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Bone homeostasis within the skeletal system is predominantly maintained by bone formation and resorption. Where formation of new bone involves maturation of stromal cells to mineral and matrix secreting mature osteoblasts, which requires cellular energy or adenosine triphosphate (ATP). Alterations in systemic metabolism can influence osteoblast functioning. In line with this, type 2 diabetes mellitus (T2DM), a common metabolic disorder is also associated with reduced bone formation and increased risk of fracture. Impairment in lipid metabolism is one of the key features associated with T2DM-related pathologies in multiple tissues. Therefore, we tested the hypothesis that the reduced bone formation reported in obese murine models of impaired glucose tolerance is a function of disrupted lipid metabolism in osteoblasts. We first confirmed that mice fed a high fat diet have reduced bone microarchitecture along with lower bone formation rates. Interestingly, osteoblasts from obese mice harbor higher numbers of cytosolic lipid droplets along with decreased bioenergetic profiles compared to control cells. Further supporting this observation, bone tibia cortex demonstrated higher total lipid content in high fat diet fed mice compared to control-fed mice. As a further proof of principle, we generated a novel murine model to conditionally delete Plin2 in osteoblast-progenitor cells using Prrx1-Cre, to enhance lipid droplet breakdown. Our data demonstrate that knocking down Plin2 in an osteoprogenitor specific manner protects from high-fat diet induced osteoblast dysfunction. Furthermore, the mechanism of action involves enhanced osteoblast fatty acid oxidation. In conclusion, the current studies establish that high fat diet induced glucose intolerance leads to perturbations in osteoblast lipid metabolism, thus causing lower bone formation, which can be protected against by increasing fatty acid oxidation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Immune cells are involved in the pathogenesis of pain by directly activating or sensitizing nociceptor sensory neurons. However, because the immune system also has the capacity to self-regulate through anti-inflammatory mechanisms that drive the resolution of inflammation, it might promote pain resolution and prevention. Here, we describe how immune cell-derived cytokines can act directly on sensory neurons to inhibit pain hypersensitivity and how immune-derived endogenous opioids promote analgesia. We also discuss how immune cells support healthy tissue innervation by clearing debris after nerve injury, protecting against axon retraction from target tissues and enhancing regeneration, preventing the development of chronic neuropathic pain. Finally, we review the accumulating evidence that manipulating immune activity positively alters somatosensation, albeit with currently unclear molecular and cellular mechanisms. Exploration of immune-mediated analgesia and pain prevention could, therefore, be important for the development of novel immune therapies for the treatment of clinical pain states., Competing Interests: Competing interests: C.J.W. is a founder of Nocion Therapeutics, Quralis and Blackbox Bio, and a Scientific Advisory Board member of Lundbeck, Axonis and Tafalgie Therapeutics. The remaining authors declare no competing interests., (© 2024. Springer Nature America, Inc.)

It has been found that the way high-performance coaches lead influences both athletes' performance and mental health. However, limited research exists on the Social Identity Approach to leadership in elite sports, despite growing interest in coaching science regarding interpersonal behaviours and leadership. This study investigates the empirical links between coaches' leadership, sport performance and mental health from a social identity approach. One hundred and forty-five elite athletes ( M age  = 20.6 years; SD  = 4.1; 62% women, 38% men) answered questionnaires measuring coaches' social identity leadership, sport performance satisfaction and mental health. The overall structural equation model (SEM) accounted for 36% and 19% of the variances in athletes' mental health and mental illness dimensions, respectively. There was a positive association between perceived coaches' social identity leadership and sport performance satisfaction, explaining 10% of its variance. Coaches' social identity leadership predicted athletes' mental health but not mental illness. Sport performance satisfaction positively influenced mental health and negatively impacted mental illness. Fostering a sense of "we" and "us" within elite sport training groups is instrumental in promoting sport performance satisfaction and, consequently, enhancing the mental health of athletes. Coaching educational courses may benefit from social identity leadership in interpersonal behaviours.

In the last decades, novel therapeutics with anabolic bone properties have been developed and are currently used in the management of osteoporosis particularly in patients with high-risk of fragility fractures. These drugs include PTH-Related Analogues, teriparatide and abaloparatide, and the anti-sclerostin agent romosozumab, this latter drug currently approved only in female patients. Their efficacies in preventing fragility fractures are widely demonstrated and their potential serious side effects were progressively downgraded, including risk of malignancies in teriparatide- and cardiovascular events in romosozumab-users, respectively. Further data are warranted about their efficacy in glucocorticoids-induces osteoporosis and fracture healings., Competing Interests: Disclosures The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Hazardous drugs are inherently toxic and present a potential occupational exposure risk to nurses and midwives. Hazardous drugs require special handling to minimise the risk of exposure and adverse health effects. Although the use of hazardous drugs in oncology services is well recognised, they are also used in other healthcare areas where nurses and midwives may be unaware there is a risk., Objective: To investigate what nurses and midwives know and do about their occupational exposure to hazardous drugs, and what factors affect their knowledge and practice., Design: Mixed methods systematic review., Methods: A systematic review was conducted, and studies were included if the authors described what nurses or midwives knew about hazardous drugs, or what they did in their clinical practice to reduce their risk of occupational exposure (PROSPERO registration CRD42024437493). The databases were searched for any year until the 26th of January 2024.Two independent reviewers extracted data using Covidence and assessed the risk of bias. The data were extracted into the categories of knowledge of risk and safe handling practices, attitude and factors affecting these, and activities that posed the greatest risk of exposure (preparation, administration, and disposal of hazardous drugs, cleaning hazardous drug spills, and handling excreta from patients who had recently been treated with hazardous drugs)., Results: Of the 2702 articles that were identified, 59 quantitative and 3 qualitative studies were included in this review. No studies reported on midwives handling hazardous drugs. Most studies investigated nurses working in oncology services. Nurses reported a lack of education about the risk and safe handling. They were often responsible for preparing hazardous drugs and there was inconsistency in their compliance when using personal protective equipment. Nurses did not always perceive that there was a real risk of exposure, were concerned about the effect of wearing personal protective equipment on their relationship with patients and perceived they lacked the time to don equipment., Conclusions: The risk of occupational exposure to hazardous drugs outside of oncology services was rarely investigated. There were no studies reporting what midwives knew and did about their risk of occupational exposure to hazardous drugs. When nurses were aware of the risks, this did not necessarily translate into the implementation of safe handling practices or the consistent use of personal protective equipment because of a perceived low risk, lack of personal protective equipment availability, and prioritising personal or patient comfort over safety measures., Tweetable Abstract: Nurses and midwives are often unknowingly exposed to the toxic effects of hazardous drugs when they prepare and administer these drugs for patients, although knowledge does not always equal safe handling practices., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Occupational exposure of healthcare workers to hazardous medications can be potentially harmful. Hazardous medications can be carcinogenic, developmentally toxic, reproductively toxic, genotoxic and/or toxic to organs at low doses. These hazardous medications can be used in many healthcare settings, but published research of occupational exposure has focused almost exclusively on cancer services., Aim: To identify the healthcare settings where nurses and midwives are responsible for the administration of hazardous medications., Method: A retrospective cohort study was undertaken of all medication administration events occurring during a two-week period at a public metropolitan health service in 2023. All medication administration events from six hospital sites were identified using the electronic (Oracle Health-Cerner-Millennium®) and paper (Chemotherapy Chart) medication administration records. From all of the medications administered, the subset of medications classified as hazardous were identified based on the Victorian Therapeutics Advisory Group Framework for Handling of Hazardous Medicines (2021) and other guidelines. Poisson regression modelling was used to explore associations between the number of hazardous medications and the healthcare area where they were administered (p < 0.001)., Results: Of the 121,567 administration events, 6054 (5.0 %) involved hazardous medications. The healthcare areas with the highest rate of hazardous medication administration events, as a proportion of all medication administration events, were outpatient cancer service (301/695, 43.3 %), birth suite (13/86, 15.1 %) and mental health (404/4011, 10.1 %) areas. During the two-week period, 6054 hazardous medication administration events occurred, involving 117 different medications. The greatest number of these events took place in the medical (1729/6054, 28.6 %) and geriatric (1579/6054, 26.1 %) inpatient healthcare areas. A total of 1258 nurses and midwives were directly involved in either administering, or checking and witnessing the administration of hazardous medications to 996 patients (25.2 % of the total 3958 patients). Most hazardous medications administered to patients were in an oral dosage form (5426/6054, 89.6 %)., Conclusion: Hazardous medications were administered in all healthcare areas, with the exception of endoscopy services. Nurses and midwives were at risk of occupational exposure from hazardous medications., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The past decade has witnessed significant advances in our understanding of skeletal homeostasis and the mechanisms that mediate the loss of bone in primary and secondary osteoporosis. Recent breakthroughs have primarily emerged from identifying disease-causing mutations and phenocopying human bone disease in rodents. Notably, using genetically-modified rodent models, disrupting the reciprocal relationship with tropic pituitary hormone and effector hormones, we have learned that pituitary hormones have independent roles in skeletal physiology, beyond their effects exerted through target endocrine glands. The rise of follicle-stimulating hormone (FSH) in the late perimenopause may account, at least in part, for the rapid bone loss when estrogen is normal, while low thyroid-stimulating hormone (TSH) levels may contribute to the bone loss in thyrotoxicosis. Admittedly speculative, suppressed levels of adrenocorticotropic hormone (ACTH) may directly exacerbate bone loss in the setting of glucocorticoid-induced osteoporosis. Furthermore, beyond their established roles in reproduction and lactation, oxytocin and prolactin may affect intergenerational calcium transfer and therefore fetal skeletal mineralization, whereas elevated vasopressin levels in chronic hyponatremic states may increase the risk of bone loss.. Here, we discuss the interaction of each pituitary hormone in relation to its role in bone physiology and pathophysiology., Competing Interests: Declarations. Competing interests: M.Z. is inventor on issued and pending patents on the use of FSH as a target for osteoporosis, obesity and Alzheimer’s disease. M.Z., T.Y. and S.R. are inventors on a pending patent on the formulation of a monoclonal antibody against FSH. The patents will be held by Icahn School of Medicine at Mount Sinai, and M.Z, T.Y. and S.R. would be recipients of royalties, per institutional policy, should the patents be granted. The other authors declare no competing financial interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Context.—: Mutant KRAS is the main oncogenic driver in pancreatic ductal adenocarcinomas (PDACs). However, the clinical and phenotypic implications of harboring different mutant KRAS alleles remain poorly understood., Objective.—: To characterize the potential morphologic and clinical outcome differences in PDACs harboring distinct mutant KRAS alleles., Design.—: Cohort 1 consisted of 127 primary conventional PDACs with no neoadjuvant therapy, excluding colloid/mucinous, adenosquamous, undifferentiated, and intraductal papillary mucinous neoplasm-associated carcinomas, for which an in-house 42-gene mutational panel had been performed. A morphologic classification system was devised wherein each tumor was assigned as conventional, papillary/large duct (P+LD, defined as neoplastic glands with papillary structure and/or with length ≥0.5 mm), or poorly differentiated (when the aforementioned component was 60% or more of the tumor). Cohort 2 was a cohort of 88 PDACs in The Cancer Genome Atlas, which were similarly analyzed., Results.—: In both cohorts, there was significant enrichment of P+LD morphology in PDACs with KRAS G12V and G12R compared with G12D. In the entire combined cohort, Kaplan-Meier analyses showed longer overall survival (OS) with KRAS G12R as compared with G12D (median OS of 1255 versus 682 days, P = .03) and in patients whose PDACs displayed P+LD morphology as compared with conventional morphology (median OS of 1175 versus 684 days, P = .04). In the adjuvant-only subset, KRAS G12R had the longest OS compared with G12D, G12V, and other alleles (median OS unreached/undefined versus 1009, 1129, and 1222 days, respectively)., Conclusions.—: PDACs with different mutant KRAS alleles are associated with distinct morphologies and clinical outcomes, with KRAS G12R allele associated with P+LD morphology and longer OS when compared with G12D using Kaplan-Meier studies., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Background: Obstetric patient blood management (PBM) strategies were used at Corniche Hospital in 2018, initially focusing on minimizing bleeding, with other clinical strategies implemented incrementally. This study assesses program outcomes in patients with major obstetric hemorrhage of 2000 mL or greater., Methods: A retrospective study of 353 women admitted to The Corniche Hospital between 2018 and 2023 who experienced major obstetric hemorrhage of 2000 mL or greater. The primary outcome measure was units of red blood cell (RBC), fresh-frozen plasma (FFP), and platelet units transfused. Secondary outcomes included pretransfusion hemoglobin in patients with no active bleeding, hemoglobin levels 3 weeks postdischarge, anemia predelivery, blood product-acquisition cost savings, mortality, composite morbidity (transfusion reaction, acute lung injury, thrombosis, sepsis, postpartum hysterectomy), hospital and high-dependency unit length of stay, and all-cause emergency readmissions within 28 days., Results: Comparing baseline (2018) with the final year (2023), the mean units of RBCs, FFP, and platelets transfused per admission decreased from 4.18 to 0.67 (P-trend <.001), resulting in blood acquisition savings of US$ 175,705. Over the same period the percentage of women anemic predelivery decreased from 40.3% to 23.8% (P-trend = 0.015) and the mean pretransfusion hemoglobin level in nonactively bleeding patients decreased from 7.54 g/dL to 6.35 g/dL (P-trend < .001). The mean hemoglobin rise 3 weeks postdischarge increased from 2.41 g/dL in 2018 to 4.26 g/dL in 2023. There were no changes in adjusted composite morbidity, hospital, or high-dependency unit length of stay., Conclusions: In women with a major obstetric hemorrhage of 2000 mL or greater, the implementation of an obstetric PBM program was associated with reduced blood product utilization, reduced costs, reduced anemia, and increased hemoglobin rise postdischarge., Competing Interests: Conflicts of Interest, Funding: Please see DISCLOSURES at the end of this article., (Copyright © 2024 International Anesthesia Research Society.)

High post-menopausal levels of the pituitary gonadotropin follicle-stimulating hormone (FSH) are strongly associated with the onset of Alzheimer's disease (AD). We have shown recently that FSH directly activates the hippocampal FSH receptors (FSHRs) to drive AD-like pathology and memory loss in mice. To unequivocally establish a role for FSH in memory loss, we depleted the Fshr on a 3xTg background and utilized Morris Water Maze to study deficits in spatial memory. 3xTg;Fshr +/+ mice displayed impaired spatial memory at 5 months of age. The loss of memory acquisition and retrieval were both rescued in 3xTg;Fshr -/- mice and, to a lesser extent, in 3xTg;Fshr +/- mice-documenting clear gene-dose-dependent prevention of spatial memory loss. Furthermore, at 5 and 8 months, sham-operated 3xTg;Fshr -/- mice showed better memory performance during the learning and/or retrieval phases, further suggesting that Fshr deletion prevents age-related progression of memory deficits. This prevention was not seen when mice were ovariectomized, except in the 8-month-old 3xTg;Fshr -/- mice. There was also a gene-dose-dependent reduction mainly in the amyloid β40 isoform in whole brain extracts. Finally, serum FSH levels <8 ng/mL in 16-month-old APP/PS1 mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial memory deficits in mice and lay a firm foundation for the use of an FSH-blocking agent for the early prevention of memory loss in post-menopausal women., Competing Interests: Competing interests MZ is inventor on issued and pending patients on the use of FSH as a target for osteoporosis, obesity and Alzheimer’s disease. MZ, SR and TY are inventors on a pending patent on an FSH antibody that is formulated at ultrahigh concentration. The patents will be held by the Icahn School of Medicine at Mount Sinai, and MZ, SR and TY would be recipient of royalties, per institutional policy. The other authors declare no competing financial interests. Ethics approval All methods were performed in accordance with the relevant guidelines and regulations. Animal handling and use were compliant with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals, and approved by the Icahn School of Medicine at Mount Sinai Institutional Animal Care and Use Committee (IACUC Approval # 2018-0047)., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

There is limited research on associations of per- and polyfluoroalkyl substances (PFAS) with areal bone mineral density (aBMD) through adolescence and whether bone-strengthening factors ameliorate effects. In the Project Viva cohort ( N = 484; 50% female), we used sex-stratified linear regression and quantile g-computation mixture models to examine associations of mid-childhood (median: 7.8 years; 2007-2010) plasma PFAS concentrations with a dual-energy X-ray absorptiometry total-body aBMD Z-score in early and late adolescence (median: 12.9 and 17.6 years, respectively). We explored stratum-specific estimates by parent/self-reported physical activity and dairy intake. Using linear mixed models, we evaluated associations with aBMD accrual from mid-childhood through late adolescence. Females with higher perfluorooctanoate (PFOA) and perfluorodecanoate (PFDA) had lower early adolescent aBMD Z-score [e.g., β(95%CI)] per doubling PFOA: -0.19(-0.41, 0.03)]. Youth with higher PFOA and PFDA had lower late adolescent aBMD Z-score, but CIs were wide [e.g., PFOA: females, -0.12(-0.40, 0.16); males, -0.10(-0.42, 0.21)]. Mixture models generally corroborated single PFAS results, and in linear mixed models, females with higher PFAS concentrations, and males with higher PFOA, had slower aBMD accrual. Less active males with higher PFOA, PFDA, and the PFAS mixture had lower late adolescent aBMD Z-score. Some PFAS appeared more negatively associated with the aBMD Z-score among those who consumed less dairy, but there was not consistent evidence of effect modification. Exposure to select PFAS may affect bone accrual through adolescence, with possible resilience conferred by greater physical activity and dairy intake.

Hox transcription factors play crucial roles in organizing developmental patterning across metazoa, but how these factors trigger regional morphogenesis has largely remained a mystery. In the developing gut, Hox genes help demarcate identities of intestinal subregions early in embryogenesis, which ultimately leads to their specialization in both form and function. Although the midgut forms villi, the hindgut develops sulci that resolve into heterogeneous outgrowths. Combining mechanical measurements of the embryonic chick intestine and mathematical modeling, we demonstrate that the posterior Hox gene HOXD13 regulates biophysical phenomena that shape the hindgut lumen. We further show that HOXD13 acts through the transforming growth factor β (TGF-β) pathway to thicken, stiffen, and promote isotropic growth of the subepithelial mesenchyme-together, these features lead to hindgut-specific surface buckling. TGF-β, in turn, promotes collagen deposition to affect mesenchymal geometry and growth. We thus identify a cascade of events downstream of positional identity that direct posterior intestinal morphogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Elite athletes often make large personal sacrifices to pursue excellence, but there is insufficient support for them when they leave elite sport. Identity loss is central to athletes' transition trajectories and hence the management of identity change is a crucial area for support. The More Than Sport (MTS) program is a novel digital intervention that aims to provide this support-helping athletes manage identity change in the process of leaving elite sport. The present research aims to study elite athletes' experiences with the MTS program and their perceptions of its usefulness in managing the transition away from elite sport. We undertook a qualitative study with athletes (N = 25) from three countries (the United Kingdom, Australia and Belgium) using reflexive thematic analysis to explore their experiences of the program and their feedback on program content. We identified three key themes and eight subthemes. The first key theme was Value of the Program, and this was underpinned by four sub-themes that centred on Program importance and novelty, how Positive and confronting experiences afford insight, the Value of developing shared understanding, and Realising the value of social groups. The second key theme was Engagement with Program Elements and here participants commented on Program content and Delivery format. The final key theme was Time and Place for Identity Management Programs which included the sub-themes of Optimal timing and Additional program beneficiaries. Overall, the results highlight the value of MTS specifically, and identity management efforts more broadly, to help elite athletes adjust successfully to life beyond sport., Competing Interests: Declaration of competing interest Authors CH, TC, AC, KF, PC and CH are the developers of More than Sport and thus have an academic interest in the program., (Copyright © 2024. Published by Elsevier Ltd.)

Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition with potentially serious manifestations. Management has traditionally comprised therapies to palliate symptoms and implantable cardioverter-defibrillators to prevent sudden cardiac death. The need for disease-modifying therapies has been recognized for decades. More recently, an increasing number of novel and repurposed therapies hypothesized to target HCM disease pathways have been evaluated, culminating in the recent regulatory approval of mavacamten, a novel oral myosin inhibitor. HCM poses several unique challenges for clinical trials, which are important to recognize when designing trials and interpreting findings. This manuscript discusses the key considerations in the context of recent and ongoing randomized trials, including the roles of genotype, phenotype and symptom status in patient selection, the evidence base for clinical and mechanistic outcome measurements, trial duration and sample size., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

This paper outlines a novel method for leadership researchers and practitioners to understand how and why effective and ineffective leadership look different in different groups. Leadership is a complex and contextually dependent process influenced by the interplay between leaders, followers, the group, and their environment. The social identity approach to leadership describes how a group's identity shapes the ways in which people can lead effectively. It also implies that (in)effective leadership looks different across diverse groups and teams. Accordingly, it follows that there is no single correct way to lead. To explore these ideas, we propose ethnographic methods, where researchers and practitioners immerse themselves in a group environment, as a novel type of method for examining leadership in action. We suggest the social identity approach as a framework to help guide researchers' data collection and sense-making of leadership behaviours. Additionally, we explain that ethnographic data can be represented well through creative non-fiction stories that capture the context surrounding leadership behaviours. These stories could support leadership consultancy and development programs to demonstrate the complex interplay between leaders, followers, and the group context.

Context: Higher levels of FSH are associated with bone loss among women during the perimenopausal transition and among older men, independent of estradiol and testosterone levels, but whether higher FSH is an independent fracture risk factor is unknown., Objective: Determine whether baseline FSH level predicts subsequent hip fracture in older adults., Setting, Design, Participants: Using a case-cohort design, we randomly sampled 295 participants stratified by sex from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort, including 25 participants with incident hip fracture within 10 years after baseline. We sampled an additional 230 sex-stratified participants with incident hip fracture. Serum FSH and sex hormone levels were measured at baseline. Robust weighted Cox proportional hazards models were used to determine the relationship between FSH and hip fracture risk., Main Outcome: Incident hip fracture., Results: As no interaction was identified between FSH and sex for the relationship with fracture, men and women were pooled for analysis. Higher levels of FSH were associated with a significantly increased risk of incident hip fracture in models adjusted for age and sex [hazard ratio (HR) 1.24 (95% CI 1.04-1.48, p=0.02)] and after further adjustment for estradiol, testosterone, and sex hormone binding globulin levels [HR 1.20 (95% CI 1.01-1.44, p=0.04) per sex-specific SD increase in FSH level]., Conclusions: Higher FSH is associated with increased risk of subsequent hip fracture. Our findings support a growing body of evidence for direct pleiotropic effects of FSH on bone, and for a role for FSH in aging and disability independent of sex hormone levels., (Published by Oxford University Press on behalf of the Endocrine Society 2024.)

Canagliflozin (CANA) is a sodium glucose cotransporter-2 inhibitor that reduces blood glucose levels. Sodium glucose cotransporter-2 is primarily expressed in the kidney, but not in any bone cells, therefore effects on the skeleton are likely to be non-cell autonomous. Originally developed to treat type II diabetes, CANA use has expanded to treat cardiovascular and renovascular disease. Clinical trials examining CANA in diabetic patients have produced contradictory reports on fracture risk, but there are limited data of CANA in nondiabetic conditions. In nondiabetic preclinical models, short-term treatment with CANA negatively affected trabecular bone whereas long-term treatment reduced cortical bone mineralization in male but not female mice. To investigate the skeletal effects of an intermediate period of CANA treatment, we treated male and female C57BL/6 J mice with CANA (180 ppm) for 6 months. Age at treatment initiation was also evaluated, with cohorts starting CANA prior to skeletal maturity (3-months-old) or in adulthood (6-months-old). Longitudinal assessments of bone mineral density revealed early benefits of CANA treatment in female mice. At euthanasia, both trabecular and cortical bone morphology were improved by CANA treatment in males and females. Bone formation was reduced at the endosteal surface. CANA decreased osteoblast number in male mice and bone marrow adiposity in females. Overall, more skeletal benefits were recorded in CANA-treated females than males. Urinary calcium output increased with CANA treatment, but parathyroid hormone was not changed. Despite reduced fasting blood glucose, body composition and whole-body metabolism were minimally changed by CANA treatment. For all outcome measures, limited differences were recorded based on age at treatment initiation. This study demonstrated that in nondiabetic C57BL/6 J mice, an intermediate period of CANA treatment improved bone morphology, but reduced osteoblast and bone marrow adipocyte number as well as serum procollagen type 1 N-terminal pro-peptide in a sex-specific manner., Competing Interests: The authors declare no conflict of interest. All authors have read and agreed to the published version of the manuscript., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

In naive individuals, sensory neurons directly detect and respond to allergens, leading to both the sensation of itch and the activation of local innate immune cells, which initiate the allergic immune response 1,2 . In the setting of chronic allergic inflammation, immune factors prime sensory neurons, causing pathologic itch 3-7 . Although these bidirectional neuroimmune circuits drive responses to allergens, whether immune cells regulate the set-point for neuronal activation by allergens in the naive state is unknown. Here we describe a γδ T cell-IL-3 signalling axis that controls the allergen responsiveness of cutaneous sensory neurons. We define a poorly characterized epidermal γδ T cell subset 8 , termed GD3 cells, that produces its hallmark cytokine IL-3 to promote allergic itch and the initiation of the allergic immune response. Mechanistically, IL-3 acts on Il3ra-expressing sensory neurons in a JAK2-dependent manner to lower their threshold for allergen activation without independently eliciting itch. This γδ T cell-IL-3 signalling axis further acts by means of STAT5 to promote neuropeptide production and the initiation of allergic immunity. These results reveal an endogenous immune rheostat that sits upstream of and governs sensory neuronal responses to allergens on first exposure. This pathway may explain individual differences in allergic susceptibility and opens new therapeutic avenues for treating allergic diseases., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Immunoprevention is an emerging consideration for solid tumors, including pancreatic ductal adenocarcinoma (PDAC). We and others have shown that Kras mutations in genetic models of spontaneous pancreatic intraepithelial neoplasia (PanIN), which is a precursor to PDAC, results in CD73 expression in the neoplastic epithelium and some populations of infiltrating immune cells, including macrophages and CD8 T cells. CD73 is an ecto-enzyme that converts extracellular adenosine monophosphate to adenosine, a critical immune inhibitory molecule in PDAC. We hypothesized inhibition of CD73 would reduce the incidence of PanIN formation and alter the immune microenvironment. To test our hypothesis, we used the KrasG12D; PdxCre1 (KC) genetically engineered mouse model and tested the utility of AB-680, a small molecule inhibitor targeting CD73, to inhibit PanIN progression. AB-680, or vehicle control, was administered using oral gavage delivery 3 days/week at 10 mg/kg, beginning when the mice were 2 months old and lasting 3 months. We euthanized the mice at 5 months old. In the KC model, we quantified significantly less pancreatitis, early and advanced PanIN, and quantified a significant increase in M1 macrophages in AB-680-treated mice. Single-cell RNA sequencing (scRNA-seq) of pancreata of AB-680-treated mice revealed increased infiltration of CD4+ T cells, CD8+ T cells, and mature B cells. The scRNA-seq analysis showed that CD73 inhibition reduced M2 macrophages, acinar, and PanIN cell populations. CD73 inhibition enhanced immune surveillance and expanded unique clonotypes of TCR and BCR, indicating that inhibition of CD73 augments adaptive immunity early in the neoplastic microenvironment. Prevention Relevance: Previous studies found PanIN lesions in healthy pancreata. Not all progress to PDAC, suggesting a window for enhanced antitumor immunity through immunoprevention therapy. CD73 inhibition in our study prevents PanIN progression, reduces immune-suppressive macrophages and expands TCR and BCR unique clonotypes, highlighting an encouraging therapeutic avenue for high-risk individuals., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objective: The skeleton is one of the largest organs in the body, wherein metabolism is integrated with systemic energy metabolism. However, the bioenergetic programming of osteocytes, the most abundant bone cells coordinating bone metabolism, is not well defined. Here, using a mouse model with partial penetration of an osteocyte-specific PPARG deletion, we demonstrate that PPARG controls osteocyte bioenergetics and their contribution to systemic energy metabolism independently of circulating sclerostin levels, which were previously correlated with metabolic status of extramedullary fat depots., Methods: In vivo and in vitro models of osteocyte-specific PPARG deletion, i.e. Dmp1 Cre Pparγ flfl male and female mice (γOT KO ) and MLO-Y4 osteocyte-like cells with either siRNA-silenced or CRISPR/Cas9-edited Pparγ. As applicable, the models were analyzed for levels of energy metabolism, glucose metabolism, and metabolic profile of extramedullary adipose tissue, as well as the osteocyte transcriptome, mitochondrial function, bioenergetics, insulin signaling, and oxidative stress., Results: Circulating sclerostin levels of γOT KO male and female mice were not different from control mice. Male γOT KO mice exhibited a high energy phenotype characterized by increased respiration, heat production, locomotion and food intake. This high energy phenotype in males did not correlate with "beiging" of peripheral adipose depots. However, both sexes showed a trend for reduced fat mass and apparent insulin resistance without changes in glucose tolerance, which correlated with decreased osteocytic responsiveness to insulin measured by AKT activation. The transcriptome of osteocytes isolated from γOT KO males suggested profound changes in cellular metabolism, fuel transport, mitochondria dysfunction, insulin signaling and increased oxidative stress. In MLO-Y4 osteocytes, PPARG deficiency correlated with highly active mitochondria, increased ATP production, and accumulation of reactive oxygen species (ROS)., Conclusions: PPARG in male osteocytes acts as a molecular break on mitochondrial function, and protection against oxidative stress and ROS accumulation. It also regulates osteocyte insulin signaling and fuel usage to produce energy. These data provide insight into the connection between osteocyte bioenergetics and their sex-specific contribution to the balance of systemic energy metabolism. These findings support the concept that the skeleton controls systemic energy expenditure via osteocyte metabolism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Caloric restriction (CR), commonly used as both a lifestyle choice and medical strategy, has been shown to adversely impact appendicular bone mass. However, its influence on alveolar bone health and the underlying mechanisms remain poorly understood. In this study, 8-week-old C57BL/6 J mice were fed with 30 % CR for 8 weeks. Micro-architecture, histologic parameters, and in vitro trajectories of osteoblast and adipocyte differentiation were examined. To further explore the underlying mechanisms, metabolic cages and in vitro bioenergetics were performed. Our results showed that 8 weeks of CR led to trabecular and cortical bone loss in the mandibles of female mice. CR in female mice decreased bone formation and bone resorption activities but induced adiposity in the mandibles. After CR, the adipogenesis in mesenchymal cells from orofacial bones (OMSCs) was greatly accelerated, whereas osteogenic differentiation was reduced in females. Undifferentiated CR OMSCs showed marked suppression in ATP production rates from mitochondria in female mice. ATP production rates decreased after osteogenesis but were upregulated during adipogenesis in female mice. Conversely, the generation of reactive oxygen species (ROS) was heightened during both osteoblastic and adipogenic differentiation in female CR groups. Collectively, our study indicated that CR could cause significant bone loss in the mandibles of female mice, almost certainly related to a reduced ATP supply and the unregulated generation of ROS., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the enduring disparities in adverse COVID-19 events between urban and rural communities in the United States, focusing on the effects of SARS-CoV-2 vaccination and therapeutic advances on patient outcomes., Methods: Using National COVID Cohort Collaborative (N3C) data from 2021 to 2023, this retrospective cohort study examined COVID-19 hospitalization, inpatient death, and other adverse events. Populations were categorized into urban, urban-adjacent rural (UAR), and nonurban-adjacent rural (NAR). Adjustments included demographics, variant-dominant waves, comorbidities, region, and SARS-CoV-2 treatment and vaccination. Statistical methods included Kaplan-Meier survival estimates, multivariable logistic, and Cox regression., Findings: The study included 3,018,646 patients, with rural residents constituting 506,204. These rural dwellers were older, had more comorbidities, and were less vaccinated than their urban counterparts. Adjusted analyses revealed higher hospitalization odds in UAR and NAR (aOR 1.07 [1.05-1.08] and 1.06 [1.03-1.08]), greater inpatient death hazard (aHR 1.30 [1.26-1.35] UAR and 1.37 [1.30-1.45] NAR), and greater risk of other adverse events compared to urban dwellers. Delta increased, while Omicron decreased, inpatient adverse events relative to pre-Delta, with rural disparities persisting throughout. Treatment effectiveness and vaccination were similarly protective across all cohorts, but dexamethasone post-ventilation was effective only in urban areas. Nirmatrelvir/ritonavir and molnupiravir better protected rural residents against hospitalization., Conclusions: Despite advancements in treatment and vaccinations, disparities in adverse COVID-19 outcomes persist between urban and rural communities. The effectiveness of some therapeutic agents appears to vary based on rurality, suggesting a nuanced relationship between treatment and geographic location while highlighting the need for targeted rural health care strategies., (© 2024 The Author(s). The Journal of Rural Health published by Wiley Periodicals LLC on behalf of National Rural Health Association.)

Background and Objectives: Anatomic features of neuromas have been explored in imaging studies. However, there has been limited research into these features using resected, ex vivo human neuroma specimens. The aim of this study was to investigate the influence that time may have on neuroma growth and size, and the clinical significance of these parameters., Methods: Patients who underwent neuroma excision between 2022 through 2023 were prospectively included in this study. Neuroma specimens were obtained after operative resection. Standardized neuroma size measurements, expressed as a neuroma-to-nerve ratio (NNR), were conducted with ImageJ software. Pain data (numeric rating scale, 0-10) were prospectively recorded during preoperative evaluation, and patient factors were collected from chart reviews., Results: Fifty terminal neuroma specimens from 31 patients were included, with 94.0% of the neuromas obtained from individuals with amputations. Most neuromas were excised from the lower extremities (n = 44, 88.0%). The neuromas had a median NNR of 2.45, and the median injury to neuroma excision interval was 6.3 years. Larger NNRs were associated with a longer injury to neuroma excision interval and with a smaller native nerve diameter. In addition, sensory nerves were associated with a larger NNR compared with mixed nerves. NNR was not associated with preoperative pain or with anatomical nerve distribution., Conclusion: This study suggests that neuromas seem to continue to grow over time and that smaller nerves may form relatively larger neuromas. In addition, sensory nerves develop relatively larger neuromas compared with mixed nerves. Neuroma size does not appear to correlate with pain severity. These findings may stimulate future research efforts and contribute to a better understanding of symptomatic neuroma development., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

We sought to explore the strategies and behaviours employed by University serial winning coaches during seasons of both low performance and a maladaptive team culture. We interviewed seven University team sport coaches and subsequently analyzed the data using a reflexive thematic analysis (RTA). Results indicated that our coaches generally felt unprepared for the unexpected and challenging season, leading to increased stress and decreased psychological well-being. Coaches experienced frustration, disappointment, and self-doubt, which was either exacerbated or mitigated by their access to social support. Despite the emotional turmoil coaches experienced, they were able to reflect on their actions and take away key lessons, helping them perform well in the future. Findings provide insight into how winning coaches manage and overcome inevitable adverse situations. Moreover, these results provide a deeper understanding of how these highly successful coaches navigate these key challenges that over time can inform policy and practice in coach development. These coaching strategies may help coaches of all levels overcome barriers to success and may be transferable to leaders of all levels across a range of disciplines outside of sport., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Emergency Department (ED) care is provided for a diverse range of patients, clinical acuity and conditions. This diversity often calls for different vital signs monitoring requirements. Requirements often change depending on the circumstances that patients experience during episodes of ED care., Aim: To describe expert consensus on vital signs monitoring during ED care in the Australasian setting to inform the content of a joint Australasian College for Emergency Medicine (ACEM) and College of Emergency Nursing Australasia (CENA) position statement on vital signs monitoring in the ED., Method: A 4-hour online nominal group technique workshop with follow up surveys., Results: Twelve expert ED nurses and doctors from adult, paediatric and mixed metropolitan and regional ED and research facilities spanning four Australian states participated in the workshop and follow up surveys. Consensus building generated 14 statements about vital signs monitoring in ED. Good consensus was reached on whether vital signs should be assessed for 15 of 19 circumstances that patients may experience., Conclusion: This study informed the creation of a joint position statement on vital signs monitoring in the Australasian ED setting, endorsed by CENA and ACEM. Empirical evidence is needed for optimal, safe and achievable policy on this fundamental practice., Competing Interests: Declaration of Competing Interest All authors are Fellows of CENA or ACEM., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sensory neurons generated from induced pluripotent stem cells (iSNs) are used to model human peripheral neuropathies, however current differentiation protocols produce sensory neurons with an embryonic phenotype. Peripheral glial cells contact sensory neurons early in development and contribute to formation of the canonical pseudounipolar morphology, but these signals are not encompassed in current iSN differentiation protocols. Here, we show that terminal differentiation of iSNs in co-culture with rodent Dorsal Root Ganglion satellite glia (rSG) advances their differentiation and maturation. Co-cultured iSNs develop a pseudounipolar morphology through contact with rSGs. This transition depends on semaphorin-plexin guidance cues and on glial gap junction signaling. In addition to morphological changes, iSNs terminally differentiated in co-culture exhibit enhanced spontaneous action potential firing, more mature gene expression, and increased susceptibility to paclitaxel induced axonal degeneration. Thus, iSNs differentiated in coculture with rSGs provide a better model for investigating human peripheral neuropathies.

Postoperative pain affects most patients after major surgery and can transition to chronic pain. The considerable side effects and limited efficacy of current treatments underline the need for new therapeutic options. We observed increased amounts of the metabolites BH4 and serotonin after skin injury. Mast cells were primary postoperative sources of Gch1 , the rate-limiting enzyme in BH4 synthesis, itself an obligate cofactor in serotonin production by tryptophan hydroxylase (Tph1). Mice deficient in mast cells or in mast cell-specific Gch1 or Tph1 showed drastically decreased postoperative pain. We found that injury induced the nociceptive neuropeptide substance P, mast cell degranulation, and granule nerve colocalization. Substance P triggered serotonin release in mouse and human mast cells, and substance P receptor blockade substantially ameliorated pain hypersensitivity. Our findings highlight the importance of mast cells at the neuroimmune interface and substance P-driven mast cell BH4 and serotonin production as a therapeutic target for postoperative pain treatment.

Calorie restriction (CR) can lead to weight loss and decreased substrate availability for bone cells. Ultimately, this can lead to impaired peak bone acquisition in children and adolescence and bone loss in adults. But the mechanisms that drive diet-induced bone loss in humans are not well characterized. To explore those in greater detail, we examined the impact of 30% CR for 4 and 8 wk in both male and female 8-wk-old C57BL/6 J mice. Body composition, areal bone mineral density (aBMD), skeletal microarchitecture by micro-CT, histomorphometric parameters, and in vitro trajectories of osteoblast and adipocyte differentiation were examined. After 8 wk, CR mice lost weight and exhibited lower femoral and whole-body aBMD vs ad libitum (AL) mice. By micro-CT, CR mice had lower cortical bone area fraction vs AL mice, but males had preserved trabecular bone parameters and females showed increased bone volume fraction compared to AL mice. Histomorphometric analysis revealed that CR mice had a profound suppression in trabecular as well as endocortical and periosteal bone formation in addition to reduced bone resorption compared to AL mice. Bone marrow adipose tissue was significantly increased in CR mice. In vitro, the pace of adipogenesis in bone marrow stem cells was greatly accelerated with higher markers of adipocyte differentiation and more oil red O staining, whereas osteogenic differentiation was reduced. qRT-PCR and western blotting suggested that the expression of Wnt16 and the canonical β-catenin pathway was compromised during CR. In sum, CR causes impaired peak cortical bone mass due to a profound suppression in bone remodeling. The increase in marrow adipocytes in vitro and in vivo is related to both progenitor recruitment and adipogenesis in the face of nutrient insufficiency. Long-term CR may lead to lower bone mass principally in the cortical envelope, possibly due to impaired Wnt signaling., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Metformin (dimethyl-biguanide) can claim its origins in the use of Galega officinalis as a plant treatment for symptoms ascribed to diabetes. Since the first clinical use of metformin as a glucose-lowering agent in 1957, this medicine has emerged as a first-line pharmacological option to support lifestyle interventions in the management of type 2 diabetes (T2D). It acts through multiple cellular pathways, principally in the gut, liver and muscle, to counter insulin resistance and lower blood glucose without weight gain or risk of overt hypoglycaemia. Other effects include improvements in lipid metabolism, decreased inflammation and lower long-term cardiovascular risk. Metformin is conveniently combined with other diabetes medications, can be prescribed in prediabetes to reduce the risk of progression to T2D, and is used in some regions to assist glycaemic control in pregnancy. Consistent with its diversity of actions, established safety profile and cost-effectiveness, metformin is being assessed for further possible clinical applications. The use of metformin requires adequate renal function for drug elimination, and may cause initial gastrointestinal side effects, which can be moderated by taking with meals or using an extended-release formulation. Thus, metformin serves as a valuable therapeutic resource for use throughout the natural history of T2D., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objectives: To measure changes in cause of death dynamics in 2019 and 2020 and the relationship between the concurrent occurrence of the COVID-19 pandemic and mortality outcome by race and ethnicity., Patients and Methods: We used resident mortality data from the Minnesota Department of Health (MDH) to conduct a retrospective statistical analysis of deaths in Minnesota in 2019 relative to 2020 to assess changes in mortality in a pre-pandemic and pandemic period., Results: COVID-19 strongly contributed to ethnicity-related mortality disparities in Minnesota. Not only was there a greater proportion of COVID-19 decedents within Black and Hispanic populations, but their average decedent age was markedly lower relative to the White population. The Black population experienced a disproportionate increase in decedents with a 34% increase during 2020 compared to 2019., Conclusions: This retrospective analysis of death dynamics and mortality outcomes in Minnesota from 2019 to 2020 demonstrated an increase in adverse mortality outcomes relative to the pre-pandemic period that disproportionately impacted Black and Hispanic minority populations., (© 2023. W. Montague Cobb-NMA Health Institute.)

Introduction: Differences in the prevalence of psychiatric conditions such as psychosis as well as patterns of comorbidity for psychosis have been reported between racial and ethnic groups. It is unclear whether those differences are consistent for comorbid psychosis., Methods: Self-reported diagnostic data from American adults ages 18-99 participating in the Collaborative Psychiatric Epidemiology Surveys (CPES) (N ~ 11,844) were used to test the association between four racial and ethnic group categories (White, Asian, Hispanic, Black) and comorbid psychosis. Comorbid psychosis was measured as a 4-level categorical variable (No mental illness nor psychosis, Mental Illness, Psychosis only, comorbid psychosis (i.e., Psychosis + Mental Illness). Chi-square tests were used to determine significant differences in the prevalence of comorbid psychosis by race and ethnicity. A multinomial logistic regression was used to test the association between racial and ethnic classifications and comorbid psychosis after adjusting for common demographic characteristics (i.e., education, sex, income, and age)., Results: Relative to White participants, Hispanic and Asian participants were less likely to be affected with comorbid psychosis. (Adjusted Odds Ratio, AOR Asian = 0.32, CI = 0.22 - 0.47, p <0.0001, AOR Hispanic = 0.66, CI = 0.48 - 0.92, p = 0.012). Relative to White participants there was not significant association for comorbid psychosis in Black participants (AOR Black = 0.91, CI = 0.70 - 1.20, p = 0.52) In contrast Hispanic and Black participants were more likely to report psychosis alone (AOR Hispanic = 1.94, CI = 1.27-2.98, p = 0.002, AOR Black = 1.86, 1.24-2.82, p = 0.003) compared to White participants., Conclusion: There were different patterns of associations by race and ethnicity for psychosis and comorbid psychosis. The lower prevalence of comorbid psychosis in non-White groups may be due to underdiagnosis or underreporting of other mental disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sankoh, Clifford, Peterson and Prom-Wormley.)

Study Objective: Assessing if Transcatheter Edge to Edge Repair (TEER) with Mitraclip™ in patients with moderate to severe mitral regurgitation (MR) and cardiogenic shock (CS) improves outcomes compared to medical management alone., Design: A single-center, retrospective study was performed in an urban tertiary referral center., Setting: Rush University Medical Center, United States., Participants: Adult patients presenting with CS and moderate to severe MR between 2012 and 2021 were included., Interventions: Undergoing Mitral TEER with Mitraclip versus medical management alone., Main Outcome Measures: Major adverse cardiovascular events (MACE) defined as cardiovascular death, heart failure admission, stroke, and myocardial infarction assessed at 30 days, 6 months, and 1 year. The secondary outcome was a change in New York Heart Association (NYHA) classification at 30 days and 6 months., Results: There were 28 patients included in the medical management and 33 in the mitral valve TEER groups. There was a decreased MACE in the intervention group at 30 days (24.2 % vs. 46.4 %, p  ≤0.001) and 6 months (27 % vs. 75 %, p  = 0.002), though not at 1 year (29.4 % vs. 41.7 %, p  = 0.42). At 30 days, more patients in the mitral valve TEER group improved to NYHA classes I/II compared to medical management alone (10 [35.7 %] vs. 16 [50 %], p  = 0.043). There were no differences in NYHA classes I/II at 6 months (7 [43.7 %] vs. 13 [54.2 %], p  = 0.63)., Conclusion: Mitral valve TEER using the Mitraclip™ system improves mid-term cardiovascular compared to medical management alone in patients with CS but does not improve mortality., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient's quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles - AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic., (© 2024. The Author(s).)

Tissue buckling is an increasingly appreciated mode of morphogenesis in the embryo, but it is often unclear how geometric and material parameters are molecularly determined in native developmental contexts to generate diverse functional patterns. Here, we study the link between differential mechanical properties and the morphogenesis of distinct anteroposterior compartments in the intestinal tract-the esophagus, small intestine, and large intestine. These regions originate from a simple, common tube but adopt unique forms. Using measured data from the developing chick gut coupled with a minimal theory and simulations of differential growth, we investigate divergent lumen morphologies along the entire early gut and demonstrate that spatiotemporal geometries, moduli, and growth rates control the segment-specific patterns of mucosal buckling. Primary buckling into wrinkles, folds, and creases along the gut, as well as secondary buckling phenomena, including period-doubling in the foregut and multiscale creasing-wrinkling in the hindgut, are captured and well explained by mechanical models. This study advances our existing knowledge of how identity leads to form in these regions, laying the foundation for future work uncovering the relationship between molecules and mechanics in gut morphological regionalization., Competing Interests: Competing interests statement:The authors declare no competing interest.

Purpose of Review: Patent foramen ovale (PFO) has been previously linked to left circulation thromboembolism and stroke. This review article aims to discuss the latest evidence, updated societal guidelines, diagnostic algorithms and novel therapeutic devices for PFO closure., Recent Findings: PFO closure for cryptogenic stroke and systemic embolization is supported by a large body of evidence and has a strong societal recommendation. Limited data are available for platypnea-orthodeoxia syndrome, although closure appears to be beneficial. Current data do not support routine closure for migraines and decompression Illness. Development of heart-brain teams can improve identification of patients most likely to benefit from closure, utilizing a combination of imaging test and risk score algorithms. Multiple novel devices aiming at reducing complications and improving the long-term impact of current available devices are being evaluated. PFO closure has significantly progressed over the last years, with new data supporting its superiority in reducing risk of recurrent embolic stroke in patients with PFO-related stroke. Additional clinical data are required to provide further refinements on patient selection and guidance on treatment of specific subgroups., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hypercholesterolemia is frequently intertwined with hepatosteatosis, hypertriglyceridemia, and hyperglycemia. This study is designed to assess the therapeutic efficacy of miR-206 in contrast to statins in the context of managing hypercholesterolemia in mice. We previously showed that miR-206 is a potent inhibitor of de novo lipogenesis (DNL), cholesterol synthesis, and gluconeogenesis in mice. Given that these processes occur within hepatocytes, we employed a mini-circle (MC) system to deliver miR-206 specifically to hepatocytes (designated as MC-miR-206). A single intravenous injection of MC-miR-206 maintained high levels of miR-206 in the liver for at least two weeks, thereby maintaining suppression of hepatic DNL, cholesterol synthesis, and gluconeogenesis. MC-miR-206 significantly reduced DNA damage, endoplasmic reticulum and oxidative stress, and hepatic toxicity. Therapeutically, both MC-miR-206 and statins significantly reduced total serum cholesterol and triglycerides as well as LDL cholesterol and VLDL cholesterol in mice maintained on the normal chow and high-fat high-cholesterol diet. MC-miR-206 reduced liver weight, hepatic triglycerides and cholesterol, and blood glucose, while statins slightly increased hepatic cholesterol and blood glucose and failed to affect levels of liver weight and hepatic triglycerides. Mechanistically, miR-206 alleviated hypercholesterolemia by inhibiting hepatic cholesterol synthesis, while statins increased HMGCR activity, hepatic cholesterol synthesis, and fecal-neutral steroid excretion. MiR-206 facilitates the regression of hypercholesterolemia, hypertriglyceridemia, hyperglycemia, and hepatosteatosis. MiR-206 outperforms statins by reducing hyperglycemia, hepatic cholesterol levels, and hepatic toxicity., Competing Interests: Conflict of interests The authors involved in this study declared that they have nothing to disclose regarding funding or conflict of interest with respect to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Small fiber neuropathy (SFN) is a common and debilitating disease in which the terminals of small diameter sensory axons degenerate, producing sensory loss, and in many patients neuropathic pain. While a substantial number of cases are attributable to diabetes, almost 50% are idiopathic. An underappreciated aspect of the disease is its late onset in most patients. Animal models of human genetic mutations that produce SFN also display age-dependent phenotypes suggesting that aging is an important contributor to the risk of development of the disease. In this review we define how particular sensory neurons are affected in SFN and discuss how aging may drive the disease. We also evaluate how animal models of SFN can define disease mechanisms that will provide insight into early risk detection and suggest novel therapeutic interventions., Competing Interests: Declaration of competing interest DGT has no interests to declare. CJW is a founder of Nocion Therapeutics and on the SAB of Lundbeck Pharma., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Retirement is one of the most impactful career transitions athletes face. Researchers recognise the role that athletic identity plays in this, but analysis of identity content and change processes is limited. Addressing this gap, we conducted a qualitative study exploring the experience of identity change in 21 competitive and successful elite athletes who had retired from sport. All participated in a one-session psychoeducational program that explored the challenges of transitioning out of sport before being interviewed about their understanding of identity in sport, and their experiences negotiating identity loss and change in retirement. Using reflexive thematic analysis, we identified three themes: (i) the role of identity and self-categorizations in shaping sport performance, (ii) adjusting to identity loss (with subthemes indicating that this experience varied depending on the extent to which a person had multiple or exclusive identities), and (iii) attempts to remoor identity in the transition (with subthemes of searching for a new identity and actively repurposing identity). We interpret these themes through the lens of the Social Identity Model of Identity Change and show that this provides a framework for extending our understanding the complexities of identity change associated with retirement from elite sport., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Inflammatory pain results from the heightened sensitivity and reduced threshold of nociceptor sensory neurons due to exposure to inflammatory mediators. However, the cellular and transcriptional diversity of immune cell and sensory neuron types makes it challenging to decipher the immune mechanisms underlying pain. Here we used single-cell transcriptomics to determine the immune gene signatures associated with pain development in three skin inflammatory pain models in mice: zymosan injection, skin incision and ultraviolet burn. We found that macrophage and neutrophil recruitment closely mirrored the kinetics of pain development and identified cell-type-specific transcriptional programs associated with pain and its resolution. Using a comprehensive list of potential interactions mediated by receptors, ligands, ion channels and metabolites to generate injury-specific neuroimmune interactomes, we also uncovered that thrombospondin-1 upregulated by immune cells upon injury inhibited nociceptor sensitization. This study lays the groundwork for identifying the neuroimmune axes that modulate pain in diverse disease contexts., (© 2024. The Author(s).)

Post-COVID-19 conditions (long COVID) has impacted many individuals, yet risk factors for this condition are poorly understood. This retrospective analysis of 88,943 COVID-19 patients at a multi-state US health system compares phenotypes, laboratory tests, medication orders, and outcomes for 1,086 long-COVID patients and their matched controls. We found that history of chronic pulmonary disease (CPD) (odds ratio: 1.9, 95% CI: [1.5, 2.6]), migraine (OR: 2.2, [1.6, 3.1]), and fibromyalgia (OR: 2.3, [1.3, 3.8]) were more common for long-COVID patients. During the acute infection phase long COVID patients exhibited high triglycerides, low HDL cholesterol, and a high neutrophil-lymphocyte ratio; and were more likely hospitalized (5% vs. 1%). Our findings suggest severity of acute infection and history of CPD, migraine, chronic fatigue syndrome (CFS), or fibromyalgia as risk factors for long COVID. These results suggest that suppressing acute disease severity proactively, especially in patients at high risk, can reduce incidence of long COVID., Competing Interests: P.G. was an employee of nference and is a current employee of ConcertAI and has financial interests in these companies and the successful application of this research. M.N., C.P., H.B., U.Y., P.L., P.K., M.N., J.R., S.A., and A.V. are employees of nference and have financial interests in the company and in the successful application of this research. V.S. is an employee of nference and Anumana and has financial interests in these companies and in the successful application of this research. J.O. has received small grants from nference, Inc., and personal consulting fees from Bates College and Elsevier Inc. All of these activities are outside of the present work. R.H. has received a small grant from nference, Inc. and Zealand Pharmaceuticals, and consulting fees from Nestle Nutrition. C.R. acknowledges funding from the National Institutes of Health (1OT2HL162096-01). A.T. is an employee and shareholder of Vir Biotechnology Inc., (© 2024 The Author(s).)

Sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli to the central nervous system. Single-cell RNA sequencing has provided insights into the diversity of sensory ganglia cell types in rodents, nonhuman primates, and humans, but it remains difficult to compare cell types across studies and species. We thus constructed harmonized atlases of the DRG and TG that describe and facilitate comparison of 18 neuronal and 11 non-neuronal cell types across six species and 31 datasets. We then performed single-cell/nucleus RNA sequencing of DRG from both human and the highly regenerative axolotl and found that the harmonized atlas also improves cell type annotation, particularly of sparse neuronal subtypes. We observed that the transcriptomes of sensory neuron subtypes are broadly similar across vertebrates, but the expression of functionally important neuropeptides and channels can vary notably. The resources presented here can guide future studies in comparative transcriptomics, simplify cell-type nomenclature differences across studies, and help prioritize targets for future analgesic development.

Parents play a central role in children's ongoing participation and enjoyment of sport. Despite compelling evidence that parental behaviour can undermine the quality of children's experiences in sport, little research has examined whether strategies to support parents to engage in positive sports parenting behaviour are effective. In this paper, we report two studies that had the overall aim of developing, implementing and evaluating a program designed to promote positive parental involvement and improve spectator behaviour in junior rugby league in Australia. Study 1 involved the development of a prototype version of the program, named Play Well Triple P, which was qualitatively evaluated through interviews with 19 parents about their satisfaction with the program. In Study 2, we used feedback from Study 1 to refine the program and develop a pilot version, which was then evaluated in a quasi-experimental feasibility study with 101 parents (mean age = 38.42 years; 72% mothers) of junior rugby league players. The pilot version involved one interactive online module and text messages to reinforce content and prompt strategy implementation across the season. Participation in Play Well Triple P was associated with increased positive sports parenting behaviour and reduced controlling and intrusive sports parenting behaviour, with a trend towards reducing over-reactive parenting practices at home. These findings are discussed in relation to the feasibility of implementing a brief and engaging sports parenting intervention in the context of a broader integrated system designed to facilitate ongoing participation of children in sport., (© 2024. The Author(s).)

Biomaterial properties have recently been shown to modulate extracellular vesicle (EV) secretion and cargo; however, the effects of substrate composition on EV production remain underexplored. This study investigates the impacts of surface coatings composed of collagen I (COLI), fibronectin (FN), and poly l-lysine (PLL) on EV secretion for applications in therapeutic EV production and to further understanding of how changes in the extracellular matrix microenvironment affect EVs. EV secretion from primary bone marrow-derived mesenchymal stromal cells (BMSCs), primary adipose-derived stem cells (ASCs), HEK293 cells, NIH3T3 cells, and RAW264.7 cells was characterized on the different coatings. Expression of EV biogenesis genes and cellular adhesion genes was also analyzed. COLI coatings significantly decreased EV secretion in RAW264.7 cells, with associated decreases in cell viability and changes in EV biogenesis-related and cell adhesion genes at day 4. FN coatings increased EV secretion in NIH3T3 cells, while PLL coatings increased EV secretion in ASCs. Surface coatings had significant effects on the capacity of EVs derived from RAW264.7 and NIH3T3 cells to impact in vitro macrophage proliferation. Overall, surface coatings had different cell-specific effects on EV secretion and in vitro functional capacity, thus highlighting the potential of substrate coatings to further the development of clinical EV production systems.

While voltage-gated potassium channels have critical roles in controlling neuronal excitability, they also have non-ion-conducting functions. Kv8.1, encoded by the KCNV1 gene, is a 'silent' ion channel subunit whose biological role is complex since Kv8.1 subunits do not form functional homotetramers but assemble with Kv2 to modify its ion channel properties. We profiled changes in ion channel expression in amyotrophic lateral sclerosis patient-derived motor neurons carrying a superoxide dismutase 1(A4V) mutation to identify what drives their hyperexcitability. A major change identified was a substantial reduction of KCNV1/Kv8.1 expression, which was also observed in patient-derived neurons with C9orf72 expansion. We then studied the effect of reducing KCNV1/Kv8.1 expression in healthy motor neurons and found it did not change neuronal firing but increased vulnerability to cell death. A transcriptomic analysis revealed dysregulated metabolism and lipid/protein transport pathways in KCNV1/Kv8.1-deficient motor neurons. The increased neuronal vulnerability produced by the loss of KCNV1/Kv8.1 was rescued by knocking down Kv2.2, suggesting a potential Kv2.2-dependent downstream mechanism in cell death. Our study reveals, therefore, unsuspected and distinct roles of Kv8.1 and Kv2.2 in amyotrophic lateral sclerosis-related neurodegeneration., Competing Interests: C.J.W. and K.C.E. are founders of QurAlis Corporation and K.C.E. works at BioMarin Pharmaceutical Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)