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Abstract Background Infectious diseases including Newcastle disease (ND) impair poultry productivity and represent a significant burden to sustainable agriculture in Nigeria. This study aimed to investigate the active circulation and seroprevalence of Newcastle disease virus (NDV) caused by virulent forms of avian paramyxovirus type-1 (APMV-1) in poultry at live bird markets (LBMs) across Nigeria. Methods A cross-sectional study of 18 LBMs was conducted within three states in Nigeria (Kano, Oyo, and Abuja). Paired swab and tissue samples (n = 413) were collected from birds on FTA cards and tested for APMV-1 using real-time reverse transcription polymerase chain reaction (rRT-PCR). A subset of rRT-PCR-positive samples were selected for whole genome sequencing based on the originating species (chicken, duck, geese), date, and market location to provide a broad range of isolates for characterisation. Blood samples (n = 405) were also collected from birds and the seroprevalence of APMV-1 antibodies was measured using an enzyme-linked immunosorbent assay (ELISA). Results APMV-1 RNA was detected in 21.5% (89/413) of samples from LBMs by rRT-PCR. At least one APMV-1 positive sample was detected in 55.6% (10/18) of LBMs. The largest proportion of APMV-1-positive markets was in Kano (83.3%, 5/6), whereas the lowest was in Oyo (16.7%, 1/6). Assessment of genetic data demonstrated that genotype XIV.2 APMV-1 was circulating within Nigeria with the viruses detected clustering closely with other Nigerian isolates described previously. The seroprevalence of APMV-1 in birds was 45.9% (186/405) and 94.4% (17/18) of LBMs had at least one APMV-1 seropositive sample (i.e., with at least one APMV-1-antibody-positive bird). The LBMs in Kano had the lowest seroprevalence (88.3%, 5/6). Conclusions This study demonstrated that APMV-1 continues to circulate in LBMs in Nigeria. LBM traders, poultry producers, and related industry and policy stakeholders should be aware of the occurrence of APMV-1 and how ND may negatively impact upon poultry production and the livelihoods of poultry farmers and LBM traders. Training initiatives aimed at improving the knowledge of APMV-1 infection and improvements in biosecurity practises and the role of disease mitigation through vaccination are required to reduce the impact of this threat to food security.

Abstract Background Since older adults spend significant time in their neighborhood environment, environmental factors such as neighborhood socioeconomic disadvantage, high racial segregation, low healthy food availability, low access to recreation, and minimal social engagement may have adverse effects on cognitive function and increase susceptibility to dementia. DNA methylation, which is associated with neighborhood characteristics as well as cognitive function and white matter hyperintensity (WMH), may act as a mediator between neighborhood characteristics and neurocognitive outcomes. Methods In this study, we examined whether DNA methylation in peripheral blood leukocytes mediates the relationship between neighborhood characteristics and cognitive function (N = 542) or WMH (N = 466) in older African American (AA) participants without preliminary evidence of dementia from the Genetic Epidemiology Network of Arteriopathy (GENOA). Results For a 1-mile buffer around a participant’s residence, each additional fast food destination or unfavorable food store with alcohol per square mile was nominally associated with a 0.05 (95%CI: 0.01, 0.09) and a 0.04 (0.00, 0.08) second improvement in visual conceptual tracking score, respectively. Also, each additional alcohol drinking place per square mile was nominally associated with a 0.62 (0.05, 1.19) word increase in delayed recall score, indicating better memory function (all p

Abstract The remarkable diversity of insect pigmentation offers a captivating avenue for studying evolution and genetics. In tephritids, understanding the molecular basis of mutant traits is also crucial for applied entomology, enabling the creation of genetic sexing strains through genome editing, thus facilitating sex-sorting before sterile insect releases. Here, we present evidence from classical and modern genetics showing that the black pupae (bp) phenotype in the GUA10 strain of Anastrepha ludens is caused by a large deletion at the ebony locus, removing the gene’s entire coding region. Targeted knockout of ebony induced analogous bp phenotypes across six major tephritid agricultural pests, demonstrating that disruption of Ebony alone is sufficient to produce the mutant trait in distantly related species. This functional characterization further allowed a deeper exploration of Ebony’s role in pigmentation and development across life stages in diverse species. Our findings offer key insights for molecular engineering of sexing strains based on the bp marker and for future evolutionary developmental biology studies in tephritids.

Abstract Emerging infectious diseases are of major concern to animal and human health. Recent emergence of high pathogenicity avian influenza virus (HPAIV) (H5N1 clade 2.3.4.4b) led to substantial global mortality across a range of host species. Co-occurring species showed marked differences in mortality, generating an urgent need for better epidemiological understanding within affected populations. We therefore tested for antibodies, indicative of previous exposure and recovery, and for active viral infection in apparently healthy individuals (n = 350) across five co-occurring seabird species on the Isle of May, Scotland, during 2023, following H5N1 HPAIV associated mortality in the preceding summer. Antibody prevalence to AIV subtypes varied substantially between species, ranging from 1.1% in European shags (Gulosus aristotelis) (to H5) to 78.7% in black-legged kittiwakes (Rissa tridactyla) (to H16 or both H13 and H16), and between 31 and 41% for three auk species (H5, H16 or both). At least 20.4% of auks had antibodies to an as yet unidentified subtype, suggesting further subtypes circulating in the population. We found low levels of active, but asymptomatic, AIV infection in individuals (1.6–4.5%), but excluded this as H5N1. Our results emphasise the importance of testing healthy individuals to understand the prevalence of co-circulating AIV subtypes in wild populations, and the potential for future reassortment events which could alter virus behaviour and impact.

Abstract Triple negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer, whose high frequency of relapse is often due to resistance to chemotherapy. Here, we identify inosine monophosphate dehydrogenase 2 (IMPDH2) as a contributor to doxorubicin resistance, in multiple TNBC models. Analysis of publicly available datasets reveals elevated IMPDH2 expression to associate with worse overall TNBC prognosis in the clinic, including lower recurrence-free survival post adjuvant/neoadjuvant therapy. Importantly, both genetic depletion and pharmacological inhibition of IMPDH2 leads to reduction of pro-tumorigenic phenotypes in multiple doxorubicin-resistant TNBC models, both in vitro and in vivo. Overall, we propose IMPDH2 as a novel vulnerability that could be leveraged therapeutically to suppress and/or prevent the growth of chemo-resistant lesions.

Abstract Infertility affects one-in-six couples, often necessitating in vitro fertilization treatment (IVF). IVF generates complex data, which can challenge the utilization of the full richness of data during decision-making, leading to reliance on simple ‘rules-of-thumb’. Machine learning techniques are well-suited to analyzing complex data to provide data-driven recommendations to improve decision-making. In this multi-center study (n = 19,082 treatment-naive female patients), including 11 European IVF centers, we harnessed explainable artificial intelligence to identify follicle sizes that contribute most to relevant downstream clinical outcomes. We found that intermediately-sized follicles were most important to the number of mature oocytes subsequently retrieved. Maximizing this proportion of follicles by the end of ovarian stimulation was associated with improved live birth rates. Our data suggests that larger mean follicle sizes, especially those >18 mm, were associated with premature progesterone elevation by the end of ovarian stimulation and a negative impact on live birth rates with fresh embryo transfer. These data highlight the potential of computer technologies to aid in the personalization of IVF to optimize clinical outcomes pending future prospective validation.

Abstract Background Posterior Cortical Atrophy (PCA) is a clinical syndrome characterized by progressive visuospatial and visuoperceptual impairment. As the neurodegenerative disease progresses, patients lose independent functioning due to the worsening of initial symptoms and development of symptoms in other cognitive domains. The timeline of clinical progression is variable across patients, and the field currently lacks robust methods for prognostication. Here, evaluated the utility of MRI-based cortical atrophy as a predictor of longitudinal clinical decline in a sample of PCA patients. Methods PCA patients were recruited through the Massachusetts General Hospital Frontotemporal Disorders Unit PCA Program. All patients had cortical thickness estimates from baseline MRI scans, which were used to predict longitudinal change in clinical impairment assessed by the CDR Sum-of-Boxes (CDR-SB) score. Multivariable linear regression was used to estimate the magnitude of cortical atrophy in PCA patients relative to a group of amyloid-negative cognitively unimpaired participants. Linear mixed-effects models were used to test hypotheses about the utility of baseline cortical atrophy for predicting longitudinal clinical decline. Results Data acquired from 34 PCA patients (mean age = 65.41 ± 7.90, 71% females) and 24 controls (mean age = 67.34 ± 4.93, 50% females) were analyzed. 62% of the PCA patients were classified as having mild cognitive impairment (CDR 0.5) at baseline, with the rest having mild dementia (CDR 1). Each patient had at least one clinical follow-up, with the mean duration of 2.78 ± 1.62 years. Relative to controls, PCA patients showed prominent baseline atrophy in the posterior cortical regions, with the largest effect size observed in the visual network of the cerebral cortex. Cortical atrophy localized to the dorsal attention network, which supports higher-order visuospatial function, selectively predicted the rate of subsequent clinical decline. Conclusions These results demonstrate the utility of a snapshot measure of cortical atrophy of the dorsal attention network for predicting the rate of subsequent clinical decline in PCA. If replicated, this topographically-specific MRI-based biomarker could be useful as a clinical prognostication tool that facilitates personalized care planning.

Abstract Background Exposure to psychosocial stress is linked to a variety of negative health outcomes, including cardiovascular disease and its cardiometabolic risk factors. DNA methylation has been associated with both psychosocial stress and cardiometabolic disease; however, little is known about the mediating role of DNA methylation on the association between stress and cardiometabolic risk. Thus, using the high-dimensional mediation testing method, we conducted an epigenome-wide mediation analysis of the relationship between psychosocial stress and ten cardiometabolic risk factors in a multi-racial/ethnic population of older adults (n = 2668) from the Health and Retirement Study (mean age = 70.4 years). Results A total of 50, 46, 7, and 12 CpG sites across the epigenome mediated the total effects of stress on body mass index, waist circumference, high-density lipoprotein cholesterol, and C-reactive protein, respectively. When reducing the dimensionality of the CpG mediators to their top 10 uncorrelated principal components (PC), the cumulative effect of the PCs explained between 35.8 and 46.3% of these associations. Conclusions A subset of the mediating CpG sites were associated with the expression of genes enriched in pathways related to cytokine binding and receptor activity, as well as neuron development. Findings from this study help to elucidate the underlying mechanisms through which DNA methylation partially mediates the relationship between psychosocial stress and cardiometabolic risk factors.

Laser powder bed fusion (L-PBF) is a metal additive manufacturing (AM) technique that produces a unique microstructure significantly different from wrought microstructure. Inconel 625 (IN625) is an alloy widely used to manufacture complex parts, but it comes with its own unique challenges. The alloy is prone to precipitation under elevated temperatures, which makes designing suitable heat treatment to tailor the desired microstructure and mechanical properties critical. Traditional heat treatment for wrought IN625 cannot be applied to L-PBF IN625; therefore, it is vital to understand the evolution of precipitates on the way to complete recrystallization. This study focuses on these precipitates in IN625 produced by the L-PBF technique. Heat treatments at 700 °C, 900 °C, and 1050 °C were performed separately to encourage the precipitation of strengthening γ″, the detrimental δ phase, and the dissolution of precipitates, respectively. γ″ precipitates were found in the as-printed condition and at 700 °C. δ precipitates were detected at 700 and 900 °C. Carbides and Al-rich oxides were observed in all conditions of L-PBF IN625. Texture analysis showed grain growth along the build direction with strong (100) texture at temperatures up to 900 °C. Weak and random texture with equiaxed grains was observed at 1050 °C, which is similar to wrought IN625.

Abstract Circulating tumor DNA (ctDNA) in plasma cell free DNA (cfDNA) of cancer patients is associated with poor prognosis, but is challenging to detect from low plasma volumes. In metastatic castration-resistant prostate cancer (mCRPC), ctDNA assays are needed to prognosticate outcomes of patients treated with androgen receptor (AR) inhibitors. We develop a custom targeted cfDNA sequencing assay, named AR-ctDETECT, to detect ctDNA in limiting plasma cfDNA available from mCRPC patients in the Alliance A031201 randomized phase 3 trial of enzalutamide with or without abiraterone. Of 776 patients, 59% are ctDNA-positive, with 26% having high ctDNA aneuploidy and 33% having low ctDNA aneuploidy but displaying AR gain or structural rearrangement, MYC/MYCN gain, or a pathogenic mutation. ctDNA-positive patients have significantly worse median overall survival than ctDNA-negative patients (29.0 months vs. 47.4 months, respectively). Here, we show that mCRPC patients identified as ctDNA-positive using the AR-ctDETECT assay have poor survival despite treatment with potent AR inhibitors in a phase 3 trial.

Background: Atrial fibrillation (AF) is a recognized risk factor for mortality after transcatheter aortic valve replacement for severe aortic stenosis, but the impact of different types of AF on clinical outcomes remains unclear. Methods: This retrospective study included 982 patients divided into 3 groups: no AF, paroxysmal AF, and nonparoxysmal AF (persistent or permanent). Clinical outcomes were analyzed using inverse probability weighting and multivariate models. Results: There were 610, 211, and 161 patients in the no-AF, paroxysmal AF, and nonparoxysmal AF groups, respectively. For the entire cohort, the mean (SD) age was 82 (7.7) years, and the periprocedural, 1-year, and 5-year mortality rates were 2.0%, 12%, and 50%, respectively. After inverse probability weighting, the periprocedural mortality rate was higher in the nonparoxysmal AF group than in the no-AF group (odds ratio, 4.71 [95% CI, 1.24-17.9]). During 5 years of follow-up (median [IQR], 22 [0-69] months), all-cause mortality was higher in the nonparoxysmal AF group than in the no-AF group (hazard ratio [HR], 1.56 [95% CI, 1.14-2.14]; P = .006). The paroxysmal AF group was not associated with worse clinical outcomes than the no-AF group (HR, 1.02 [95% CI, 0.81-1.49]) for all-cause mortality. Stroke rates were comparable among the 3 groups. Multivariate analysis also showed increased all-cause mortality in the nonparoxysmal AF group compared with the no-AF group (adjusted HR, 1.43 [95% CI, 1.06-1.93]; P = .018), while all-cause mortality was comparable between the paroxysmal AF and no-AF groups (adjusted HR, 1.00 [95% CI, 0.75-1.33]). Conclusion: In patients undergoing transcatheter aortic valve replacement for severe aortic stenosis, having nonparoxysmal AF was associated with a higher risk of periprocedural and all-cause mortality compared with having no AF. Paroxysmal AF showed no such association.

Abstract Despite being a common urologic disorder with potentially complicated sequela, the genetic background of adult hydrocele has not previously been described. We performed a multi-population genome-wide association study of 363,460 men in the United Kingdom BioBank and FinnGen cohorts. We identified 6,548 adult men with hydrocele. We analyzed common variants (minor allele frequency > 0.01) associated with hydrocele and set the threshold for genome-wide significance at p

Abstract Background Since the elimination of numerical scoring of the United States Medical Licensing Examination (USMLE) Step 1, the perceived importance of USMLE Step 2 Clinical Knowledge (CK) scores in residency placement has increased. It is known that socioeconomic status (SES) and other demographic factors can be barriers to success in standardized assessment, but few recent studies report the relationship between student demographics, including SES, with Step 2 CK scores in the context of exam practice material access and usage. In this study, we investigated predictors of Step 2 CK success across two years at one institution. Methods A survey regarding Step 2 CK exam preparation and demographic factors was administered to two student cohorts at a New York medical school in 2022 and 2023. The cohorts were comprised of all students in a given class year who had taken Step 2 CK. De-identified survey responses were linked to metrics including Step 1, Step 2 CK, shelf exam, and Medical College Admission Test (MCAT) scores. Results The mean Step 2 CK score among the respondents (n = 213) was 254 ± 13. There was a strong positive correlation between Step 2 CK score and composite shelf scores (rho = 0.80, p

Abstract Background Cardiometabolic risk factors among youth are rising. Epigenetic age acceleration, a biomarker for aging and disease-risk, has been associated with adiposity in children, but its association with other cardiometabolic risk markers remains understudied. We employed data from the Health Outcomes and Measures of the Environment (HOME) study, a prospective pregnancy and birth cohort in the greater Cincinnati metropolitan area, to examine whether accelerated epigenetic age at birth as well as accelerated epigenetic age and faster pace of biological aging at age 12 years were associated with higher cardiometabolic risk in adolescents. Results After adjusting for potential confounders, including estimated cell type proportions, epigenetic gestational age acceleration at birth, derived from the Bohlin, Knight, and Haftorn clocks using cord blood DNA methylation data, was not associated with cardiometabolic risk z-scores or individual cardiometabolic risk score components (visceral fat, leptin to adiponectin ratio, HOMA-IR, triglycerides to HDL-C ratio, HbA1c, or systolic blood pressure) at age 12 years. We also did not observe any associations of epigenetic age acceleration, calculated with Horvath’s skin and blood, Hannum’s, and Wu’s epigenetic clocks using peripheral blood at age 12 years, with these same cardiometabolic risk markers. In contrast, faster pace of biological aging was associated with higher cardiometabolic risk [βs (95% CIs)] cardiometabolic risk score 0.25 (0.07, 0.42); visceral fat 0.21 (0.05, 0.38); and hemoglobin A1c 0.23 (0.05, 0.41) per standard deviation increase in pace of biological aging. Faster pace of biological aging was also positively associated with systolic blood pressure, triglycerides to HDL-C ratio, HOMA-IR, and leptin to adiponectin ratio, although these associations were not statistically significant. Conclusions Our findings provide evidence that faster pace of biological aging was associated with higher cardiometabolic risk score, visceral fat, and HbA1c at age 12 years. Further research is needed to determine whether these associations persist from adolescence through adulthood.

Abstract Lassa virus (LASV) is a rodent-borne mammarenavirus that causes tens to hundreds of thousands of human infections annually in Western Africa. Approximately 20% of these infections progress to Lassa fever (LF), an acute disease with case–fatality rates from ≈20–70%. Currently, there are no approved vaccines or specific therapeutics to prevent or treat LF. The LASV genome consists of a small (S) segment that has two genes, GP and NP, and a large (L) segment that has two genes, L and Z. In both segments, the two genes are separated by non-coding intergenic regions (IGRs). Recombinant LASVs (rLASVs), in which the L segment IGR was replaced with the S segment IGR or in which the GP gene was codon-deoptimized, lost fitness in vitro, were highly attenuated in vivo, and, when used as vaccines, protected domesticated guinea pigs from otherwise lethal LASV exposure. Here, we report the generation of rLASV/IGR-CD, which includes both determinants of attenuation and further enhances the safety of the vaccine compared with its predecessors. rLASV/IGR-CD grew to high titers in Vero cells, which are approved for human vaccine production, but did not cause signs of disease or pathology in guinea pigs. Importantly, guinea pigs vaccinated with rLASV/IGR-CD were completely protected from disease and death after a typically lethal exposure to wild-type LASV. Our data support the development of rLASV/IGR-CD as a live-attenuated LF vaccine with stringent safety features.

Abstract Microplastics (MPs) have been found in a diverse range of organisms across trophic levels. While a majority of the information on organismal exposure to plastics in the environment comes from gastrointestinal (GI) data, the prevalence of MP particles in other tissues is not well understood. Additionally, many studies have not been able to detect the smallest, most prevalent, MPs (1 µm – 5 mm) that are the most likely to distribute to tissues in the body. To address these knowledge gaps, MPs in the GI tract and muscle of Atlantic killifish (Fundulus heteroclitus) collected from two sites (Falmouth and Bourne) on Buzzards Bay, Cape Cod, MA were quantified down to 2 µm in size. Eight fish from Falmouth and 10 fish Bourne site were analyzed. Fourier-transform infrared spectroscopy and Raman spectroscopy were used to identify all particles. The mean concentrations of MPs in the GI tract and muscle from fish collected from Falmouth was 85.5 ± 70.2 and 11 ± 12.5 particles per gram wet weight, respectively. Fish collected from Bourne site had mean particle concentrations of 12.2 ± 18.1 and 1.69 ± 5.36 particles per gram wet weight. Of the 2,008 particles analyzed in various fish tissue samples, only 3.4% (69 particles) were identified as plastic; polymers included nylon, polyethylene, polypropylene, and polyurethane. MPs detected in the GI tract samples also tended to be more diverse in both size and polymer type than those found in the muscle. We found that MPs

Abstract A female protective effect has long been postulated as the primary explanation for the four-fold increase of autism spectrum disorder (ASD) diagnoses in males versus females. However, genetic and epidemiological investigations of this hypothesis have so far failed to explain the large difference in ASD prevalence between the sexes. To address this knowledge gap, we examined sex chromosome aneuploidy in a large ASD case-control cohort to evaluate the relationship between X and Y chromosome dosage and ASD risk. From these data, we modeled three relationships between sex chromosome dosage and ASD risk: the extra Y effect, the extra X effect, and sex chromosome haploinsufficiency. We found that the extra Y effect increased ASD risk significantly more than the extra X effect. Among females, we observed a large association between 45, X and ASD, confirming sex chromosome haploinsufficiency as a strong ASD risk factor. These results provide a framework for understanding the relationship between X and Y chromosome dosage on ASD, which may inform future research investigating genomic contributors to the observed sex difference.

Abstract Omaveloxolone is a nuclear factor (erythroid‐derived 2)‐like 2 activator approved in the United States and the European Union for the treatment of patients with Friedreich ataxia aged ≥16 years, with a recommended dosage of 150 mg orally once daily on an empty stomach. The effect of the US Food and Drug Administration (FDA) high‐fat breakfast on the pharmacokinetic profile of omaveloxolone observed in study 408‐C‐1703 (NCT03664453) deviated from the usual linear correlation between fed/fasted maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) ratios reported for various oral drugs across 323 food effect studies. Here, physiologically based biopharmaceutics modeling (PBBM) was implemented to predict and explain the effect of the FDA high‐fat breakfast on a 150‐mg dose of omaveloxolone. The model was developed and validated based on dissolution and pharmacokinetic data available across dose‐ranging, food effect, and drug–drug interaction clinical studies. PBBM predictions support clinical observations of the unique effect of a high‐fat meal on omaveloxolone pharmacokinetic profile, in which the Cmax increased by 350% with only a 15% increase in the AUC. Key parameters influencing omaveloxolone pharmacokinetics in the fasted state based on a parameter sensitivity analysis included bile salt solubilization, CYP3A4 activity, drug substance particle size distribution, and permeability. Mechanistically, in vivo omaveloxolone absorption was solubility and dissolution rate limited. However, in the fed state, higher bile salt solubilization led to more rapid dissolution with predominant absorption in the upper gastrointestinal tract, resulting in increased susceptibility to first‐pass gut extraction; this accounts for the lack of correlation between Cmax and AUC for omaveloxolone.

Objective: To determine factors significantly associated with alternative discharge destination (ADCD) following lobectomy, including the modified 5-item Frailty Index (mFI-5). Methods: Patients in the 2017-2020 NSQIP who underwent elective lobectomy and were admitted from home were included, with ADCD defined as a patient who was discharged to any nonhome location. Four multivariable logistic regression models for ADCD were evaluated for predictive power. Model A was created from backward selection of variables significantly associated with ADCD in bivariate analyses, model B was the mFI-5, model C was mFI-5 and a minimally invasive approach, and model D was mFI-5 and age group. Results: Among the 15,868 patients, 687 (4.3%) experienced ADCD. Model A identified older age, hypertension, dyspnea, history of chronic obstructive pulmonary disease, and increased length of stay as significantly associated with ADCD. A minimally invasive approach was significantly protective of ADCD. Model A had the best predictive power of the models tested (C-statistic = 0.785). Model B, which assessed mFI-5 alone, had fair predictive power (C-statistic = 0.637). Adding surgical approach (C-statistic = 0.673; model C) or age group (C-statistic = 0.682; model D) as independent variables with mFI-5 improved model fit. Conclusions: Patients who were frail or age >75 years were more likely to have postlobectomy ADCD. Although the variables identified in model A better predict ADCD, consideration of surgical approach or age with mFI-5 can help surgeons anticipate discharge destination following lobectomy.

Abstract Background Epigenome‐wide association studies have identified multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. This study aimed to test the hypothesis that an alcohol consumption epigenetic risk score (ERS) is associated with blood pressure (BP) traits. Results We implemented an ERS based on a previously reported epigenetic signature of 144 alcohol-associated CpGs in meta-analysis of participants of European ancestry. We found a one-unit increment of ERS was associated with eleven drinks of alcohol consumed per day, on average, across several cohorts (p

Abstract Until recent events, the Antarctic was the only major geographical region in which high pathogenicity avian influenza virus (HPAIV) had never previously been detected. Here we report on the detection of clade 2.3.4.4b H5N1 HPAIV in the Antarctic and sub-Antarctic regions of South Georgia and the Falkland Islands, respectively. We initially detected H5N1 HPAIV in samples collected from brown skuas at Bird Island, South Georgia on 8th October 2023. Since this detection, mortalities were observed in several avian and mammalian species at multiple sites across South Georgia. Subsequent testing confirmed H5N1 HPAIV across several sampling locations in multiple avian species and two seal species. Simultaneously, we also confirmed H5N1 HPAIV in southern fulmar and black-browed albatross in the Falkland Islands. Genetic assessment of the virus indicates spread from South America, likely through movement of migratory birds. Critically, genetic assessment of sequences from mammalian species demonstrates no increased risk to human populations above that observed in other instances of mammalian infections globally. Here we describe the detection, species impact and genetic composition of the virus and propose both introductory routes and potential long-term impact on avian and mammalian species across the Antarctic region. We also speculate on the threat to specific populations following recent reports in the area.

Abstract Background To assess the characteristics of patients enrolled in the ILD-PRO Registry. Methods The ILD-PRO Registry is a multicentre US registry of patients with progressive pulmonary fibrosis. This registry is enrolling patients with an interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis who have reticular abnormality and traction bronchiectasis on HRCT, and who meet criteria for ILD progression within the prior 24 months. Patient characteristics were analysed based on the number of patients with available data. Results Of the first 491 patients enrolled, the majority were white (75.4%) and female (60.6%); 47.4% had a history of smoking. Reported ILDs were autoimmune disease-associated ILDs (47.2%), hypersensitivity pneumonitis (17.5%), idiopathic non-specific interstitial pneumonia (9.1%), interstitial pneumonia with autoimmune features (8.9%), unclassifiable ILD (7.6%), other ILDs (9.7%). At enrolment, median (Q1, Q3) FVC % predicted was 62.2 (49.4, 72.4) and DLco % predicted was 39.2 (30.2, 49.2). Median (Q1, Q3) total score on the St. George’s Respiratory Questionnaire was 50.8 (35.9, 64.7). The most common comorbidities were gastroesophageal reflux disease (61.1%) and sleep apnoea (29.6%). Overall, 64.5% of patients were receiving immunosuppressive or cytotoxic therapy, 61.1% proton-pump inhibitors, 53.2% oral steroids, 19.8% nintedanib and 3.6% pirfenidone. Conclusions Patients enrolled into the ILD-PRO Registry have a variety of ILD diagnoses, marked impairment in lung function and health-related quality of life, and high medication use. Longitudinal data from this registry will further our knowledge of the course of progressive pulmonary fibrosis. Trial Registration ClinicalTrials.gov, NCT01915511; registered August 5, 2013.

Abstract Metastases to the brain are rare in prostate cancer. Here, we describe a patient with two treatment-emergent metastatic lesions, one to the brain with neuroendocrine prostate cancer (NEPC) histology and one to the dural membrane of adenocarcinoma histology. We performed genomic, transcriptomic, and proteomic characterization of these lesions and the primary tumor to investigate molecular features promoting these metastases. The two metastatic lesions had high genomic similarity, including TP53 mutation and PTEN deletion, with the most striking difference being the additional loss of RB1 in the NEPC lesion. Interestingly, the dural lesion expressed both androgen receptor and neuroendocrine markers, suggesting amphicrine carcinoma (AMPC). When analyzing pioneer transcription factors, the AMPC lesion exhibited elevated FOXA1 activity while the brain NEPC lesion showed elevated HOXC10, NFYB, and OTX2 expression suggesting novel roles in NEPC formation or brain tropism. Our results highlight the utility of performing multi-omic characterization, especially in rare cancer subtypes.

BackgroundRacial and ethnic disparities in cardiovascular disease (CVD) risk factors are well-documented. However, racial and ethnic differences in the longitudinal changes among multiple CVD risk factors are unknown.MethodsWe used prospective cohort data of U.S. adults aged ≥50 in the 2006-2016 Health and Retirement Study. Group-based multi-trajectory models characterized age-related trajectories of systolic blood pressure ([BP] mmHg), non-HDL cholesterol (mg/dL), diabetes mellitus (DM), and smoking. Racial and ethnic differences in the multi-trajectory profiles were examined using multinomial logistic regression. Karlson-Holm-Breen methods were used to assess factors contributing to these associations.ResultsAmong 10,292 participants (median age: 61), approximately 32% had an overall favorable profile of CVD risk factors. Compared with non-Hispanic White adults, non-Hispanic Black adults were more likely to exhibit elevated systolic BP with high risks of DM (relative risk ratio [RRR] = 3.36; 95% CI, 2.69-4.21; P < .001) and with low risks of DM (RRR = 3.23; 95% CI, 2.38-4.38; P < .001). Non-Hispanic Black adults were also more likely to exhibit high rates of smoking with and without other co-occurring risk factors. Hispanic adults were most likely to exhibit high risks of DM with elevated systolic BP (RRR = 1.74; 95% CI, 1.28-2.38; P < .001) and without elevated systolic BP (RRR = 1.90; 95% CI, 1.50-2.40; P < .001). Education, income, and country-of-origin were significantly associated with the excess CVD risks observed among racial and ethnic minority groups.ConclusionsSignificant racial and ethnic disparities were observed in trajectories of CVD risk factors in U.S. adults. Social determinants largely contributed to these associations in non-Hispanic Black adults and Hispanic adults.

Summary: Localized prostate cancer can be cured by radiation or surgery, but advanced prostate cancer continues to be a clinical challenge. Altered alternative polyadenylation occurs in numerous cancers and can downregulate tumor-suppressor genes and upregulate oncogenes. We found that the cleavage and polyadenylation specificity factor (CPSF) complex factor CPSF1 is upregulated in patients with advanced prostate cancer, with high CPSF1 expression correlating with worse progression-free survival. Knockdown of CPSF1 selectively inhibited the growth of prostate cancer cells and reduced glycolytic output. Evaluating the changes in global poly(A) site usage in prostate cancer cells following CPSF1 knockdown revealed widespread usage of intergenic poly(A) sites distal to annotated 3′ UTRs, which lengthened 3′ UTRs and decreased levels of thousands of mRNAs, including key glycolysis genes. These findings uncover a role for CPSF1 in the suppression of intergenic poly(A) sites in prostate cancer and nominate CPSF1 as a therapeutic target in advanced prostate cancer.

Background Meta‐analyses have suggested that the risk of cardiovascular disease events is significantly higher after a chronic obstructive pulmonary disease (COPD) exacerbation, but the populations at highest risk have not been well characterized to date. Methods and Results The authors analyzed the risk of atherosclerotic cardiovascular disease (ASCVD) hospitalizations after COPD hospitalization compared with before COPD hospitalization and patient factors associated with ASCVD hospitalizations after COPD hospitalization among 2 high‐risk patient cohorts. The primary outcome was risk of an ASCVD hospitalization composite outcome (myocardial infarction, coronary artery bypass graft, percutaneous coronary intervention, stroke, transient ischemic accident) after COPD hospitalization relative to before COPD hospitalization. Additional analyses evaluated for risk factors associated with the composite ASCVD hospitalization outcome. In the high‐risk primary prevention cohort, the hazard ratio (HR) estimate following adjustment for the composite ASCVD hospitalization outcome after COPD hospitalization versus before COPD hospitalization for 30 days was 0.74 (95% CI, 0.66–0.82; P≤0.0001); for 90 days, 0.69 (95% CI, 0.64–0.75; P≤0.0001); and for 1 year, 0.78 (95% CI, 0.73–0.82; P≤0.0001). In the secondary prevention cohort, the HR for 30‐day hospitalization was 1.15 (95% CI, 1.05–1.26; P=0.0036); 90‐day hospitalization, 1.08 (95% CI, 1.01–1.15; P=0.0178); and 1‐year hospitalization, 1.07 (95% CI, 1.02–1.11; P=0.0026). Among the 19 characteristics evaluated, hyperlipidemia and history of acute ASCVD event were associated with the highest risk of ASCVD events 1 year after COPD hospitalization in the high‐risk primary and secondary prevention cohorts. Conclusions The risk of ASCVD hospitalization was higher in patients with established ASCVD and lower among high‐risk patients without established ASCVD after‐COPD hospitalization relative to before hospitalization. We identified multiple risk factors for ASCVD hospitalization after COPD hospitalization.

NIR spectroscopy is a rapid and accurate green technology for high-throughput biomass characterization, including sorghum (Sorghum bicolor), a promising energy crop for the biofuel industry. This study assessed the influence of particle size on NIR spectroscopic analysis (wavelength range: 867–2535 nm) of sorghum biomass composition. Grown under field conditions, a total of 113 types of genetically diverse sorghum accessions were dried, ground, and sieved ( 850 µm particle size) for developing partial least square regression (PLSR) prediction models for moisture, ash, extractive, glucan, xylan, acid-soluble lignin (ASL), acid-insoluble lignin (AIL), and total lignin (ASL + AIL). Overall, smaller particle sizes provided better model performance, while no single particle size provided the best performance for all the selected components. With only 9 selected bands and 4 latent variables (LVs), the best PLSR model was obtained for moisture with particle size of 600–850 µm with the square root of the coefficient of determination (R) of 0.85, the ratio of prediction to deviation (RPD) of 2.2, and the root mean square error (RMSE) of 0.46 % in external validation. Similar model performances were also obtained for ash, extractive, glucan, and xylan. This study showed that size reduction could effectively improve NIR spectroscopic analysis for lipid-producing sorghum biomass for the biofuel industry.

Background Neighborhood characteristics serve as risk factors for metabolic syndrome (MetS). However, the intermediary factors linking this relationship remain understudied. Thus, we investigated the sex‐specific mediating role of C‐reactive protein, physical activity (PA), and perceived stress in the associations of perceived neighborhood social environment (PNSE) with MetS severity among Black adults. Methods and Results This cross‐sectional study included 3185 adults (64% women) from exam 1 (2000–2004) of the Jackson Heart Study. MetS severity Z scores were calculated based on the Adult Treatment Panel III criteria formula. PNSE included neighborhood violence, problems, and social cohesion. Men and women were analyzed separately. A bootstrap resampling technique with 95% bias‐corrected CI (95% BC CI) was used to evaluate whether C‐reactive protein, PA, and perceived stress mediated the association between each PNSE and MetS severity, adjusting for covariates. All PNSE factors were directly related to MetS severity in women but not in men. In women, neighborhood problems were indirectly associated with MetS severity mediated through PA (β=0.02 [95% BC CI, 0.00–0.05]). In men, neighborhood violence, problems, and social cohesion were indirectly associated with MetS severity mediated through PA (β=0.05 [95% BC CI, 0.01–0.10]; β=0.03 [95% BC CI, 0.00–0.06]; and β=−0.04 [95% BC CI, −0.09 to −0.01], respectively). Neither C‐reactive protein nor perceived stress mediated such associations in either women or men. Conclusions All PNSEs (violence, problems, and social cohesion) were directly related to MetS severity in women only. PA mediated the relationship between each PNSE and MetS in a sex‐specific manner. Efforts focusing on local conditions are needed to better understand why such disparities exist for at‐risk minoritized groups.

The NANOGrav 15 yr data provide compelling evidence for a stochastic gravitational-wave (GW) background at nanohertz frequencies. The simplest model-independent approach to characterizing the frequency spectrum of this signal consists of a simple power-law fit involving two parameters: an amplitude A and a spectral index γ . In this Letter, we consider the next logical step beyond this minimal spectral model, allowing for a running (i.e., logarithmic frequency dependence) of the spectral index, ${\gamma }_{{\rm{run}}}(f)=\gamma +\beta \mathrm{ln}\left(f/{f}_{{\rm{ref}}}\right)$ . We fit this running-power-law (RPL) model to the NANOGrav 15 yr data and perform a Bayesian model comparison with the minimal constant-power-law (CPL) model, which results in a 95% credible interval for the parameter β consistent with no running, $\beta \in \left[-0.80,2.96\right]$ , and an inconclusive Bayes factor, ${ \mathcal B }\left({\rm{RPL}}\,{\rm{versus}}\,{\rm{CPL}}\right)=0.69\pm 0.01$ . We thus conclude that, at present, the minimal CPL model still suffices to adequately describe the NANOGrav signal; however, future data sets may well lead to a measurement of nonzero β . Finally, we interpret the RPL model as a description of primordial GWs generated during cosmic inflation, which allows us to combine our results with upper limits from Big Bang nucleosynthesis, the cosmic microwave background, and LIGO–Virgo–KAGRA.

Sulforaphane (SFN) is an isothiocyanate derived from cruciferous vegetables that has demonstrated anti-cancer, anti-microbial and anti-oxidant properties. SFN ameliorates various disease models in rodents (e.g., cancer, diabetes, seizures) that are likewise mitigated by dietary restrictions leading us to test the hypothesis that this compound elicits cellular responses consistent with being a fasting/caloric restriction mimetic. Using immortalized human retinal pigment epithelial cells, we report that SFN impacted multiple nutrient-sensing pathways consistent with a fasted state. SFN treatment (i) increased mitochondrial mass and resistance to oxidative stress, (ii) acutely suppressed markers of mTORC1/2 activity via inhibition of insulin signaling, (iii) upregulated autophagy and further amplified autophagic flux induced by rapamycin or nutrient deprivation while concomitantly promoting lysosomal biogenesis, and (iv) acutely decreased glucose uptake and lactate secretion followed by an adaptive rebound that coincided with suppressed protein levels of thioredoxin-interacting protein (TXNIP) due to early transcriptional down-regulation. This early suppression of TXNIP mRNA expression could be overcome with exogenous glucosamine consistent with SFN inhibiting glutamine F6P amidotransferase, the rate limiting enzyme of the hexosamine biosynthetic pathway. SFN also altered levels of multiple glycolytic and tricarboxylic acid (TCA) cycle intermediates while reducing the inhibitory phosphorylation on pyruvate dehydrogenase, indicative of an adaptive cellular starvation response directing pyruvate into acetyl coenzyme A for uptake by the TCA cycle. RNA-seq of cells treated for 4 h with SFN confirmed the activation of signature starvation-responsive transcriptional programs. Collectively, these data support that the fasting-mimetic properties of SFN could underlie both the therapeutic efficacy and potential toxicity of this phytochemical.

Background Idiopathic interstitial pneumonias (IIPs), such as idiopathic pulmonary fibrosis and interstitial pneumonia with autoimmune features, present diagnostic and therapeutic challenges due to their heterogeneous nature. This study aimed to identify intrinsic molecular signatures within the lung microenvironment of these IIPs through proteomic analysis of bronchoalveolar lavage fluid (BALF). Methods Patients with IIP (n=23) underwent comprehensive clinical evaluation including pre-treatment bronchoscopy and were compared with controls without lung disease (n=5). Proteomic profiling of BALF was conducted using label-free quantitative methods. Unsupervised cluster analyses identified protein expression profiles that were then analysed to predict survival outcomes and investigate associated pathways. Results Proteomic profiling successfully differentiated IIP from controls. k-means clustering based on protein expression revealed three distinct IIP clusters, which were not associated with age, smoking history, or baseline pulmonary function. These clusters had unique survival trajectories and provided more accurate survival predictions than the Gender Age Physiology index (concordance index 0.794 versus 0.709). The cluster with the worst prognosis featured decreased inflammatory signalling and complement activation, with pathway analysis highlighting altered immune response pathways related to immunoglobulin production and B-cell-mediated immunity. Conclusions The unsupervised clustering of BALF proteomics provided a novel stratification of IIP patients, with potential implications for prognostic and therapeutic targeting. The identified molecular phenotypes underscore the diversity within the IIP classification and the potential importance of personalised treatments for these conditions. Future validation in larger, multi-ethnic cohorts is essential to confirm these findings and to explore their utility in clinical decision-making for patients with IIP.

Category: Bunion; Midfoot/Forefoot Introduction/Purpose: First tarsometatarsal (TMT) arthrodesis is one of the most common procedures performed each year for the correction of hallux valgus deformity (HVD) and there are currently over 100 different techniques that have been described. Non-union rates for first TMT arthrodesis are commonly reported to be between 5-15%. A systematic review found that 10.6% of patients reported dissatisfaction following their surgery to correct HVD and 4.9% had recurrent deformity. Multiple techniques featuring an intramedullary nail for first TMT arthrodesis have been described with promising early results in biomechanical studies and studies involving small numbers of patients. The purpose of this study was to evaluate radiographic and patient-reported outcomes of an intramedullary nail system in patients requiring first TMT arthrodesis for HVD. Methods: An ambispective, multi-surgeon, consecutive case series was conducted, with retrospective and prospective collection of patient-reported outcome measure (PROM) data (Foot and Ankle Ability Measure (FAAM), Pain Interference, Pain Score (scale of 0-10), and Neuro-Quality-of-Life Mobility Lower Extremity (Neuro QOL)) and subsequent radiographic measures (intermetatarsal angle (IMA), hallux valgus angle (HVA), distal metatarsal articular angle (DMAA), Meary’s angle (MA), 1st metatarsal declination angle, tibial sesamoid position, and relative metatarsal length). Patients who underwent first TMT arthrodesis from July 2019–July 2022 for HVD with a Phantom ® Small Bone Intramedullary Nail system and had adequate records for a minimum of three months post-operation (±4 weeks) were included. The indication for surgery was a painful HVD with failure of conservative treatment options. A patient chart review was conducted to collect basic demographic data, surgical data, and patient comorbidities. Results: 70 patients were included in the final analysis (N =68 for radiographic measures), with a median prospective PROM follow-up of 1.6 years. There was an overall union rate of 91.4% (64/70 patients), with 92.4% (61/66) of primary hallux valgus surgeries achieving union. Nine patients required secondary procedures; two experienced migration of the proximal peg and two experienced irritation from the index device. Hardware was completely removed in the 5 primary nonunions, and it was broken in 3 of these 5 patients. PROMs demonstrated significant improvement in FAAM, Pain Interference, overall pain, and Neuro-QOL scores; IMA, HVA, DMAA, MA, and tibial sesamoid position showed significant improvement at follow-up (P< 0.05) (Table 1). 1st Metatarsal Declination angle was not significantly altered and there was minimal (2.4 mm) metatarsal shortening. Conclusion: In the current sample of 70 feet, there were 6 non-unions, resulting in an overall union rate of 91.4%. The overall nonunion rate for first TMT arthrodesis is commonly reported to be between 5 and 15%. Similarly, PROMs and radiographic measurements collected showed significant improvement post-surgery. The results suggest that this system parallels other procedures for first TMT arthrodesis in terms of nonunion, complication rate, and various PROMs. With over 100 different surgical techniques for TMT arthrodesis, the results of this case series support that the intramedullary nail system can be considered as an option for surgeons.

Abstract Future flood risk assessment has primarily focused on heavy rainfall as the main driver, with the assumption that projected increases in extreme rain events will lead to subsequent flooding. However, the presence of and changes in vegetation have long been known to influence the relationship between rainfall and runoff. Here, we extract historical (1850–1880) and projected (2070–2100) daily extreme rainfall events, the corresponding runoff, and antecedent conditions simulated in a prominent large Earth system model ensemble to examine the shifting extreme rainfall and runoff relationship. Even with widespread projected increases in the magnitude (78% of the land surface) and number (72%) of extreme rainfall events, we find projected declines in event‐based runoff ratio (runoff/rainfall) for a majority (57%) of the Earth surface. Runoff ratio declines are linked with decreases in antecedent soil water driven by greater transpiration and canopy evaporation (both linked to vegetation greening) compared to areas with runoff ratio increases. Using a machine learning regression tree approach, we find that changes in canopy evaporation is the most important variable related to changes in antecedent soil water content in areas of decreased runoff ratios (with minimal changes in antecedent rainfall) while antecedent ground evaporation is the most important variable in areas of increased runoff ratios. Our results suggest that simulated interactions between vegetation greening, increasing evaporative demand, and antecedent soil drying are projected to diminish runoff associated with extreme rainfall events, with important implications for society.

Cet article présente la perspective ambivalente sur la chasse qui ressort des textes littéraires de Julien Gravelle. Dans Musher (2014), un conducteur de traîneau à neige prône une pratique cynégétique éthique pour le bien-être des animaux, humains et non humains. Tout en décriant les maux de l’élevage industriel, le musher propose que le respect des animaux dans le monde occidental passe par un retour à la chasse. Son argument s’appuie sur des perceptions exogènes communes de la pratique cynégétique chez les Autochtones du Québec. En parallèle, sur le registre de l’ironie, le cas de Musher ainsi que la nouvelle « L’homme de vers » (2015) dramatisent la putative invraisemblance d’un retour à une culture fondée sur la chasse dans le monde occidental, d’autant plus qu’aux yeux des narrateurs les cultures autochtones sont elles-mêmes vouées à l’extinction. Alors que l’écrivain d’origine française souscrit au mythe de « la disparition de l’Indien », un dialogue entre Blancs et Autochtones sur l’importance du rôle de la chasse pour l’avenir des rapports éthiques entre les humains et l’écosystème – rôle prématurément exclu dans les textes de Gravelle – se développe par d’autres auteurs contemporains, blancs et autochtones, européens et québécois.

Introduction au dossier "Entre proie et prédateur : le récit de chasse dans la littérature québécoise"

Long-term psychosocial stress is strongly associated with negative physical and mental health outcomes, as well as adverse health behaviours; however, little is known about the role that stress plays on the epigenome. One proposed mechanism by which stress affects DNA methylation is through health behaviours. We conducted an epigenome-wide association study (EWAS) of cumulative psychosocial stress (n = 2,689) from the Health and Retirement Study (mean age = 70.4 years), assessing DNA methylation (Illumina Infinium HumanMethylationEPIC Beadchip) at 789,656 CpG sites. For identified CpG sites, we conducted a formal mediation analysis to examine whether smoking, alcohol use, physical activity, and body mass index (BMI) mediate the relationship between stress and DNA methylation. Nine CpG sites were associated with psychosocial stress (all p

Systemic low-grade inflammation is a feature of chronic disease. C-reactive protein (CRP) is a common biomarker of inflammation and used as an indicator of disease risk; however, the role of inflammation in disease is not completely understood. Methylation is an epigenetic modification in the DNA which plays a pivotal role in gene expression. In this study we evaluated differential DNA methylation patterns associated with blood CRP level to elucidate biological pathways and genetic regulatory mechanisms to improve the understanding of chronic inflammation. The racially and ethnically diverse participants in this study were included as 50% White, 41% Black or African American, 7% Hispanic or Latino/a, and 2% Native Hawaiian, Asian American, American Indian, or Alaska Native (total n = 13,433) individuals. We replicated 113 CpG sites from 87 unique loci, of which five were novel (CADM3, NALCN, NLRC5, ZNF792, and cg03282312), across a discovery set of 1,150 CpG sites associated with CRP level (p

Europe has suffered unprecedented epizootics of high pathogenicity avian influenza (HPAI) clade 2.3.4.4b H5N1 since Autumn 2021. As well as impacting upon commercial and wild avian species, the virus has also infected mammalian species more than ever observed previously. Mammalian species involved in spill over events have primarily been scavenging terrestrial carnivores and farmed mammalian species although marine mammals have also been affected. Alongside reports of detections of mammalian species found dead through different surveillance schemes, several mass mortality events have been reported in farmed and wild animals. In November 2022, an unusual mortality event was reported in captive bush dogs (Speothos venaticus) with clade 2.3.4.4b H5N1 HPAIV of avian origin being the causative agent. The event involved an enclosure of 15 bush dogs, 10 of which succumbed during a nine-day period with some dogs exhibiting neurological disease. Ingestion of infected meat is proposed as the most likely infection route.

A free-range organic broiler (Gallus gallus domesticus) premises in Staffordshire was infected by high pathogenicity avian influenza virus (HPAIV) H5N8 during the 2020–2021 epizootic in the United Kingdom (UK). Following initial confirmation of the infection in poultry, multiple wild bird species were seen scavenging on chicken carcasses. Detected dead wild birds were subsequently demonstrated to have been infected and succumbed to HPAIV H5N8. Initially, scavenging species, magpie (Pica pica) and raven (Corvus corax) were found dead on the premises but over the following days, buzzards (Buteo buteo) were also found dead within the local area with positive detection of HPAIV in submitted carcasses. The subacute nature of microscopic lesions within a buzzard was consistent with the timeframe of infection. Finally, a considerable number of free-living pheasants (Phasianus colchicus) were also found dead in the surrounding area, with carcasses having higher viral antigen loads compared to infected chickens. Limited virus dissemination was observed in the carcasses of the magpie, raven, and buzzard. Further, an avirulent avian paramyxovirus type 1 (APMV-1) was detected within poultry samples as well as in the viscera of a magpie infected with HPAIV. Immunohistochemistry did not reveal colocalization of avian paramyxovirus antigens with lesions, supporting an avirulent APMV-1 infection. Overall, this case highlights scenarios in which bi-directional transmission of avian viral diseases between commercial and wild bird species may occur. It also underlines the importance of bio separation and reduced access when infection pressure from HPAIV is high.

Background Student wellness is of increasing concern in medical education. Increased rates of burnout, sleep disturbances, and psychological concerns in medical students are well documented. These concerns lead to impacts on current educational goals and may set students on a path for long-term health consequences.Methods Undergraduate medical students were recruited to participate in a novel longitudinal wellness tracking project. This project utilized validated wellness surveys to assess emotional health, sleep health, and burnout at multiple timepoints. Biometric information was collected from participant Fitbit devices that tracked longitudinal sleep patterns.Results Eighty-one students from three cohorts were assessed during the first semester of their M1 preclinical curriculum. Biometric data showed that nearly 30% of the students had frequent short sleep episodes (

Summary: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous synthetic chemicals that threaten public health, and serum albumin binding of PFAS represents one major variable influencing PFAS toxicokinetics. In this protocol, we describe a differential scanning fluorimetry (DSF) assay suitable for the rapid determination of the relative binding affinities of serum albumin proteins to different PFAS. Herein, we address common experimental challenges related to PFAS solubility constraints, the high background fluorescence of DSF with serum albumins, and the limitations of using DSF-derived dissociation constants (KD) to quantify PFAS-albumin interactions.For complete details on the use and execution of this protocol, please refer to Jackson et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Background Kidneys are at risk from drug-induced toxicity, with a significant proportion of acute kidney injury (AKI) linked to medications, particularly cisplatin. Existing cytoprotective drugs for cisplatin-AKI carry side effects, prompting a search for better biological therapies. Mesenchymal Stem Cells (MSCs) are under consideration given their regenerative properties, yet their clinical application has not achieved their full potential, mainly due to variability in the source of MSC tested. In addition, translating treatments from rodent models to humans remains challenging due to a lack of standardized dosing and understanding potential differential responses to cisplatin between animal strains. Method In the current study, we performed a time-course analysis of the effect of cisplatin across different mouse strains and evaluated gender related differences to create a robust preclinical model that could then be used to explore the therapeutic efficacy of different sources of MSCs for their ability to reverse AKI. Result Our data indicated that different mouse strains produce differential responses to the same cisplatin dosing regimen. Despite this, we did not observe any gender-related bias towards cisplatin nephrotoxicity. Furthermore, our time-course analysis identified that cisplatin-induced inflammation was driven by a strong CXCL1 response, which was used as a putative biomarker to evaluate the comparative therapeutic efficacy of different MSC sources in reversing AKI. Our data indicates that UC-MSCs have a stronger anti-inflammatory effect compared to BM-MSCs and AD-MSCs, which helped to ameliorate cisplatin-AKI. Conclusion Overall, our data underscores the importance of using an optimized preclinical model of cisplatin-AKI to test different therapies. We identified CXCL1 as a potential biomarker of cisplatin-AKI and identified the superior efficacy of UC-MSCs in mitigating cisplatin-AKI. Graphical abstract

Societal Impact Statement Morels (Morchella spp.) are specialty mushrooms that fetch high prices from wild‐foraged or indoor grown suppliers. Outdoor cultivation could expand availability and diversify morel crops. Participatory research trials in the United States during 2021–2023 resulted in low, uneven yields. Cost accounting reveals that in 2023, a producer needed to achieve an average morel yield of 0.16 lb/ft of row to break even. This threshold was sensitive to prices and labor costs. While these findings are preliminary due to a small sample and experimental conditions, they establish baseline indicators for the yields needed for outdoor morel cultivation to break even financially.

Abstract Background Changing cell-type proportions can confound studies of differential gene expression or DNA methylation (DNAm) from peripheral blood mononuclear cells (PBMCs). We examined how cell-type proportions derived from the transcriptome versus the methylome (DNAm) influence estimates of differentially expressed genes (DEGs) and differentially methylated positions (DMPs). Methods Transcriptome and DNAm data were obtained from PBMC RNA and DNA of Kenyan children (n = 8) before, during, and 6 weeks following uncomplicated malaria. DEGs and DMPs between time points were detected using cell-type adjusted modeling with Cibersortx or IDOL, respectively. Results Most major cell types and principal components had moderate to high correlation between the two deconvolution methods (r = 0.60–0.96). Estimates of cell-type proportions and DEGs or DMPs were largely unaffected by the method, with the greatest discrepancy in the estimation of neutrophils. Conclusion Variation in cell-type proportions is captured similarly by both transcriptomic and methylome deconvolution methods for most major cell types.

Abstract The I148M variant of PNPLA3 is closely associated with hepatic steatosis. Recent evidence indicates that the I148M mutant functions as an inhibitor of PNPLA2/ATGL-mediated lipolysis, leaving the role of wild-type PNPLA3 undefined. Despite showing a triglyceride hydrolase activity in vitro, PNPLA3 has yet to be established as a lipase in vivo. Here, we show that PNPLA3 preferentially hydrolyzes polyunsaturated triglycerides, mobilizing polyunsaturated fatty acids for phospholipid desaturation and enhancing hepatic secretion of triglyceride-rich lipoproteins. Under lipogenic conditions, mice with liver-specific knockout or acute knockdown of PNPLA3 exhibit aggravated liver steatosis and reduced plasma VLDL-triglyceride levels. Similarly, I148M-knockin mice show decreased hepatic triglyceride secretion during lipogenic stimulation. Our results highlight a specific context whereby the wild-type PNPLA3 facilitates the balance between hepatic triglyceride storage and secretion, and suggest the potential contribution of a loss-of-function by the I148M variant to the development of fatty liver disease in humans.

Abstract Spaceflight induces an immune response in astronauts. To better characterize this effect, we generated single-cell, multi-ome, cell-free RNA (cfRNA), biochemical, and hematology data for the SpaceX Inspiration4 (I4) mission crew. We found that 18 cytokines/chemokines related to inflammation, aging, and muscle homeostasis changed after spaceflight. In I4 single-cell multi-omics data, we identified a “spaceflight signature” of gene expression characterized by enrichment in oxidative phosphorylation, UV response, immune function, and TCF21 pathways. We confirmed the presence of this signature in independent datasets, including the NASA Twins Study, the I4 skin spatial transcriptomics, and 817 NASA GeneLab mouse transcriptomes. Finally, we observed that (1) T cells showed an up-regulation of FOXP3, (2) MHC class I genes exhibited long-term suppression, and (3) infection-related immune pathways were associated with microbiome shifts. In summary, this study reveals conserved and distinct immune disruptions occurring and details a roadmap for potential countermeasures to preserve astronaut health.

Abstract Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts’ increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR.

Abstract Background Spaceflight poses a unique set of challenges to humans and the hostile spaceflight environment can induce a wide range of increased health risks, including dermatological issues. The biology driving the frequency of skin issues in astronauts is currently not well understood. Methods To address this issue, we used a systems biology approach utilizing NASA’s Open Science Data Repository (OSDR) on space flown murine transcriptomic datasets focused on the skin, biochemical profiles of 50 NASA astronauts and human transcriptomic datasets generated from blood and hair samples of JAXA astronauts, as well as blood samples obtained from the NASA Twins Study, and skin and blood samples from the first civilian commercial mission, Inspiration4. Results Key biological changes related to skin health, DNA damage & repair, and mitochondrial dysregulation are identified as potential drivers for skin health risks during spaceflight. Additionally, a machine learning model is utilized to determine gene pairings associated with spaceflight response in the skin. While we identified spaceflight-induced dysregulation, such as alterations in genes associated with skin barrier function and collagen formation, our results also highlight the remarkable ability for organisms to re-adapt back to Earth via post-flight re-tuning of gene expression. Conclusion Our findings can guide future research on developing countermeasures for mitigating spaceflight-associated skin damage.

Abstract It is now widely recognised that the environment in space activates a diverse set of genes involved in regulating fundamental cellular pathways. This includes the activation of genes associated with blood homeostasis and erythropoiesis, with a particular emphasis on those involved in globin chain production. Haemoglobin biology provides an intriguing model for studying space omics, as it has been extensively explored at multiple -omic levels, spanning DNA, RNA, and protein analyses, in both experimental and clinical contexts. In this study, we examined the developmental expression of haemoglobin over time and space using a unique suite of multi-omic datasets available on NASA GeneLab, from the NASA Twins Study, the JAXA CFE study, and the Inspiration4 mission. Our findings reveal significant variations in globin gene expression corresponding to the distinct spatiotemporal characteristics of the collected samples. This study sheds light on the dynamic nature of globin gene regulation in response to the space environment and provides valuable insights into the broader implications of space omics research.

Introduction: Acute upper gastrointestinal bleeding is one of the most common medical emergencies that present to the hospital, and delineating the underlying etiology is essential to provide adequate definitive treatment. The purpose of this case report was to review the diagnosis and treatment of a rare complication known as radiation-induced hemorrhagic gastritis (RIHG) that can occur in patients with prior radiation exposure. The motivation for this study arose from the identification of a case within our institution. Case Presentation: The study involved a review of the diagnosis and management of a patient who presented with anemia and recurrent episodes of gastrointestinal bleeding at our institution after undergoing treatment for metastatic biliary adenocarcinoma. With the advent of new therapies, we aimed to investigate the various techniques utilized to manage these patients and highlight the importance of maintaining a high index of suspicion for RIHG as a potential etiology of gastrointestinal bleeding in patients with a relevant medical history of radiation exposure. Despite the literature review, we found that there is a lack of guidelines in the approach to the management of these patients. Conclusion: This case report underscores the rarity of radiation-induced gastritis and the complications that may arise from its diagnosis, including recurrent GI bleeding. Further investigation into identifying definitive treatment and creating guidelines for its management is desperately needed.