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Objective: Serious mental illness (SMI) remains a leading cause of disability worldwide. However, there is limited Australian evidence of community-based programs to enhance the psychosocial wellbeing of adults experiencing SMI. Foundations is a long-term community-based psychosocial outreach support program delivered in Tasmania, Australia. A longitudinal non-randomised controlled trial was conducted to examine the effectiveness of the Foundations program on adults’ psychosocial functioning, clinical symptomology, and hospital readmissions, in comparison to standard care only. Method: Participants were adults aged 18-64 years experiencing SMI. Control participants received standard clinical care only. Intervention participants were engaged in the Foundations program in addition to standard care. Data were collected at program commencement, midpoint, closure, and six-months post-closure. Linear mixed modelling was used to examine differences between groups. Results: Intervention participants achieved better psychosocial functioning in comparison to the control group by program closure and at six-month follow-up. No significant differences were observed for clinical mental health symptomology or hospital readmission rates. Length of readmission stay was significantly shorter for intervention participants. Conclusions: The findings highlight the additional value of community-based, recovery-oriented, psychosocial outreach support alongside clinical mental health care to enhance the psychosocial wellbeing of adults experiencing SMI.

Abstract Background The COVID-19 pandemic resulted in unprecedented changes to cancer care in many countries, impacting cancer patients’ lives in numerous ways. This study examines the impact of changes in cancer care on patient’s health-related quality of life (HRQL), which is a key outcome in cancer care. The study aims to estimate patients’ self-reported HRQL before and during the pandemic and identify predictive factors for their physical and mental wellbeing. Method The study employed the large-scale Outpatient Cancer Care (OCC) Patient Experience Survey, including the Veterans RAND 12-Item Health Survey, to evaluate cancer patients’ experiences and HRQL before (January to May 2020) and during the COVID-19 pandemic (May to July 2021). Paired t-tests were conducted to compare differences in Physical Component Scores (PCS) and Mental Component Scores (MCS) before and during the pandemic. Multivariable linear regressions were employed to investigate the factors (sociodemographic, clinical, and patient-reported experience) influencing PCS and MCS during the pandemic. Results PCS decreased significantly during the pandemic, while MCS remained stable. Lower PCS contributors included older age, more telehealth visits, self-reported hospitalization, and a longer time since the last cancer diagnosis. Higher PCS was associated with urban residence, higher MCS during the pandemic, and perceived active Healthcare Provider (HCP) involvement. For MCS, lower scores related to female gender and more telehealth visits, while higher scores were associated with being white, higher education, high MCS before the pandemic, and perceived active HCP involvement. Conclusion The OCC Patient Experience Survey provides a unique patient level data set measuring HRQL pre- and post- the onset of the COVID-19 pandemic. The study highlights challenges faced by cancer patients during the pandemic, with a significant reduction in PCS. However, the stability in MCS suggests effective coping mechanisms. Sociodemographic, clinical, and telehealth-related variables play a complex role in shaping both PCS and MCS. Perceived HCP involvement emerges as a crucial factor correlating with higher PCS and MCS. Navigating the post-pandemic era necessitates interventions fortifying patient-provider relationships, optimizing healthcare support systems, such as telehealth services, and prioritizing mental-well-being given its impact on both PCS and MCS.

Abstract 3D point cloud data, as an immersive detailed data source, has been increasingly used in numerous applications. To deal with the computational and storage challenges of this data, it needs to be compressed before transmission, storage, and processing, especially in real-time systems. Instead of decoding the compressed data stream and subsequently conducting downstream tasks on the decompressed data, analyzing point clouds directly in their compressed domain has attracted great interest. In this paper, we dive into the realm of compressed point cloud classification (CPCC), aiming to achieve high point cloud classification accuracy in a bitrate-saving way by ensuring the bit stream contains a high degree of representative information of the point cloud. Edge information is one of the most important and representative attributes of the point cloud because it can display the outlines or main shapes. However, extracting edge points or information from point cloud models is challenging due to their irregularity and sparsity. To address this challenge, we adopt an advanced edge-sampling method that enhances existing state-of-the-art (SOTA) point cloud edge-sampling techniques based on attention mechanisms and consequently develop a novel CPCC method “CPCC-PES” that focuses on point cloud’s edge information. The result obtained on the benchmark ModelNet40 dataset shows that our model has superior rate-accuracy trade-off performance than SOTA works. Specifically, our method achieves over 90% Top-1 Accuracy with a mere 0.08 bits-per-point (bpp), marking a remarkable over 96% reduction in BD-bitrate compared with specialized codecs. This means that our method only consumes 20% of the bitrate of other SOTA works while maintaining comparable accuracy. Furthermore, we propose a new evaluation metric named BD-Top-1 Accuracy to evaluate the trade-off performance between bitrate and Top-1 Accuracy for future CPCC research.

Abstract We present a flora and fauna dataset for the Mira-Mataje binational basins. This is an area shared between southwestern Colombia and northwestern Ecuador, where both the Chocó and Tropical Andes biodiversity hotspots converge. We systematized data from 120 sources in the Darwin Core Archive (DwC-A) standard and geospatial vector data format for geographic information systems (GIS) (shapefiles). Sources included natural history museums, published literature, and citizen science repositories across 13 countries. The resulting database has 33,460 records from 6,821 species, of which 540 have been recorded as endemic, and 612 as threatened. The diversity represented in the dataset is equivalent to 10% of the total plant species and 26% of the total terrestrial vertebrate species in both hotspots. The dataset can be used to estimate and compare biodiversity patterns with environmental parameters and provide value to ecosystems, ecoregions, and protected areas. The dataset is a baseline for future assessments of biodiversity in the face of environmental degradation, climate change, and accelerated extinction processes.

Abstract Laser-driven compact particle accelerators can provide ultrashort pulses of broadband X-rays, well suited for undertaking X-ray absorption spectroscopy measurements on a femtosecond timescale. Here the Extended X-ray Absorption Fine Structure (EXAFS) features of the K-edge of a copper sample have been observed over a 250 eV window in a single shot using a laser wakefield accelerator, providing information on both the electronic and ionic structure simultaneously. This capability will allow the investigation of ultrafast processes, and in particular, probing high-energy-density matter and physics far-from-equilibrium where the sample refresh rate is slow and shot number is limited. For example, states that replicate the tremendous pressures and temperatures of planetary bodies or the conditions inside nuclear fusion reactions. Using high-power lasers to pump these samples also has the advantage of being inherently synchronised to the laser-driven X-ray probe. A perspective on the additional strengths of a laboratory-based ultrafast X-ray absorption source is presented.

Abstract Background The effect of empagliflozin, a sodium-glucose-co-transporter-2 inhibitor, on risk for myocardial infarction has not been fully characterized. Methods This study comprised prespecified and post-hoc analyses of the EMPA-REG OUTCOME trial in which 7020 people with type 2 diabetes (T2D) and cardiovascular disease [mostly atherosclerotic (ASCVD)] were randomized to empagliflozin or placebo and followed for a median 3.1 years. We assessed the effect of empagliflozin on total (first plus recurrent) events of centrally adjudicated fatal and non-fatal myocardial infarction (MI) using a negative binomial model with robust confidence intervals (CI) that preserves randomization and accounts for the within-patient correlation of multiple events. Post hoc, we analyzed types of MI: type 1 (related to plaque-rupture/thrombus), type 2 (myocardial supply–demand imbalance), type 3 (sudden-death related, i.e. fatal MI), type 4 (percutaneous coronary intervention-related), and type 5 (coronary artery bypass graft-related). MIs could be assigned to > 1 type. Results There were 421 total MIs (including recurrent); 299, 86, 26, 19, and 1 were classified as type 1, 2, 3, 4, and 5 events, respectively. Overall, empagliflozin reduced the risk of total MI events by 21% [rate ratio for empagliflozin vs. placebo, 0.79 (95% CI, 0.620–0.998), P = 0.0486], largely driven by its effect on type 1 [rate ratio, 0.79 (95% CI, 0.61–1.04)] and type 2 MIs [rate ratio, 0.67 (95% CI, 0.41–1.10)]. Conclusions In T2D patients with ASCVD, empagliflozin reduced the risk of MIs, with consistent effects across the two most common etiologies, i.e. type 1 and 2. Trail Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01131676.

Introduction: The human plasma glycoproteome holds enormous potential to identify personalized biomarkers for diagnostics. Glycoproteomics has matured into a technology for plasma N-glycoproteome analysis but further evolution towards clinical applications depends on the clinical validity and understanding of protein- and site-specific glycosylation changes in disease. Objectives: Here, we exploited the uniqueness of a patient cohort of genetic defects in well-defined glycosylation pathways to assess the clinical applicability of plasma N-glycoproteomics. Methods: Comparative glycoproteomics was performed of blood plasma from 40 controls and 74 patients with 13 different genetic diseases that impact the protein N-glycosylation pathway. Baseline glycosylation in healthy individuals was compared to reference glycome and intact transferrin protein mass spectrometry data. Use of glycoproteomics data for biomarker discovery and sample stratification was evaluated by multivariate chemometrics and supervised machine learning. Clinical relevance of site-specific glycosylation changes were evaluated in the context of genetic defects that lead to distinct accumulation or loss of specific glycans. Integrated analysis of site-specific glycoproteome changes in disease was performed using chord diagrams and correlated with intact transferrin protein mass spectrometry data. Results: Glycoproteomics identified 191 unique glycoforms from 58 unique peptide sequences of 34 plasma glycoproteins that span over 3 magnitudes of abundance in plasma. Chemometrics identified high-specificity biomarker signatures for each of the individual genetic defects with better stratification performance than the current diagnostic standard method. Bioinformatic analyses revealed site-specific glycosylation differences that could be explained by underlying glycobiology and protein-intrinsic factors. Conclusion: Our work illustrates the strong potential of plasma glycoproteomics to significantly increase specificity of glycoprotein biomarkers with direct insights in site-specific glycosylation changes to better understand the glycobiological mechanisms underlying human disease.

Abstract Background Mammalian display is an appealing technology for therapeutic antibody development. Despite the advantages of mammalian display, such as full-length IgG display with mammalian glycosylation and its inherent ability to select antibodies with good biophysical properties, the restricted library size and large culture volumes remain challenges. Bxb1 serine integrase is commonly used for the stable genomic integration of antibody genes into mammalian cells, but presently lacks the efficiency required for the display of large mammalian display libraries. To increase the Bxb1 integrase-mediated stable integration efficiency, our study investigates factors that potentially affect the nuclear localization of Bxb1 integrase. Methods In an attempt to enhance Bxb1 serine integrase-mediated integration efficiency, we fused various nuclear localization signals (NLS) to the N- and C-termini of the integrase. Concurrently, we co-expressed multiple proteins associated with nuclear transport to assess their impact on the stable integration efficiency of green fluorescent protein (GFP)-encoding DNA and an antibody display cassette into the genome of Chinese hamster ovary (CHO) cells containing a landing pad for Bxb1 integrase-mediated integration. Results The nucleoplasmin NLS from Xenopus laevis, when fused to the C-terminus of Bxb1 integrase, demonstrated the highest enhancement in stable integration efficiency among the tested NLS fusions, exhibiting over a 6-fold improvement compared to Bxb1 integrase lacking an NLS fusion. Subsequent additions of extra NLS fusions to the Bxb1 integrase revealed an additional 131% enhancement in stable integration efficiency with the inclusion of two copies of C-terminal nucleoplasmin NLS fusions. Further improvement was achieved by co-expressing the Ran GTPase-activating protein (RanGAP). Finally, to validate the applicability of these findings to more complex proteins, the DNA encoding the membrane-bound clinical antibody abrilumab was stably integrated into the genome of CHO cells using Bxb1 integrase with two copies of C-terminal nucleoplasmin NLS fusions and co-expression of RanGAP. This approach demonstrated over 14-fold increase in integration efficiency compared to Bxb1 integrase lacking an NLS fusion. Conclusions This study demonstrates that optimizing the NLS sequence fusion for Bxb1 integrase significantly enhances the stable genomic integration efficiency. These findings provide a practical approach for constructing larger libraries in mammalian cells through the stable integration of genes into a genomic landing pad.

Niraparib was recently funded in Canada for the maintenance treatment of ovarian cancer following platinum-based chemotherapy. However, the drug’s safety profile in the real world remains uncertain. We conducted a cohort study to describe the patient population using niraparib and the proportion that experienced adverse events between June 2019 and December 2022 in four Canadian provinces (Ontario, Alberta, British Columbia [BC], and Quebec). We used administrative data and electronic medical records from Ontario Health, Alberta Health Services, and BC Cancer, and registry data from Exactis Innovation. We summarized baseline characteristics using descriptive statistics and reported safety outcomes using cumulative incidence. We identified 514 patients receiving niraparib. Mean age was 67 years and most were initiated on a daily dose of 100 or 200 mg/day. Grade 3/4 anemia, neutropenia, and thrombocytopenia occurred in 11–16% of the cohort. In Ontario, the three-month cumulative incidence of grade 3/4 thrombocytopenia was 11.6% (95% CI, 8.3–15.4%), neutropenia was 7.1% (95% CI, 4.6–10.4%), and anemia was 11.3% (95% CI, 8.0–15.2%). Cumulative incidences in the remaining provinces were similar. Initial daily dose and proportions of hematological adverse events were low in the real world and may be related to cautious prescribing and close monitoring by clinicians.

Work integrated learning (WIL), particularly placement-based WIL (P-WIL), has gained momentum in Higher Education over the last decade as an educational strategy for enhancing student employability. However, there is very limited guidance on effective ways to embed and scaffold WIL assessments across courses (degree programs). We present the findings from an action-research study, purposed with building academic confidence to review and re-design existing assessments to have intentional and explicit employability foci. Key to the study was the sharing of existing WIL frameworks to build practitioner expertise. What arose was a notable intersection of similar, but unplanned assessments focused on career development learning, authentic assessment, and/or demonstrations of theory-to-practice performance during WIL activities. What was lacking was a means for designing an intentional holistic schema that tagged a suite of assessments dedicated to the development and demonstration of student employability across the course. An outcome was the creation of a novel meta-assessment WIL framework (WAM-F) that supported and purposefully integrated previously independent items: 1) career development learning; 2) transferable skills development; 3) reflections from professional practice theory-to-practice WIL experiences; and explicitly tethered these to the discipline orientation of the course. The overt tethering of discipline-specific learning outcomes to a range of WIL activities, via a course-wide approach, not only assures the regulatory requirement for all WIL experiences to contribute to, scaffold and develop the learning outcomes of a course, but also makes sense of emerging educational approaches for STEM teaching teams not always familiar or confident with how to embed fit-for-purpose employability learning.

Invariant natural killer T (iNKT) cells are a subset of lipid-reactive, unconventional T cells that have anti-tumor properties that make them a promising target for cancer immunotherapy. Recent studies have deciphered the developmental pathway of human MAIT and Vγ9Vδ2 γδ-T cells as well as murine iNKT cells, yet our understanding of human NKT cell development is limited. Here, we provide an update in our understanding of how NKT cells develop in the human body and how knowledge regarding their development could enhance human treatments by targeting these cells.

Artisanal small-scale mining (ASM) is an environmentally damaging activity in many developing countries, particularly in the wet tropics, yet serves as a crucial economic resource for millions of people. The lack of effective mapping methods hinders quantifying the spatial extent of ASM and management efforts. This study presents a novel approach to integrate multi-spectral and imaging radar datasets within the Google Earth Engine (GEE) platform to map ASGM in a tropical rainforest. We used a case study of gold mining in central Kalimantan and diverse training and validation data sources. The methodology involved pre-processing multispectral and radar imagery, generating and standardizing covariates, applying feature-level data fusion for the Random Forest algorithm in GEE, and training and classifying data with optimized parameters through iterative loops. This approach achieved a classification accuracy of 81% in detecting ASM activities, surpassing the accuracy of a map constructed solely from Sentinel-2 multispectral data by 14%. Through the inclusion of evaluation metrics such as the f(β) score and Matthews Correlation Coefficient (MCC), our approach demonstrates its robustness in accurately identifying target instances, while reducing false positives and addressing imbalanced class sizes by 6.25% and 60%, respectively. Our model’s efficacy underscores its potential to accurately map ASM at larger regional scales (104 – 10⁶ km2) in wet-tropical forests, while being scalable and resource-efficient. Opportunities to further improve this approach by mitigating false-positive errors involve integrating texture filtering with optical and radar data sets. Despite some inherent limitations, our approach overcomes some current challenges of mapping small-scale, but extensive, environmental changes in the wet tropics and thus advances improvements in the continual surveillance, management, and regulation of ASM and other activities that involve selective clearing.

Over the last two decades, patient engagement in cancer research has evolved significantly, especially in addressing the unique challenges faced by adolescent and young adult (AYA) cancer populations. This paper introduces a framework for meaningful engagement with AYA cancer patient research partners, drawing insights from the “FUTURE” Study, a qualitative study that utilizes focus groups to explore the impact of cancer diagnosis and treatment on the sexual and reproductive health of AYA cancer patients in Canada. The framework’s development integrates insights from prior works and addresses challenges with patient engagement in research specific to AYA cancer populations. The framework is guided by overarching principles (safety, flexibility, and sensitivity) and includes considerations that apply across all phases of a research study (collaboration; iteration; communication; and equity, diversity, and inclusion) and tasks that apply to specific phases of a research study (developing, conducting, and translating the study). The proposed framework seeks to increase patient engagement in AYA cancer research beyond a supplementary aspect to an integral component for conducting research with impact on patients.

Abstract Background Mutations in the epidermal growth factor receptor (EGFR) kinase domain are common in non-small cell lung cancer. Conventional tyrosine kinase inhibitors target the mutation site in the ATP binding pocket, thereby inhibiting the receptor's function. However, subsequent treatment resistance mutations in the ATP binding site are common. The EGFR allosteric inhibitor, EAI045, is proposed to have an alternative mechanism of action, disrupting receptor signaling independent of the ATP-binding site. The antibody cetuximab is hypothesized to increase the number of accessible allosteric pockets for EAI045, thus increasing the potency of the inhibitor. This work aimed to gain further knowledge on pharmacokinetics, the EGFR mutation-targeting potential, and the influence of cetuximab on the uptake by radiolabeling EAI045 with carbon-11 and tritium. Results 2-(5-fluoro-2-hydroxyphenyl)-2-((2-iodobenzyl)amino)-N-(thiazol-2-yl)acetamide and 2-(5-fluoro-2-hydroxyphenyl)-N-(5-iodothiazol-2-yl)-2-(1-oxoisoindolin-2-yl)acetamide were synthesized as precursors for the carbon-11 and tritium labeling of EAI045, respectively. [11C]EAI045 was synthesized using [11C]CO in a palladium-catalyzed ring closure in a 10 ± 1% radiochemical yield (decay corrected to end of [11C]CO2 production), > 97% radiochemical purity and 26 ± 1 GBq/µmol molar activity (determined at end of synthesis) in 51 min. [3H]EAI045 was synthesized by a tritium-halogen exchange in a 0.2% radiochemical yield, 98% radiochemical purity, and 763 kBq/nmol molar activity. The ability of [11C]EAI045 to differentiate between L858R/T790M mutated EGFR expressing H1975 xenografts and wild-type EGFR expressing A549 xenografts was evaluated in female nu/nu mice. The uptake was statistically significantly higher in H1975 xenografts compared to A549 xenografts (0.45 ± 0.07%ID/g vs. 0.31 ± 0.10%ID/g, P = 0.0166). The synergy in inhibition between EAI045 and cetuximab was evaluated in vivo and in vitro. While there was some indication that cetuximab influenced the uptake of [3H]EAI045 in vitro, this could not be confirmed in vivo when tumor-bearing mice were administered cetuximab (0.5 mg), 24 h prior to injection of [11C]EAI045. Conclusions EAI045 was successfully labeled with tritium and carbon-11, and the in vivo results indicated [11C]EAI045 may be able to distinguish between mutated and non-mutated EGFR in non-small cell lung cancer mouse models. Cetuximab was hypothesized to increase EAI045 uptake; however, no significant effect was observed on the uptake of [11C]EAI045 in vivo or [3H]EAI045 in vitro in H1975 xenografts and cells.

Background Intracranial hemorrhage is a critical finding on computed tomography (CT) of the head. This study compared the accuracy of an artificial intelligence (AI) model (Annalise Enterprise CTB Triage Trauma) to consensus neuroradiologist interpretations in detecting 4 hemorrhage subtypes: acute subdural/epidural hematoma, acute subarachnoid hemorrhage, intra‐axial hemorrhage, and intraventricular hemorrhage. Methods A retrospective stand‐alone performance assessment was conducted on data sets of cases of noncontrast CT of the head acquired between 2016 and 2022 at 5 hospitals in the United States for each hemorrhage subtype. The cases were obtained from patients aged ≥18 years. The positive cases were selected on the basis of the original clinical reports using natural language processing and manual confirmation. The negative cases were selected by taking the next negative case acquired from the same CT scanner after positive cases. Each case was interpreted independently by up to 3 neuroradiologists to establish consensus interpretations. Each case was then interpreted by the AI model for the presence of the relevant hemorrhage subtype. The neuroradiologists were provided with the entire CT study. The AI model separately received thin (≤1.5 mm) and thick (>1.5 and ≤5 mm) axial series as available. Results The 4 cohorts included 571 cases of acute subdural/epidural hematoma, 310 cases of acute subarachnoid hemorrhage, 926 cases of intra‐axial hemorrhage, and 199 cases of intraventricular hemorrhage. The AI model identified acute subdural/epidural hematoma with area under the curve of 0.973 (95% CI, 0.958–0.984) on thin series and 0.942 (95% CI, 0.921–0.959) on thick series; acute subarachnoid hemorrhage with area under the curve 0.993 (95% CI, 0.984–0.998) on thin series and 0.966 (95% CI, 0.945–0.983) on thick series; intraaxial hemorrhage with area under the curve of 0.969 (95% CI, 0.956–0.980) on thin series and 0.966 (95% CI, 0.953–0.976) on thick series; and intraventricular hemorrhage with area under the curve of 0.987 (95% CI, 0.969–0.997) on thin series and 0.983 (95% CI, 0.968–0.994) on thick series. Each finding had at least 1 operating point with sensitivity and specificity >80%. Conclusion The assessed AI model accurately identified intracranial hemorrhage subtypes in this CT data set. Its use could assist the clinical workflow, especially through enabling triage of abnormal CTs.

Abstract The ocean is responsible for taking up approximately 25% of anthropogenic CO2 emissions and stores >50 times more carbon than the atmosphere. Biological processes in the ocean play a key role, maintaining atmospheric CO2 levels approximately 200 ppm lower than they would otherwise be. The ocean's ability to take up and store CO2 is sensitive to climate change, however the key biological processes that contribute to ocean carbon storage are uncertain, as are how those processes will respond to, and feedback on, climate change. As a result, biogeochemical models vary widely in their representation of relevant processes, driving large uncertainties in the projections of future ocean carbon storage. This review identifies key biological processes that affect how ocean carbon storage may change in the future in three thematic areas: biological contributions to alkalinity, net primary production, and interior respiration. We undertook a review of the existing literature to identify processes with high importance in influencing the future biologically‐mediated storage of carbon in the ocean, and prioritized processes on the basis of both an expert assessment and a community survey. Highly ranked processes in both the expert assessment and survey were: for alkalinity—high level understanding of calcium carbonate production; for primary production—resource limitation of growth, zooplankton processes and phytoplankton loss processes; for respiration—microbial solubilization, particle characteristics and particle type. The analysis presented here is designed to support future field or laboratory experiments targeting new process understanding, and modeling efforts aimed at undertaking biogeochemical model development.

Abstract The Southern Ocean, its ecosystem, and inhabitants are vulnerable to climate‐mediated shifts in habitat conditions. These changes can affect marine predators in the long term through changes in the distribution, density, and quality of prey. To understand how these changes affect vital rates requires longitudinal studies integrating demography and environmental states. We analyzed 22 years of capture–mark–recapture data to quantify the influence of broad‐scale climate on the survival of male southern elephant seals from Macquarie Island, Tasmania, Australia. Weaning mass was incorporated as a quadratic predictor of survival to account for the known influence of maternal investment. First‐year survival was greatest for weaners weighing 160 kg. Subsequent developmental stages were grouped into juvenile, subordinate, and breeding adult states to reflect the known life history of individuals. We found increased juvenile and subordinate survival with positive values of the previous years' Southern Annular Mode. This is likely due to the northward shift of westerly winds increasing productivity and prey availability in the Sub‐Antarctic region. In contrast to females of this population, the Southern Oscillation Index did not affect male survival. In this highly polygynous mating system, sex‐dependent differences in foraging behavior may be causing the small number of successful breeding adult males to be less susceptible to external influences after reaching the minimum age and body size required to be socially competitive for mating. These extremely large bulls will breed with multiple females and thus make a disproportionate contribution to the gene pool of the next generation. Considering the susceptibility of males to climate influences is therefore highly relevant to assessing the future adaptive capability of the species.

Background Transcatheter renal denervation (RDN) has had inconsistent efficacy and concerns for durability of denervation. We aimed to investigate long‐term safety and efficacy of transcatheter microwave RDN in vivo in normotensive sheep in comparison to conventional radiofrequency ablation. Methods and Results Sheep underwent bilateral RDN, receiving 1 to 2 microwave ablations (maximum power of 80–120 W for 240 s–480 s) and 12 to 16 radiofrequency ablations (180 s–240 s) in the main renal artery in a paired fashion, alternating the side of treatment, euthanized at 2 weeks (acute N=15) or 5.5 months (chronic N=15), and compared with undenervated controls (N=4). Microwave RDN produced substantial circumferential perivascular injury compared with radiofrequency at both 2 weeks [area 239.8 (interquartile range [IQR] 152.0–343.4) mm2 versus 50.1 (IQR, 32.0–74.6) mm2, P

Abstract Data on respiratory syncytial virus (RSV) incidence and household transmission are limited. To describe RSV incidence and transmission, we conducted a prospective cohort study in rural and urban communities in South Africa over two seasons during 2017-2018. Nasopharyngeal swabs were collected twice-weekly for 10 months annually and tested for RSV using PCR. We tested 81,430 samples from 1,116 participants in 225 households (follow-up 90%). 32% (359/1116) of individuals had ≥1 RSV infection; 10% (37/359) had repeat infection during the same season, 33% (132/396) of infections were symptomatic, and 2% (9/396) sought medical care. Incidence was 47.2 infections/100 person-years and highest in children 10 days were more likely to transmit; household contacts aged 1-4 years vs. ≥65 years were more likely to acquire infection. Within two South African communities, RSV attack rate was high, and most infections asymptomatic. Young children were more likely to introduce RSV into the home, and to be infected. Future studies should examine whether vaccines targeting children aged

Abstract CAR (CARSKNKDC) is a wound-homing peptide that recognises angiogenic neovessels. Here we discover that systemically administered CAR peptide has inherent ability to promote wound healing: wounds close and re-epithelialise faster in CAR-treated male mice. CAR promotes keratinocyte migration in vitro. The heparan sulfate proteoglycan syndecan-4 regulates cell migration and is crucial for wound healing. We report that syndecan-4 expression is restricted to epidermis and blood vessels in mice skin wounds. Syndecan-4 regulates binding and internalisation of CAR peptide and CAR-mediated cytoskeletal remodelling. CAR induces syndecan-4-dependent activation of the small GTPase ARF6, via the guanine nucleotide exchange factor cytohesin-2, and promotes syndecan-4-, ARF6- and Cytohesin-2-mediated keratinocyte migration. Finally, we show that genetic ablation of syndecan-4 in male mice eliminates CAR-induced wound re-epithelialisation following systemic administration. We propose that CAR peptide activates syndecan-4 functions to selectively promote re-epithelialisation. Thus, CAR peptide provides a therapeutic approach to enhance wound healing in mice; systemic, yet target organ- and cell-specific.

Societal Impact Statement Plants are fundamental to terrestrial and aquatic ecosystems and are key to human livelihoods. To protect plant diversity, systematic approaches to conservation assessment are needed. Many nations have legislation or other policy instruments that seek to protect biodiversity (including plants), and species‐level assessments are essential for identifying the most threatened species that require special and immediate protection measures. Some plants occur in only one place (for instance, a single country) and here we have estimated how many of these ‘endemic’ species have had their threats assessed in each country or close country‐equivalent worldwide. We show that the level of assessment completion is only weakly related to the income of countries or the likely level of threat that species face. Summary The Global Strategy for Plant Conservation ambitiously called for an assessment of the conservation status of all recognised plant taxa by 2020. This target was not met in the short term. Nevertheless, the need for conservation assessments remains urgent as plants go extinct and face increasing threats from human impacts on the biosphere. Here, the completeness of threat assessments for endemic flora in 179 countries or their close equivalents was assessed. To do so, distribution information from the World Checklist of Vascular Plants was combined with assessments collated in the ThreatSearch database. The completeness of assessments was expected to be associated with the objective affluence of countries (measured using inequality‐adjusted Human Development Index (IHDI)) and/or the exposure of their plant species to threats associated with human impacts (measured using Global Human Modification index (GHM)). The number of endemic species per country was also hypothesised to influence the completion of assessments. Overall, 58% of all country‐based endemic species examined have no conservation assessment (127,643 species). Countries' progress toward the completion of threat assessments for endemic plants could not be confidently predicted by IHDI, GHM or the richness of endemic plant flora. The shortfall in threat assessments identified here restricts national regulation of actions which imperil plant species, with particular consequences for endemic plant species subject to local laws. Some nations with high IHDI scores (i.e. wealthier nations) are not systematically assessing extinction risk in their endemic species. Scarce funding should be directed to global hotspots of endemism with few available resources for assessment.

Understanding land-use dynamics and patterns and how they respond to management scenarios helps to develop sustainable land use policies. This study simulated future land uses in Brantas River Basin (BRB), East Java, Indonesia using Land Change Modeler (LCM) under policy scenarios. Following identification of twelve important biophysical and socio-economic spatial drivers, the LCM accurately simulated land-use changes over the period 1995–2015, with validation against the 1995 land use map giving an overall accuracy of 85–88 %. Under a business-as-usual scenario, the LCM predicted that during the period 2015 to 2035 continuing deforestation may leave forest cover accounting for only 4 % of the total BRB area, and cause declines in dryland from 45 % to 40 % and in rice-field farming from 24 % to 22 %. The results of that scenario also indicate the prospect of massive urban development, increasing from 18 % of the BRB area in 2015 to 30 % in 2035, with increasing threats to food security and water resources. Both percentage changes and a mean-weighted fractal dimension index suggest increased risks of forest fragmentation and urban aggregation. A spatial planning-influenced scenario, which aims to reduce forest loss and support watershed protection, is predicted to lead to 5.5 % forest cover, 37 % dryland, 29 % rice-field farming and 24 % urban area in 2035. Sensitivity analysis of the LCM showed that the model results were more sensitive to drivers, spatial resolution, and policy scenarios than to uncertainty in model parameters. It is concluded that despite some limitations, the LCM successfully provided'' insights into policy impacts on land-uses in BRB, and the roles of forest and rice-field protection in spatial planning are essential in controlling urban development for watershed sustainability.

Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity and mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell activation has been identified as a central mechanism for promoting fibrosis downstream of TGFβ. IL11 signaling has recently been reported to promote fibroblast-to-myofibroblast transition, thus leading to various pro-fibrotic phenotypic changes. We confirmed increased mRNA expression of IL11 and IL11Rα in fibrotic diseases by OMICs approaches and in situ hybridization. However, the vital role of IL11 as a driver for fibrosis was not recapitulated. While induction of IL11 secretion was observed downstream of TGFβ signaling in human lung fibroblasts and epithelial cells, the cellular responses induced by IL11 was quantitatively and qualitatively inferior to that of TGFβ at the transcriptional and translational levels. IL11 blocking antibodies inhibited IL11Rα-proximal STAT3 activation but failed to block TGFβ-induced profibrotic signals. In summary, our results challenge the concept of IL11 blockade as a strategy for providing transformative treatment for fibrosis.

Abstract Rapid and robust strategies to evaluate the efficacy and effectiveness of novel and existing pharmacotherapeutic interventions (repurposed treatments) in future pandemics are required. Observational “real‐world studies” (RWS) can report more quickly than randomized controlled trials (RCTs) and would have value were they to yield reliable results. Both RCTs and RWS were deployed during the coronavirus disease 2019 (COVID‐19) pandemic. Comparing results between them offers a unique opportunity to determine the potential value and contribution of each. A learning review of these parallel evidence channels in COVID‐19, based on quantitative modeling, can help improve speed and reliability in the evaluation of repurposed therapeutics in a future pandemic. Analysis of all‐cause mortality data from 249 observational RWS and RCTs across eight treatment regimens for COVID‐19 showed that RWS yield more heterogeneous results, and generally overestimate the effect size subsequently seen in RCTs. This is explained in part by a few study factors: the presence of RWS that are imbalanced for age, gender, and disease severity, and those reporting mortality at 2 weeks or less. Smaller studies of either type contributed negligibly. Analysis of evidence generated sequentially during the pandemic indicated that larger RCTs drive our ability to make conclusive decisions regarding clinical benefit of each treatment, with limited inference drawn from RWS. These results suggest that when evaluating therapies in future pandemics, (1) large RCTs, especially platform studies, be deployed early; (2) any RWS should be large and should have adequate matching of known confounders and long follow‐up; (3) reporting standards and data standards for primary endpoints, explanatory factors, and key subgroups should be improved; in addition, (4) appropriate incentives should be in place to enable access to patient‐level data; and (5) an overall aggregate view of all available results should be available at any given time.

Abstract Background Low-dose analgesic methoxyflurane (Penthrox®) was approved in Europe for emergency relief of moderate to severe pain in conscious adults with trauma in 2015. A comparative post-authorisation safety study (PASS) was conducted to assess the risk of hepatotoxicity and nephrotoxicity with methoxyflurane during routine clinical practice. Methods This was a comparative hybrid prospective-retrospective cohort study. The comparative cohorts consisted of adults who were given methoxyflurane (methoxyflurane cohort) or another analgesic (concurrent cohort) routinely used for moderate to severe trauma and associated pain in the emergency setting (ambulance and Emergency Department) in the UK between December 2016 and November 2018. Hepatic and renal events were captured in the ensuing 12 weeks. A blinded clinical adjudication committee assessed events. A historical comparator cohort (non-concurrent cohort) was identified from patients with fractures in the English Hospital Episode Statistics (HES) accident and emergency database from November 2013 and November 2015 (before commercial launch of methoxyflurane). Hepatic and renal events were captured in the ensuing 12 weeks via linkage with the Clinical Practice Research Datalink (CPRD) and HES hospital admissions databases. Results Overall, 1,236, 1,101 and 45,112 patients were analysed in the methoxyflurane, concurrent and non-concurrent comparator cohorts respectively. There was no significant difference in hepatic events between the methoxyflurane and concurrent cohorts (1.9% vs. 3.0%, P = 0.079) or between the methoxyflurane and non-concurrent cohorts (1.9% vs. 2.5%, P = 0.192). Renal events were significantly less common in the methoxyflurane cohort than in the concurrent cohort (2.3% vs. 5.6%, P

The estimation of water quality properties through satellite remote sensing relies on (1) the optical characteristics of the water body, (2) the resolutions (spatial, spectral, radiometric and temporal) of the sensor and (3) algorithm(s) applied. More than 80% of global water bodies fall under Case I (open ocean) waters, dominated by scattering and absorption associated with phytoplankton in the water column. Globally, previous studies show significant correlations between satellite-based retrieval methods and field measurements of absorbing and scattering constituents, while limited research from Australian coastal water bodies appears. This study presents a methodology to extract chlorophyll a properties from surface waters from near-coastal environments, within 2 km of coastline, in Tasmania, south-eastern Australia. We use general purpose, global, long-time series, multi-spectral satellite data, as opposed to ocean colour-specific sensor data. This approach may offer globally applicable tools for combining global satellite image archives with in situ field sensors for water quality monitoring. To enable applications from local to global scales, a cloud-based geospatial analysis workflow was developed and tested on several sites. This work represents the initial stage in developing a semi-automated near-coastal water-quality workflow using easily accessed, fully corrected global multi-spectral datasets alongside large-scale computation and delivery capabilities. Our results indicated a strong correlation between the in situ chlorophyll concentration data and blue-green band ratios from the multi-spectral sensor. In line with published research, environment-specific empirical models exhibited the highest correlations between in situ and satellite measurements, underscoring the importance of tailoring models to specific coastal waters. Our findings may provide the basis for developing this workflow for other sites in Australia. We acknowledge the use of general purpose multi-spectral data such as the Sentinel-2 and Landsat Series, their corrections and algorithms may not be as accurate and precise as ocean colour satellites. The data we are using are more readily accessible and also have true global coverage with global historic archives and regular, global collection will continue at least 10 years in the future. Regardless of sensor specifications, the retrieval method relies on localised algorithm calibration and validation using in situ measurements, which demonstrates close-to-realistic outputs. We hope this approach enables future applications to also consider these globally accessible and regularly updated datasets that are suited to coastal environments.

The Rich spatial and angular information in light field images enables accurate depth estimation, which is a crucial aspect of environmental perception. However, the abundance of light field information also leads to high computational costs and memory pressure. Typically, selectively pruning some light field information can significantly improve computational efficiency but at the expense of reduced depth estimation accuracy in the pruned model, especially in low-texture regions and occluded areas where angular diversity is reduced. In this study, we propose a lightweight disparity estimation model that balances speed and accuracy and enhances depth estimation accuracy in textureless regions. We combined cost matching methods based on absolute difference and correlation to construct cost volumes, improving both accuracy and robustness. Additionally, we developed a multi-scale disparity cost fusion architecture, employing 3D convolutions and a UNet-like structure to handle matching costs at different depth scales. This method effectively integrates information across scales, utilizing the UNet structure for efficient fusion and completion of cost volumes, thus yielding more precise depth maps. Extensive testing shows that our method achieves computational efficiency on par with the most efficient existing methods, yet with double the accuracy. Moreover, our approach achieves comparable accuracy to the current highest-accuracy methods but with an order of magnitude improvement in computational performance.

Summary: Background: There is no consensus on reporting light characteristics in studies investigating non-visual responses to light. This project aimed to develop a reporting checklist for laboratory-based investigations on the impact of light on non-visual physiology. Methods: A four-step modified Delphi process (three questionnaire-based feedback rounds and one face-to-face group discussion) involving international experts was conducted to reach consensus on the items to be included in the checklist. Following the consensus process, the resulting checklist was tested in a pilot phase with independent experts. Findings: An initial list of 61 items related to reporting light-based interventions was condensed to a final checklist containing 25 items, based upon consensus among experts (final n = 60). Nine items were deemed necessary to report regardless of research question or context. A description of each item is provided in the accompanying Explanation and Elaboration (E&E) document. The independent pilot testing phase led to minor textual clarifications in the checklist and E&E document. Interpretation: The ENLIGHT Checklist is the first consensus-based checklist for documenting and reporting ocular light-based interventions for human studies. The implementation of the checklist will enhance the impact of light-based research by ensuring comprehensive documentation, enhancing reproducibility, and enabling data aggregation across studies. Funding: Network of European Institutes for Advanced Study (NETIAS) Constructive Advanced Thinking (CAT) programme; Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust, 204686/Z/16/Z); Netherlands Organisation for Health Research and Development VENI fellowship (2020–09150161910128); U.S. Department of Defense Grant (W81XWH-16-1-0223); National University of Singapore (NUHSRO/2022/038/Startup/08); and National Research Foundation Singapore (NRF2022-THE004-0002).

Objectives Compared with ST-segment elevation myocardial infarction (STEMI) patients, non-STEMI (NSTEMI) patients have more comorbidities and extensive coronary artery disease. Contemporary comparative data on the long-term prognosis of stable post-myocardial infarction subtypes are needed.Design Long-Term rIsk, clinical manaGement and healthcare Resource utilisation of stable coronary artery dISease (TIGRIS) was a multinational, observational and longitudinal cohort study.Setting Patients were enrolled from 350 centres, with >95% coming from cardiology practices across 24 countries, from 19 June 2013 to 31 March 2017.Participants This study enrolled 8277 stable patients 1–3 years after myocardial infarction with ≥1 additional risk factor.Outcome measures Over a 2 year follow-up, cardiovascular events and deaths and self-reported health using the EuroQol 5-dimension questionnaire score were recorded. Relative risk of clinical events and health resource utilisation in STEMI and NSTEMI patients were compared using multivariable Poisson regression models, adjusting for prognostically relevant patient factors.Results Of 7752 patients with known myocardial infarction type, 46% had NSTEMI; NSTEMI patients were older with more comorbidities than STEMI patients. NSTEMI patients had significantly poorer self-reported health and lower prevalence of dual antiplatelet therapy at hospital discharge and at enrolment 1–3 years later. NSTEMI patients had a higher incidence of combined myocardial infarction, stroke and cardiovascular death (5.6% vs 3.9%, p

ABSTRACT: Salmonella and Campylobacter are common foodborne pathogens in chickens, but their persistence mechanisms within flocks are not fully understood. In this study, 4 groups of SPF Leghorn chickens (n = 50) were orally inoculated with 108 Salmonella Enteritidis and 108 Campylobacter jejuni, housed in BSL-2 rooms inside containers with autoclaved bedding and beetles (n = 200). Phase I (wk 1–3): the infected chickens remained in the containers and were then euthanized while beetles and litter remained in the container (group A), beetles were removed and litter remained in the container (group B), beetles remained and litter was removed (group C), and beetles and litter were removed (group D). Phase II (wk 5–7): autoclaved bedding was added to containers in groups C and D, and new SPF chickens (n = 50) were introduced and kept. Phase III (wk 8–20): all chickens were euthanized, and the litter and/or beetles remained in the containers for 17 wk. The prevalence of Salmonella Enteritidis and Campylobacter was significantly higher when detected by PCR compared to culture. In phase II, when infected chickens were removed and new chickens were introduced, 1 fecal sample in group B and 3 litter samples in groups B and C were found positive for Salmonella Enteritidis, and Campylobacter was still detected in groups A, B, and C litter samples, but not in beetles. In phase III, when all chickens were removed, Salmonella Enteritidis was identified in beetle samples from group A and the litter samples of all tested groups A, B, and C, and C. jejuni was positive in litter samples from groups A and B but not in the beetle. Sixty-nine days after removing infected chickens, culturable Salmonella was still found in beetles. Salmonella and Campylobacter were detectable in litter up to 127 d after removing infected chickens. This study highlights the transmission of Salmonella and Campylobacter via beetles and litter to new flocks in successive rearing cycles. Intensive control programs should target insect exclusion and implement strict poultry litter management or litter changes between flocks.

Summary: Background: Shifting from cytology to human papillomavirus (HPV)-based cervical cancer screening will initially increase colposcopy referrals. The anticipated impact on health systems has been raised as a concern for implementation. It is unclear if the higher rate of colposcopy referrals is sustained after initial HPV-based screens or reverts to new lower baselines due to earlier detection and treatment of precancer. This study aimed to investigate long-term rates of colposcopy referrals after participation in HPV-based screening. Methods: Participants of HPV for Cervical Cancer Screening trial (HPV FOCAL) received one (HPV1, N = 6204) or two (HPV2, N = 9540) HPV-based screens. After exit, they returned to British Columbia's (BC) cytology screening program. A comparison cohort from the BC screening population (BCS, N = 1,140,745) was identified, mirroring trial inclusion criteria. All participants were followed for 10–14 years through the provincial screening registry. Colposcopy referral rates per 1000 screens were calculated for each group. Trial colposcopy referrals for HPV1 and HPV2 were calculated under two referral scenarios: (1) all HPV positive referred to colposcopy; (2) cytology triage with ASCUS or greater referred to colposcopy. Colposcopy referrals from post-trial screens in HPV1 an HPV2 and all screens in BCS were based on actual recommendations from the screening program. A multivariable flexible survival regression model compared hazard ratios (HR) throughout follow-up. Findings: Scenario 2 referral rates were higher during initial HPV screen(s) vs cytology screen (HPV1: 28 per 1000 screens (95% CI: 24, 33), HPV2: 32 per 1000 screens (95% CI: 29, 36), BCS: 8 per 1000 screens (95% CI: 8.9)). However, post-trial rates in HPV1 and HPV2 were significantly lower than in BCS. Cumulative rates in HPV1 and HPV2 approached the cumulative rate in BCS 11–12 years after HPV-based screening (HPV1: 11 per 1000 screens (95% CI: 10, 12), HPV2: 16 per 1000 screens (95% CI: 15–17), BCS: 11 per 1000 screens (95% CI: 10, 11)). Adjusted models demonstrated reductions in referral rates in HPV1 (HR = 0.6, 95% CI: 0.5, 0.7) and HPV2 (HR = 0.7, 95% CI: 0.6, 0.8) relative to BCS by 54 and 72 months post-final HPV screen respectively. Interpretation: Reduced colposcopy referral rates were observed after initial rounds of HPV-based screening. After initial HPV screening, referral rates to colposcopy after cytology triage were below the current rates seen in a centralized cytology program after approximately four years. Any expected increase in referrals at initiation of HPV-based screening could be countered by staged program implementation. Funding: This work was supported by the National Institutes of Health (R01 CA221918), Michael Smith Health Research BC (RT-2021-1595), and the Canadian Institutes of Health Research (MCT82072).

The Canadian Real-world Evidence for Value of Cancer Drugs (CanREValue) collaboration developed an MCDA rating tool to assess and prioritize potential post-market real-world evidence (RWE) questions/uncertainties emerging from public drug funding decisions in Canada. In collaboration with a group of multidisciplinary stakeholders from across Canada, the rating tool was developed following a three-step process: (1) selection of criteria to assess the importance and feasibility of an RWE question; (2) development of rating scales, application of weights and calculating aggregate scores; and (3) validation testing. An initial MCDA rating tool was developed, composed of seven criteria, divided into two groups. Group A criteria assess the importance of an RWE question by examining the (1) drug’s perceived clinical benefit, (2) magnitude of uncertainty identified, and (3) relevance of the uncertainty to decision-makers. Group B criteria assess the feasibility of conducting an RWE analysis including the (1) feasibility of identifying a comparator, (2) ability to identify cases, (3) availability of comprehensive data, and (4) availability of necessary expertise and methodology. Future directions include partnering with the Canadian Agency for Drugs and Technology in Health’s Provincial Advisory Group for further tool refinement and to gain insight into incorporating the tool into drug funding deliberations.

With the ambition to identify novel chemical starting points that can be further optimized into small drug-like inhibitors of insulin-regulated aminopeptidase (IRAP) and serve as potential future cognitive enhancers in the clinic, we conducted an ultra-high-throughput screening campaign of a chemically diverse compound library of approximately 400,000 drug-like small molecules. Three biochemical and one biophysical assays were developed to enable large-scale screening and hit triaging. The screening funnel, designed to be compatible with high-density microplates, was established with two enzyme inhibition assays employing either fluorescent or absorbance readouts. As IRAP is a zinc-dependent enzyme, the remaining active compounds were further evaluated in the primary assay, albeit with the addition of zinc ions. Rescreening with zinc confirmed the inhibitory activity for most compounds, emphasizing a zinc-independent mechanism of action. Additionally, target engagement was confirmed using a complementary biophysical thermal shift assay where compounds causing positive/negative thermal shifts were considered genuine binders. Triaging based on biochemical activity, target engagement, and drug-likeness resulted in the selection of 50 qualified hits, of which the IC50 of 32 compounds was below 3.5 µM. Despite hydroxamic acid dominance, diverse chemotypes with biochemical activity and target engagement were discovered, including non-hydroxamic acid compounds. The most potent compound (QHL1) was resynthesized with a confirmed inhibitory IC50 of 320 nM. Amongst these compounds, 20 new compound structure classes were identified, providing many new starting points for the development of unique IRAP inhibitors. Detailed characterization and optimization of lead compounds, considering both hydroxamic acids and other diverse structures, are in progress for further exploration.

Early Mars was likely habitable, but could life actually have started there? While cellular life emerged from prebiotic chemistry through a pre-Darwinian selection process relevant to both Earth and Mars, each planet posed unique selection ‘hurdles’ to this process. We focus on drivers of selection in prebiotic chemistry generic to Earth-like worlds and specific to Mars, such as an iron-rich surface. Iron, calcium, and magnesium cations are abundant in hydrothermal settings on Earth and Mars, a promising environment for an origin of life. We investigated the impact of cations on the stability and disruption of different primitive cell membranes under different pH conditions. The relative destabilizing effect of cations on membranes observed in this study is Ca2+ > Fe2+ > Mg2+. Cation concentrations in Earth systems today are too low to disrupt primitive membranes, but on Mars concentrations could have been elevated enough to disrupt membranes during surface dehydration. Membranes and RNA interact during dehydration–rehydration cycles to mutually stabilize each other in cation-rich solutions, and optimal membrane composition can be ‘selected’ by environmental factors such as pH and cation concentrations. We introduce an approach that considers how life may have evolved differently under the Martian planetary conditions and selective pressures.

Antimicrobial resistance (AMR) in non-typhoidal Salmonella is a pressing public health concern in the United States, necessitating continuous surveillance. We conducted a retrospective analysis of 251 Salmonella isolates from 11 animal species recovered between 1982 and 1999, utilizing serotyping, antimicrobial susceptibility testing, and whole-genome sequencing (WGS). Phenotypic resistance was observed in 101 isolates, with S. Typhimurium, S. Dublin, S. Agona, and S. Muenster prevailing among 36 identified serovars. Notably, resistance to 12 of 17 antibiotics was detected, with ampicillin being most prevalent (79/251). We identified 38 resistance genes, primarily mediating aminoglycoside (n = 13) and β-lactamase (n = 6) resistance. Plasmid analysis unveiled nine distinct plasmids associated with AMR genes in these isolates. Chromosomally encoded blaSCO-1 was present in three S. Typhimurium and two S. Muenster isolates from equine samples, conferring resistance to amoxicillin/clavulanic acid. Phylogenetic analysis revealed three distinct clusters for these five isolates, indicating evolutionary divergence. This study represents the first report of blaSCO-1 in the USA, and our recovered isolates harboring this gene as early as 1989 precede those of all other reports. The enigmatic nature of blaSCO-1 prompts further research into its function. Our findings highlight the urgency of addressing antimicrobial resistance in Salmonella for effective public health interventions.

Background: Ordinalised vascular outcomes incorporating event severity are more informative than binary outcomes that just include event numbers. The TARDIS trial was the first vascular prevention study to use an ordinalised vascular outcome as its primary efficacy and safety measures and collected severity information for other vascular events. Methods: TARDIS was an international prospective randomised open-label blinded-endpoint trial assessing one month of intensive versus guideline antiplatelet therapy in patients with acute non-cardioembolic stroke or TIA. Vascular events and their severity were recorded up to final follow-up at 90 days post randomisation. For each outcome, statistical techniques compared ordinal/continuous (10 models) and dichotomous (5 models) analyses; results were then ranked with the smallest p-value being given the smallest rank. Outcomes were also assessed within the pre-defined subgroup of participants with mild stroke (NIHSS≤3), or TIA recruited within 24 h. Results: Ordinal versions of vascular event outcomes were created in 3096 participants for stroke, myocardial infarction, major cardiac events, bleeding events, serious adverse events and venous thromboembolism (VTE), with 32 outcomes being created overall (29 in the subgroup population due to the absence of VTE events). Overall, the tests run on ordinal outcomes tended to rank higher than tests performed on binary outcomes. 764 (24.7%) participants were recruited within 24 h of a mild stroke/TIA; again, tests run on ordinal outcomes ranked higher. Conclusions: In TARDIS, tests performed on ordinal vascular outcomes tended to attain a higher rank than those performed on binary outcomes. Trial registration: ISRCTN47823388

Members of the archaeal order Caldarchaeales (previously the phylum Aigarchaeota) are poorly sampled and are represented in public databases by relatively few genomes. Additional representative genomes will help resolve their placement among all known members of Archaea and provide insights into their roles in the environment. In this study, we analyzed 16S rRNA gene amplicons belonging to the Caldarchaeales that are available in public databases, which demonstrated that archaea of the order Caldarchaeales are diverse, widespread, and most abundant in geothermal habitats. We also constructed five metagenome-assembled genomes (MAGs) of Caldarchaeales from two geothermal features to investigate their metabolic potential and phylogenomic position in the domain Archaea. Two of the MAGs were assembled from microbial community DNA extracted from fumarolic lava rocks from Mauna Ulu, Hawai‘i, and three were assembled from DNA obtained from hot spring sinters from the El Tatio geothermal field in Chile. MAGs from Hawai‘i are high quality bins with completeness >95% and contamination

Self-collection may provide an opportunity for innovation within population-based human papillomavirus (HPV) cervical cancer screening programs by providing an alternative form of engagement for all individuals. The primary objective was to determine willingness to self-collect a vaginal sample for primary HPV screening and factors that impact willingness in individuals who participated in the Human Papillomavirus For Cervical Cancer (HPV FOCAL) screening trial, a large randomized controlled cervical screening trial. A cross-sectional online survey was distributed between 2017 and 2018 to 13,176 eligible participants exiting the FOCAL trial. Bivariate and multivariable logistic regression assessed factors that influence willingness to self-collect on 4945 respondents. Overall, 52.1% of respondents indicated willingness to self-collect an HPV sample. In multivariable analysis, the odds of willingness to self-collect were significantly higher in participants who agreed that screening with an HPV test instead of a Pap test was acceptable to them (odds ratio (OR): 1.45 (95% confidence interval (CI): 1.15, 1.82), those who indicated that collecting their own HPV sample was acceptable to them (p < 0.001), and those with higher educational ascertainment (OR: 1.31, 95% CI: 1.12, 1.54). The findings offer insight into the intentions to self-collect in those already engaged in screening, and can inform cervical cancer screening programs interested in offering alternative approaches to HPV-based screening.

Measurement(s) ecosystem occurrence Technology Type(s) earth observation Sample Characteristic - Environment tidal flats • coastal wetlands Sample Characteristic - Location global

Abstract Background Given the rising incidence of young-onset colorectal cancer (yCRC) among individuals younger than 50 years old, understanding the economic burden of yCRC is required to inform the delivery of healthcare services. Therefore, we conducted a systematic review of studies assessing the direct medical costs of yCRC, and where relevant average-age onset CRC (aCRC). Methods We searched MEDLINE, EMBASE, and Web of Science from inception to May 2022 for original, peer-reviewed studies, that reported direct medical costs (e.g., chemotherapy, radiotherapy, outpatient visits, inpatient care, prescription medications) for yCRC and aCRC. We used a modified version of the Consolidated Health Economic Evaluation Reporting Standards checklist to appraise the studies. Costs were inflation-adjusted to 2020 US dollars. Results We included 14 studies from 10 countries, including the USA, England, France, Korea, Vietnam, China, Italy, Australia, Canada and Japan. Five studies focused on prevalent disease and reported annualized per-capita cost of prevalent yCRC, ranging from $2,263 to $16,801 and $1,412 to $14,997 among yCRC and aCRC cases, respectively. Nine studies estimated the cost of incident disease. Synthesis of per-capita costs incurred 12 months following colorectal cancer diagnosis ranged from $23,368 to $89,945 for yCRC and $19,929 to $67,195 for aCRC. Five studies used multivariable approaches to compare costs associated with yCRC and aCRC, four showed no differences and one suggested greater costs with yCRC. Conclusion Our synthesis of direct medical costs of yCRC across multiple jurisdictions provide relevant information for healthcare decisions, including on-going considerations for expanding CRC screening strategies to younger adults.

Robust prediction of population responses to changing environments requires the integration of factors controlling population dynamics with processes affecting distribution. This is true everywhere but especially in polar pelagic environments. Biological cycles for many polar species are synchronised to extreme seasonality, while their distributions may be influenced by both the prevailing oceanic circulation and sea-ice distribution. Antarctic krill (krill, Euphausia superba) is one such species exhibiting a complex life history that is finely tuned to the extreme seasonality of the Southern Ocean. Dependencies on the timing of optimal seasonal conditions have led to concerns over the effects of future climate on krill’s population status, particularly given the species’ important role within Southern Ocean ecosystems. Under a changing climate, established correlations between environment and species may breakdown. Developing the capacity for predicting krill responses to climate change therefore requires methods that can explicitly consider the interplay between life history, biological conditions, and transport. The Spatial Ecosystem And Population Dynamics Model (SEAPODYM) is one such framework that integrates population and general circulation modelling to simulate the spatial dynamics of key organisms. Here, we describe a modification to SEAPODYM, creating a novel model – KRILLPODYM – that generates spatially resolved estimates of krill biomass and demographics. This new model consists of three major components: (1) an age-structured population consisting of five key life stages, each with multiple age classes, which undergo age-dependent growth and mortality, (2) six key habitats that mediate the production of larvae and life stage survival, and (3) spatial dynamics driven by both the underlying circulation of ocean currents and advection of sea-ice. We present the first results of KRILLPODYM, using published deterministic functions of population processes and habitat suitability rules. Initialising from a non-informative uniform density across the Southern Ocean our model independently develops a circumpolar population distribution of krill that approximates observations. The model framework lends itself to applied experiments aimed at resolving key population parameters, life-stage specific habitat requirements, and dominant transport regimes, ultimately informing sustainable fishery management.

Background The Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial-2 (RIGHT-2) reported no overall treatment difference between glyceryl trinitrate (GTN) and sham at day 90. Here we assess participants’ outcomes 1 year after randomisation.Methods RIGHT-2 was an ambulance-based prospective randomised controlled trial where patients with presumed stroke and systolic blood pressure (BP) of >120 mm Hg received either GTN (5 mg/day) or sham patch. Centralised blinded telephone follow-up was performed at days 90 (primary endpoint) and 365 (secondary endpoint). The lead outcome was dependency assessed with the modified Rankin Scale (mRS).Results 1149 patients were recruited to RIGHT-2 between October 2015 and May 2018, and 1097 (95.5%) had outcome data recorded at day 365. At baseline, the patients were; female (48%), had a mean age of 73 (15) years, BP of 162 (25)/92 (18) mm Hg, onset to randomisation of 70 (45–115) min, diagnosis of ischaemic stroke (52%), intracerebral haemorrhage (ICH) (13%), transient ischaemic attack (TIA) (9%) and mimics (26%). There was no effect of GTN on mRS score at day 365 in participants with confirmed stroke/TIA (adjusted common odds ratio (acOR) 1.10, 95% CI 0.86 to 1.42) or in all patients. In patients randomised to GTN, mRS at day 365 tended to be worse in those with ICH (acOR 1.65, 95% CI 0.84 to 3.25) and better in those with a mimic diagnosis (acOR 0.53, 95% CI 0.33 to 0.84).Conclusion At 1 year post randomisation, dependency did not differ between GTN and sham treatment in either the target population or overall. In prespecified subgroup analyses, GTN was associated with reduced dependency in participants with a final diagnosis of mimic and a non-significant worse outcome in participants with ICH.Trial registration number ISRCTN26986053.

Commercial tree plantations of fast-growing species have become increasingly important in Southeast Asia to meet global demand for wood and wood fiber products. There is a growing need to understand more about their value for wildlife and how they can be managed for biodiversity. We evaluated the effects of landscape attributes on mammal communities in a timber concession consisting of 83 % secondary forest and 17 % tree plantations in northern Sabah, Malaysia. Using camera traps, we compared mammalian species assemblages of secondary forest and commercial tree plantation stands and identified habitat predictors associated with total mammal species detections and species richness in the landscape mosaic. We used 87 camera stations deployed for 23 days across two major land-use types: 62 sites in secondary forest (previously logged natural forest) and 25 sites in tree plantations. We evaluated variation in species richness in these two major land-use categories and assessed the effects of natural and anthropogenic predictors on variation in total mammal detections and species richness. We detected at least 23 large and medium-sized mammal species over 2035 trap nights. Fourteen of those species were classified as threatened or near-threatened by the International Union for the Conservation of Nature. Rarefaction did not reveal differences in mammal species richness or diversity between camera sites placed in tree plantations and secondary forests, likely because most camera sites in tree plantations were close to secondary forest and comprised

Mammalian display enables the selection of biophysically favorable antibodies from a large IgG antibody library displayed on the plasma membrane of mammalian cells. We constructed and validated a novel mammalian display platform utilizing the commercially available Flp-In CHO cell line as a starting point. We introduced a single copy of a landing pad for Bxb1 integrase-driven recombinase-mediated cassette exchange into the FRT site of the Flp-In CHO line to facilitate the efficient single-copy integration of an antibody display cassette into the genome of the cell line. We then proceeded to demonstrate the ability of our platform to select biophysically favorable antibodies from a library of 1 × 106 displayed antibodies designed to improve the biophysical properties of bococizumab via randomization of problematic hydrophobic surface residues of the antibody. Enrichment of bococizumab variants via fluorescence-activated cell sorting selections was followed by next generation sequencing and thorough characterization of biophysical properties of 10 bococizumab variants that subsequently allowed attribution of the mutations to the biophysical properties of the antibody variants. The mammalian displayed variants exhibited reduced aggregation propensity and polyreactivity, while critically retaining its target binding thereby demonstrating the utility of this valuable tool.

The rupture of an abdominal aortic aneurysm (AAA) causes about 200,000 deaths worldwide each year. However, there are currently no effective drug therapies to prevent AAA formation or, when present, to decrease progression and rupture, highlighting an urgent need for more research in this field. Increased vascular inflammation and enhanced apoptosis of vascular smooth muscle cells (VSMCs) are implicated in AAA formation. Here, we investigated whether hydralazine, which has anti-inflammatory and anti-apoptotic properties, inhibited AAA formation and pathological hallmarks. In cultured VSMCs, hydralazine (100 μM) inhibited the increase in inflammatory gene expression and apoptosis induced by acrolein and hydrogen peroxide, two oxidants that may play a role in AAA pathogenesis. The anti-apoptotic effect of hydralazine was associated with a decrease in caspase 8 gene expression. In a mouse model of AAA induced by subcutaneous angiotensin II infusion (1 µg/kg body weight/min) for 28 days in apolipoprotein E-deficient mice, hydralazine treatment (24 mg/kg/day) significantly decreased AAA incidence from 80% to 20% and suprarenal aortic diameter by 32% from 2.26 mm to 1.53 mm. Hydralazine treatment also significantly increased the survival rate from 60% to 100%. In conclusion, hydralazine inhibited AAA formation and rupture in a mouse model, which was associated with its anti-inflammatory and anti-apoptotic properties.

Background: Patients have had their cancer care either postponed or changed to telehealth visits to reduce exposure to COVID-19. However, it is unclear how these changes may have affected their experiences. We aim to identify patient characteristics that affect telehealth experiences and evaluate their preferences for using telehealth in the future. Methods: Patients who completed the Outpatient Cancer Care (OCC) Patient Experience Survey were invited to participate. They comepleted the modified OCC Survey, which focused on telehealth during the pandemic. Linear and logistic regression analyses were used to identify patient characteristics that influenced telehealth experiences and preferences for future telehealth use. Results: Perceived ease of participation in telehealth is a significant predictor of the change in patients’ ratings of their telehealth experience. We found that cancer patients had lower preferences for using telehealth in the future if they were older, female, or non-white; resided in an urban area; had no previous telehealth experience; had lower education; and had poorer mental health. Conclusions: To optimize cancer care and improve equitable access to high-quality telehealth care during the pandemic and beyond, clinicians and policymakers will need to consider patients’ self-reported experiences and their personal characteristics.

Mitochondrial metabolism has been associated with tumourigenesis in acute myeloid leukaemia (AML) and currently considered as a potential therapeutic target. Here, the authors show, in patients with AML, that germline mutations in mitochondrial complex I are mutually exclusive with somatic mutations in the metabolic enzyme IDH1, and find IDH1 mutant cells have increased sensitivity to complex I inhibitors.