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Data Availability Statement: All data are included in the Supporting Information for publication online. Supporting Information is available online at https://setac.onlinelibrary.wiley.com/doi/10.1002/etc.5620#support-information-section . Copyright © 2023 Crown copyright and The Authors. While chemicals are vital to modern society through materials, agriculture, textiles, new technology, medicines, and consumer goods, their use is not without risks. Unfortunately, our resources seem inadequate to address the breadth of chemical challenges to the environment and human health. Therefore, it is important we use our intelligence and knowledge wisely to prepare for what lies ahead. The present study used a Delphi-style approach to horizon-scan future chemical threats that need to be considered in the setting of chemicals and environmental policy, which involved a multidisciplinary, multisectoral, and multinational panel of 25 scientists and practitioners (mainly from the United Kingdom, Europe, and other industrialized nations) in a three-stage process. Fifteen issues were shortlisted (from a nominated list of 48), considered by the panel to hold global relevance. The issues span from the need for new chemical manufacturing (including transitioning to non-fossil-fuel feedstocks); challenges from novel materials, food imports, landfills, and tire wear; and opportunities from artificial intelligence, greater data transparency, and the weight-of-evidence approach. The 15 issues can be divided into three classes: new perspectives on historic but insufficiently appreciated chemicals/issues, new or relatively new products and their associated industries, and thinking through approaches we can use to meet these challenges. Chemicals are one threat among many that influence the environment and human health, and interlinkages with wider issues such as climate change and how we mitigate these were clear in this exercise. The horizon scan highlights the value of thinking broadly and consulting widely, considering systems approaches to ensure that interventions appreciate synergies and avoid harmful trade-offs in other areas. We recommend further collaboration between researchers, industry, regulators, and policymakers to perform horizon scanning to inform policymaking, to develop our ability to meet these challenges, and especially to extend the approach to consider also concerns from countries with developing economies. Environ Toxicol Chem 2023;00:1–17. © 2023 Crown copyright and The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article is published with the permission of the Controller of HMSO and the King's Printer for Scotland. Department for Environment, Food and Rural Affairs

The objective of this study was to evaluate the role of adrenal venous sampling (AVS) in guiding the management of patients with corticotropin (ACTH)-independent glucocorticoid secretory autonomy and bilateral adrenal masses.A cohort with 25 patients underwent AVS and surgical management.Cortisol was measured from the adrenal veins (AVs) and inferior vena cava (IVC). AV/IVC cortisol ratio and cortisol lateralization ratio (CLR) (dominant AV cortisol concentration divided by the nondominant AV cortisol concentration) were calculated. Posthoc receiver-operating characteristic curves were generated to determine the specificity of revised AV/IVC cortisol ratio and CLR in differentiating unilateral from bilateral disease.Patients underwent unilateral (n = 21) or bilateral (n = 4) adrenalectomy. The mean AV/IVC cortisol ratio for unilateral adrenalectomy was 12.1 ± 9.6 (dominant) and 4.7 ± 3.8 (contralateral) with a mean CLR of 3.6 ± 3.5. The mean AV/IVC cortisol ratio for bilateral adrenalectomy was 7.5 ± 2.1, with a mean CLR of 1.1 ± 0.6. At a mean follow-up of 22 months, one patient who underwent unilateral adrenalectomy for the predicted bilateral disease developed recurrent mild autonomous cortisol secretion. Posthoc analyses demonstrated a specificity of 95%-100% for unilateral disease with AV/IVC cortisol ratio9 for one side,2.0 for the opposite side and a CLR 2.3. The specificity was 80%-90% for bilateral disease with AV/IVC cortisol ratio5.1 bilaterally and a CLR 1.1.Among patients with bilateral adrenal masses and ACTH-independent autonomous cortisol secretion, AVS can distinguish between unilateral and bilateral disease with high specificity and may guide surgical management.

The storage effect is a general explanation for coexistence in a variable environment. Unfortunately, the storage effect is poorly understood, in part because the generality of the storage effect precludes an interpretation that is simultaneously simple, intuitive and correct. Here, we explicate the storage effect by dividing one of its key conditions-covariance between environment and competition-into two pieces, namely that there must be a strong causal relationship between environment and competition, and that the effects of the environment do not change too quickly. This finer-grained definition can explain a number of previous results, including (1) that the storage effect promotes annual plant coexistence when the germination rate fluctuates, but not when the seed yield fluctuates, (2) that the storage effect is more likely to be induced by resource competition than the apparent competition, and (3) why the storage effect arises readily in models with either stage structure or environmental autocorrelation. Additionally, our expanded definition suggests two novel mechanisms by which the temporal storage effect can arise-transgenerational plasticity and causal chains of environmental variables-thus suggesting that the storage effect is a more common phenomenon than previously thought.

Cancer cells display persistent underlying chromosomal instability, with individual tumour types intriguingly exhibiting characteristic subsets of whole, and subchromosomal aneuploidies. Few methods to induce specific aneuploidies will exist, hampering investigation of functional consequences of recurrent aneuploidies, as well as the acute consequences of specific chromosome mis-segregation. We therefore investigated the possibility of sabotaging the mitotic segregation of specific chromosomes using nuclease-dead CRISPR-Cas9 (dCas9) as a cargo carrier to specific genomic loci. We recruited the kinetochore-nucleating domain of centromere protein CENP-T to assemble ectopic kinetochores either near the centromere of chromosome 9, or the telomere of chromosome 1. Ectopic kinetochore assembly led to increased chromosome instability and partial aneuploidy of the target chromosomes, providing the potential to induce specific chromosome mis-segregation events in a range of cell types. We also provide an analysis of putative endogenous repeats that could support ectopic kinetochore formation. Overall, our findings provide new insights into ectopic kinetochore biology and represent an important step towards investigating the role of specific aneuploidy and chromosome mis-segregation events in diseases associated with aneuploidy.

Scanning tunneling luminescence microscopy (STLM) along with scanning tunneling spectroscopy (STS) is applied to a step-bunched, oxidized 4H-SiC surface prepared on the silicon face of a commercial, n-type SiC wafer using a silicon melt process. The step-bunched surface consists of atomically smooth terraces parallel to the [0001] crystal planes, and rougher risers consisting of nanoscale steps formed by the termination of these planes. The rather striking topography of this surface is well resolved with large tip biases of the order of -8 V and set currents of magnitude less than 1 nA. Hysteresis in the STS spectra is preferentially observed on the risers suggesting that they contain a higher density of surface charge traps than the terraces where hysteresis is more frequently absent. Similarly, at 50 K intense sub-gap light emission centered around 2.4 eV is observed mainly on the risers albeit only with larger tunneling currents of magnitude equal to or greater than 10 nA. These results demonstrate that STLM holds great promise for the observation of impurities and defects responsible for sub-gap light emission with spatial resolutions approaching the length scale of the defects themselves., Comment: 13 pages, 5 figures; work presented at the International Conference on the Physics of Semiconductors, Sydney, 2022

The Wisconsin Alzheimer's Institute (WAI) Dementia Diagnostic Clinic Network is a community of practice formed in 1998 as a collaboration of community-based clinics from various healthcare systems throughout the state. Its purpose is to promote the use of evidence-based strategies to provide high quality care throughout Wisconsin for people with dementia. The purpose of this study is to describe the use of a community of practice to facilitate education of healthcare providers on best practices in dementia care, and the implementation of an interprofessional approach to diagnose and manage dementia and related disorders.Cross-sectional study of the members of the WAI's Dementia Diagnosis Clinic Network. Characteristics of clinics and healthcare teams, learners' participation in educational events and educational outcomes were collected from evaluation forms. Number and characteristics of patients seen in the memory clinics were collected from de-identified data forms submitted by members to a centralized location for data analysis.The clinic network currently has 38 clinics affiliated with 26 different healthcare systems or independent medical groups in 21 of 72 Wisconsin counties. Most (56%) are based in primary care, 15% in psychiatry, and 29% in neurology. Between 2018 and 2021, we received data on 4710 patients; 92% were ≥65 years old, 60% were female, and 92% were white. Network members meet in-person twice a year to learn about innovations in the field of dementia care and to share best practices. Educational events associated with the network are shown to be relevant, useful, and improve knowledge and skills of participants.Communities of practice provide added value via shared best practices and educational resources, continuing education of the health workforce, continuous quality improvement of clinical practices, and adoption of new diagnostic and management approaches in dementia care.

The field of otolaryngology has one of the lowest rates of racial and ethnic diversity. An anonymous survey was distributed to members of the Student National Medical Association at different medical schools to identify factors that may contribute to this disparity. Responses were received from 104 students at 36 allopathic medical schools. Most respondents identified as black (86.5%). One-third of students (34.6%) noted that they were discouraged from pursuing otolaryngology due to lack of mentorship, and among these students, most noted that they lack mentors of the same race (75%). One-fourth of respondents (25%) indicated that they lack a home otolaryngology program. The most common reasons for participants' disinterest in otolaryngology included competitiveness, inadequate exposure, research, and the high board scores needed to match. This hypothesis-generating, proof-of-concept study highlights potential barriers that may discourage underrepresented medical students from pursuing a career in otolaryngology.

Black Americans are disproportionately affected by dementia. To expand our understanding of mechanisms of this disparity, we look to Alzheimer's disease (AD) biomarkers. In this review, we summarize current data, comparing the few studies presenting these findings. Further, we contextualize the data using two influential frameworks: the National Institute on Aging-Alzheimer's Association (NIA-AA) Research Framework and NIA's Health Disparities Research Framework. The NIA-AA Research Framework provides a biological definition of AD that can be measured in vivo. However, current cut-points for determining pathological versus non-pathological status were developed using predominantly White cohorts-a serious limitation. The NIA's Health Disparities Research Framework is used to contextualize findings from studies identifying racial differences in biomarker levels, because studying biomakers in isolation cannot explain or reduce inequities. We offer recommendations to expand study beyond initial reports of racial differences. Specifically, life course experiences associated with racialization and commonly used study enrollment practices may better account for observations than exclusively biological explanations.

The shikimate pathway plays a central role in the biosynthesis of aromatic amino acids and specialized metabolites in plants. The first enzyme, 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAHPS) serves as a key regulatory point for the pathway in various organisms. These enzymes are important in regulating the shikimate pathway in multiple microbial systems. The mechanism of regulation of DAHPS is poorly understood in plants, and the role of tyrosine (Tyr) with respect to the three DAHPS isozymes from Arabidopsis thaliana was investigated. In vitro enzymatic analyses established that Tyr does not function as an allosteric regulator for the A. thaliana DAHPS isozymes. In contrast, Arabidopsis T-DNA insertional mutants for the DAHPS1 locus, dahps1, are hypersensitive to elevated Tyr. Tyr hypersensitivity can be reversed with tryptophan and phenylalanine supplementation, indicating that Tyr is affecting the shikimate pathway flux in the dahps1 mutant. Tyr treatment of Arabidopsis seedlings showed reduced accumulation of overexpressed DAHPS2 in the chloroplast. Further, bimolecular fluorescence complementation studies revealed that DAHPS2 interacts with a 14-3-3 protein in the cytosol, and this interaction is enhanced with Tyr treatment. This interaction with 14-3-3 may retain DAHPS2 in the cytosol, which prevents its ability to function in the chloroplast with elevated Tyr.

Background Rodent paradigms and human genome-wide association studies (GWAS) on drug use have the potential to provide biological insight into the pathophysiology of addiction. Methods Using GeneWeaver, we created rodent alcohol and nicotine gene-sets derived from 19 gene expression studies on alcohol and nicotine outcomes. We partitioned the SNP-heritability of these gene-sets using four large human GWAS: 1) alcoholic drinks per week, 2) problematic alcohol use, 3) cigarettes per day and 4) smoking cessation. We benchmarked our findings with curated human alcoholism and nicotine addiction gene-sets and performed specificity analyses using other rodent gene-sets (e.g., locomotor behavior) and other human GWAS (e.g., height). Results The rodent alcohol gene-set was enriched for heritability of drinks per week, cigarettes per day, and smoking cessation, but not problematic alcohol use. However, the rodent nicotine gene-set was not significantly associated with any of these traits. Both rodent gene-sets showed enrichment for several non-substance use GWAS, and the extent of this relationship tended to increase as a function of trait heritability. In general, larger gene-sets demonstrated more significant enrichment. Finally, when evaluating human traits with similar heritabilities, both rodent gene-sets showed greater enrichment for substance use traits. Conclusion Our results suggest that rodent gene expression studies can help to identify genes that contribute to heritability of some substance use traits in humans, yet there was less specificity than expected. We outline various limitations, interpretations and considerations for future research.

Higher body mass index (BMI) may have a protective effect on survival in patients with head and neck cancer. The aim of this study was to determine the effect of BMI on overall survival (OS) in veterans with head and neck squamous cell carcinoma (HNSCC).A cohort of 702 patients diagnosed with HNSCC between 1995 and 2019 were identified at the Washington DC Veterans Affairs Medical Center, and 342 patients were included for analysis. Records were queried for clinical-demographic data, BMI, and outcomes.HNSCC patients categorized as overweight or obese at time of diagnosis had a lower 3-year risk of death (p = 0.033) and improved OS (p 0.001) compared to patients who were underweight or normal weight. The majority of locoregional recurrences occurred in patients with low or normal pretreatment BMI.Higher BMI at diagnosis may have a protective effect on OS in veterans with HNSCC.