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Abstract Background Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p

Abstract Primary open-angle glaucoma typically presents as two subtypes. This study aimed to elucidate the shared and distinct genetic architectures of normal-tension (NTG) and high-tension glaucoma (HTG), motivated by the need to develop intraocular pressure (IOP)-independent drug targets for the disease. We conducted a comprehensive multi-ethnic meta-analysis, prioritized variants based on functional annotation, and explored drug-gene interactions. We further assessed the genetic overlap between NTG and HTG using pairwise GWAS analysis. We identified 22 risk loci associated with NTG, 17 of which have not previously been reported for NTG. Two loci, BMP4 and TBKBP1, have not previously been associated with glaucoma at the genome-wide significance level. Our results indicate that while there is a significant overlap in risk loci between tension subtypes, the magnitude of the effect tends to be lower in NTG compared to HTG, particularly for IOP-related loci. Additionally, we identified a potential role for biologic immunomodulatory treatments as neuroprotective agents.

Abstract Central nervous system germ cell tumors (CNS-GCT) are malignant neoplasms that arise predominantly during adolescence and young adulthood. These tumors are typically sensitive to treatment, but resulting long-term health deficits are common. Additional clinical challenges include surgical risks associated with tumor biopsy, and need to determine treatment response for adapting radiotherapy protocols. The aim of this study was to establish the detectability of circulating-tumor DNA (ctDNA) from cerebrospinal fluid (CSF) of children with CNS-GCT as a potential biomarker. We obtained CSF from patients with CNS-GCT by lumbar puncture or intra-operatively. Cell-free DNA (cfDNA) was extracted and subjected to low-pass whole genome sequencing (LP-WGS). Copy-number alterations (CNAs) were inferred and served as a marker of measurable residual disease (MRD). Comparisons with imaging findings and tumor marker levels were made. A total of 29 CSF samples from 21 patients (16 with germinoma, 5 with non-germinomatous GCT) were sequenced. Twenty samples from 19 patients were collected at diagnosis, and 9 samples from 7 patients were collected during or after therapy. Among the diagnostic samples, CNAs were detected in samples from 17/19 patients (89%), which included 8 with marker-negative tumors. Specific clinical scenarios suggested that serial cfDNA analysis may carry utility in tracking treatment responses as well as clarifying indeterminate imaging findings. Our results provide evidence for the high-sensitivity in detecting ctDNA from CSF of CNS-GCT patients using LP-WGS, with potential utility for non-invasive diagnosis and disease monitoring in upcoming CNS-GCT studies.

Abstract Objective A promising strategy to increase population physical activity is through promotion of dog walking. Informed by multi-process action control and nascent dog-walking theory, we examined the effectiveness of a 3-month technology-based (dog tracker) 2-arm randomised controlled dog-walking intervention to increase dog-owner daily physical activity in the general community in Sydney, Australia. Results 37 participants were allocated to the intervention group (mean age = 43.2 [SD 11.9]) and 40 to the control group (mean age = 42.3 [SD 11.9]). Both groups averaged more than 10,500 steps/day at baseline. There was no evidence of within- or between-group physical activity differences across timepoints. The results remained consistent after exclusion of participants who had data collected during COVID-19 lockdowns. Compared with baseline, both groups had significant increases in sedentary time during the post-intervention, and 6 month follow-up. The absence of significant differences between-group physical activity differences may be attributable to the ceiling effect of both groups already being sufficiently active. These results provide useful guidance to future studies intended to assess the efficacy of technology-based dog-walking interventions. Future dog-walking interventions should specifically target physically inactive dog owners. Trial Registration: ACTRN12619001391167 (10/10/2019); Retrospectively registered.

Abstract Wolverine distribution contracted along the southern periphery of its range in North America during the 19th and 20th centuries due primarily to human influences. This history, along with low densities, sensitivity to climate change, and concerns about connectivity among fragmented habitats spurred the recent US federal listing of threatened status and special concern status in Canada. To help inform large scale landscape connectivity, we collected 882 genetic samples genotyped at 19 microsatellite loci. We employed multiple statistical models to assess the landscape factors (terrain complexity, human disturbance, forest configuration, and climate) associated with wolverine genetic connectivity across 2.2 million km2 of southwestern Canada and the northwestern contiguous United States. Genetic similarity (positive spatial autocorrelation) of wolverines was detected up to 555 km and a high-to-low gradient of genetic diversity occurred from north-to-south. Landscape genetics analyses confirmed that wolverine genetic connectivity has been negatively influenced by human disturbance at broad scales and positively influenced by forest cover and snow persistence at fine- and broad–scales, respectively. This information applied across large landscapes can be used to guide management actions with the goal of maintaining or restoring population connectivity.

Abstract Northern forests are an important carbon sink, but our understanding of the driving factors is limited due to discrepancies between dynamic global vegetation models (DGVMs) and atmospheric inversions. We show that DGVMs simulate a 50% lower sink (1.1 ± 0.5 PgC yr−1 over 2001–2021) across North America, Europe, Russia, and China compared to atmospheric inversions (2.2 ± 0.6 PgC yr−1). We explain why DGVMs underestimate the carbon sink by considering how they represent disturbance processes, specifically the overestimation of fire emissions, and the lack of robust forest demography resulting in lower forest regrowth rates than observed. We reconcile net sink estimates by using alternative disturbance-related fluxes. We estimate carbon uptake through forest regrowth by combining satellite-derived forest age and biomass maps. We calculate a regrowth flux of 1.1 ± 0.1 PgC yr−1, and combine this with satellite-derived estimates of fire emissions (0.4 ± 0.1 PgC yr−1), land-use change emissions from bookkeeping models (0.9 ± 0.2 PgC yr−1), and the DGVM-estimated sink from CO2 fertilisation, nitrogen deposition, and climate change (2.2 ± 0.9 PgC yr−1). The resulting ‘bottom-up’ net flux of 2.1 ± 0.9 PgC yr−1 agrees with atmospheric inversions. The reconciliation holds at regional scales, increasing confidence in our results.

Abstract Coronary artery calcium (CAC) scans contain valuable information beyond the Agatston Score which is currently reported for predicting coronary heart disease (CHD) only. We examined whether new artificial intelligence (AI) applied to CAC scans can predict non-CHD events, including heart failure, atrial fibrillation, and stroke. We applied AI-enabled automated cardiac chambers volumetry and calcified plaque characterization to CAC scans (AI-CAC) of 5830 asymptomatic individuals (52.2% women, age 61.7 ± 10.2 years) in the multi-ethnic study of atherosclerosis during 15 years of follow-up, 1773 CVD events accrued. The AUC at 1-, 5-, 10-, and 15-year follow-up for AI-CAC vs. Agatston score was (0.784 vs. 0.701), (0.771 vs. 0.709), (0.789 vs. 0.712) and (0.816 vs. 0.729) (p

Abstract Oestradiol and progesterone levels are higher in menstruating women than men of the same age, and their receptors are present in their neurosensory retina and retinal pigment epithelium. However, the impact of this hormonal environment on retinal physiology in women remains unclear. Using self-reported menstrual cycle phases as a surrogate for fluctuating hormonal levels, we investigated associations with retinovascular indices on colour fundus photograph and retinal thickness in optical coherence tomography across regularly menstruating women in the UK Biobank. We found no differences in retinal thickness across the cycle; however, vessel density, arteriolar and venular, and fractal dimension were higher in the luteal phase than follicular. The calibre of the central retinal vessels did not differ. This study suggests that the menstrual cycle phase might be associated with retinal microvasculature density in non-invasive imaging. It raises awareness for this understudied area, providing insights into neuroscience fields and epidemiological studies.

Societal Impact Statement Free‐air CO2 enrichment (FACE) experiments provide essential data on forest responses to increasing atmospheric CO2 for evaluations of climate change impacts on humanity. Understanding and reducing the uncertainty in the experimental results is critical to ensure scientific and public confidence in the models and policy initiatives that derive therefrom. One source of uncertainty is the estimation of tree biomass using mathematical relationships between biomass and easily obtained and non‐destructive measurements (allometry). We evaluated the robustness of the allometric relationships established at the beginning of a FACE experiment and discuss the challenges and opportunities for the new generation of FACE experiments. Summary Long‐term field experiments to elucidate forest responses to rising atmospheric CO2 concentration require allometric equations to estimate tree biomass from non‐destructive measurements of tree size. We analyzed whether the allometric equations established at the beginning of a free‐air CO2 enrichment (FACE) experiment in a Liquidambar styraciflua plantation were still valid at the end of the 12 year experiment. Aboveground woody biomass was initially predicted by an equation that included bole diameter, taper, and height, assuming that including taper and height as predictors would accommodate changes in tree structure that might occur over time and in response to elevated CO2. At the conclusion of the FACE experiment, we harvested 23 trees, measured dimensions and dry mass of boles and branches, and extracted and measured the woody root mass of 10 trees. Although 10 of the harvested trees were larger than the trees used to establish the allometric relationship, measured aboveground woody biomass was well predicted by the original allometry. The initial linear equation between bole basal area and woody root biomass underestimated final root biomass by 28%, but root biomass was just 21% of total wood mass, and errors in aboveground and belowground estimates were offsetting. The allometry established at the beginning of the experiment provided valid predictions of tree biomass throughout the experiment. New allometric approaches using terrestrial laser scanning should reduce an important source of uncertainty in decade‐long forest experiments and in assessments of centuries‐long forest biomass accretion used in evaluating carbon offsets and climate mitigation.

This study focused on the co-fermentation of goat milk with functional lactic acid bacteria (LAB) and traditional yoghurt starter culture. The fermentation process was optimised by single factor experiment and response surface methodology (RSM). The physicochemical and sensory properties of goat milk yoghurt were evaluated under chilled (4 °C) storage for 21 days. The optimised conditions were selected as the inoculum amount of Lactobacillus paracasei NM-8 (1.1 × 107 CFU.mL-1; CFU - colony forming unit), sucrose addition (6.8%) and fermentation temperature (41 °C). During milk coagulation, the pH declined to be 4.45 and the viable LAB number arrived at 8.77 log CFU.mL-1. The content of exopolysaccharides (EPS) increased to be 2.13 g.L-1. These changes led to the better viscosity (941.33-792.33 cP) and higher water holding capacity (63.24-56.20%) of yoghurt fermented using L. paracasei NM-8 in storage, compared with those of yoghurt without L. paracasei NM-8. This study provided a theoretical basis for eliminating the whey precipitation and rough texture of goat milk yoghurt.

Abstract Human biomonitoring (HBM) data indicate that exposure to pyrethroids is widespread in Europe, with significantly higher exposure observed in children compared to adults. Epidemiological, toxicological, and mechanistic studies raise concerns for potential human health effects, particularly, behavioral effects such as attention deficit hyperactivity disorder (ADHD) in children at low levels of exposure. Based on an exposure-response function from a single European study and on available quality-assured and harmonized HBM data collected in France, Germany, Iceland, Switzerland, and Israel, a preliminary estimate of the environmental burden of disease for ADHD associated with pyrethroid exposure was made for individuals aged 0–19 years. The estimated annual number of prevalence-based disability-adjusted life years (DALYs) per million inhabitants were 27 DALYs for Israel, 21 DALYs for France, 12 DALYs for both Switzerland and Iceland, and 3 DALYs for Germany; while the annual ADHD cases per million inhabitants attributable to pyrethroids were 2189 for Israel, 1710 for France, 969 for Iceland, 944 for Switzerland, and 209 for Germany. Direct health costs related to ADHD ranged between 0.3 and 2.5 million EUR yearly per million inhabitants for the five countries. Additionally, a substantial number of ADHD cases, on average 18%, were associated with pyrethroid exposure. Yet, these figures should be interpreted with caution given the uncertainty of the estimation. A sensitivity analysis showed that by applying a different exposure-response function from outside the EU, the population attributable fraction decreased from an average of 18 to 7%. To ensure more robust disease burden estimates and adequate follow-up of policy measures, more HBM studies are needed, along with increased efforts to harmonize the design of epidemiological studies upfront to guarantee meta-analysis of exposure-response functions. This is particularly important for pyrethroids as evidence of potential adverse health effects is continuously emerging.

Abstract Magmatic volatile phases play a major role in igneous systems, but indirect sampling of the magmatic fluid, especially for basic magmas, remains challenging to document. Here, we report compelling evidence of primary fluid inclusions trapped within magmatic ilmenite from two different basic intrusive settings: Armorican Massif (France) and Central Iberian Zone (Spain). Fluid inclusions have a solute chemistry dominated by sodium, calcium, chlorine, sulfur and iron, with detectable contents of metals and metalloids and thus likely record the onset of late-stage magmatic volatile saturation in these basic magmas. Hence, we argue the presence of fluid inclusions in ilmenite may be a good indicator for magma degassing in these settings and importantly records the magmatic-hydrothermal transition. Additionally, this study suggests that the trapping of the magmatic volatile phase during ilmenite (and other opaque minerals) crystallization may be more common but at present an underappreciated phenomenon in basic igneous magmatic systems.

Abstract Chronic kidney disease (CKD) affects ~10% of the population and cardiovascular disease is its commonest complication. Despite treatment, patient outcomes remain poor and newer therapies are urgently needed. Here, we investigated the systemic and renal effects of apelin in CKD. In a randomized, double-blind, placebo-controlled, crossover study, 24 subjects (12 patients with CKD and 12 matched healthy subjects) received pyroglutamated apelin-13 ([Pyr1]apelin-13, 1 nmol/min and 30 nmol/min) or matched placebo on two separate visits. Systemic and renal hemodynamics were monitored throughout. The co-primary endpoints were change in systemic vascular resistance index and renal blood flow. Secondary endpoints were change in blood pressure, cardiac output, pulse wave velocity, glomerular filtration rate, natriuresis, free water clearance and urinary protein excretion. In both health and CKD, 30 nmol/min [Pyr1]apelin-13 reduced mean arterial pressure by ~4%, systemic vascular resistance by ~12%, and increased cardiac index by ~10%, compared to placebo (p

Purpose – This paper is motivated by the need to assess the risk profiles associated with the substantial number of items within military supply chains. The scale of supply chain management processes creates difficulties in both the complexity of the analysis and in performing risk assessments that are based on the manual (human analyst) assessment methods. Thus, analysts require methods that can be automated and that can incorporate on-going operational data on a regular basis. Design/methodology/approach – The approach taken to address the identification of supply chain risk within an operational setting is based on aspects of multiobjective decision analysis (MODA). The approach constructs a risk and importance index for supply chain elements based on operational data. These indices are commensurate in value, leading to interpretable measures for decision-making. Findings – Risk and importance indices were developed for the analysis of items within an example supply chain. Using the data on items, individual MODA models were formed and demonstrated using a prototype tool. Originality/value – To better prepare risk mitigation strategies, analysts require the ability to identify potential sources of risk, especially in times of disruption such as natural disasters.

Prader–Willi syndrome (PWS) is a rare orphan disease and complex genetic neurodevelopmental disorder, with a birth incidence of approximately 1 in 10,000–30,000. Management of people with PWS requires a multi-disciplinary approach, ideally through a multi-disciplinary team (MDT) clinic with community support. Hypotonia, poor feeding and faltering growth are characteristic features in the neonatal period, followed by hyperphagia and risk of rapid weight gain later in childhood. Children and adolescents (CA) with PWS usually display developmental delay and mild learning disability and can develop endocrinopathies, scoliosis, respiratory difficulties (both central and obstructive sleep apnoea), challenging behaviours, skin picking, and mental health issues, especially into adulthood. This consensus statement is intended to be a reference document for clinicians managing children and adolescents (up to 18 years of age) with PWS. It considers the bio-psycho-social domains of diagnosis, clinical assessment, and management in the paediatric setting as well as during and after transition to adult services. The guidance has been developed from information gathered from peer-reviewed scientific reports and from the expertise of a range of experienced clinicians in the United Kingdom and Ireland involved in the care of patients with PWS.

Zinc (Zn) and iron (Fe) are necessary for structural and metabolic functions of the body like, immune competence, physical growth, reproductive function, and neurobehavioral development. The deficiency of micronutrients is a severe public health distress in nearly all developing countries which leads to the syndrome of malnutrition mostly in children and women. The present study was conducted to compare the effect of different levels of Fe and Zn on feed intake (FI), feed conversion ratio (FCR), daily egg production, and Fe and Zn depositions in the egg yolk of laying hens. For this purpose, 80 commercial laying birds were allocated into four groups consisting of four replicates each (n = 5). The basal ration was provided to the control group (C) while three different levels (100, 200, and 300 mg/kg diet/element) of Fe and Zn (1:1) were provided to the FZ100, FZ200, and FZ300 groups, respectively. Overall FI, hen day egg production, and FCR were not affected (p > 0.05). The Fe and Zn content in egg yolk were significantly increased in the FZ300 group after 4 weeks of supplementation. The cost per egg produced in response to different levels of Fe and Zn supplementation was not affected however a numerical increase in cost/egg was found in the FZ300 group. In conclusion, Fe and Zn supplementation (300 mg/kg diet/element) significantly enhanced the egg Fe and Zn contents without adversely affecting production parameters including FI, egg production, and FCR of laying hens.

This study assessed the potential of a commercial probiotic mixture on performance, gut health and nutrient utilisation of broilers-fed poultry by-product meal (PBM)-based diet. Three-hundred-and-twenty Ross-308-day-old broiler chicks were obtained from a commercial poultry hatchery. The chicks were randomly assigned to four different treatment groups, each consisting of four replicates (n = 10) in a randomised complete design. The positive control group (CON) was fed commercial poultry ration, and the negative control group (N-CON) was fed PBM partially replacing soybean meal at a 65% level. The MSP1 and MSP2 groups contained the same diet as the N-CON group but supplemented with multi-strain probiotics (MSP) at 50 mg/kg and 100 mg/kg. Overall N-CON group performed poorly, but the addition of probiotics in group MSP1 and MSP2 diets significantly improved performance. Feed efficiency and bird weight gain were improved (p

Abstract Exposure to traumatic events is associated with post-traumatic stress symptomology (PTSS) in a variety of populations. PTSS is also associated with self-reported everyday cognitive failures, which are acknowledged attentional lapses experienced in one’s naturalistic everyday environment. While a growing literature suggests that PTSS is associated with both traumatic events and attentional functions, little is known regarding similar associations in elite military cohorts, such as Special Operations Forces (SOF) personnel. Herein, we investigate if prior combat experience is associated with everyday cognitive failures, while considering the possible mediating role of PTSS. SOF personnel (N = 119) completed self-report questionnaires assessing prior combat experience, PTSS, and everyday cognitive failures. Direct and indirect associations between these metrics were examined using structural equation modeling. Mediation analyses revealed that the correspondence between combat experiences and everyday cognitive failures is mediated by the severity of subclinical levels of PTSS. Such findings suggest that greater attention to subclinical PTSS is warranted due to its significant association with everyday cognitive failures that may contribute to deleterious mission-related failures in high-demand tactical professionals, such as SOF.

Abstract Background Syndrome of apparent mineralocorticoid excess (AME) is characterized by excessive MR stimulation despite low levels of aldosterone. 11Beta-hydroxysteroid dehydrogenase-2 (11βDSH-2) inactivates cortisol to cortisone, preventing cortisol-induced MR activation. Genetic defects in 11βDSH-2 cause AME through accumulation of cortisol in the distal nephron, leading to MR activation induced hypertension, hypokalemia and metabolic alkalosis. Acquired AME can occur due to the ingestion of glycyrrhizic acid, found in licorice root, which inhibits 11βDSH-2 and has additional effects on cortisol homeostasis through inhibition of 11βDSH-1. Case report We present a case of acquired AME with a hyperadrenergic symptoms induced by ingestion of Advanced Liver Support, a nutritional supplement produced by Advanced BioNutritionals(R), in a 65-year-old Caucasian female who presented with accelerated hypertension, hypokalemia, metabolic alkalosis and adrenergic symptoms. Cessation of the licorice-containing supplement resulted in complete resolution of the patient's hypertension, symptoms and abnormal lab values. To our knowledge this is the first reported case of AME from this supplement, and the first to describe accompanying hyperadrenergic symptoms. Conclusions Glycyrrhizic acid is increasingly being found in unregulated nutritional supplements and has the potential to induce a reversable syndrome of AME. Acquired AME should be suspected in individuals who present with hypertension along with hypokalemia, metabolic alkalosis and low plasma renin and serum aldosterone levels.

Abstract Despite the promising capacity of large language model (LLM)-powered chatbots to diagnose diseases, they have not been tested for obsessive-compulsive disorder (OCD). We assessed the diagnostic accuracy of LLMs in OCD using vignettes and found that LLMs outperformed medical and mental health professionals. This highlights the potential benefit of LLMs in assisting in the timely and accurate diagnosis of OCD, which usually entails a long delay in diagnosis and treatment.

Abstract Brown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue. Leveraging the use of [18F]F-AraG, a mitochondrial metabolic tracer capable of tracking activated lymphocytes and adipocytes simultaneously, we demonstrate, in models of glioblastoma and multiple sclerosis, the correlation between intracerebral immune infiltration and changes in brown- and bone marrow adipose tissue. Significantly, we show initial evidence that a neuroinflammation-adipose tissue link may also exist in humans. This study proposes the concept of an intricate immuno-neuro-adipose circuit, and highlights brown- and bone marrow adipose tissue as an intermediary in the communication between the immune and nervous systems. Understanding the interconnectedness within this circuitry may lead to advancements in the treatment and management of various conditions, including cancer, neurodegenerative diseases and metabolic disorders.

Abstract Background People with serious mental health problems (SMHP) are more likely to be admitted to psychiatric hospital following contact with crisis services. Admissions can have significant personal costs, be traumatic and are the most expensive form of mental health care. There is an urgent need for treatments to reduce suicidal thoughts and behaviours and reduce avoidable psychiatric admissions. Methods A multi-stage, multi-arm (MAMS) randomised controlled trial (RCT) with four arms conducted over two stages to determine the clinical and cost effectiveness of three psychosocial treatments, compared to treatment as usual (TAU), for people with SMHP who have had recent suicidal crisis. Primary outcome is any psychiatric hospital admissions over a 6-month period. We will assess the impact on suicidal thoughts and behaviour, hope, recovery, anxiety and depression. The remote treatments delivered over 3 months are structured peer support (PREVAIL); a safety planning approach (SAFETEL) delivered by assistant psychologists; and a CBT-based suicide prevention app accessed via a smartphone (BrighterSide). Recruitment is at five UK sites. Stage 1 includes an internal pilot with a priori progression criteria. In stage 1, the randomisation ratio was 1:1:1:2 in favour of TAU. This has been amended to 2:2:3 in favour of TAU following an unplanned change to remove the BrighterSide arm following the release of efficacy data from an independent RCT. Randomisation is via an independent remote web-based randomisation system using randomly permuted blocks, stratified by site. An interim analysis will be performed using data from the first 385 participants from PREVAIL, SAFETEL and TAU with outcome data at 6 months. If one arm is dropped for lack of benefit in stage 2, the allocation ratio of future participants will be 1:1. The expected total sample size is 1064 participants (1118 inclusive of BrighterSide participants). Discussion There is a need for evidence-based interventions to reduce psychiatric admissions, via reduction of suicidality. Our focus on remote delivery of established brief psychosocial interventions, utilisation of different modalities of delivery that can provide sustainable and scalable solutions, which are also suitable for a pandemic or national crisis context, will significantly advance treatment options. Trial registration ISRCTN33079589. Registered on June 20, 2022.

Abstract Virus infectivity is traditionally determined by endpoint titration in cell cultures, and requires complex processing steps and human annotation. Here we developed an artificial intelligence (AI)-powered automated framework for ready detection of virus-induced cytopathic effect (DVICE). DVICE uses the convolutional neural network EfficientNet-B0 and transmitted light microscopy images of infected cell cultures, including coronavirus, influenza virus, rhinovirus, herpes simplex virus, vaccinia virus, and adenovirus. DVICE robustly measures virus-induced cytopathic effects (CPE), as shown by class activation mapping. Leave-one-out cross-validation in different cell types demonstrates high accuracy for different viruses, including SARS-CoV-2 in human saliva. Strikingly, DVICE exhibits virus class specificity, as shown with adenovirus, herpesvirus, rhinovirus, vaccinia virus, and SARS-CoV-2. In sum, DVICE provides unbiased infectivity scores of infectious agents causing CPE, and can be adapted to laboratory diagnostics, drug screening, serum neutralization or clinical samples.

IntroductionArylamine N-acetyltransferase 2 (NAT2) expresses a well-defined genetic polymorphism in humans that modifies drug and xenobiotic metabolism. Recent studies and genome wide association studies have reported that genetic variants of NAT2 are associated with differential risks of developing dyslipidemia and cardiometabolic disorders, suggesting a previously unrecognized role of NAT2 in pathophysiology of metabolic disorders. In support of this notion, we recently showed that human NAT2 expression is differentially regulated by glucose and insulin. Moreover, our in silico analysis showed that NAT2 is co-expressed with nuclear receptors enriched in the liver, e.g., NR1H4 (FXR) and NR1I2 (PXR), that have been previously implicated in regulation of hepatic glucose and lipid homeostasis. Identification of transcriptional regulator(s) of human NAT2 would aid in understanding novel functions that it may play in the liver. Thus, the present study was designed to investigate if NAT2 is transcriptionally regulated by hepatic nuclear receptors.MethodsTo test this, we treated cryopreserved human hepatocytes with agonists towards four different hepatic transcription factors/nuclear hormone receptors, namely FXR (NR1H4), PXR (NR1I2), LXR (NR1H3), and PPARα (PPARA), and measured their effects on the level of NAT2 mRNA.ResultsWhile the treatment with a FXR, PXR, or LXR agonist (i.e., GW-4064, SR-12813, or GW-3965) significantly induced their respective target genes, treatment with these agonists did not significantly alter the transcript level of NAT2 in human hepatocytes. PPARα agonist, GW-7647, treatment resulted in a statistically significant decrease in the NAT2 transcript level. However, its magnitude was marginal.ConclusionIn summary, hepatic nuclear receptors we examined in the present study (FXR, PXR, LXR, and PPARα) did not significantly alter NAT2 expression in cryopreserved human hepatocytes. Additional studies are needed to identify transcriptional regulators of hepatic NAT2 expression.

Background Altered structural brain development has been identified in fetuses with congenital heart disease (CHD), suggesting that the neurodevelopmental impairment observed later in life might originate in utero. There are many interacting factors that may perturb neurodevelopment during the fetal period and manifest as structural brain alterations, such as altered cerebral substrate delivery and aberrant fetal hemodynamics. Methods and Results We extracted structural covariance networks from the log Jacobian determinants of 435 in utero T2 weighted image magnetic resonance imaging scans, (n=67 controls, 368 with CHD) acquired during the third trimester. We fit general linear models to test whether age, sex, expected cerebral substrate delivery, and CHD diagnosis were significant predictors of structural covariance. We identified significant effects of age, sex, cerebral substrate delivery, and specific CHD diagnosis across a variety of structural covariance networks, including primary motor and sensory cortices, cerebellar regions, frontal cortex, extra‐axial cerebrospinal fluid, thalamus, brainstem, and insula, consistent with widespread coordinated aberrant maturation of specific brain regions over the third trimester. Conclusions Structural covariance networks offer a sensitive, data‐driven approach to explore whole‐brain structural changes without anatomical priors. We used them to stratify a heterogenous patient cohort with CHD, highlighting similarities and differences between diagnoses during fetal neurodevelopment. Although there was a clear effect of abnormal fetal hemodynamics on structural brain maturation, our results suggest that this alone does not explain all the variation in brain development between individuals with CHD.

Summary: Humans flexibly adapt expressions of emotional messages when interacting with others. However, detailed information on how specific parts of the face and hands move in socio-emotional contexts is missing. We identified individual gesture and facial movements (through automated face tracking) of N = 80 participants in the UK, produced while watching amusing, fearful, or neutral movie scenes either alone or with a social partner. Amusing and fearful scenes, more so than neutral scenes, led to an overall increase in facial and gesture movements, confirming emotional responding. Furthermore, social context facilitated movements in the lower instead of upper facial areas, as well as gesture use. These findings highlight emotional signaling components that likely underwent selection for communication, a result we discuss in comparison with the nonhuman primate literature. To facilitate ecologically valid and cross-cultural comparisons on human emotion communication, we additionally offer a new stimuli database of the recorded naturalistic facial expressions.

Background: Mindfulness training (MT) programs have demonstrated utility as cognitive training tools, but there is little consensus on the neurophysiological processes that may underlie its benefits. It has been posited that intrinsic brain activity recorded at rest reflects the functional connectivity of large-scale brain networks and may provide insight into neuroplastic changes that support MT. In the current study, we indexed changes in several resting-state electroencephalography (EEG) parameters to investigate the neurophysiological underpinnings of MT. Methods: Resting-state EEG data were collected from active-duty U.S. military personnel (N = 80) at 2 testing sessions: before (time [T] 1) and after (T2) engaging in an 8-week MT or active comparison intervention (positivity training). We examined longitudinal and/or groupwise differences in several EEG parameters through parameterization of power spectra (individual alpha frequency and 1/f activity) and microstate analysis. Results: While no significant group × time differences were observed in individual alpha frequency, significant group × time effects were observed in several EEG parameters from T1 to T2. Compared with MT, positivity training was associated with a steepening of the 1/f slope and higher 1/f intercepts together with decreased duration and increased global field power of microstates. Conclusions: Taken together, these results suggest that the effects of interventions may be differentiated in resting-state brain activity in a sample of military personnel. Such findings provide insight into the neural underpinnings of MT-related brain changes, but more research is required to elucidate how these may relate to task-related neural and performance changes with MT and whether results generalize to other mindfulness interventions in alternative cohorts and contexts.

ABSTRACT Viruses display large variability across all stages of their life cycle, including entry, gene expression, replication, assembly, and egress. We previously reported that the immediate early adenovirus (AdV) E1A transcripts accumulate in human lung epithelial A549 cancer cells with high variability, mostly independent of the number of incoming viral genomes, but somewhat correlated to the cell cycle state at the time of inoculation. Here, we leveraged the classical Luria–Delbrück fluctuation analysis to address whether infection variability primarily arises from the cell state or stochastic noise. The E1A expression was measured by the expression of green fluorescent protein (GFP) from the endogenous E1A promoter in AdV-C5_E1A-FS2A-GFP and found to be highly correlated with the viral plaque formation, indicating reliability of the reporter virus. As an ensemble, randomly picked clonal A549 cell isolates displayed significantly higher coefficients of variation in the E1A expression than technical noise, indicating a phenotypic variability larger than noise. The underlying cell state determining infection variability was maintained for at least 9 weeks of cell cultivation. Our results indicate that preexisting cell states tune adenovirus infection in favor of the cell or the virus. These findings have implications for antiviral strategies and gene therapy applications.IMPORTANCEViral infections are known for their variability. Underlying mechanisms are still incompletely understood but have been associated with particular cell states, for example, the eukaryotic cell division cycle in DNA virus infections. A cell state is the collective of biochemical, morphological, and contextual features owing to particular conditions or at random. It affects how intrinsic or extrinsic cues trigger a response, such as cell division or anti-viral state. Here, we provide evidence that cell states with a built-in memory confer high or low susceptibility of clonal human epithelial cells to adenovirus infection. Results are reminiscent of the Luria–Delbrück fluctuation test with bacteriophage infections back in 1943, which demonstrated that mutations, in the absence of selective pressure prior to infection, cause infection resistance rather than being a consequence of infection. Our findings of dynamic cell states conferring adenovirus infection susceptibility uncover new challenges for the prediction and treatment of viral infections.

The emerging fungal pathogen Batrachochytrium salamandrivorans (Bsal) threatens the diversity of amphibians, particularly in North America where it is projected to invade. Amphibian skin defenses include a mucosal layer containing microorganisms that can potentially modulate host response to pathogens such as Bsal. In this study, we focused on the composition of the skin microbiome across life stages of spotted salamanders (Ambystoma maculatum). We also evaluated the stress hormone corticosterone and skin microbiome response to inoculations with Bsal and probiotics at both the larval and juvenile developmental stages, and the response to different environmental conditions. Results indicated that both bacterial and fungal communities found on the skin significantly differed in structure and diversity between life stages of A. maculatum. Exposure to three different probiotics (Bacillus thuringiensis, Chryseobacterium rhizoplanae, and Penicillium sp.) and Bsal evoked shifts in the microbiome of larvae and juveniles, and the metabolite profile of the larval mucosal layer of A. maculatum. Despite changes in the microbiome, all tested probiotics and Bsal were unable to persist on the skin. Larval bacterial microbiomes shifted in response to Bsal and B. thuringiensis with no significant impacts on antifungal function or bacteria richness, however fungi strongly responded to Bsal and B. thuringiensis application. This indicates that developmental shifts in the microbiome can be initiated by microbial applications such as B. thuringiensis, a widely used mosquito larvicide. Overall, experimental results indicate that life stage, growth and development, and environmental conditions appeared to be the main factors driving changes in the amphibian skin microbiome and potential anti-Batrachochytrium function.

Background Current injury prevention programmes in football are limited by a one-size-fits-all approach, which predominantly focuses on preventive exercise programmes while ignoring differences in risk profiles between individuals and teams.Objective To address this gap, we developed a new data-driven, customisable approach based on the principles of risk management. We collaborated with key stakeholders to identify focus areas for injury and illness prevention and determine their priorities.Setting The team medical and coaching staff included members from 17 professional football clubs, the national team and a youth football academy in Qatar.Methods In 2015, we launched a series of annual workshops under the Aspetar Sports Injury and Illness Prevention Programme. The workshops included club medical personnel and fitness coaches in a process to develop team-specific programmes for injury and illness prevention based on the principle of risk management. Over 2 years, workshops refined focus areas through discussions, surveys and small-group presentations, culminating in the creation a novel programme for football injury prevention.Results Out of 44 focus areas first identified, 23 were selected as priorities for inclusion in multimodal injury and illness prevention programmes. The identified focus areas represent a variety of aspects, including social/behavioural/lifestyle, exercise programmes/training, load management, recovery and equipment. The top priorities included communication, the Nordic hamstring exercise, training load, recovery strategies, nutrition, sleep, warm-up, the Copenhagen adduction exercise and core and dynamic stability.Conclusion We have developed a comprehensive framework for preventing injuries and illnesses in football grounded in the general principles of risk management. This framework has proven feasible and led to the creation of a new multicomponent programme, The Aspetar IP2 (Injury and Illness Prevention for Performance) NetWork, focusing on a range of areas beyond preventive exercise programmes only.

Objective: Carotenoids are lipophilic plant molecules with antioxidant properties. Some carotenoids such as β-carotene also serve as vitamin A precursors, playing a key role in human health. Carotenoids are transported in lipoproteins with other lipids such as cholesterol, however, the mechanisms responsible for carotenoid storage in tissues and their non-enzymatic elimination remain relatively unexplored. The goal of this study was to examine the contribution of the low-density lipoprotein receptor (LDLR) in the bodily distribution and disposal of carotenoids. Methods: We employed mice lacking one or both carotenoid-cleaving enzymes as suitable models for carotenoid accumulation. We examined the contribution of LDLR in carotenoid distribution by crossbreeding these mice with Ldlr-/- mice or overexpressing LDLR in the liver. Results: Our results show that LDLR plays a dual role in carotenoid homeostasis by simultaneously favoring carotenoid storage in the liver and adipose tissue while facilitating their fecal elimination. Conclusions: Our results highlight a novel role of the LDLR in carotenoid homeostasis, and unveil a previously unrecognized disposal pathway for these important bioactive molecules.

The advent of biobanks with vast quantities of medical imaging and paired genetic measurements creates huge opportunities for a new generation of genotype–phenotype association studies. However, disentangling biological signals from the many sources of bias and artifacts remains difficult. Using diverse medical images and time-series (ie, magnetic resonance imagings [MRIs], electrocardiograms [ECGs], and dual-energy X-ray absorptiometries [DXAs]), we show how registration, both spatial and temporal, guided by domain knowledge or learned de novo , helps uncover biological information. A multimodal autoencoder comparison framework quantifies and characterizes how registration affects the representations that unsupervised and self-supervised encoders learn. In this study we (1) train autoencoders before and after registration with nine diverse types of medical image, (2) demonstrate how neural network-based methods (VoxelMorph, DeepCycle, and DropFuse) can effectively learn registrations allowing for more flexible and efficient processing than is possible with hand-crafted registration techniques, and (3) conduct exhaustive phenotypic screening, comprised of millions of statistical tests, to quantify how registration affects the generalizability of learned representations. Genome- and phenome-wide association studies (GWAS and PheWAS) uncover significantly more associations with registered modality representations than with equivalently trained and sized representations learned from native coordinate spaces. Specifically, registered PheWAS yielded 61 more disease associations for ECGs, 53 more disease associations for cardiac MRIs, and 10 more disease associations for brain MRIs. Registration also yields significant increases in the coefficient of determination when regressing continuous phenotypes (eg, 0.36 ± 0.01 with ECGs and 0.11 ± 0.02 for DXA scans). Our findings reveal the crucial role registration plays in enhancing the characterization of physiological states across a broad range of medical imaging data types. Importantly, this finding extends to more flexible types of registration, such as the cross-modal and the circular mapping methods presented here.

Introduction: In 2020, Michigan implemented its first Naloxone Leave-Behind Program for Emergency Medical Service (EMS) field providers. Under the program, EMS field providers leave naloxone kits to individuals aged 15 or older they encounter in the field who have overdosed, who indicate they have a substance use disorder, or exhibit signs of opioid use and/or to bystanders, friends, or family that are present at the encounter. Methods: Survey of EMS field providers and administrators to assess perspectives on the Michigan NLB program. Comparisons of perspectives between field providers and administrators working in EMS agencies operating in medical control authorities (MCAs) participating in the NLB program (i.e., participating agencies) with field providers and administrators working for EMS agencies serving non-participating MCAs. Results: Most EMS field providers and administrators supported the Michigan NLB program. However, some were concerned about the unintended consequences of leaving behind naloxone, including the potential for recipients to use more drugs or be less likely to seek treatment. Perspectives of NLB program effectiveness were similar between EMS administrators and field providers. Participating administrators’ top-cited barrier to implementation was convincing field providers to leave behind naloxone, while non-participating administrators were concerned with stocking naloxone kits. Conclusions: Additional engagement and training to address concerns by EMS field providers and administrators about the benefits of the NLB program are needed to expand program participation intensity. Streamlining naloxone procurement and increasing messaging about free access to naloxone for participating in the program may help increase adoption.

Background: Acute myocardial infarction (AMI) remains a common reason for admission to the intensive care unit (ICU). However, there is limited data comparing outcomes for patients with AMI admitted to specific ICUs. Objectives: The purpose of this study was to assess clinical outcomes between patients with AMI requiring invasive mechanical ventilation admitted to the medical ICU (MICU) compared to cardiac (CICU). Methods: We utilized the Vizient Clinical Data Base to identify patients with a primary diagnosis of AMI between October 2015 and December 2019 and requiring invasive mechanical ventilation. Using multivariable logistic regression, we compared clinical outcomes for patients admitted to the MICU vs CICU. Results: We identified 12,639 patients, 25.2% (n = 3,185) of which were admitted to a MICU and 74.8% (n = 9,454) to a CICU. Patients admitted to a CICU were more likely to present with STEMI (57.0% vs 42.8%), cardiogenic shock (46.0% vs 37.4%), and require mechanical circulatory support and vasoactive medications (all, P 750 beds), and teaching hospitals (all, P

Purpose: Hyperglycemia is a major risk factor for early lesions of diabetic retinal disease (DRD). Updating the DRD staging system to incorporate relevant basic and cellular mechanisms pertinent to DRD is necessary to better address early disease, disease progression, the use of therapeutic interventions, and treatment effectiveness. Design: We sought to review preclinical and clinical evidence on basic and cellular mechanisms potentially pertinent to DRD that might eventually be relevant to update the DRD staging system. Participants: Not applicable. Methods: The Basic and Cellular Mechanisms Working Group (BCM-WG) of the Mary Tyler Moore Vision Initiative carefully and extensively reviewed available preclinical and clinical evidence through multiple iterations and classified these. Main Outcome Measures: Classification was made into evidence grids, level of supporting evidence, and anticipated future relevance to DRD. Results: A total of 40 identified targets based on pathophysiology and other parameters for DRD were grouped into concepts or evaluated as specific candidates. VEGFA, peroxisome proliferator-activated receptor-alpha related pathways, plasma kallikrein, and angiopoietin 2 had strong agreement as promising for use as biomarkers in diagnostic, monitoring, predictive, prognostic, and pharmacodynamic responses as well as for susceptibility/risk biomarkers that could underlie new assessments and eventually be considered within an updated DRD staging system or treatment, based on the evidence and need for research that would fit within a 2-year timeline. The BCM-WG found there was strong reason also to pursue the following important concepts regarding scientific research of DRD acknowledging their regulation by hyperglycemia: inflammatory/cytokines, oxidative signaling, vasoprotection, neuroprotection, mitophagy, and nutrients/microbiome. Conclusion: Promising targets that might eventually be considered within an updated DRD staging system or treatment were identified. Although the BCM-WG recognizes that at this stage little can be incorporated into a new DRD staging system, numerous potential targets and important concepts deserve continued support and research, as they may eventually serve as biomarkers and/or therapeutic targets with measurable benefits to patients with diabetes. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

ABSTRACT: Mycotoxin contaminated corn poses a risk to poultry production. Although mycotoxin regulatory guidelines are based on the hazards of individual mycotoxin contamination, feed and feed ingredients may be contaminated with multiple mycotoxins. The objective of this study was to assess mycotoxin co-contamination and its impact on the nutrient content of corn grain. Corn samples (n = 328) originating from various regions in the Southeastern U.S. were quantitatively analyzed for fumonisin (FUM), deoxynivalenol (DON), aflatoxin (AFB1) and zearalenone (ZEA) by HPLC-MS/MS. Nutritional content was analyzed by near-infrared spectroscopy, and color data were collected. All 328 samples were found to be contaminated with at least 1 mycotoxin: 100% contained FUM (19-24,680 µg/kg), 69.82% contained DON (0-9,640 µg/kg), 17.07% contained AFB1 (0–939 µg/kg), and 43.60% had detectable levels of ZEA (0-8,093.5 µg/kg). Most of the samples were contaminated with 2 or more mycotoxins, with only 18.29% of the samples containing a single mycotoxin. 38.41% of the samples had 2 mycotoxins present, 36.59 % had 3 mycotoxins, and 4.88% of the samples had all 4 tested mycotoxins present. Samples contaminated with AFB1 had significantly lower fat (P = 0.007) and lightness (P = 0.007); samples contaminated with DON had significantly higher starch (P < 0.001) and lower protein (P < 0.001). Samples contaminated with FUM had significantly higher protein (P = 0.008) and moisture (P = 0.019) and lower starch (P < 0.001). ZEA contaminated samples had significantly lower starch (P = 0.034). A correlation was observed between mycotoxin contamination and altered nutrient content in corn. This study provides further evidence that co-contamination of mycotoxins is the norm in corn, and that mycotoxin contamination correlates with impacts on the nutrient profile of feed corn.

Abstract Congenital heart disease (CHD) is the most common congenital malformation and is associated with adverse neurodevelopmental outcomes. The placenta is crucial for healthy fetal development and placental development is altered in pregnancy when the fetus has CHD. This study utilized advanced combined diffusion-relaxation MRI and a data-driven analysis technique to test the hypothesis that placental microstructure and perfusion are altered in CHD-affected pregnancies. 48 participants (36 controls, 12 CHD) underwent 67 MRI scans (50 control, 17 CHD). Significant differences in the weighting of two independent placental and uterine-wall tissue components were identified between the CHD and control groups (both pFDR

Abstract The genomes of charophyte green algae, close relatives of land plants, typically do not show signs of developmental regulation by phytohormones. However, scattered reports of endogenous phytohormone production in these organisms exist. We performed a comprehensive analysis of multiple phytohormones in Viridiplantae, focusing mainly on charophytes. We show that auxin, salicylic acid, ethylene and tRNA-derived cytokinins including cis-zeatin are found ubiquitously in Viridiplantae. By contrast, land plants but not green algae contain the trans-zeatin type cytokinins as well as auxin and cytokinin conjugates. Charophytes occasionally produce jasmonates and abscisic acid, whereas the latter is detected consistently in land plants. Several phytohormones are excreted into the culture medium, including auxin by charophytes and cytokinins and salicylic acid by Viridiplantae in general. We note that the conservation of phytohormone biosynthesis and signaling pathways known from angiosperms does not match the capacity for phytohormone biosynthesis in Viridiplantae. Our phylogenetically guided analysis of established algal cultures provides an important insight into phytohormone biosynthesis and metabolism across Streptophyta.

Abstract Introduction The PRESERFLO™ MicroShunt (PMS) has been proven to significantly lower intraocular pressure (IOP) in patients with glaucoma and has been available for use since 2019. With increasing published evidence and growing experience of glaucoma surgeons, the aim of this modified Delphi panel was to build on the findings of a previous Delphi panel conducted in 2021 and provide further guidance on the role of the PMS to treat patients with glaucoma in Europe. Methods Thirteen European glaucoma surgeons experienced in the PMS procedure participated in a 3-round modified Delphi panel. A targeted literature review and expert steering committee guided Round 1 questionnaire development. Consensus was pre-defined at a threshold of ≥ 70% of panellists selecting ‘strongly agree’/‘agree’ or ‘strongly disagree’/‘disagree’ for 6-point Likert scale questions or ≥ 70% selecting the same option for multiple or single-choice questions. Questions not reaching consensus were restated/revised for the next round, following guidance from free­text responses/scoping questions. Results In total, 28% (n = 9/32), 52% (n = 16/31) and 91% (n = 10/11) of statements reached consensus in Rounds 1, 2 and 3, respectively. There was agreement that the PMS may be used in patients with pigmentary, post-trauma or post-vitrectomy glaucoma and for patients with uveitic glaucoma without active inflammation. The PMS may be more suitable for patients with contact lenses than other subconjunctival filtering surgeries, without eliminating bleb-associated risks. Consensus was reached that combining PMS implantation and phacoemulsification may be as safe as standalone PMS surgery, but further efficacy data are required. Following a late rise in IOP ≥ 4 months post-surgery, topical aqueous suppressant drops or bleb revision may be suitable management options. Conclusions This Delphi panel builds on the considerations explored in the 2021 Delphi panel and provides further detailed guidance for glaucoma surgeons on the use of the PMS, reflecting the availability of novel evidence and surgical experience. Videos are available for this article.

Background: Managing reinfection in patients who inject drugs and have undergone cardiac surgery could reduce mortality. A significant gap exists in the management of addiction in this population and it is rarely addressed during index hospitalization for surgical intervention. This study sought to determine if management of addiction changed rates of readmission for reinfection. Methods: This study was a retrospective chart review and analysis. Patients who underwent cardiac surgery for infective endocarditis due to injection drug use underwent a full chart review to determine if they received management of their addiction (addictions medicine consultation, social work consultation, medication- and/or opioid-assisted treatment, and community follow-up) following their surgical intervention. Results: A total of 41 patients were identified who met the inclusion criteria. For addictions management, 43.2% of patients received an addictions medicine consultation, 67.6% received a social work consultation, 40.5% received medication- and/or opioid-assisted treatment, and 56.8% received community follow-up. Overall mortality of these patients was 21.6%, and 56.8% of patients were readmitted with reinfection. Multivariate logistic regression showed that patients who received intervention were 1.6 times more likely to be readmitted with reinfection (odds ratio 1.65, 95% confidence interval 0.29-9.41, P = 0.5736). Female patients had a significantly higher odds of reinfection, when adjusted for gender (odds ratio 9.95, 95% confidence interval 1.42-69.72, P = 0.021). Conclusions: We demonstrated a nonstandardized approach to consultation and varying approaches to management of addiction. Patients who received intervention for addiction were more likely to be readmitted for reinfection, but this difference was not significant. Future efforts can include promotion of formalized addictions consultation services for high-risk patients. Résumé: Contexte: La prise en charge de la réinfection chez les patients qui s’injectent des drogues et ont subi une intervention chirurgicale cardiaque pourrait réduire la mortalité. Il existe des lacunes importantes dans la gestion de la dépendance dans cette population, et celle-ci est rarement abordée lors de la première hospitalisation pour l’intervention chirurgicale. Cette étude a cherché à déterminer si la gestion de la dépendance peut changer les taux de réadmission pour réinfection. Méthodologie: Cette étude consistait en une analyse rétrospective de dossiers de patients. Les patients ayant subi une intervention chirurgicale cardiaque pour une endocardite infectieuse due à l’usage de drogues injectables ont fait l’objet d’un examen complet de leur dossier afin de déterminer s’ils avaient reçu une prise en charge de leur dépendance (consultation en médecine des dépendances, consultation en travail social, traitement médicamenteux associant ou non des opioïdes et suivi communautaire) après l’intervention chirurgicale. Résultats: Au total, 41 patients répondaient aux critères d’inclusion. En ce qui concerne la gestion des dépendances, 43,2 % des patients avaient effectué une consultation en médecine des dépendances, 67,6 %, en travail social, 40,5 % avaient reçu un traitement médicamenteux associant ou non des opioïdes et 56,8 % avaient fait l’objet d’un suivi communautaire. Le taux de mortalité globale chez ces patients était de 21,6 %, et 56,8 % des patients avaient subi une réinfection ayant nécessité une nouvelle hospitalisation. Une analyse de régression logistique multivariée a montré que les patients ayant reçu une intervention avaient une probabilité 1,6 fois supérieure de subir une nouvelle hospitalisation en raison d’une réinfection (rapport de cotes de 1,65, intervalle de confiance à 95 % de 0,29 à 9,41, p = 0,5736). Après ajustement en fonction du sexe, les femmes avaient une probabilité sensiblement plus élevée de réinfection (rapport de cotes de 9,95, intervalle de confiance à 95 % de 1,42 à 69,72, p = 0,021). Conclusions: Nous avons présenté une approche non normalisée de la consultation et des diverses approches de la gestion de la dépendance. Les patients ayant reçu une intervention pour la dépendance étaient plus susceptibles de subir une nouvelle hospitalisation en raison d’une réinfection, sans que cette différence soit significative. Les efforts futurs peuvent inclure la promotion de services officiels de consultation sur les dépendances pour les patients à risque élevé.

Salmonella enterica serovar Abortusovis is a ovine-adapted pathogen that causes spontaneous abortion. Salmonella Abortusovis was reported in poultry in 2009 and has since been reported in human infections in New South Wales, Australia. Phylogenomic analysis revealed a clade of 51 closely related isolates from Australia originating in 2004. That clade was genetically distinct from ovine-associated isolates. The clade was widespread in New South Wales poultry production facilities but was only responsible for sporadic human infections. Some known virulence factors associated with human infections were only found in the poultry-associated clade, some of which were acquired through prophages and plasmids. Furthermore, the ovine-associated clade showed signs of genome decay, but the poultry-associated clade did not. Those genomic changes most likely led to differences in host range and disease type. Surveillance using the newly identified genetic markers will be vital for tracking Salmonella Abortusovis transmission in animals and to humans and preventing future outbreaks.

Abstract Considering growing efforts to understand and improve the solute-specific selectivity of nanofiltration (NF) membranes, we explored the ion-specific effects that govern the charge and performance of a loose polyamide NF membrane that is commonly used for solute-solute separations. Specifically, we systematically evaluated the zeta potential of the membrane under different conditions of pH, salinity, and ionic composition, and correlated the obtained data with membrane performance tested under similar conditions. Our results identify the pK a of both carboxylic and amine groups bonded to the membrane surface and suggest that the highly polarizable chloride anions in the solution adsorb to the polyamide, increasing its negative charge. We also show that monovalent cations of different “stickiness” can neutralize the negative membrane charge to different extents due to their varying tendency to sorb to the polymer matrix or screen the fixed carboxyl groups on the membrane surface. Notably, our correlation between zeta potential measurements and permeability experiments indicates the substantial contribution of solution ions to Donnan exclusion in NF membranes.

Abstract Evidence is strong for adverse fetal effects of high level or chronic prenatal alcohol exposure (PAE), but many pregnant women continue to drink at lower levels. The ‘Asking Questions about Alcohol in pregnancy’ prospective cohort aimed to determine the neurodevelopmental consequences at 6–8 years of age of low to moderate PAE. 1570 women from seven public antenatal clinics in Melbourne, Australia, provided information on frequency and quantity of alcohol use, and obstetric, lifestyle and socio-environmental confounders at four gestation timepoints. PAE was classified into five trajectories plus controls. At 6–8 years, 802 of 1342 eligible families took part and completed a questionnaire (60%) and 696 children completed neuropsychological assessments (52%). Multiple linear regressions examined mean outcome differences between groups using complete case and multiple imputation models. No meaningful relationships were found between any of the PAE trajectories and general cognition, academic skills, motor functioning, behaviour, social skills, social communication, and executive function. Maternal education most strongly influenced general cognition and academic skills. Parenting behaviours and financial situation were associated with academic skills, behaviour, social skills and/or executive function. The lack of association between PAE and neurodevelopment at 6–8 years may partly be explained by cumulative positive effects of socio-environmental factors.

In public-health crises, members of multilingual communities must be able to access, understand, trust and act upon behaviour-change messaging. The role of translators is therefore critical, not only for the relaying of information but also in the transcreation of texts, understood as adaptation to suit the characteristics of an intended audience. Failure to use transcreation may produce messaging that is culturally inappropriate and thus ineffective. This study analyses healthcare resources created by governments in Australia with a view to identifying formatting and other visual features that would benefit from transcreation. A mixed-method approach combined numerical evaluation of four documents using the Patient Education Materials Assessment Tool (PEMAT) and a bottom-up thematic analysis of the way the same texts were discussed by 58 members of a broad range of ethnocultural and linguistic groups in Victoria, Australia. The findings point to a need to go beyond the linguistic aspects of the translation and take into account the discourse organisation, layout, images and cultural appropriateness of health messaging. The implications of applying the PEMAT criteria are not only that start texts will become more accessible and better able to facilitate understanding-based trust relations, but also that translators are well placed to participate in the transcreations that may be required in the various target languages.

Abstract Directed evolution of computationally designed enzymes has provided new insights into the emergence of sophisticated catalytic sites in proteins. In this regard, we have recently shown that a histidine nucleophile and a flexible arginine can work in synergy to accelerate the Morita-Baylis-Hillman (MBH) reaction with unrivalled efficiency. Here, we show that replacing the catalytic histidine with a non-canonical N δ-methylhistidine (MeHis23) nucleophile leads to a substantially altered evolutionary outcome in which the catalytic Arg124 has been abandoned. Instead, Glu26 has emerged, which mediates a rate-limiting proton transfer step to deliver an enzyme (BHMeHis1.8) that is more than an order of magnitude more active than our earlier MBHase. Interestingly, although MeHis23 to His substitution in BHMeHis1.8 reduces activity by 4-fold, the resulting His containing variant is still a potent MBH biocatalyst. However, analysis of the BHMeHis1.8 evolutionary trajectory reveals that the MeHis nucleophile was crucial in the early stages of engineering to unlock the new mechanistic pathway. This study demonstrates how even subtle perturbations to key catalytic elements of designed enzymes can lead to vastly different evolutionary outcomes, resulting in new mechanistic solutions to complex chemical transformations.

Cancer-associated macrophage-like cells (CAMLs) are myeloid-lineage cells associated with cancer-derived material that are detectable in the blood. In addition to circulating tumor cells, CAMLs are a promising liquid biopsy biomarker which may assist with prognostication for patient stratification and monitoring response to chemotherapy and radiotherapy in solid tumors. CAMLs have been detected in blood samples from patients with various tumors including lung, pancreas, breast, oesophageal, and colorectal cancers, and to date have not been detected in healthy individuals. However, the optimal method of detection, their origin, function in the circulation, and ultimate utility have not been fully elucidated. This review provides an overview of CAML-related studies and explores their future potential to guide clinical decision-making.

Using a weight of evidence approach, natural capital outcomes associated with regenerative grazing and silvopastoral systems were compared to those associated with conventional grazing systems. The aim of the review was to better understand how grazing management influences 16 natural capital indicators likely to be material from both an economic and sustainability perspective for grazing enterprises and to assess the evidence for associated impacts, positive or negative, on the natural capital resources required to sustain the system. Material natural capital issues reviewed included water availability and security, water quality, soil health and pasture productivity, biodiversity and climate change and greenhouse gas emissions.The review confirms previous evidence that moderate to high levels of grazing tends to degrade natural capital, relative to light to moderate levels of grazing. In relation to regenerative grazing practices the responses were less clear. Regenerative grazing practices may have a positive impact on natural capital, particularly in relation to soil biodiversity and live weight gain on a per head basis. However, the evidence base suggests that the effect size may be small and may take some years to be realised. For 12 of the 16 indicators reviewed, the natural capital outcomes were inconclusive or unresolved even though for five of these indicators, the evidence base was considered to be robust. For the remainder of these the evidence base was insufficient to support an analysis of potential impacts. Similarly, for silvopastoral grazing management systems, there was some evidence to suggest that this type of grazing management could lead to improved natural capital outcomes. However, the evidence base was generally insufficient to definitively attribute the changes in grazing management practices to natural capital outcomes.Although the evidence base for many of the natural capital outcomes associated with differing grazing management practices is incomplete, it should not be interpreted that this indicates a lack of a beneficial response, where a beneficial response would be characterised by improved natural capital and enterprise productivity. Rather it highlights shortcomings in the underlying evidence. Very few studies have the capacity to fully account for the benefits of changes in management practices on the natural capital outcomes and the productivity of the enterprise simultaneously and over a sufficient period of time to observe change. This was particularly evident in relation to carbon storage. While there have been many studies that have examined changes in the individual stocks, e.g. soil carbon or emissions in relation to grazing management very few studies have examined the whole farm carbon balance. Increased adoption of processes such as natural capital accounting, although in their infancy, could help to address this challenge and facilitate a more systematic analysis an enterprises natural capital and financial performance.