in pure tritium at high T-NBI power. Carefully conducted for safe operation with tritium, the new T and D–T experiments used 1 kg of T (vs 100 g in DTE1), yielding the most fusion reactor relevant D–T plasmas to date and expanding our understanding of isotopes and D–T mixture physics. Furthermore, since the JET T and DTE2 campaigns occurred almost 25 years after the last major D–T tokamak experiment, it was also a strategic goal of the European fusion programme to refresh operational experience of a nuclear tokamak to prepare staff for ITER operation. The key physics results of the JET T and DTE2 experiments, carried out within the EUROfusion JET1 work package, are reported in this paper. Progress in the technological exploitation of JET D–T operations, development and validation of nuclear codes, neutronic tools and techniques for ITER operations carried out by EUROfusion (started within the Horizon 2020 Framework Programme and continuing under the Horizon Europe FP) are reported in (Litaudon et al Nucl. Fusion accepted), while JET experience on T and D–T operations is presented in (King et al Nucl. Fusion submitted).

JET, the world’s largest operating tokamak with unique Be/W wall and tritium handling capability, completed a Deuterium-Tritium (D-T) campaign in 2021 (Maggi et al 29th Fusion Energy Conf. ) following a decade of preparatory experiments, dedicated enhancements, technical rehearsals and training (Horton et al 2016 Fusion Eng. Des. 109–111 925). Operation with tritium raises significant technical, safety and scientific challenges not encountered in standard protium or deuterium operation. This contribution describes the tritium operational requirements, pulses and technical preparations, new operating procedures, lessons learned and details on the achieved operational availability and performance. The preparation and execution of the recent JET tritium experiments benefitted from the previous experience in 1991 (Preliminary Tritium Experiment), 1997 (DTE1 campaign) and 2003 (Trace Tritium Campaigns) and consisted of the following five phases: technical rehearsals and scenario preparation, tritium commissioning, 100% tritium campaign, D-T campaign (DTE2), tritium clean-up. Following the clean-up JET resumed normal operation and is currently undertaking a further D-T campaign (DTE3).

We present the results from a pair of high-resolution, long-timescale (∼10 ^5 GM / c ^3 ), global, three-dimensional magnetohydrodynamical accretion disk simulations with differing initial magnetic plasma β in order to study the effects of the initial toroidal field strength on the production of a large-scale poloidal field. We initialize our disks in approximate equilibrium with purely toroidal magnetic fields of strength β _0 = 5 and 200. We also perform a limited resolution study. We find that simulations of differing field strengths diverge early in their evolution and remain distinct over the time studied, indicating that the initial magnetic conditions leave a persistent imprint in our simulations. Neither simulation enters the magnetically arrested disk regime. Both simulations are able to produce poloidal fields from initially toroidal fields, with the β _0 = 5 simulation evolving clear signs of a large-scale poloidal field. We make a cautionary note that computational artifacts in the form of large-scale vortices may be introduced in the combination of initially weak field and disk-internal mesh refinement boundaries, as evidenced by the production of an m = 1 mode overdensity in the weak field simulation. Our results demonstrate that the initial toroidal field strength plays a vital role in the simulated disk evolution for the models studied.

Case summary A 3-year-old neutered domestic shorthair cat with a long history of idiopathic immune-mediated haemolytic anaemia and thrombocytopenia treated with ciclosporin and prednisolone was referred 2 months after the appearance of nodular dermatitis. A single pigmented nodule was present in the lateral carpal region of the right foreleg. The lesion was 7 mm in diameter, non-exudative and cutaneous to subcutaneous. Fine-needle aspiration of the mass revealed the presence of pigmented fungal elements. Excisional surgery was planned; in the meantime, a plaque-like lesion developed in the interorbital region. Histopathological examination confirmed the presumptive diagnosis of phaeohyphomycosis, and Exophiala spinifera was identified as the aetiological agent. Itraconazole, given orally at a dose of 10 mg/kg for 8 weeks following surgery, enabled clinical resolution despite continued use of immunosuppressants. The follow-up was carried out over 14 weeks. Relevance and novel information This case report provides the first evidence of multifocal cutaneous phaeohyphomycosis caused by E spinifera with clinical resolution after combined surgical and itraconazole treatment in an immunocompromised cat.

Abstract Translation of animal-based preclinical research is hampered by poor validity and reproducibility issues. Unfortunately, preclinical research has ‘fallen between the stools’ of competing study design traditions. Preclinical studies are often characterised by small sample sizes, large variability, and ‘problem’ data. Although Fisher-type designs with randomisation and blocking are appropriate and have been vigorously promoted, structured statistically-based designs are almost unknown. Traditional analysis methods are commonly misapplied, and basic terminology and principles of inference testing misinterpreted. Problems are compounded by the lack of adequate statistical training for researchers, and failure of statistical educators to account for the unique demands of preclinical research. The solution is a return to the basics: statistical education tailored to non-statistician investigators, with clear communication of statistical concepts, and curricula that address design and data issues specific to preclinical research. Statistics curricula should focus on statistics as process: data sampling and study design before analysis and inference. Properly-designed and analysed experiments are a matter of ethics as much as procedure. Shifting the focus of statistical education from rote hypothesis testing to sound methodology will reduce the numbers of animals wasted in noninformative experiments and increase overall scientific quality and value of published research.

Our surveys of nurses modeled after the Capability, Opportunity, and Motivation Model of Behavior (COM-B model) revealed that opportunity and motivation factors heavily influence urine-culture practices (behavior), in addition to knowledge (capability). Understanding these barriers is a critical step towards implementing targeted interventions to improving urine-culture practices.

Abstract Powassan virus (POWV) is a neuroinvasive flavivirus transmitted to mammals by the bite of ixodid ticks. In this study, we sought to investigate the impact of tick salivary gland extract (SGE) on POWV neuroinvasion. BALB/c mice were footpad inoculated with either a high dose or a low dose of POWV, with and without Ixodes scapularis salivary gland extract. Brain and spinal cord were extracted daily, and immunohistochemical techniques were used for temporal tracking of POWV antigen. The temporal pattern of POWV staining showed a caudal to rostral spread of POWV in the brains of mice from both high dose infection groups. For the high dose infection groups, the presence of tick SGE did not influence the spread of POWV in the brain. Mice infected with the low dose of virus alone did not present POWV staining in the brain; however, in the presence of SGE, low dose infected mice presented scattered foci of POWV-infected cells throughout the brain. This study shows that tick SGE facilitates POWV neuroinvasion when mice are infected with the lower dose of POWV. We also found two patterns of central nervous system invasion that were directly influenced by the dose of POWV administered.

Abstract A critical step to evaluate the potential in vivo antiviral activity of a drug is to connect the in vivo exposure to its in vitro antiviral activity. The Anti–SARS‐CoV‐2 Repurposing Drug Database is a database that includes both in vitro anti–SARS‐CoV‐2 activity and in vivo pharmacokinetic data to facilitate the extrapolation from in vitro antiviral activity to potential in vivo antiviral activity for a large set of drugs/compounds. In addition to serving as a data source for in vitro anti–SARS‐CoV‐2 activity and in vivo pharmacokinetic information, the database is also a calculation tool that can be used to compare the in vitro antiviral activity with in vivo drug exposure to identify potential anti–SARS‐CoV‐2 drugs. Continuous development and expansion are feasible with the public availability of this database.

BackgroundMucinous colorectal cancer (CRC) represents 10% of all CRC and is associated with chemotherapy resistance. This study aimed to determine expression of apoptosis and necroptosis mediators in mucinous CRC.MethodsRNA gene expression data were extracted from TCGA. Protein levels in 14 mucinous and 39 non-mucinous tumors were measured by multiplexed immunofluorescence. Levels of apoptosis and necroptosis signalling proteins were analysed in SW1463 (mucinous rectal), SW837 (non-mucinous rectal), LS174T (mucinous colon) and HCT116 (non-mucinous colon) cell lines by western blot. Cell death was investigated by flow cytometry measurement of propidium iodide stained cells.ResultsHigh cleaved-Caspase 3 expression was noted in resected mucinous tumors. Western blot identified alterations in apoptosis proteins in mucinous CRC, most prominently downregulation of Bcl-xL protein levels (p=0.029) which was also observed at the mRNA level in patients by analysis of TCGA gene expression data (p

Abstract Background Central line-associated bloodstream infections (CLABSIs) result in approximately 28,000 deaths and approximately $2.3 billion in added costs to the U.S. healthcare system each year, and yet, many of these infections are preventable. At two large health systems in the southeast United States, CLABSIs continue to be an area of opportunity. Despite strong evidence for interventions to prevent CLABSI and reduce associated patient harm, such as use of chlorhexidine gluconate (CHG) bathing, the adoption of these interventions in practice is poor. The primary objective of this study was to assess the effect of a tailored, multifaceted implementation program on nursing staff’s compliance with the CHG bathing process and electronic health record (EHR) documentation in critically ill patients. The secondary objectives were to examine the (1) moderating effect of unit characteristics and cultural context, (2) intervention effect on nursing staff’s knowledge and perceptions of CHG bathing, and (3) intervention effect on CLABSI rates. Methods A stepped wedged cluster-randomized design was used with units clustered into 4 sequences; each sequence consecutively began the intervention over the course of 4 months. The Grol and Wensing Model of Implementation helped guide selection of the implementation strategies, which included educational outreach visits and audit and feedback. Compliance with the appropriate CHG bathing process and daily CHG bathing documentation were assessed. Outcomes were assessed 12 months after the intervention to assess for sustainability. Results Among the 14 clinical units participating, 8 were in a university hospital setting and 6 were in community hospital settings. CHG bathing process compliance and nursing staff’s knowledge and perceptions of CHG bathing significantly improved after the intervention (p = .009, p = .002, and p = .01, respectively). CHG bathing documentation compliance and CLABSI rates did not significantly improve; however, there was a clinically significant 27.4% decrease in CLABSI rates. Conclusions Using educational outreach visits and audit and feedback implementation strategies can improve adoption of evidence-based CHG bathing practices. Trial registration ClinicalTrials.gov, NCT03898115 , Registered 28 March 2019.

Abstract Both mutualistic and pathogenic soil microbes are known to play important roles in shaping the fitness of plants, likely affecting plants at different life cycle stages. In order to investigate the differential effects of native soil mutualists and pathogens on plant fitness, we compared survival and reproduction of two annual tallgrass prairie plant species (Chamaecrista fasciculata and Coreopsis tinctoria) in a field study using 3 soil inocula treatments containing different compositions of microbes. The soil inocula types included fresh native whole soil taken from a remnant prairie containing both native mutualists and pathogens, soil enhanced with arbuscular mycorrhizal (AM) fungi derived from remnant prairies, and uninoculated controls. For both species, plants inoculated with native prairie AM fungi performed much better than those in uninoculated soil for all parts of the life cycle. Plants in the native whole prairie soil were either generally similar to plants in the uninoculated soil or had slightly higher survival or reproduction. Overall, these results suggest that native prairie AM fungi can have important positive effects on the fitness of early successional plants. As inclusion of prairie AM fungi and pathogens decreased plant fitness relative to prairie AM fungi alone, we expect that native pathogens also can have large effects on fitness of these annuals. Our findings support the use of AM fungi to enhance plant establishment in prairie restorations.

Uropathogenic E. coli can adhere to vaginal epithelial cells preceding urinary tract infection (UTI). Here, Brannon et al. show that urinary E. coli isolates can not only adhere to, but also invade vaginal cells in mouse UTI models and in clinical samples obtained from women with recurrent UTI.

Background and AimsMucinous colorectal cancer has traditionally been associated with high rates of recurrence and poor long-term survival. There is limited published data on outcomes for patients undergoing liver resection for metastatic mucinous colorectal cancer. The aim of this study was to compare the clinicopathological outcomes for patients with mucinous colorectal cancer liver metastases (CRCLM) undergoing liver resection to a matched group of patients with adenocarcinoma not otherwise specified (NOS) and to evaluate the accurary of preoperative magnetic resonance imaging (MRI) at detecting the presence of mucin in liver metastases.Materials and MethodsPatients with mucinous CRCLM undergoing liver resection were matched 1:3 to patients with adenocarcinoma NOS CRCLM. Clinicopathological data from the primary tumour and metastatic lesion were collected and compared between the groups. Hepatic recurrence-free, disease-free and overall survival were compared between the groups. The ability of preoperative MRI to detect mucin in CRCLM was also evaluated.ResultsA total of 25 patients with mucinous CRCLM underwent surgery over the 12-year period and were matched to 75 patients with adenocarcinoma NOS. Clinicopathological findings were similar between the groups. Resection of mucinous CRCLM was feasible and safe with similar levels of morbidity to adenocarcinoma NOS. There were no differences identified in hepatic recurrence-free (p=0.85), disease-free (p=0.25) and overall survival (p=0.98) between the groups. MRI had a sensitivity of 31.3% in detecting the presence of mucin in CRCLM.ConclusionPatients with mucinous CRCLM in this study had similar outcomes to patients with adenocarcinoma NOS. Based on our findings, histological subtype should not be taken into account when deciding on resectability of CRCLM.

The laboratory mouse is a key player in preclinical oncology research. However, emphasis of techniques reporting at the expense of critical animal-related detail compromises research integrity, animal welfare, and, ultimately, the translation potential of mouse-based oncology models. To evaluate current reporting practices, we performed a cross-sectional survey of 400 preclinical oncology studies using mouse solid-tumour models. Articles published in 2020 were selected from 20 journals that specifically endorsed the ARRIVE (Animal Research: Reporting of In Vivo Experiments) preclinical reporting guidelines. We assessed reporting compliance for 22 items in five domains: ethical oversight assurance, animal signalment, husbandry, welfare, and euthanasia. Data were analysed using hierarchical generalised random-intercept models, clustered on journal. Overall, reporting of animal-related items was poor. Median compliance over all categories was 23%. There was little or no association between extent of reporting compliance and journal or journal impact factor. Age, sex, and source were reported most frequently, but verifiable strain information was reported for

Non-aversive handling is a well-documented refinement measure for improving rodent welfare. Because maternal stress is related to reduced productivity, we hypothesized that welfare benefits associated with non-aversive handling would translate to higher production and fewer litters lost in a laboratory mouse breeding colony. We performed a randomized controlled trial to examine the effects of a standard method of handling (tail-lift with forceps) versus non-aversive handling with transfer tunnels ('tunnel-handled') on breeding performance in 59 C57BL/6J mouse pairs. Intervention assignments could not be concealed from technicians, but were concealed from assessors and data analyst. An operationally significant effect of tunnel-handling (large enough differences to warrant programmatic change) was defined before study initiation as a 5% increase in productivity, or one extra pup over the reproductive lifetime of each pair. Pairs were randomly allocated to handling intervention and cage rack location, and monitored over an entire 6-month breeding cycle. For each group, we measured number of pups born and weaned, and number of entire litters lost prior to weaning. Differences between transfer methods were estimated by two-level hierarchical mixed models adjusted for parental effects and parity. Compared to tail-lift mice, tunnel-handled mice averaged one extra pup per pair born (+1.0; 95% CI 0.9, 1.1; P = 0.41) and weaned (+1.1, 95% CI 0.9, 1.2; P = 0.33). More tunnel-handled pairs successfully weaned all litters produced (13/29 pairs, 45% vs 4/30 pairs, 13%; P = 0.015), averaged fewer litter losses prior to weaning (11/29 pairs [38%] vs 26/30 pairs [87%]; P

Axion-like particles (ALPs) are well-motivated extensions of the Standard Model of Particle Physics and a generic prediction of some string theories. X-ray observations of bright active galactic nuclei (AGNs) hosted by rich clusters of galaxies are excellent probes of very-light ALPs, with masses $\mathrm{log}({m}_{{\rm{a}}}/\mathrm{eV})\lt -12.0$ . We evaluate the potential of future X-ray observatories, particularly Athena and the proposed AXIS, to constrain ALPs via observations of cluster-hosted AGNs, taking NGC 1275 in the Perseus cluster as our exemplar. Assuming perfect knowledge of the instrument calibration, we show that a modest exposure (200 ks) of NGC 1275 by Athena permits us to exclude all photon–ALP couplings g _a _γ > 6.3 × 10 ^−14 GeV ^−1 at the 95% confidence level, as previously shown by Conlon et al., representing a factor of 10 improvement over current limits. We then proceed to assess the impact of realistic calibration uncertainties on the Athena projection by applying a standard Cash likelihood procedure, showing the projected constraints on g _a _γ weaken by a factor of 10 (back to the current most sensitive constraints). However, we show how the use of a deep neural network can disentangle the energy-dependent features induced by instrumental miscalibration and those induced by photon–ALP mixing, allowing us to recover most of the sensitivity to the ALP physics. In our explicit demonstration, the machine learning applied allows us to exclude g _a _γ > 2.0 × 10 ^−13 GeV ^−1 , complementing the projected constraints of next-generation ALP dark matter birefringent cavity searches for very-light ALPs. Finally, we show that a 200 ks AXIS/on-axis observation of NGC 1275 will tighten the current best constraints on very-light ALPs by a factor of 3.

We present the results from a coordinated XMM-Newton + NuSTAR observation of the Seyfert 1 galaxy ESO 511−G030. With this joint monitoring program, we conduct a detailed variability and spectral analysis. The source remained in a low flux and very stable state throughout the observation period, although there are slight fluctuations of flux over long timescales. The broadband (0.3–78 keV) spectrum shows the presence of a power-law continuum with a soft excess below 2 keV, a relatively narrow iron K α emission (∼6.4 keV), and an obvious cutoff at high energies. We find that the soft excess can be modeled by two different possible scenarios: a warm ( kT _e ∼ 0.19 keV) and optically thick ( τ = 18–25) Comptonizing corona or a relativistic reflection from a high-density ( $\mathrm{log}[{n}_{{\rm{e}}}/{\mathrm{cm}}^{-3}]=17.1\mbox{--}18.5$ ) inner disk. All models require a low temperature ( kT _e ∼ 13 keV) for the hot corona.

The utilization of venovenous bypass in liver transplantation (LT) has become less frequent and more center dependent over time. Unfortunately, this has left many transplant surgeons, particularly younger trainees, unfamiliar with the techniques and indications for its utilization. We present a case of LT in a patient with complete superior vena cava (SVC) occlusion prohibiting direct vascular access. A multi-disciplinary approach involving interventional radiology, anesthesiology, cardiac surgery, and transplant surgery, was used to diagnose, evaluate, and develop an operative plan for successful LT. In doing so, a novel approach to portosystemic bypass was utilized involving a right mini-thoracotomy with direct cannulation of the right atrium to gain central venous access and optimize venous return during LT. As a center that does not routinely use venovenous bypass, this multidisciplinary approach was crucial identifying the need for a rarely used technique for vascular access and performance of a successful LT.

Postoperative recurrence after ileocaecal resection for fibrostenotic terminal ileal Crohn's disease is a significant issue for patients as it can result in symptom recurrence and requirement for further surgery. There are very few modifiable factors, aside from smoking cessation, that can reduce the risk of postoperative recurrence. Until relatively recently, the surgical technique used for resection and anastomosis had little or no impact on postoperative recurrence rates. Novel surgical techniques such as the Kono-S anastomosis and extended mesenteric excision have shown promise as ways to reduce postoperative recurrence rates. This manuscript will review and discuss the evidence regarding a range of surgical techniques and their potential role in reducing disease recurrence. Some of the techniques have been shown to be associated with significant benefits for patients and have already been integrated into the routine clinical practice of some surgeons, while other techniques remain under investigation. Current techniques such as resection of the mesentery close to the intestine and stapled side to side anastomosis are being challenged. It is looking more likely that surgeons will have a major role to play when it comes to reducing recurrence rates for patients undergoing ileocaecal resection for Crohn's disease.

The human gut symbiont Ruminococcus gnavus displays strain-specific repertoires of glycoside hydrolases (GHs) contributing to its spatial location in the gut. Sequence similarity network analysis identified strain-specific differences in blood-group endo-β-1,4-galactosidase belonging to the GH98 family. We determined the substrate and linkage specificities of GH98 from R. gnavus ATCC 29149, RgGH98, against a range of defined oligosaccharides and glycoconjugates including mucin. We showed by HPAEC-PAD and LC-FD-MS/MS that RgGH98 is specific for blood group A tetrasaccharide type II (BgA II). Isothermal titration calorimetry (ITC) and saturation transfer difference (STD) NMR confirmed RgGH98 affinity for blood group A over blood group B and H antigens. The molecular basis of RgGH98 strict specificity was further investigated using a combination of glycan microarrays, site-directed mutagenesis, and X-ray crystallography. The crystal structures of RgGH98 in complex with BgA trisaccharide (BgAtri) and of RgGH98 E411A with BgA II revealed a dedicated hydrogen network of residues, which were shown by site-directed mutagenesis to be critical to the recognition of the BgA epitope. We demonstrated experimentally that RgGH98 is part of an operon of 10 genes that is overexpresssed in vitro when R. gnavus ATCC 29149 is grown on mucin as sole carbon source as shown by RNAseq analysis and RT-qPCR confirmed RgGH98 expression on BgA II growth. Using MALDI-ToF MS, we showed that RgGH98 releases BgAtri from mucin and that pretreatment of mucin with RgGH98 confered R. gnavus E1 the ability to grow, by enabling the E1 strain to metabolise BgAtri and access the underlying mucin glycan chain. These data further support that the GH repertoire of R. gnavus strains enable them to colonise different nutritional niches in the human gut and has potential applications in diagnostic and therapeutics against infection.