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Abstract We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.

Abstract Darier disease (DD) is a rare severe acantholytic skin disease caused by mutations in the ATP2A2 gene that encodes for the sarco/endoplasmic reticulum calcium ATPase isoform 2 (SERCA2). SERCA2 maintains endoplasmic reticulum calcium homeostasis by pumping calcium into the ER, critical for regulating cellular calcium dynamics and cellular function. To date, there is no treatment that specifically targets the disease mechanisms in DD. Dantrolene sodium (Dl) is a ryanodine receptor antagonist that inhibits calcium release from ER to increase ER calcium levels and is currently used for non-dermatological indications. In this study, we first identified dysregulated genes and molecular pathways in DD patient skin, demonstrating downregulation of cell adhesion and calcium homeostasis pathways, as well as upregulation of ER stress and apoptosis. We then show in various in vitro models of DD and SERCA2 inhibition that Dl aided in the retention of ER calcium and promoted cell adhesion. In addition, Dl treatment reduced ER stress and suppressed apoptosis. Our findings suggest that Dl specifically targets pathogenic mechanisms of DD and may be a potential treatment.

Abstract Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators – Caspase-8, RIPK1, RIPK3 and MLKL – in formalin-fixed mouse and human tissues. We observed surprising heterogeneity in protein expression within tissues, whereby short-lived immune barrier cells were replete with necroptotic effectors, whereas long-lived cells lacked RIPK3 or MLKL expression. Local changes in the expression of necroptotic effectors occurred in response to insults such as inflammation, dysbiosis or immune challenge, consistent with necroptosis being dysregulated in disease contexts. These methods will facilitate the precise localisation and evaluation of necroptotic signaling in vivo.

Abstract Protagonists allege that artificial intelligence (AI) is revolutionising contemporaneous mindscapes. Here, we authoritatively review the status quo of AI and machine learning application in irrigated agriculture, evaluating the potential of, and challenges associated with, a wide range of existential AI approaches. We contend that aspiring developers of AI irrigation systems may benefit from human-centred AI, a nascent algorithm that captures diverse end-user views, behaviours and actions, potentially facilitating refinement of proposed systems through iterative stakeholder feedback. AI-guided human–machine collaboration can streamline integration of user needs, allowing customisation towards situational farm management adaptation. Presentation of big data in intuitive, legible and actionable forms for specialists and laypeople also urgently requires attention: here, AI-explainable interpretability may help harness human expertise, enabling end-users to contribute their experience within an AI pipeline for bespoke outputs. Transfer learning holds promise in contextualising place-based AI to agroecological regions, production systems or enterprise mixes, even with limited data inputs. We find that the rate of AI scientific and software development in recent times has outpaced the evolution of adequate legal and institutional regulations, and often social, moral and ethical license to operate, revealing consumer issues associated with data ownership, legitimacy and trust. We opine that AI has great potential to elicit sustainable outcomes in food security, social innovation and environmental stewardship, albeit such potential is more likely to be realised through concurrent development of appropriate ethical, moral and legal dimensions.

Abstract This article explores the interplay between crises, opportunities and democratic change in the United Kingdom. A vast body of scholarship underlines that crises open ‘windows of opportunity’ that can occasionally lead to radical shifts in the role of the state and the design of public policy. Even when a radical shift occurs, however, it has often proved temporary, with relationships and processes quickly reverting to pre-crisis modes once the immediacy of the crisis abates. This may not be true of our present period of crisis following the COVID-19 pandemic. The consequences of decades of underinvestment in infrastructure and increasing concentration of resources in a small minority of individuals and organisations are being exacerbated by climate change, geopolitical conflict and new waves of disease. The challenge for policymakers in the UK now is heightened by evidence that suggests that nudging, a libertarian paternalist means of promoting certain ends, is ineffective. Policymakers who have long used state neutrality between conceptions of the good as the justification for not promoting certain ends now have to confront a real ethical dilemma: coerce to achieve specific outcomes or invest in addressing the social determinants that actually affect behaviour. This article suggests that contrary to decades of opposition to redistribution among UK policymakers, only the latter is consistent with libertarian paternalism.

Abstract Fragile X syndrome (FXS) is the leading cause of inherited autism and intellectual disabilities. Aberrant protein synthesis due to the loss of fragile X messenger ribonucleoprotein (FMRP) is the major defect in FXS, leading to a plethora of cellular and behavioral abnormalities. However, no treatments are available to date. In this study, we found that activation of metabotropic glutamate receptor 7 (mGluR7) using a positive allosteric modulator named AMN082 represses protein synthesis through ERK1/2 and eIF4E signaling in an FMRP-independent manner. We further demonstrated that treatment of AMN082 leads to a reduction in neuronal excitability, which in turn ameliorates audiogenic seizure susceptibility in Fmr1 KO mice, the FXS mouse model. When evaluating the animals’ behavior, we showed that treatment of AMN082 reduces repetitive behavior and improves learning and memory in Fmr1 KO mice. This study uncovers novel functions of mGluR7 and AMN082 and suggests the activation of mGluR7 as a potential therapeutic approach for treating FXS.

Abstract This paper examines the formation of legal institutions in Qing China and Tokugawa Japan with a focus on the rice market. In both countries in the 18th century, rice was the most important commodity. By the end of 18th century, Japan offered strong legal rights to rice market participants, while China managed the rice market with weak legal institutions. We develop a subversive regime game model to explain some of the social and political reasons behind this divergence. Supported by historical evidence from Qing China and Tokugawa Japan, we find that with lower suppression capacity and high risks of domestic threats to power, Edo Japan’s central government (Bakufu) was more likely to enforce legal rights than Qing China’s central government (Imperial Court). Japan’s institutional configuration facilitated the growth of rice markets such as the Doujima market in Osaka, because participants did not need to invest as much in informal protections for their own rights. Moreover, our analysis suggests that a state’s relative strength matters the most in determining its attitude toward legal rights, which further influences the state’s stability and longevity.

Abstract The impact of digital platforms on the implementation of the United Nations’ (UN) Sustainable Development Goals (SDGs), especially the business sustainability of micro, small and medium-sized enterprises (MSMEs), under different containment policies during and after the COVID-19 pandemic has not yet been studied in detail. Using detailed administrative data from Alibaba Group’s online on-demand food delivery platform, we found that the digital platform contributed to the food security, wellbeing, employment and business sustainability of MSMEs both during and after the pandemic. We uncovered merchants’ heterogeneous responses to the COVID-19 pandemic during and after the implementation of different containment policies in China. On the extensive margin, the period of complete lockdown left long-term scarring on online merchants by decreasing the number of entrants, especially in the cooked food industry. In contrast, on the intensive margin, chain stores, especially those with large chain networks or multiapp stores, exhibited stronger resilience than their counterparts during and after lockdown. Thus, specialization (at the outlet level) and wider coverage (at the network level) emerged as key factors that enable business sustainability under challenging economic circumstances.

Abstract The discipline of knowledge translation (KT) emerged as a way of systematically understanding and addressing the challenges of applying health and medical research in practice. In light of ongoing and emerging critique of KT from the medical humanities and social sciences disciplines, KT researchers have become increasingly aware of the complexity of the translational process, particularly the significance of culture, tradition and values in how scientific evidence is understood and received, and thus increasingly receptive to pluralistic notions of knowledge. Hence, there is now an emerging view of KT as a highly complex, dynamic, and integrated sociological phenomenon, which neither assumes nor creates knowledge hierarchies and neither prescribes nor privileges scientific evidence. Such a view, however, does not guarantee that scientific evidence will be applied in practice and thus poses a significant dilemma for KT regarding its status as a scientific and practice-oriented discipline, particularly within the current sociopolitical climate. Therefore, in response to the ongoing and emerging critique of KT, we argue that KT must provide scope for relevant scientific evidence to occupy an appropriate position of epistemic primacy in public discourse. Such a view is not intended to uphold the privileged status of science nor affirm the “scientific logos” per se. It is proffered as a counterbalance to powerful social, cultural, political and market forces that are able to challenge scientific evidence and promote disinformation to the detriment of democratic outcomes and the public good.

Abstract Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The advent of approved treatments for this devastating condition has significantly changed SMA patients' life expectancy and quality of life. Nevertheless, these are not without limitations, and research efforts are underway to develop new approaches for improved and long‐lasting benefits for patients. Protein arginine methyltransferases (PRMTs) are emerging as druggable epigenetic targets, with several small‐molecule PRMT inhibitors already in clinical trials. From a screen of epigenetic molecules, we have identified MS023, a potent and selective type I PRMT inhibitor able to promote SMN2 exon 7 inclusion in preclinical SMA models. Treatment of SMA mice with MS023 results in amelioration of the disease phenotype, with strong synergistic amplification of the positive effect when delivered in combination with the antisense oligonucleotide nusinersen. Moreover, transcriptomic analysis revealed that MS023 treatment has minimal off‐target effects, and the added benefit is mainly due to targeting neuroinflammation. Our study warrants further clinical investigation of PRMT inhibition both as a stand‐alone and add‐on therapy for SMA.

Abstract High‐risk endometrial cancer has poor prognosis and is increasing in incidence. However, understanding of the molecular mechanisms which drive this disease is limited. We used genetically engineered mouse models (GEMM) to determine the functional consequences of missense and loss of function mutations in Fbxw7, Pten and Tp53, which collectively occur in nearly 90% of high‐risk endometrial cancers. We show that Trp53 deletion and missense mutation cause different phenotypes, with the latter a substantially stronger driver of endometrial carcinogenesis. We also show that Fbxw7 missense mutation does not cause endometrial neoplasia on its own, but potently accelerates carcinogenesis caused by Pten loss or Trp53 missense mutation. By transcriptomic analysis, we identify LEF1 signalling as upregulated in Fbxw7/FBXW7‐mutant mouse and human endometrial cancers, and in human isogenic cell lines carrying FBXW7 mutation, and validate LEF1 and the additional Wnt pathway effector TCF7L2 as novel FBXW7 substrates. Our study provides new insights into the biology of high‐risk endometrial cancer and suggests that targeting LEF1 may be worthy of investigation in this treatment‐resistant cancer subgroup.

Controlling the formation and growth of ice is essential to successfully cryopreserve cells, tissues and biologics. Current efforts to identify materials capable of modulating ice growth are guided by iterative changes and human intuition, with a major focus on proteins and polymers. With limited data, the discovery pipeline is constrained by a poor understanding of the mechanisms and the underlying structure-activity relationships. In this work, this barrier is overcome by constructing machine learning models capable of predicting the ice recrystallisation inhibition activity of small molecules. We generate a new dataset via experimental measurements of ice growth, then harness predictive models combining state-of-the-art descriptors with domain-specific features derived from molecular simulations. The models accurately identify potent small molecule ice recrystallisation inhibitors within a commercial compound library. Identified hits can also mitigate cellular damage during transient warming events in cryopreserved red blood cells, demonstrating how data-driven approaches can be used to discover innovative cryoprotectants and enable next-generation cryopreservation solutions for the cold chain. Controlling ice formation is crucial for cryopreservation. Here, authors developed machine learning models to predict ice recrystallisation inhibition by small molecules, showcasing a data-driven approach for cryoprotectant discovery. [ABSTRACT FROM AUTHOR]

The remarkable pace of genomic data generation is rapidly transforming our understanding of life at the micron scale. Yet this data stream also creates challenges for team science. A single microbe can have multiple versions of genome architecture, functional gene annotations, and gene identifiers; additionally, the lack of mechanisms for collating and preserving advances in this knowledge raises barriers to community coalescence around shared datasets. "Digital Microbes" are frameworks for interoperable and reproducible collaborative science through open source, community-curated data packages built on a (pan)genomic foundation. Housed within an integrative software environment, Digital Microbes ensure real-time alignment of research efforts for collaborative teams and facilitate novel scientific insights as new layers of data are added. Here we describe two Digital Microbes: 1) the heterotrophic marine bacterium Ruegeria pomeroyi DSS-3 with > 100 transcriptomic datasets from lab and field studies, and 2) the pangenome of the cosmopolitan marine heterotroph Alteromonas containing 339 genomes. Examples demonstrate how an integrated framework collating public (pan)genome-informed data can generate novel and reproducible findings. [ABSTRACT FROM AUTHOR]

New gambling products have been developed over time as technology permits. For example, early mechanical slot machines were later replaced by electronic gaming machines (EGMs), which enabled a faster speed of play and more immersive experience. EGMs have in the decades since their invention become one of the main drivers of gambling expenditure worldwide and are one of the gambling products most strongly associated with harm. This literature review considers research relevant to a new subcategory of EGM, 'skill-based' EGMs, termed 'SGMs' here. SGMs can be highly varied in content, with some representing a minimal departure from EGMs, where the typical bonus round is replaced by some skill-based activity, such as a simple video game, which could increase the machine's appeal. Other SGMs feature more radical departures from conventional EGMs, such as multiplayer games using intellectual property from popular TV shows or video games. These skill-based elements could tap into common gambling fallacies such as the illusion of control, and therefore facilitate harmful engagement. SGMs could also be less harmful than current EGMs, if skill-based elements break the dissociative states associated with EGM gambling. The intellectual property used in SGMs may increase their appeal among people who generally do not gamble, and the skill-based elements could increase their interest among gamblers who predominately prefer skill-based gambling formats such as sports betting. The novelty and varied content of SGMs present many open questions, which research should aim to address in future. [ABSTRACT FROM AUTHOR]

The Alaska Volcano Observatory (AVO) uses multidisciplinary data to monitor and study dozens of active and potentially active volcanoes. Here, we provide an overview of internally and externally generated data types, tools and resources used in their management, and challenges faced. Data sources include the following: (1) a multiparameter (seismic, infrasound, GNSS, web cameras) ground-based monitoring network that spans 3000 km and transmits data in real time; (2) a variety of satellite-borne sensors that provide information about surface change and volcanic emissions; (3) geologic and gas field campaigns; and (4) other external data products that provide situation awareness. Each data type requires distinct acquisition, processing, storage, visualization, and archiving approaches. AVO uses a variety of externally and internally developed tools to handle individual data types as well as multidisciplinary volcanological data. A primary tool is the Geologic Database of Information on Volcanoes in Alaska (GeoDIVA), which stores detailed, searchable information on more than 140 volcanoes and over 1000 eruptions and unrest events, including images, eruption descriptions, and geologic station and sample data, metadata, and analyses. It interacts with other internal tools that store monitoring reports and other operational records. Additional data management resources used by AVO assist with alarms and alerts, state-of-health monitoring, and multiparameter visualization. Requirements for 24/7 accessibility, the ever-expanding portfolio of data, and transitioning new tools from development to operations are all challenges faced by AVO and other volcano observatories. AVO strives to meet FAIR data practices and ensure that data are available to national and international community efforts using external repositories as well as those hosted by AVO and its parent institutions. [ABSTRACT FROM AUTHOR]

This article presents a case study of a 35-year-old male with HIV who developed chylothorax, a condition characterized by the accumulation of chylous fluid in the pleural space. The patient underwent various treatments, including thoracic duct ligation, but continued to have high chylous output. A CT scan revealed an occlusion of the superior mesenteric vein (SMV), and the patient subsequently underwent SMV recanalization and stenting. Following the procedure, the chylous output significantly decreased, and the patient's symptoms improved. This case highlights the complexity of diagnosing and managing chylous fluid accumulation and demonstrates the successful use of SMV recanalization and stenting as a treatment option. [Extracted from the article]

Purpose: Targeted treatment options for non-small cell lung cancer (NSCLC) brain metastases (BMs) may be combined with stereotactic radiosurgery (SRS) to optimize survival. We assessed patient outcomes after SRS for NSCLC BMs, identifying survival trajectories associated with targetable mutations. Methods: In this retrospective time-dependent analysis, we analyzed median overall survival of patients who received ≥ 1 SRS courses for BM from NSCLC from 2001 to 2021. We compared survival of patients with and without targetable mutations based on clinical variables and treatment. Results: Among the 213 patients included, 87 (40.8%) had targetable mutations—primarily EGFR (22.5%)—and 126 (59.2%) did not. Patients with targetable mutations were more often female (63.2%, p <.001) and nonsmokers (58.6%, p <.001); had higher initial lung-molGPA (2.0 vs. 1.5, p <.001) and lower cumulative tumor volume (3.7 vs. 10.6 cm3, p <.001); and received more concurrent (55.2% vs. 36.5%, p =.007) and total (median 3 vs. 2, p <.001) systemic therapies. These patients had lower mortality rates (74.7% vs. 91.3%, p <.001) and risk (HR 0.298 [95%CI 0.190-0.469], p <.001) and longer median overall survival (20.2 vs. 7.4 months, p <.001), including survival ≥ 3 years (p =.001). Survival was best predicted by SRS with tumor resection in patients with non-targetable mutations (HR 0.491 [95%CI 0.318–757], p =.001) and by systemic therapy with SRS for those with targetable mutations (HR 0.124 [95%CI 0.013-1.153], p =.067). Conclusion: The presence of targetable mutations enhances survival in patients receiving SRS for NSCLC BM, particularly when used with systemic therapies. Survival for patients without targetable mutations was longest with SRS and surgical resection. These results inform best practices for managing patients with NSCLC BM based on driver mutation status. [ABSTRACT FROM AUTHOR]

Individualism and collectivism are dimensions of cultural variation thought to shape differences in emotion regulation tendencies, yet research to date has examined these cultural dimensions as country-level features, emphasizing variability across nations. The present study takes the approach of examining cultural differences within nations as predictors of emotion regulation strategies, shifting the perspective instead to individual differences. This present study aimed to address how individual endorsement of individualism-collectivism (i.e. prioritizing individual versus group goals) and vertical-horizontal attitudes (preference for hierarchy versus equality) are associated with use of emotion regulation strategies (i.e., reappraisal and suppression) among college students from seven countries (n = 5,900; female = 70.80%). Overall, we found that individual differences in individualism-collectivism and vertical-horizontal attitudes had strong connections with young adults' emotion regulation styles. Results of our multivariate (i.e., all variables were simultaneously examined) regression model revealed: a) higher endorsement of horizontal individualism and horizontal collectivism were associated with higher use of reappraisal strategies; b) higher endorsement of horizontal individualism and vertical collectivism were associated with higher use of suppression strategies; while higher endorsement of horizontal collectivism was associated with lower use of suppression strategies. A multi-group model supported the generalizability of these associations across countries. These findings demonstrate the value of approaching cultural differences in emotion regulation from an individual differences framework, and not assuming country-level differences are representative of individuals' affective experiences. Further work is needed examining models within-country to examine cultural variation in individualism vs collectivism compared to country-level norms. [ABSTRACT FROM AUTHOR]

Immunochemotherapy has been the mainstay of treatment for newly diagnosed diffuse large B-cell lymphoma (ndDLBCL) yet is inadequate for many patients. In this work, we perform unsupervised clustering on transcriptomic features from a large cohort of ndDLBCL patients and identify seven clusters, one called A7 with poor prognosis, and develop a classifier to identify these clusters in independent ndDLBCL cohorts. This high-risk cluster is enriched for activated B-cell cell-of-origin, low immune infiltration, high MYC expression, and copy number aberrations. We compare and contrast our methodology with recent DLBCL classifiers to contextualize our clusters and show improved prognostic utility. Finally, using pre-clinical models, we demonstrate a mechanistic rationale for IKZF1/3 degraders such as lenalidomide to overcome the low immune infiltration phenotype of A7 by inducing T-cell trafficking into tumors and upregulating MHC I and II on tumor cells, and demonstrate that TCF4 is an important regulator of MYC-related biology in A7. Researchers identified 7 biological group of diffuse large B-cell lymphoma, one with poor prognosis. They developed a gene expression classifier to detect these groups, potentially improving prognosis and future treatments for the high-risk patients. [ABSTRACT FROM AUTHOR]

Standardised proficiency-based progression is the cornerstone of safe robotic skills acquisition, however, is currently lacking within surgical training curricula. Expert consensuses have defined a modular pathway to accredit surgeons. This study aimed to address the lack of a formal, pre-clinical core robotic skills, proficiency-based accreditation curriculum in the UK. Novice robotic participants underwent a four-day pre-clinical core robotic skills curriculum incorporating multimodal assessment. Modifiable-Global Evaluative Assessment of Robotic Skills (M-GEARS), VR-automated performance metrics (APMs) and Objective Clinical Human Reliability Analysis (OCHRA) error methodology assessed performance at the beginning and end of training. Messick's validity concept and a curriculum evaluation model were utilised. Feedback was collated. Proficiency-based progression, benchmarking, tool validity and reliability was assessed through comparative and correlational statistical methods. Forty-seven participants were recruited. Objective assessment of VR and dry models across M-GEARS, APMs and OCHRA demonstrated significant improvements in technical skill (p < 0.001). Concurrent validity between assessment tools demonstrated strong correlation in dry and VR tasks (r = 0.64–0.92, p < 0.001). OCHRA Inter-rater reliability was excellent (r = 0.93, p < 0.001 and 81% matched error events). A benchmark was established with M-GEARS and for the curriculum at 80%. Thirty (63.82%) participants passed. Feedback was 5/5 stars on average, with 100% recommendation. Curriculum evaluation fulfilled all five domains of Messick's validity. Core robotic surgical skills training can be objectively evaluated and benchmarked to provide accreditation in basic robotic skills. A strategy is necessary to enrol standardised curricula into national surgical training at an early stage to ensure patient safety. [ABSTRACT FROM AUTHOR]

This document explores the use of mechanical ventilation and the titration of inspired oxygen in critically ill adults. It discusses various randomized trials comparing lower versus higher oxygenation targets and their effects on patient outcomes. The results of these trials have been conflicting, with some showing no significant difference and others showing better outcomes with either lower or higher oxygenation targets. The document also examines potential explanations for these conflicting results, including the possibility of heterogeneity of treatment effect. It suggests that machine learning models may provide more accurate predictions of individualized treatment effects, but further validation and a randomized clinical trial are needed before implementing individualized oxygenation targets in clinical practice. [Extracted from the article]

The dynamic interaction between cliff, beach and shore-platform is key to assessing the sediment balance for coastal erosion risk assessments, but this is poorly understood. We present a dataset containing daily, 3D,colour LiDAR scans of a 450 m coastal section at Happisburgh, Norfolk, UK. This previously para-glaciated region comprises mixed sand-gravel sediments, which are less well-understood and well-studied than sandy beaches. From Apr-Dec 2019, 236 daily surveys were carried out. The dataset presented includes: survey areas, transects LiDAR scans, georeferenced orthophotos, meteorological- and oceanographical conditions during the Apr-Dec observation period. Full LiDAR point-clouds are available for 67 scans (Oct-Dec). Hourly time-series of offshore sea-state parameters (significant wave height, mean propagation direction, selected spectral periods) were obtained by downscaling the ERA5 global reanalysis data (global atmosphere, land surface and ocean waves) using the numerical model Simulating Waves Nearshore (SWAN). We indicate how to obtain hourly precipitation time-series by interpolating ERA5 data. This dataset is important for researchers understanding the interaction between cliff, beach and shore-platform in open-coast mixed-sand-gravel environments. [ABSTRACT FROM AUTHOR]

A long-standing challenge is how to formulate proteins and vaccines to retain function during storage and transport and to remove the burdens of cold-chain management. Any solution must be practical to use, with the protein being released or applied using clinically relevant triggers. Advanced biologic therapies are distributed cold, using substantial energy, limiting equitable distribution in low-resource countries and placing responsibility on the user for correct storage and handling. Cold-chain management is the best solution at present for protein transport but requires substantial infrastructure and energy. For example, in research laboratories, a single freezer at −80 °C consumes as much energy per day as a small household1. Of biological (protein or cell) therapies and all vaccines, 75% require cold-chain management; the cost of cold-chain management in clinical trials has increased by about 20% since 2015, reflecting this complexity. Bespoke formulations and excipients are now required, with trehalose2, sucrose or polymers3 widely used, which stabilize proteins by replacing surface water molecules and thereby make denaturation thermodynamically less likely; this has enabled both freeze-dried proteins and frozen proteins. For example, the human papilloma virus vaccine requires aluminium salt adjuvants to function, but these render it unstable against freeze–thaw4, leading to a very complex and expensive supply chain. Other ideas involve ensilication5 and chemical modification of proteins6. In short, protein stabilization is a challenge with no universal solution7,8. Here we designed a stiff hydrogel that stabilizes proteins against thermal denaturation even at 50 °C, and that can, unlike present technologies, deliver pure, excipient-free protein by mechanically releasing it from a syringe. Macromolecules can be loaded at up to 10 wt% without affecting the mechanism of release. This unique stabilization and excipient-free release synergy offers a practical, scalable and versatile solution to enable the low-cost, cold-chain-free and equitable delivery of therapies worldwide.A stiff hydrogel gel is presented that encapsulates and stabilizes proteins without additives or excipients and uses mechanical strain to release them, offering low-cost and versatile delivery of therapies. [ABSTRACT FROM AUTHOR]

Spin accumulation in semiconductor structures at room temperature and without magnetic fields is key to enable a broader range of optoelectronic functionality1. Current efforts are limited owing to inherent inefficiencies associated with spin injection across semiconductor interfaces2. Here we demonstrate spin injection across chiral halide perovskite/III–V interfaces achieving spin accumulation in a standard semiconductor III–V (AlxGa1−x)0.5In0.5P multiple quantum well light-emitting diode. The spin accumulation in the multiple quantum well is detected through emission of circularly polarized light with a degree of polarization of up to 15 ± 4%. The chiral perovskite/III–V interface was characterized with X-ray photoelectron spectroscopy, cross-sectional scanning Kelvin probe force microscopy and cross-sectional transmission electron microscopy imaging, showing a clean semiconductor/semiconductor interface at which the Fermi level can equilibrate. These findings demonstrate that chiral perovskite semiconductors can transform well-developed semiconductor platforms into ones that can also control spin.By using a chiral halide perovskite material, spin injection at room temperature into a conventional III–V semiconductor multiple quantum well light-emitting diode is demonstrated, resulting in a semiconductor platform that can also control spin. [ABSTRACT FROM AUTHOR]

Purpose: Intestinal permeability is a critical component of gut barrier function. Barrier dysfunction can be triggered by certain stressors such as exercise, and if left unmanaged can lead to local and systemic disorders. The aim of this study was to investigate the effects of a specific whey protein fraction in alleviating exercise-induced gut permeability as assessed by recovery of lactulose/rhamnose (L/R) and lactulose/mannitol (L/M) urinary probes. Methods: Eight males and eight females (aged 18–50) completed two arms of a double-blind, placebo-controlled, crossover study. For each arm participants performed two baseline intestinal permeability assessments, following which they consumed the treatment (2 g/day of milk powder containing 200 mg of whey protein) or placebo (2 g/day of milk powder) for 14 days, before performing a post-exercise permeability assessment. The exercise protocol involved a 20-min run at 80% of maximal oxygen uptake on a 1% incline. Results: Mixed model analysis revealed an increase in L/R (23%; P < 0.001) and L/M (20%; P < 0.01) recovery following exercise. However, there was no treatment or treatment × exercise effect. Conclusion: The exercise protocol utilised in our study induces gut permeability. However, consuming whey protein, at the dose and timing prescribed, is not able to mitigate this effect. [ABSTRACT FROM AUTHOR]

Purpose: Vertical banded gastroplasty (VBG) was once the most popular bariatric procedure in the 1980's, with many patients subsequently requiring conversional surgery. However, knowledge regarding the prevalence and outcomes of these procedures remains limited. This study aims to determine the prevalence, indications, rate of 30-day serious complications, and mortality of conversional surgery after VBG. Materials and Methods: A retrospective analysis of the MBSAQIP database from 2020 to 2022 was conducted. Individuals undergoing conversional or revisional surgery after VBG were included. The primary outcomes were 30-day serious complications and mortality. Results: Of 716 VBG conversions, the common procedures included 660 (92.1%) Roux-en-Y gastric bypass (RYGB) and 56 (7.9%) sleeve gastrectomy (SG). The main indication for conversion was weight gain for RYGB (31.0%) and for SG (41.0%). RYGB had longer operative times than SG (223.7 vs 130.5 min, p < 0.001). Although not statistically significant, serious complications were higher after RYGB (14.7% vs 8.9%, p = 0.2). Leak rates were higher after SG (5.4 vs 3.5%) but this was not statistically significant (p = 0.4). Mortality was similar between RYGB and SG (1.2 vs 1.8%, p = 0.7). Multivariable regression showed higher body mass index, longer operative time, previous cardiac surgery and black race were independently associated with serious complications. Conversion to RYGB was not predictive of serious complications compared to SG (OR 0.96, 95%CI 0.34–2.67, p = 0.9). Conclusions: Conversional surgery after VBG is uncommon, and the rate of complications and mortality remains high. Patients should be thoroughly evaluated and informed about these risks before undergoing conversion from VBG. [ABSTRACT FROM AUTHOR]

Abstract Hematopoietic cell transplantation (HCT) treats many blood conditions but remains underused due to complications such as graft‐versus‐host disease (GvHD). In GvHD, donor immune cells attack the patient, requiring powerful immunosuppressive drugs like glucocorticoids (GCs) to prevent death. In this study, we tested the hypothesis that donor cell conditioning with the glucocorticoid fluticasone propionate (FLU) prior to transplantation could increase hematopoietic stem cell (HSC) engraftment and reduce GvHD. Murine HSCs treated with FLU had increased HSC engraftment and reduced severity and incidence of GvHD after transplantation into allogeneic hosts. While most T cells died upon FLU treatment, donor T cells repopulated in the hosts and appeared less inflammatory and alloreactive. Regulatory T cells (Tregs) are immunomodulatory and survived FLU treatment, resulting in an increased ratio of Tregs to conventional T cells. Our results implicate an important role for Tregs in maintaining allogeneic tolerance in FLU‐treated grafts and suggest a therapeutic strategy of pre‐treating donor cells (and not the patients directly) with GCs to simultaneously enhance engraftment and reduce GvHD upon allogeneic HCT.

Abstract While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential for the resolution of DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Further analysis identified that Peroxiredoxin 1, PRDX1, contributes to the DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage‐induced nuclear reactive oxygen species. Moreover, PRDX1 loss lowers aspartate availability, which is required for the DNA damage‐induced upregulation of de novo nucleotide synthesis. In the absence of PRDX1, cells accumulate replication stress and DNA damage, leading to proliferation defects that are exacerbated in the presence of etoposide, thus revealing a role for PRDX1 as a DNA damage surveillance factor.

Abstract Gender-affirming hormones have been shown to improve psychological functioning and quality of life among transgender and nonbinary (trans) people, yet, scant research exists regarding whether and why individuals take more or less hormones than prescribed. Drawing on survey data from 379 trans people who were prescribed hormones, we utilized multivariable logistic regression models to identify factors associated with hormone-dosing behaviors and content analysis to examine the reasons for dose modifications. Overall, 24% of trans individuals took more hormones than prescribed and 57% took less. Taking more hormones than prescribed was significantly associated with having the same provider for primary and gender-affirming care and gender-based discrimination. Income and insurance coverage barriers were significantly associated with taking less hormones than prescribed. Differences by gender identity were also observed. Addressing barriers to hormone access and cost could help to ensure safe hormone-dosing behaviors and the achievement trans people’s gender-affirmation goals.

Abstract Analysis of circulating tumor DNA (ctDNA) to monitor cancer dynamics and detect minimal residual disease has been an area of increasing interest. Multiple methods have been proposed but few studies have compared the performance of different approaches. Here, we compare detection of ctDNA in serial plasma samples from patients with breast cancer using different tumor‐informed and tumor‐naïve assays designed to detect structural variants (SVs), single nucleotide variants (SNVs), and/or somatic copy‐number aberrations, by multiplex PCR, hybrid capture, and different depths of whole‐genome sequencing. Our results demonstrate that the ctDNA dynamics and allele fractions (AFs) were highly concordant when analyzing the same patient samples using different assays. Tumor‐informed assays showed the highest sensitivity for detection of ctDNA at low concentrations. Hybrid capture sequencing targeting between 1,347 and 7,491 tumor‐identified mutations at high depth was the most sensitive assay, detecting ctDNA down to an AF of 0.00024% (2.4 parts per million, ppm). Multiplex PCR targeting 21–47 tumor‐identified SVs per patient detected ctDNA down to 0.00047% AF (4.7 ppm) and has potential as a clinical assay.

Abstract Cognitive decline is a common pathological outcome during aging, with an ill‐defined molecular and cellular basis. In recent years, the concept of inflammaging, defined as a low‐grade inflammation increasing with age, has emerged. Infiltrating T cells accumulate in the brain with age and may contribute to the amplification of inflammatory cascades and disruptions to the neurogenic niche observed with age. Recently, a small resident population of regulatory T cells has been identified in the brain, and the capacity of IL2‐mediated expansion of this population to counter neuroinflammatory disease has been demonstrated. Here, we test a brain‐specific IL2 delivery system for the prevention of neurological decline in aging mice. We identify the molecular hallmarks of aging in the brain glial compartments and identify partial restoration of this signature through IL2 treatment. At a behavioral level, brain IL2 delivery prevented the age‐induced defect in spatial learning, without improving the general decline in motor skill or arousal. These results identify immune modulation as a potential path to preserving cognitive function for healthy aging.

Abstract In this article, we outline and define for the first time the concept of shame-sensitivity and principles for shame-sensitive practice. We argue that shame-sensitive practice is essential for the trauma-informed approach. Experiences of trauma are widespread, and there exists a wealth of evidence directly correlating trauma to a range of poor social and health outcomes which incur substantial costs to individuals and to society. As such, trauma has been positioned as a significant public health issue which many argue necessitates a trauma-informed approach to health, care and social services along with public health. Shame is key emotional after effect of experiences of trauma, and an emerging literature argues that we may ‘have failed to see the obvious’ by neglecting to acknowledge the influence of shame on post-trauma states. We argue that the trauma-informed approach fails to adequately theorise and address shame, and that many of the aims of the trauma-informed are more effectively addressed through the concept and practice of shame-sensitivity. We begin by giving an overview of the trauma-informed paradigm, then consider shame as part of trauma, looking particularly at how shame manifests in post-trauma states in a chronic form. We explore how shame becomes a barrier to successful engagement with services, and finally conclude with a definition of the shame-sensitive concept and the principles for its practice.

Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3–5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6–8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity–cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19–12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.A study demonstrates that metabolic signalling and inflammatory cues associated with obesity selectively induce expression of PD-1 on tumour-associated macrophages to suppress anti-tumour immunity. [ABSTRACT FROM AUTHOR]

The 15-item Distress Tolerance Scale (DTS) is a widely used psychometric measure with evidence generally supporting its reliability and validity. However, limitations related to its ordinal response format and lack of cross-cultural comparisons have yet to be investigated using appropriate methods. The Partial Credit Rasch model was used to evaluate and enhance the psychometric properties of the DTS using responses from 2550 adult participants from the United States of America (USA), England, Canada, South Africa, Spain, and Argentina. The initial poor fit of the DTS to the Rasch model was improved by removing one item and combining locally dependent items into three testlets. These modifications resulted in the best fit of the 14-item DTS to the Rasch model for all the countries in our study, providing evidence of unidimensionality, high reliability and invariance across countries, meditation practice, and gender. Meeting the expectations of the Rasch model permitted the development of ordinal-to-interval conversion algorithms derived from person estimates of the Rasch model. Using the ordinal-to-interval conversion algorithms published in this article, ordinal DTS scores can be transformed into interval-level data, enhancing the precision of this scale for future research and clinical use across people from the six countries in this study and across the English and Spanish versions of the 14-item DTS. [ABSTRACT FROM AUTHOR]

Polyploidy, the result of whole-genome duplication (WGD), is a major driver of eukaryote evolution. Yet WGDs are hugely disruptive mutations, and we still lack a clear understanding of their fitness consequences. Here, we study whether WGDs result in greater diversity of genomic structural variants (SVs) and how they influence evolutionary dynamics in a plant genus, Cochlearia (Brassicaceae). By using long-read sequencing and a graph-based pangenome, we find both negative and positive interactions between WGDs and SVs. Masking of recessive mutations due to WGDs leads to a progressive accumulation of deleterious SVs across four ploidal levels (from diploids to octoploids), likely reducing the adaptive potential of polyploid populations. However, we also discover putative benefits arising from SV accumulation, as more ploidy-specific SVs harbor signals of local adaptation in polyploids than in diploids. Together, our results suggest that SVs play diverse and contrasting roles in the evolutionary trajectories of young polyploids. Cochlearia is an evolutionarily dynamic genus with different base chromosome numbers and ploidal levels. Here, the authors construct a graph-based pangenome for Cochlearia and reveal that whole-genome duplication associated with greater diversity of genomic structural variation and their possible function in adaptation. [ABSTRACT FROM AUTHOR]

Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis was used to identify a signature associated with high risk of early clinical failure independent of IPI and COO. Further analysis revealed the signature was associated with metabolic reprogramming and identified cases with a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. This novel and integrative approach is the first to identify a signature at diagnosis, in a real-world cohort of DLBCL, that identifies patients at high risk for early clinical failure and may have significant implications for design of therapeutic options. [ABSTRACT FROM AUTHOR]

Magnetic materials with noncoplanar magnetic structures can show unusual physical properties driven by nontrivial topology. Topologically-active states are often multi-q structures, which are challenging to stabilize in models and to identify in materials. Here, we use inelastic neutron-scattering experiments to show that the insulating double perovskites Ba2YRuO6 and Ba2LuRuO6 host a noncoplanar 3-q structure on the face-centered cubic lattice. Quantitative analysis of our neutron-scattering data reveals that these 3-q states are stabilized by biquadratic interactions. Our study identifies double perovskites as a highly promising class of materials to realize topological magnetism, elucidates the stabilization mechanism of the 3-q state in these materials, and establishes neutron spectroscopy on powder samples as a valuable technique to distinguish multi-q from single-q states, facilitating the discovery of topologically-nontrivial magnetic materials. [ABSTRACT FROM AUTHOR]

As climate change impacts increase, communicators must engage as many audiences as possible in climate action. One potentially underrated audience is video gamers. Two-thirds of Americans play video games, and video games are a potentially effective climate change communication tool. However, little research has examined whether video gamers have unique value as a target audience for climate communication, and if they do, what might be effective ways to reach them. To address this need, we use two surveys including self-identified video game players in the United States to measure their current engagement with climate change, including through video gaming. In Study 1, a nationally representative survey in the United States (N = 1,006), we found that being a video gamer was slightly positively associated with intentions to take collective action on global warming. In Study 2, restricted to gamers in the United States (N = 2,034), we found that having more friends and family who played video games, and/or being exposed to global warming content in gaming, were also positively associated with collective action intentions. These findings were consistent even after controlling for potential confounding variables such as age, political party, and global warming attitudes. Results suggest that video gamers are a worthwhile potential audience for future climate change communication, combatting the stereotype of video gamers as disengaged or antisocial, at least in the context of climate change. Our study also identifies several potential avenues for future communication with video gamers, particularly outreach to and engagement with gaming communities. [ABSTRACT FROM AUTHOR]

Background: Pneumonia-related hospitalization may be associated with advanced skeletal muscle loss due to aging (i.e., sarcopenia) or chronic illnesses (i.e., cachexia). Early detection of muscle loss may now be feasible using deep-learning algorithms applied on conventional chest CT. Objectives: To implement a fully automated deep-learning algorithm for pectoralis muscle measures from conventional chest CT and investigate longitudinal associations between these measures and incident pneumonia hospitalization according to Chronic Obstructive Pulmonary Disease (COPD) status. Materials and methods: This analysis from the Multi-Ethnic Study of Atherosclerosis included participants with available chest CT examinations between 2010 and 2012. We implemented pectoralis muscle composition measures from a fully automated deep-learning algorithm (Mask R-CNN, built on the Faster Region Proposal Network (R-) Convolutional Neural Network (CNN) with an extension for mask identification) for two-dimensional segmentation. Associations between CT-derived measures and incident pneumonia hospitalizations were evaluated using Cox proportional hazards models adjusted for multiple confounders which include but are not limited to age, sex, race, smoking, BMI, physical activity, and forced-expiratory-volume-at-1 s-to-functional-vital-capacity ratio. Stratification analyses were conducted based on baseline COPD status. Results: This study included 2595 participants (51% female; median age: 68 (IQR: 61, 76)) CT examinations for whom we implemented deep learning–derived measures for longitudinal analyses. Eighty-six incident pneumonia hospitalizations occurred during a median 6.67-year follow-up. Overall, pectoralis muscle composition measures did not predict incident pneumonia. However, in fully-adjusted models, only among participants with COPD (N = 507), CT measures like extramyocellular fat index (hazard ratio: 1.98, 95% CI: 1.22, 3.21, p value: 0.02), were independently associated with incident pneumonia. Conclusion: Reliable deep learning–derived pectoralis muscle measures could predict incident pneumonia hospitalization only among participants with known COPD. Clinical relevance statement: Pectoralis muscle measures obtainable at zero additional cost or radiation exposure from any chest CT may have independent predictive value for clinical outcomes in chronic obstructive pulmonary disease patients. Key Points: •Identification of independent and modifiable risk factors of pneumonia can have important clinical impact on patients with chronic obstructive pulmonary disease. •Opportunistic CT measures of adipose tissue within pectoralis muscles using deep-learning algorithms can be quickly obtainable at zero additional cost or radiation exposure. •Deep learning–derived pectoralis muscle measurements of intermuscular fat and its subcomponents are independently associated with subsequent incident pneumonia hospitalization. [ABSTRACT FROM AUTHOR]

This study explored how the use of smartphones can influence sports betting by young adults, compared to using computers and land-based betting facilities. Interviews with 33 Australians aged 18–29 years, who bet regularly on sports, esports, and/or fantasy sports, were analysed using adaptive grounded theory. Seven major themes related to platform functionality, sourcing betting information, physical accessibility, financial accessibility, social influences, privacy, and marketing. The grounded theory model depicts how features of smartphones, online gambling, and betting apps combine in smartphone betting to provide instantaneous access to betting, anywhere and at any time, to facilitate harmful betting behaviours. These behaviours included increased betting participation, frequency and expenditure, placing a wider variety of bets, impulsive and spontaneous betting, placing riskier bets with longer odds, chasing losses, and acting on social encouragement to bet. These findings can inform harm minimisation measures, regulation, and policy. [ABSTRACT FROM AUTHOR]

The Core Knowledge Confusions scale (CKC) was designed to predict paranormal and spiritual beliefs, alternative health beliefs and the degree to which people assign meaning to events. It measures the likelihood of individuals' tendency to accept ontologically confused content as literally true and has been used to investigate beliefs such as the paranormal. However, the psychometric properties of the CKC have not been tested, limiting the scale's practical utility. The CKC was revised and tested, internal consistency was checked, and associations to paranormal belief were assessed using a panel survey of 1010 Australian residents (Mage = 52, SD = 17.69, Female = 56%). Using structural equation modelling and regression, the revised scale (CKC-R) content deviated from previous findings. However, it demonstrated acceptable internal, construct, and divergent validity. External correlates of the CKC-R were aligned with expectations: associating with high verbal knowledge, an intuitive cognitive style, and the absorption personality trait (i.e., a tendency to experience altered states of consciousness). The CKC-R provides researchers with a validated measure predicting paranormal belief that is associated with both cognitive and personality-based traits. Interpretation of the CKC-R as a measure of ontological error is less clear and requires further investigation. [ABSTRACT FROM AUTHOR]

We introduce three architecture modifications to enhance the performance of the end-to-end (E2E) variational network (VarNet) for undersampled MRI reconstructions. We first implemented the Feature VarNet, which propagates information throughout the cascades of the network in an N-channel feature-space instead of a 2-channel feature-space. Then, we add an attention layer that utilizes the spatial locations of Cartesian undersampling artifacts to further improve performance. Lastly, we combined the Feature and E2E VarNets into the Feature-Image (FI) VarNet, to facilitate cross-domain learning and boost accuracy. Reconstructions were evaluated on the fastMRI dataset using standard metrics and clinical scoring by three neuroradiologists. Feature and FI VarNets outperformed the E2E VarNet for 4 × , 5 × and 8 × Cartesian undersampling in all studied metrics. FI VarNet secured second place in the public fastMRI leaderboard for 4 × Cartesian undersampling, outperforming all open-source models in the leaderboard. Radiologists rated FI VarNet brain reconstructions with higher quality and sharpness than the E2E VarNet reconstructions. FI VarNet excelled in preserving anatomical details, including blood vessels, whereas E2E VarNet discarded or blurred them in some cases. The proposed FI VarNet enhances the reconstruction quality of undersampled MRI and could enable clinically acceptable reconstructions at higher acceleration factors than currently possible. [ABSTRACT FROM AUTHOR]

Estuarine and adjacent inshore habitats have long been recognised as important nursery areas for fishes before they disperse to coastal habitats. Assessing nursery function supports spatial and fisheries management, yet work commonly focusses on singular habitat types. Re-considering how juvenile fish connect habitats may improve our understanding of nursery function and the scales that recruits are supplied to coastal fisheries. This study quantified the juvenile movements of two harvested fishes in south-eastern Australia, luderick (Girella tricuspidata) and yellowfin bream (Acanthopagrus australis). Acoustic tags were used to track 33 luderick and 20 yellowfin bream from seagrass meadows for up to ~400 days in Jervis Bay Marine Park. Both species had relatively small home ranges (< 7 km2) and exhibited site attachment to seagrass meadows where they were released. Most luderick and yellowfin bream were detected moving 100's metres to kilometres to reefs adjacent to seagrass, although these movements were not habitat shifts. Rather, reef-ward movements represented repeated visits that lasted days to months before fish returned to seagrass, suggesting that these movements may be explorations in search of suitable adult habitat. Strong retention within an existing marine reserve was observed, with only five of 33 fish tagged within reserves crossing the boundary into fished waters. Overall, our results demonstrate that juvenile fish use and connect multiple habitat types during their movements. These findings support the broadening of the nursery concept from single habitats to a mosaic of functionally connected habitat patches (dubbed 'seascape nurseries'). [ABSTRACT FROM AUTHOR]

Purpose of Review: Examine the current state of literature related to the impact of obesity in children and adolescents on health-related physical fitness and the resultant cardiometabolic disease risk. Recent Findings: Cardiorespiratory fitness of children and adolescents has declined over the past few decades which corresponds with an increase in obesity rates. Children with obesity are more likely to have low cardiorespiratory fitness which is associated with higher cardiometabolic disease risk and poorer mental health. The impact of obesity on muscular fitness in children and adolescents is more difficult to ascertain, but in general measures of physical function are lower in children with obesity which has also been associated with higher cardiometabolic disease risk. Summary: Components of health-related physical fitness are trending negatively in children and adolescents and appear to be related to the increase in prevalence of obesity. The resultant cardiometabolic disease risk has also risen which suggests a greater disease burden in the future. These disparaging findings highlight the need for aggressive interventions to improve physical fitness in children and adolescents. [ABSTRACT FROM AUTHOR]

This article explores the interplay between crises, opportunities and democratic change in the United Kingdom. A vast body of scholarship underlines that crises open 'windows of opportunity' that can occasionally lead to radical shifts in the role of the state and the design of public policy. Even when a radical shift occurs, however, it has often proved temporary, with relationships and processes quickly reverting to pre-crisis modes once the immediacy of the crisis abates. This may not be true of our present period of crisis following the COVID-19 pandemic. The consequences of decades of underinvestment in infrastructure and increasing concentration of resources in a small minority of individuals and organisations are being exacerbated by climate change, geopolitical conflict and new waves of disease. The challenge for policymakers in the UK now is heightened by evidence that suggests that nudging, a libertarian paternalist means of promoting certain ends, is ineffective. Policymakers who have long used state neutrality between conceptions of the good as the justification for not promoting certain ends now have to confront a real ethical dilemma: coerce to achieve specific outcomes or invest in addressing the social determinants that actually affect behaviour. This article suggests that contrary to decades of opposition to redistribution among UK policymakers, only the latter is consistent with libertarian paternalism. [ABSTRACT FROM AUTHOR]

Extracting longitudinal image quantitative data, known as delta-radiomics, has the potential to capture changes in a patient's anatomy throughout the course of radiation treatment for prostate cancer. Some of the major challenges of delta-radiomics studies are contouring the structures for individual fractions and accruing patients' data in an efficient manner. The manual contouring process is often time consuming and would limit the efficiency of accruing larger sample sizes for future studies. The problem is amplified because the contours are often made by highly trained radiation oncologists with limited time to dedicate to research studies of this nature. This work compares the use of automated prostate contours generated using a deformable image-based algorithm to make predictive models of genitourinary and changes in total international prostate symptom score in comparison to manually contours for a cohort of fifty patients. Area under the curve of manual and automated models were compared using the Delong test. This study demonstrated that the delta-radiomics models were similar for both automated and manual delta-radiomics models. [ABSTRACT FROM AUTHOR]