Search

Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery Rate P-value

PURPOSE: Anti-PD-1 therapy provides clinical benefit in 40-50% of patients with relapsed and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Selection of anti- PD-1 therapy is typically based on patient PD-L1 immunohistochemistry (IHC) which has low specificity for predicting disease control. Therefore, there is a critical need for a clinical biomarker that will predict clinical benefit to anti-PD-1 treatment with high specificity. METHODS: Clinical treatment and outcomes data for 103 RM-HNSCC patients were paired with RNA-sequencing data from formalin-fixed patient samples. Using logistic regression methods, we developed a novel biomarker classifier based on expression patterns in the tumor immune microenvironment to predict disease control with monotherapy PD-1 inhibitors (pembrolizumab and nivolumab). The performance of the biomarker was internally validated using out-of-bag methods. RESULTS: The biomarker significantly predicted disease control (65% in predicted non-progressors vs. 17% in predicted progressors, p

This paper examines the use of Monopoly® accompanied by Microsoft Excel to assess whether an active learning activity has an impact on the DFW rates in an introductory financial accounting course. (The DFW rate is the percentage of students who earn a grade of D or F or withdraw (W) from the course.) A zero credit hour Monopoly® Lab (which physically meets one hour per week during the semester) was created to enhance introductory business students' understanding of difficult accounting concepts by providing a means to record transactions and prepare financial statements. The objective is to engage students and link together the foundational aspects of accounting in a more realistic, understandable manner. The paper examined the DFW rates of the course over a ten-year period. Results of the study revealed a consistent lower DFW rate after the introduction of Monopoly® as compared to previous labs without the use of Monopoly®.

This study aims to shed light on what students like and dislike in coding bootcamps. A qualitative content analysis of student reviews for coding bootcamps was conducted, resulting in a research model and survey instrument consisting of fourteen factors that are proposed to affect coding bootcamp satisfaction. The proposed satisfaction factors include quality of instructors, value of mentors, availability of TAs, access to support staff, provision of career services, rigor of curriculum, appropriateness of pedagogy, development of peer connections, conduciveness of atmosphere, use of appropriate technology, affordability, openness of communication, quality of prep course, and level of post-bootcamp support. Each of the proposed satisfaction factors is measured with three to ten Likert-style variables. The proposed research model and survey instrument can be used by administrators and educators in coding bootcamps and traditional universities alike to better understand and ultimately improve student satisfaction in computing education.

Abstract Germline and somatic TP53 variants play a crucial role during tumorigenesis. However, genetic variations that solely affect the alternatively spliced p53 isoforms, p53β and p53γ, are not fully considered in the molecular diagnosis of Li-Fraumeni syndrome and cancer. In our search for additional cancer predisposing variants, we identify a heterozygous stop-lost variant affecting the p53β isoforms (p.*342Serext*17) in four families suspected of an autosomal dominant cancer syndrome with colorectal, breast and papillary thyroid cancers. The stop-lost variant leads to the 17 amino-acid extension of the p53β isoforms, which increases oligomerization to canonical p53α and dysregulates the expression of p53’s transcriptional targets. Our study reveals the capacity of p53β mutants to influence p53 signalling and contribute to the susceptibility of different cancer types. These findings underscore the significance of p53 isoforms and the necessity of comprehensive investigation into the entire TP53 gene in understanding cancer predisposition.

Abstract Background Home monitoring systems utilising artificial intelligence hold promise for digitally enhanced healthcare in older adults. Their real-world use will depend on acceptability to the end user i.e. older adults and caregivers. We explored the experiences of adults over the age of 60 and their social and care networks with a home monitoring system installed on hospital discharge after sustaining a moderate/severe Traumatic Brain Injury (TBI), a growing public health concern. Methods A qualitative descriptive approach was taken to explore experiential data from older adults and their caregivers as part of a feasibility study. Semi-structured interviews were conducted with 6 patients and 6 caregivers (N = 12) at 6-month study exit. Data were analysed using Framework analysis. Potential factors affecting acceptability and barriers and facilitators to the use of home monitoring in clinical care and research were examined. Results Home monitoring was acceptable to older adults with TBI and their caregivers. Facilitators to the use of home monitoring were perceived need for greater support after hospital discharge, the absence of sound and video recording, and the peace of mind provided to care providers. Potential barriers to adoption were reliability, lack of confidence in technology and uncertainty at how data would be acted upon to improve safety at home. Conclusions Remote monitoring approaches are likely to be acceptable, especially if patients and caregivers see direct benefit to their care. We identified key barriers and facilitators to the use of home monitoring in older adults who had sustained TBI, which can inform the development of home monitoring for research and clinical use. For sustained use in this demographic the technology should be developed in conjunction with older adults and their social and care networks.

Abstract Researchers have an obligation to study aspects of our world that have meaning for society. This means recognising a place-based diversity of society, of potential participants, of types of participation and of knowledge production. Therefore, developing a successful community science (CS) programme that engenders a sense of ownership for a diversity of public participants requires the prioritisation of getting to know what diverse participants value and the context of that valuation. This paper describes the necessary rigour of considering the launch of the CS programme Soilsafe Aotearoa (SA) in 2021, and its subsequent implementation and evolution based on a project commitment to diversity of social values of soil in Aotearoa New Zealand (Aotearoa NZ), delivering on public demand. We discuss how SA engages with the community by scientific screening soil metal contaminants in participants’ backyards, as well as through inclusive education and knowledge co-production in schools and community spaces. The objective in this work is to generate wider participation and dialogue on a diversity of soil value(s) so that communities in Aotearoa NZ are cognisant of what soil might represent to others, and to contextualise what a lack of soil care might mean for them and society more broadly. Here we argue that a diversity of participants and participation can support a more inclusive and contextual, place-based CS approach. We illustrate how that might be achieved through bridging arts, Indigenous knowledge production, and social, as well as conventional sciences. Through an approach that recognises that values about the world are tied to participants’ geographic, demographic and cultural contexts as well as the sectors of society they work and live with, we demonstrate the importance of researchers’ attention to not just scientific enquiry, but intersections of different knowledge production and communication for better societal and science outcomes.

Abstract Background Despite being one of the most popular measures of borderline pathology in adolescents, only one study has evaluated clinical cut-off scores for the Borderline Personality Features Scale for Children (BPFS-C) using a small sample without a healthy comparison group (Chang B, Sharp C, Ha C. The Criterion Validity of the Borderline Personality Features Scale for Children in an Adolescent Inpatient Setting. J Personal Disord. 2011;25(4):492–503. https://doi.org/10.1521/pedi.2011.25.4.492 .). The purpose of the current study was to replicate and improve on the limitations of the prior study conducted by Chang et al. to more definitively establish clinical cut-off scores for the self- and parent-report versions of the BPFS-C to detect clinical and sub-clinical borderline personality disorder (BPD) in a large sample of adolescents with BPD, other psychopathology, and no psychopathology. Methods A total of 900 adolescents ranging from ages 12–17 participated in this study. The clinical sample consisted of 622 adolescents recruited from an inpatient psychiatric facility, and the healthy control sample consisted of 278 adolescents recruited from the community. All participants completed the BPFS-C and were administered the Child Interview for DSM-IV Borderline Personality Disorder (CI-BPD). Results Using three-way ROC analyses, cut-off scores on the self- and parent-report versions of the BPFS-C distinguishing adolescents with BPD from those with subclinical BPD, and those with subclinical BPD from healthy adolescents were established. Conclusions These findings support the use of both versions of the BPFS-C to detect adolescents with BPD and sub-clinical BPD.

Abstract Background Technology is poised to bridge the gap between demand for therapies to improve gait in people with Parkinson’s and available resources. A wearable sensor, Heel2Toe™, a small device that attaches to the side of the shoe and gives a sound each time the person starts their step with a strong heel strike, has been developed and pre-tested by a team at McGill University. The objective of this study was to estimate feasibility and efficacy potential of the Heel2Toe™ sensor in changing walking capacity and gait pattern in people with Parkinson’s. Methods A pilot study was carried out involving 27 people with Parkinson’s randomized 2:1 to train with the Heel2Toe[TM] sensor and or to train with recommendations from a gait-related workbook. Results A total of 21 completed the 3-month evaluation, 14 trained with the Heel2Toe[TM] sensor, and 7 trained with the workbook. Thirteen of 14 people in the Heel2Toe group improved over measurement error on the primary outcome, the 6-Minute Walk Test, (mean change 66.4 m) and 0 of the 7 in the Workbook group (mean change − 19.4 m): 4 of 14 in the Heel2Toe group made reliable change and 0 of 7 in the Workbook group. Improvements in walking distance were accompanied by improvements in gait quality. Forty percent of participants in the intervention group were strongly satisfied with their technology experience and an additional 37% were satisfied. Conclusions Despite some technological difficulties, feasibility and efficacy potential of the Heel2Toe sensor in improving gait in people with Parkinson’s was supported.

Acute psychological stress (APS) is a complex and multifactorial phenomenon that affects metabolism, necessitating real-time detection and interventions to mitigate its effects on glycemia in people with type 1 diabetes. This study investigates the detection of APS using physiological variables measured by the Empatica E4 wristband and employs explainable machine learning to evaluate the importance of the physiological signals. The extreme gradient boosting model is developed for classification of APS and non-stress (NS) with weighted training, achieving an overall accuracy of 99.93%. The Shapley additive explanations (SHAP) technique is employed to interpret the global importance of the physiological signals, determining the order of importance for the variables from most to least as galvanic skin response (GSR), heart rate (HR), skin temperature (ST), and motion sensors (accelerometer readings). The increase in GSR and HR are positively correlated with the occurrence of APS as indicated by high positive SHAP values. The SHAP technique is also used to explain the local signal importance for particular instances of misclassified samples. The detection of APS can inform multivariable automated insulin delivery systems to intervene to counteract the APS-induced glycemic excursions in people with type 1 diabetes.

Abstract Pervasive SARS-CoV-2 infections in humans have led to multiple transmission events to animals. While SARS-CoV-2 has a potential broad wildlife host range, most documented infections have been in captive animals and a single wildlife species, the white-tailed deer. The full extent of SARS-CoV-2 exposure among wildlife communities and the factors that influence wildlife transmission risk remain unknown. We sampled 23 species of wildlife for SARS-CoV-2 and examined the effects of urbanization and human use on seropositivity. Here, we document positive detections of SARS-CoV-2 RNA in six species, including the deer mouse, Virginia opossum, raccoon, groundhog, Eastern cottontail, and Eastern red bat between May 2022–September 2023 across Virginia and Washington, D.C., USA. In addition, we found that sites with high human activity had three times higher seroprevalence than low human-use areas. We obtained SARS-CoV-2 genomic sequences from nine individuals of six species which were assigned to seven Pango lineages of the Omicron variant. The close match to variants circulating in humans at the time suggests at least seven recent human-to-animal transmission events. Our data support that exposure to SARS-CoV-2 has been widespread in wildlife communities and suggests that areas with high human activity may serve as points of contact for cross-species transmission.

Abstract Background High-Intensity Multimodal Training (HIMT) refers to all styles of high-intensity combined aerobic, resistance and/or bodyweight exercise. Previous heterogeneity in exercise prescription and reporting in HIMT reduces the understanding of which factors should be considered when prescribing HIMT (e.g., exercise volume, intensity, duration). Previous studies have demonstrated positive effects of HIMT on health and performance outcomes. However, methodological disparities limit comparisons between findings. The objective of this systematic mapping review was to examine which prescriptive considerations and health and performance outcomes have been reported on in HIMT. This review also examined the quantity and trends of research conducted on HIMT. Methods A systematic literature search was conducted using Ovid Medline, SPORTDiscus and Cochrane Library databases and additional sources to identify studies up until February 2023. A total of 37,090 records were retrieved, of which 220 were included for review. 246 individual HIMT protocols were included for categorical analysis against the Consensus on Exercise Reporting Template (CERT) and Applied Research Model for the Sport Sciences (ARMSS). Results A total of 85 unique terms were used to describe HIMT. Included studies most commonly prescribed HIMT using a consistent exercise selection and circuit format. Exercise intensity was inconsistently reported on and a large proportion of studies prescribed ‘high-intensity’ exercise at a level lower than the American College of Sports Medicine criteria for high-intensity (i.e.,

Abstract Continued exploration of the androgen receptor (AR) is crucial, as it plays pivotal roles in diverse diseases such as prostate cancer (PCa), serving as a significant therapeutic focus. Therefore, the Department of Urology Dresden hosted an international meeting for scientists and clinical oncologists to discuss the newest advances in AR research. The 2nd International Androgen Receptor Symposium was held in Dresden, Saxony, Germany, from 26–27.04.2024, organised by Dr. Holger H.H. Erb. Following the format of the first meeting, more than 35 scientists from 8 countries attended the event to discuss recent developments, research challenges, and identification of venues in AR research. An important new feature was the involvement of PhD students and young investigators, acknowledging the high scientific quality of their work. The symposium included three covers: new advances from clinical research, basic and translational research, and novel strategies to target AR. Moreover, based on its increasing clinical relevance, a PSMA theranostic mini-symposium was added at the end of the AR symposium to allow the audience to discuss the newest advances in PSMA theranostic. This report focuses on the highlights and discussions of the meeting.

Abstract As the COVID-19 pandemic enters its fourth year, the pursuit of identifying a progenitor virus to SARS-CoV-2 and understanding the mechanism of its emergence persists, albeit against the backdrop of intensified efforts to monitor the ongoing evolution of the virus and the influx of new mutations. Surprisingly, few residues hypothesized to be essential for SARS-CoV-2 emergence and adaptation to humans have been validated experimentally, despite the importance that these mutations could contribute to the development of effective antivirals. To remedy this, we searched for genomic regions in the SARS-CoV-2 genome that show evidence of past selection around residues unique to SARS-CoV-2 compared with closely related coronaviruses. In doing so, we identified a residue at position 519 in Spike within the receptor binding domain that holds a static histidine in human-derived SARS-CoV-2 sequences but an asparagine in SARS-related coronaviruses from bats and pangolins. In experimental validation, the SARS-CoV-2 Spike protein mutant carrying the putatively ancestral H519N substitution showed reduced replication in human lung cells, suggesting that the histidine residue contributes to viral fitness in the human host. Structural analyses revealed a potential role of Spike residue 519 in mediating conformational transitions necessary for Spike prior to binding with ACE2. Pseudotyped viruses bearing the putatively ancestral N519 also demonstrated significantly reduced infectivity in cells expressing the human ACE2 receptor compared to H519. ELISA data corroborated that H519 enhances Spike binding affinity to the human ACE2 receptor compared to the putatively ancestral N519. Collectively, these findings suggest that the evolutionary transition at position 519 of the Spike protein played a critical role in SARS-CoV-2 emergence and adaptation to the human host. Additionally, this residue presents as a potential drug target for designing small molecule inhibitors tailored to this site.

Abstract Background In recognition of the burden of Perinatal Mental Health problems, NHS England invested £365 million to transform women’s access to mental health care, including investment in Community Perinatal Mental Health Services. This study examined how elements of provider care affected women’s engagement with these services. Methods Semi-structured interviews were conducted with 139 women and explored their experiences of care from 10 different Community Perinatal Mental Health Teams; including which service components participants believed made a difference to their initial and continued engagement. Realist analysis was used to create context-mechanism-outcome configurations (CMOCs) across interviews, since not all parts of the configurations were always articulated within singular interviews. Results Four key pillars for engagement were identified: perinatal competence, relationship building, accurate reassurance, and reliability. The way perinatal competencies were relayed to women mattered; compassion, understanding and consistency were critical interactional styles. The extent to which these factors affected women’s engagement varied by their context and personal characteristics. Conclusions As mental health problems increase, disproportionately affecting vulnerable populations, it is critical to continue to ensure support is not only available, but appropriately meets the needs of those individuals. Our findings suggest that key staff behaviours applied at the right time can support women’s engagement and potentially contribute to better treatment outcomes.

Abstract Mapped monthly data products of surface ocean acidification indicators from 1998 to 2022 on a 0.25° by 0.25° spatial grid have been developed for eleven U.S. large marine ecosystems (LMEs). The data products were constructed using observations from the Surface Ocean CO2 Atlas, co-located surface ocean properties, and two types of machine learning algorithms: Gaussian mixture models to organize LMEs into clusters of similar environmental variability and random forest regressions (RFRs) that were trained and applied within each cluster to spatiotemporally interpolate the observational data. The data products, called RFR-LMEs, have been averaged into regional timeseries to summarize the status of ocean acidification in U.S. coastal waters, showing a domain-wide carbon dioxide partial pressure increase of 1.4 ± 0.4 μatm yr−1 and pH decrease of 0.0014 ± 0.0004 yr−1. RFR-LMEs have been evaluated via comparisons to discrete shipboard data, fixed timeseries, and other mapped surface ocean carbon chemistry data products. Regionally averaged timeseries of RFR-LME indicators are provided online through the NOAA National Marine Ecosystem Status web portal.

Abstract X-ray amorphous material comprises 15-73 wt.% of sedimentary rocks and eolian sediments in Gale crater. This material is variably siliceous and iron rich but aluminum poor. The presence of volatiles is consistent with the existence of incipient weathering products. To better understand the implications of this material for past aqueous conditions on Mars, here we investigate X-ray amorphous material formation and longevity within terrestrial iron rich soils with varying ages and environmental conditions using bulk and selective dissolution methods, X-ray diffraction, and transmission electron microscopy. Results indicate that in situ aqueous alteration is required to concentrate iron into clay-size fraction material. Cooler climates promote the formation and persistence of X-ray amorphous material whereas warmer climates promote the formation of crystalline secondary phases. Iron rich X-ray amorphous material formation and persistence on Mars are therefore consistent with past cool and relatively wet environments followed by long-term cold and dry conditions.

Identification of regulators of Toxoplasma gondii bradyzoite development and cyst formation is the most direct way to address the importance of parasite development in long-term persistence and reactivation of this parasite. Here we show that a T. gondii gene (named Regulator of Cystogenesis 1; ROCY1) is sufficient for T. gondii bradyzoite formation in vitro and in vivo. ROCY1 encodes an RNA binding protein that has a preference for 3 regulatory regions of hundreds of T. gondii transcripts, and its RNA-binding domains are required to mediate bradyzoite development. Female mice infected with ΔROCY1 parasites have reduced (>90%) cyst burden. While viable parasites can be cultivated from brain tissue for up to 6 months post-infection, chronic brain-resident ΔROCY1 parasites have reduced oral infectivity compared to wild type. Despite clear defects in bradyzoite formation and oral infectivity, ΔROCY1 parasites were able to reactivate with similar timing and magnitude as wild type parasites for up to 5 months post-infection. Therefore while ROCY1 is a critical regulator of the bradyzoite developmental pathway, it is not required for parasite reactivation, raising new questions about the persisting life stage responsible for causing recrudescent disease.

Introduction There is considerable variation in the approach to infants presenting to the emergency department (ED) with fever. The authors primary aim was to develop a robust set of algorithms using community ED data to inform modifications of broader clinical guidance. Methods The authors report the development of California Febrile Infant Risk Stratification Tool (CA FIRST) using key components of the Roseville Protocol (ROS) and American Academy of Pediatrics (AAP) Clinical Practice Guideline (CPG). Expanded guidance was derived using a retrospective analysis of a cohort of 3527 febrile infants aged 7-90 days presenting to any Kaiser Permanente Northern California ED between 2010 and 2019 who underwent a core febrile infant evaluation. Results Melding ROS and AAP CPG algorithms in infants 7-60 days old, CA FIRST Algorithms had comparable performance characteristics to ROS and AAP CPG. CA FIRST enhancements included guidance on febrile infants 61-90 days old, high-risk infants, infants with bronchiolitis, and infants who received immunizations within the prior 48 hours. This retrospective analysis revealed that of 235 febrile infants 22-90 days old with respiratory syncytial virus and 221 who had fever in the 48 hours following vaccination, there were no cases of invasive bacterial infection. Discussion CA FIRST is a set of 13 algorithms providing a thoughtful and flexible approach to the febrile infant while minimizing unnecessary interventions. Conclusions CA FIRST Algorithms empower clinicians to manage most febrile infants. Algorithms are being modified as new data become available, imparting useful and ever-current educational information within a learning health care system.

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values

Hybrid perovskite semiconductor materials are predicted to lock chirality into place and encode asymmetry into their electronic states, while softness of their crystal lattice accommodates lattice strain to maintain high crystal quality with low defect densities, necessary for high luminescence yields. We report photoluminescence quantum efficiencies as high as 39% and degrees of circularly polarized photoluminescence of up to 52%, at room temperature, in the chiral layered hybrid lead-halide perovskites (R/S/Rac)-3BrMBA2PbI4 [3BrMBA = 1-(3-bromphenyl)-ethylamine]. Using transient chiroptical spectroscopy, we explain the excellent photoluminescence yields from suppression of nonradiative loss channels and high rates of radiative recombination. We further find that photoexcitations show polarization lifetimes that exceed the time scales of radiative decays, which rationalize the high degrees of polarized luminescence. Our findings pave the way toward high-performance solution-processed photonic systems for chiroptical applications and chiral-spintronic logic at room temperature.

Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of pro-inflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis. A cryogenic electron microscopy structure reveals that KZR-8445 occupies the fully opened Se61 lateral gate and blocks access to the lumenal plug domain. KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer. Our results establish a framework for the structure-guided discovery of novel therapeutics that selectively modulate Sec61-mediated protein biogenesis.