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Abstract Background Exercise intolerance is common among adults with heart failure (HF) and is a strong prognostic indicator. We examined maximal inspiratory pressure (MIP) as an indicator of maximal and submaximal exercise capacity in older HF patients. Methods Fifty‐one patients age ≥ 50 years with HF underwent MIP testing via the PrO2 device. Peak oxygen uptake (VO2), 6 min walk distance (6MWD), 30 s sit‐to‐stand test (STS), gait speed (GS), grip strength and lower extremity muscle strength [one‐repetition maximum (1RM)] were measured. Correlation and exploratory multiple regression analyses investigated relationships between MIP, left ventricular ejection fraction (LVEF), age, body mass index (BMI) and physical function. MIP was then stratified by median (64 cm H2O), and endpoints were compared between median groups. Results The median age was 69 years [interquartile range (IQR): 66–73], and the median LVEF was 36.5% (IQR: 30%–45%). Regression identified MIP as an independent predictor for grip strength, 6MWD, 1RM weight and 30 s STS after adjustment for age, BMI and LVEF. MIP greater than the median (n = 25) independently predicted and reflected greater peak VO2 [14.2 (12.8–18.1) vs. 11.5 (9.7–13.0) mL/kg/min; P = 0.0007] as well as 6MWD, 1RM, 30 s STS and GS (all P

Abstract During endosomal recycling, Sorting Nexin 17 (SNX17) facilitates the transport of numerous membrane cargo proteins by tethering them to the Retriever complex. Despite its importance, the mechanisms underlying this interaction have remained elusive. Here, we provide biochemical, structural, cellular, and proteomic analyses of the SNX17-Retriever interaction. Our data reveal that SNX17 adopts an autoinhibited conformation in the basal state, with its FERM domain sequestering its C-terminal tail. The binding of cargo proteins to the FERM domain displaces the C-terminal tail through direct competition. The released tail engages with Retriever by binding to a highly conserved interface between its VPS35L and VPS26C subunits, as revealed by cryogenic electron microscopy (cryo-EM). Disrupting this interface impairs the Retriever-SNX17 interaction, subsequently affecting the recycling of SNX17-dependent cargoes and altering the composition of the plasma membrane proteome. Intriguingly, the SNX17-binding pocket on Retriever can be utilized by other ligands containing a consensus acidic C-terminal tail motif. Together, our findings uncover a mechanism underlying endosomal trafficking of critical cargo proteins and reveal how Retriever can potentially engage with other regulatory factors or be exploited by pathogens.

Abstract Interleukin-1 (IL-1) is a pro-inflammatory cytokine that exerts a wide range of neurological and immunological effects throughout the central nervous system (CNS) and is associated with the etiology of affective and cognitive disorders. The cognate receptor for IL-1, Interleukin-1 Receptor Type 1 (IL-1R1), is primarily expressed on non-neuronal cells (e.g., endothelial cells, choroidal cells, ventricular ependymal cells, astrocytes, etc.) throughout the brain. However, the presence and distribution of neuronal IL-1R1 (nIL-1R1) has been controversial. Here, for the first time, a novel genetic mouse line that allows for the visualization of IL-1R1 mRNA and protein expression (Il1r1 GR/GR) was used to map all brain nuclei and determine the neurotransmitter systems which express nIL-1R1 in adult male mice. The direct responsiveness of nIL-1R1-expressing neurons to both inflammatory and physiological levels of IL-1β in vivo was tested. Neuronal IL-1R1 expression across the brain was found in discrete glutamatergic and serotonergic neuronal populations in the somatosensory cortex, piriform cortex, dentate gyrus, and dorsal raphe nucleus. Glutamatergic nIL-1R1 comprises most of the nIL-1R1 expression and, using Vglut2-Cre-Il1r1 r/r mice, which restrict IL-1R1 expression to only glutamatergic neurons, an atlas of glutamatergic nIL-1R1 expression across the brain was generated. Analysis of functional outputs of these nIL-1R1-expressing nuclei, in both Il1r1 GR/GR and Vglut2-Cre-Il1r1 r/r mice, reveals IL-1R1+ nuclei primarily relate to sensory detection, processing, and relay pathways, mood regulation, and spatial/cognitive processing centers. Intracerebroventricular (i.c.v.) injections of IL-1 (20 ng) induces NFκB signaling in IL-1R1+ non-neuronal cells but not in IL-1R1+ neurons, and in Vglut2-Cre-Il1r1 r/r mice IL-1 did not change gene expression in the dentate gyrus of the hippocampus (DG). GO pathway analysis of spatial RNA sequencing 1mo following restoration of nIL-1R1 in the DG neurons reveals IL-1R1 expression downregulates genes related to both synaptic function and mRNA binding while increasing select complement markers (C1ra, C1qb). Further, DG neurons exclusively express an alternatively spliced IL-1R Accessory protein isoform (IL-1RAcPb), a known synaptic adhesion molecule. Altogether, this study reveals a unique network of neurons that can respond directly to IL-1 via nIL-1R1 through non-autonomous transcriptional pathways; earmarking these circuits as potential neural substrates for immune signaling-triggered sensory, affective, and cognitive disorders.

Abstract Background Keratinocyte carcinomas such as basal cell carcinomas and squamous cell carcinomas are a major burden affecting morbidity and mortality in solid organ transplant recipients (SOTRs). Best treatment includes frequent skin checks for early detection and surgery for high incidence of skin cancers. Sirolimus is an immunosuppressive drug which may reduce the burden of skin cancer but may be poorly tolerated when given orally. Topical sirolimus has been proven effective at reducing the burden of skin cancers in animal models, and its safety has long been established in children with tuberous sclerosis. A recent 12-week phase II trial of topical sirolimus suggested it was safe and effective at reducing the early signs of skin cancer in the absence of major side effects. The aim of the SiroSkin trial is to determine whether topical sirolimus can fill a major gap in current therapies by reducing the onset and number of new skin cancers thus reducing burden of disease and cost-effectiveness. Methods Protocol for a multi-centred phase III, participant- and clinician assessor-blinded, placebo-controlled randomised trial in SOTRs. A minimum 146 participants randomised 1:1 will be treated with 1% topical sirolimus versus placebo applied to the face on a regular basis for 24 weeks. Participation is 24 months in total—24 weeks of treatment and 18 months of follow-up. Outcomes include the number of keratinocyte carcinomas at 24 weeks of treatment compared to placebo and then at 12 and 24 months after initiation of treatment. Analysis will be as per protocol and intention to treat. Discussion The results of this trial will inform management strategies for skin cancers in SOTRs and provide evidence for cost-effectiveness. Trial registration Clinicaltrials.gov NCT05860881. Registered on June 15, 2023, and on anzctr.org.au (registration number NCT05860881).

Abstract Assessment of immune correlates of severe COVID-19 has been hampered by the low numbers of severe cases in COVID-19 vaccine efficacy (VE) trials. We assess neutralizing and binding antibody levels at 4 weeks post-Ad26.COV2.S vaccination as correlates of risk and of protection against severe-critical COVID-19 through 220 days post-vaccination in the ENSEMBLE trial (NCT04505722), constituting ~4.5 months longer follow-up than our previous correlates analysis and enabling inclusion of 42 severe-critical vaccine-breakthrough cases. Neutralizing antibody titer is a strong inverse correlate of severe-critical COVID-19, with estimated hazard ratio (HR) per 10-fold increase 0.35 (95% CI: 0.13, 0.90). In a multivariable model, HRs are 0.31 (0.11, 0.89) for neutralizing antibody titer and 1.22 (0.49, 3.02) for anti-Spike binding antibody concentration. VE against severe-critical COVID-19 rises with neutralizing antibody titer: 63.1% (95% CI: 40.0%, 77.3%) at unquantifiable [

Abstract Background The SMILE study addresses a significant need in palliative oncology by evaluating the non-inferiority of a shortened, 3-fraction stereotactic body radiotherapy (SBRT) schedule against the traditional 5-fraction approach for non-spine bone metastases in terms of pain control. Optimizing SBRT could significantly enhance the quality of life for patients by providing effective pain relief while minimizing treatment sessions. Methods This international, multicenter phase III trial will randomize 162 patients to receive either a 3-fraction regimen (9 Gy per fraction) or a standard 5-fraction regimen (7 Gy per fraction). Outcomes, assessed at 3 months post-treatment, will focus on pain response, quality of life, and control of metastasis. With a hypothesis-driven design, the study will incorporate intent-to-treat and per-protocol analyses, incorporating appropriate measures for data integrity and handling of missing information. Discussion If the 3-fraction SBRT regimen demonstrates non-inferiority, it could streamline palliative care protocols, reduce patient burden, and set a new standard for treatment, reflecting a patient-centered approach in palliative radiation oncology. Trial registration The trial has been registered prospectively on ClinicalTrials.gov under the identifier NCT05406063, as of May 3, 2022.

Abstract Optic nerve (ON) injury causes blindness in adult mammals as their retinal ganglion cells (RGCs) cannot regenerate axons. However, amphibian RGC axons do not experience the same regenerative failure. Studying the regeneration process of the ON in amphibians holds profound implications for regenerative medicine and human health. Using transgenic tadpoles and laser micro-optics, we developed a reproducible ON transection and regeneration model. Through microscopy of axon dynamics, functional testing to assess visual pathway recovery, TUNEL cell death and EdU cell proliferation assays, and RNA-seq of the retina and optic nerve, we characterized the optic nerve injury response and subsequent recovery. Our model suggests no chemoattractant gradient exists early in regeneration, with defasciculated axons sprouting in random directions from the globe-proximal cut end. Once individual axons reach the appropriate targets in the brain, their tract is reinforced by other regenerating axons, restoring normal ON morphology. Thus, guidance cues or scaffolding from brain-innervating axons likely support later stages of regeneration. After 14 days, the regenerated ON is morphologically indistinguishable from the naïve ON, and visual function is restored. We found no evidence of RGC death or new RGC formation in the model, suggesting that ON regeneration involves remodeling of injured axons of pre-existing RGCs.

Atherosclerotic cardiovascular disease (ASCVD) remains the major cause of premature death and disability; effective cardiovascular (CV) risk prevention is fundamental. The World Heart Federation (WHF) Cholesterol Roadmap provides a framework for national policy development and aims to achieve ASCVD prevention.At the invitation of the WHF, a group of experts from the Portuguese Society of Cardiology (SPC), addressed the cholesterol burden at nationally and discussed possible strategies to include in a Portuguese cholesterol roadmap. The literature review showed that the cholesterol burden in Portugal is high and especially uncontrolled in those with the highest CV risk. An infographic scorecard was built to include in the WHF collection, for a clear idea about CV risk and cholesterol burden in Portugal, which would also be useful for health policy advocacy.The expert discussion and preventive strategies proposal followed the five pillars of the WHF document: awareness improvement; population-based approaches for CV risk and cholesterol; risk assessment/population screening; system-level approaches; surveillance of cholesterol and ASCVD outcomes. These strategies were debated by all the expert participants, with the goal of creating a national cholesterol roadmap to be used for advocacy and as a guide for CV prevention.Several key recommendations were outlined: include all stakeholders in a multidisciplinary national program; create a structured activities plan to increase awareness in the population; improve the quality of continuous CV health education; increase the interaction between different health professionals and non-health professionals; increment the referral of patients to cardiac rehabilitation; screen cholesterol levels in the general population, especially high-risk groups; promote patient self-care, engage with patients’ associations; use specific social networks to spread information widely; create a national database of cholesterol levels with systematic registry of CV events; redefine strategies based on the evaluation of results; create and involve more patients’ associations – invert the pyramid order.In conclusion, ASCVD and the cholesterol burden remain a strong global issue in Portugal, requiring the involvement of multiple stakeholders in prevention. The Portuguese cholesterol roadmap can provide some solutions to help urgently mitigate the problem. Population-based approaches to improve awareness and CV risk assessment and surveillance of cholesterol and ASCVD outcomes are key factors in this change. A call to action is clearly needed to fight hypercholesterolemia and ASCVD burden. Resumo: A doença aterosclerótica cardiovascular (DACV) mantém-se a maior causa de morte prematura e de incapacidade, sendo uma prevenção eficaz de risco cardiovascular (CV) fundamental. O WHF Cholesterol Roadmap fornece enquadramento para o desenvolvimento de políticas nacionais, tendo como objetivo a prevenção de DACV. A convite da WHF, um grupo de peritos da Sociedade Portuguesa de Cardiologia (SPC) avaliou a carga do colesterol a nível nacional e discutiu possíveis estratégias para um Roadmap português.A revisão da literatura mostrou uma carga elevada de colesterol em Portugal, sobretudo em pessoas de alto risco CV. Uma infografia, Scorecard, foi construída pela WHF, para mostrar claramente o risco CV e o peso do colesterol em Portugal, sendo útil para advocacia em políticas de saúde.A discussão de peritos e proposta das estratégias preventivas seguiram os cinco pilares do documento da WHF: Melhoria da consciencialização; Abordagens do risco CV e do colesterol nas populações; Avaliação de risco/screening das populações; abordagens a nível do sistema; Seguimento do colesterol e complicações da DACV.Várias recomendações chave foram definidas: incluir todos os stakeholders em programa multidisciplinar nacional; criar plano de atividades estruturadas para aumentar a consciencialização da população; aumentar qualidade da educação contínua em saúde CV; aumentar interação entre profissionais de saúde e outros profissionais; aumentar referenciação de doentes para reabilitação cardiovascular; avaliar níveis de colesterol na população geral, especialmente em alto risco; promover autocuidado dos doentes, envolvendo associações de doentes; usar redes sociais específicas para disseminar informação; criar base nacional de níveis de colesterol com registo sistemático de eventos CV; redefinir estratégias baseadas na avaliação de resultados; criar e envolver mais doentes em associações – inverter a ordem da pirâmide!Em conclusão, a DACV e o peso de colesterol permanecem uma questão global forte em Portugal, necessitando o envolvimento de múltiplos stakeholders na prevenção. O Roadmap de colesterol português pode fornecer algumas soluções para urgentemente mitigar o problema. Abordagens a nível das populações para melhorar a consciencialização e avaliar o risco CV, seguimento do colesterol e das complicações de DACV são fatores chave nesta mudança. Uma call to action é claramente necessária para combater a carga da hipercolesterolemia e DACV.

Abstract We describe the geographical variation in tree species composition across Amazonian forests and show how environmental conditions are associated with species turnover. Our analyses are based on 2023 forest inventory plots (1 ha) that provide abundance data for a total of 5188 tree species. Within-plot species composition reflected both local environmental conditions (especially soil nutrients and hydrology) and geographical regions. A broader-scale view of species turnover was obtained by interpolating the relative tree species abundances over Amazonia into 47,441 0.1-degree grid cells. Two main dimensions of spatial change in tree species composition were identified. The first was a gradient between western Amazonia at the Andean forelands (with young geology and relatively nutrient-rich soils) and central–eastern Amazonia associated with the Guiana and Brazilian Shields (with more ancient geology and poor soils). The second gradient was between the wet forests of the northwest and the drier forests in southern Amazonia. Isolines linking cells of similar composition crossed major Amazonian rivers, suggesting that tree species distributions are not limited by rivers. Even though some areas of relatively sharp species turnover were identified, mostly the tree species composition changed gradually over large extents, which does not support delimiting clear discrete biogeographic regions within Amazonia.

Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the best curative treatment modality for many malignant hematologic disorders. In the absence of a matched related donor, matched unrelated donors (MUDs) and haploidentical donors are the most important stem cell sources. In this registry-based retrospective study, we compared the outcomes of allo-HSCTs from 10/10 MUDs with antithymocyte globulin (ATG)–based regimens (n = 7050) vs haploidentical transplants (Haplo-Tx) using posttransplant cyclophosphamide (PT-CY Haplo; n = 487) in adult patients with hematologic malignancies between 2010 and 2020. Cox proportional hazard-and competing risks regression models were formed to compare the outcomes. Overall survival (OS), Disease-free survival (DFS), and graft-versus-host disease (GVHD)–free and relapse-free survival (GRFS) were superior for 10/10 MUDs (OS [hazard ratio (HR), 1.27; 95% confidence interval (CI), 1.10-1.47; P = .001]; DFS [HR, 1.17; CI, 1.02-1.34; P = .022]; GRFS [HR, 1.34; CI, 1.19-1.50; P

We found Mycobacterium leprae, the most common etiologic agent of Hansen disease or leprosy, in tissues from 9 (18.75%) of 48 nine-banded armadillos (Dasypus novemcinctus) collected across continental Ecuador. Finding evidence of a wildlife reservoir is the first step to recognizing leprosy zoonotic transmission pathway in Ecuador or elsewhere.

Abstract Tessellations (surface architectures of arrays of hard tiles) are common in natural and man-made designs. Boxfishes (Ostracioidea) are almost completely encased in a tessellated armor and have evolved a plethora of cross-sectional carapace shapes, yet whether the scutes constructing these exhibit comparable variation is unknown. Using high-resolution microCT and semi-automatic segmentation algorithms, we quantitatively examined thousands of scutes from 13 species of diverse body form. A cluster analysis revealed that certain scute types are associated with specific carapace regions independent of carapace shape. Scute types differentiate between carapace edges and flat regions, as well as between the head region with many carapace openings and the more consistently closed abdominal region, pointing at a constructional commonality or constraint shared by all boxfish species. However, the dimensions of edge scutes varied systematically with carapace shape (e.g., scute aspect ratio tended to increase with decreasing carapace height). This suggests that protection is maintained across body forms by managing scute- and carapace-level mechanisms for increasing bending resistance. Future studies on other taxa are necessary to understand whether these architectural principles are specific evolutionary solutions for building a boxfish carapace or whether they are shared by other biological systems that serve a similar protective function.

Abstract Background A prolonged first episode of psychosis (FEP) without adequate treatment is a predictor of poor clinical, functional, and health outcomes and significant economic burden. Team-based “coordinated specialty care” (CSC) for early psychosis (EP) has established effectiveness in promoting clinical and functional recovery. However, California’s CSC program implementation has been unsystematic and could benefit from standardizing its processes and data collection infrastructure. To address this, we established a consortium of EP clinics across the state via a Learning Health Care Network (LHCN) framework to develop the Early Psychosis Intervention Network of California (EPI-CAL). EPI-CAL’s LHCN developed a core battery of evidence-based measures for service users and family members and linked them together using a unique data collection and visualization application, Beehive. Methods and objectives EPI-CAL’s LHCN collects, visualizes, and aggregates data at the individual and clinic level for EP programs across California via Beehive. Beehive was designed to: (1) collect outcomes data from service users receiving care at EP programs and their support persons, (2) provide the data to providers on a secure web-based dashboard to support measurement-based care, and (3) allow data to be used for program or research analysis. We will (1) determine the feasibility of implementing an LHCN across a diverse, decentralized network of early psychosis programs, (2) determine if the implementation of an LHCN increases the delivery of measurement-based care, and (3) determine if the implementation of measurement-based care is associated with significant improvements in key service user outcomes. EPI-CAL’s network will contribute data to the Early Psychosis Intervention Network (EPINET) program. Discussion The current study aims to establish an LHCN of EP clinics in California that implements harmonized data collection using Beehive and assesses the feasibility of establishing such a network. Our goal is for this harmonized data collection approach to be used to inform decisions and develop learning opportunities for service users, staff, and administrators, and to improve outcomes for service users and their supporters in CSC care. Further, the data will enable programs and research teams to examine what elements of care lead to program success and improved treatment outcomes for service users. Clinical trials registration www.ClinicalTrials.gov , identifier NCT04007510; registered 07/05/2019.

Abstract Dietary restriction (DR) is a potent method to enhance lifespan and healthspan, but individual responses are influenced by genetic variations. Understanding how metabolism-related genetic differences impact longevity and healthspan are unclear. To investigate this, we used metabolites as markers to reveal how different genotypes respond to diet to influence longevity and healthspan traits. We analyzed data from Drosophila Genetic Reference Panel (DGRP) strains raised under AL and DR conditions, combining metabolomic, phenotypic, and genome-wide information. We employed two computational and complementary methods across species—random forest modeling within the DGRP as our primary analysis and Mendelian randomization in human cohorts as a secondary analysis. We pinpointed key traits with cross-species relevance as well as underlying heterogeneity and pleiotropy that influence lifespan and healthspan. Notably, orotate was linked to parental age at death in humans and blocked the DR lifespan extension in flies, while threonine supplementation extended lifespan, in a strain- and sex-specific manner. Thus, utilizing natural genetic variation data from flies and humans, we employed a systems biology approach to elucidate potential therapeutic pathways and metabolomic targets for diet-dependent changes in lifespan and healthspan.

Abstract Background Cancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero, when global redistribution of DNA methylation occurs driving tissue differentiation. Methods Epigenome-wide DNA methylation was profiled in surrogate (blood) and target (bone marrow) tissues at birth, diagnosis, remission and relapse of pediatric pre-B acute lymphoblastic leukemia (pre-B ALL) patients. Double-blinded analyses was performed between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was carried out using independent technologies and populations. Results The imprinted and immuno-modulating VTRNA2-1 was hypermethylated (FDR

Abstract Climate change is currently one of humanity’s greatest threats. To help scholars understand the psychology of climate change, we conducted an online quasi-experimental survey on 59,508 participants from 63 countries (collected between July 2022 and July 2023). In a between-subjects design, we tested 11 interventions designed to promote climate change mitigation across four outcomes: climate change belief, support for climate policies, willingness to share information on social media, and performance on an effortful pro-environmental behavioural task. Participants also reported their demographic information (e.g., age, gender) and several other independent variables (e.g., political orientation, perceptions about the scientific consensus). In the no-intervention control group, we also measured important additional variables, such as environmentalist identity and trust in climate science. We report the collaboration procedure, study design, raw and cleaned data, all survey materials, relevant analysis scripts, and data visualisations. This dataset can be used to further the understanding of psychological, demographic, and national-level factors related to individual-level climate action and how these differ across countries.

Abstract Antenatal hydronephrosis (HN) impacts up to 5% of pregnancies and requires close, frequent follow-up monitoring to determine who may benefit from surgical intervention. To create an automated HN Severity Index (HSI) that helps guide clinical decision-making directly from renal ultrasound images. We applied a deep learning model to paediatric renal ultrasound images to predict the need for surgical intervention based on the HSI. The model was developed and studied at four large quaternary free-standing paediatric hospitals in North America. We evaluated the degree to which HSI corresponded with surgical intervention at each hospital using area under the receiver-operator curve, area under the precision-recall curve, sensitivity, and specificity. HSI predicted subsequent surgical intervention with > 90% AUROC, > 90% sensitivity, and > 70% specificity in a test set of 202 patients from the same institution. At three external institutions, HSI corresponded with AUROCs ≥ 90%, sensitivities ≥ 80%, and specificities > 50%. It is possible to automatically and reliably assess HN severity directly from a single ultrasound. The HSI stratifies low- and high-risk HN patients thus helping to triage low-risk patients while maintaining very high sensitivity to surgical cases. HN severity can be predicted from a single patient ultrasound using a novel image-based artificial intelligence system.

Abstract Background Embryos are regeneration and wound healing masters. They rapidly close wounds and scarlessly remodel and regenerate injured tissue. Regeneration has been extensively studied in many animal models using new tools such as single-cell analysis. However, until now, they have been based primarily on experiments assessing from 1 day post injury. Results In this paper, we reveal that critical steps initiating regeneration occur within hours after injury. We discovered the regeneration initiating cells (RICs) using single-cell and spatial transcriptomics of the regenerating Xenopus laevis tail. RICs are formed transiently from the basal epidermal cells, and their expression signature suggests they are important for modifying the surrounding extracellular matrix thus regulating development. The absence or deregulation of RICs leads to excessive extracellular matrix deposition and defective regeneration. Conclusion RICs represent a newly discovered transient cell state involved in the initiation of the regeneration process.

Abstract Sclerostin inhibitors protect against osteoporotic fractures, but their cardiovascular safety remains unclear. We conducted a cis-Mendelian randomisation analysis to estimate the causal effect of sclerostin levels on cardiovascular risk factors. We meta-analysed three GWAS of sclerostin levels including 49,568 Europeans and selected 2 SNPs to be used as instruments. We included heel bone mineral density and hip fracture risk as positive control outcomes. Public GWAS and UK Biobank patient-level data were used for the study outcomes, which include cardiovascular events, risk factors, and biomarkers. Lower sclerostin levels were associated with higher bone mineral density and 85% reduction in hip fracture risk. However, genetically predicted lower sclerostin levels led to 25–85% excess coronary artery disease risk, 40% to 60% increased risk of type 2 diabetes, and worse cardiovascular biomarkers values, including higher triglycerides, and decreased HDL cholesterol levels. Results also suggest a potential (but borderline) association with increased risk of myocardial infarction. Our study provides genetic evidence of a causal relationship between reduced levels of sclerostin and improved bone health and fracture protection, but increased risk of cardiovascular events and risk factors.

Abstract Frequent interspecies transmission of human influenza A viruses (FLUAV) to pigs contrasts with the limited subset that establishes in swine. While hemagglutinin mutations are recognized for their role in cross-species transmission, the contribution of neuraminidase remains understudied. Here, the NA’s role in FLUAV adaptation was investigated using a swine-adapted H3N2 reassortant virus with human-derived HA and NA segments. Adaptation in pigs resulted in mutations in both HA (A138S) and NA (D113A). The D113A mutation abolished calcium (Ca2+) binding in the low-affinity Ca2+-binding pocket of NA, enhancing enzymatic activity and thermostability under Ca2+-depleted conditions, mirroring swine-origin FLUAV NA behavior. Structural analysis predicts that swine-adapted H3N2 viruses lack Ca2+ binding in this pocket. Further, residue 93 in NA (G93 in human, N93 in swine) also influences Ca2+ binding and impacts NA activity and thermostability, even when D113 is present. These findings demonstrate that mutations in influenza A virus surface proteins alter evolutionary trajectories following interspecies transmission and reveal distinct mechanisms modulating NA activity during FLUAV adaptation, highlighting the importance of Ca2+ binding in the low-affinity calcium-binding pocket.

Abstract Objectives To evaluate the effect of vagus nerve stimulation (VNS) on seizure control, cognitive functions, and quality of life in individuals with drug‐resistant epilepsy. Methods An extensive search of electronic databases was carried out in order to carry out this systematic review. The databases Google Scholar, Embase, PubMed, and the Cochrane Library were searched first to carryout gray literature. To reduce the quantity of pointless studies in the advanced search, the search is limited to “human studies” and “English language” publications only. Combining keywords and Medical Subject Headings (MeSH) terms like (“Vagus Nerve Stimulation” OR “VNS”) AND (“Epilepsy” OR “Seizure Control”) AND (“Cognitive Function” OR “Quality of Life”). Studies that have been published up to November 30/2023 were included. Results The search strategy yielded a total of 392 relevant studies. The mean age of participant's ranges from 11 years to 33 years. The duration of follow‐up ranging from 6 to 36 months. Eleven studies were included in the review. The mean≥50% response rate after VNS therapy was 56.94% ranged from 48.90% to 83.00%. Four and three studies provided information about Quality of Life in Epilepsy Inventory (QOLIE‐31) and The Liverpool Seizure Severity Scale (LSSS) questionnaires respectively. Significance Epilepsy is a chronic disease characterized by sudden abnormal discharge of brain neurons, which leads to transient brain dysfunction and the presence of spontaneous recurrent seizures. Vagus nerve stimulation has recently been proposed as a potential tool in the treatment of seizure, depressive symptoms, and cognitive impairments. There has been variation in the effects of VNS treatment on seizure control, cognitive functions, and quality of life among patients with drug‐resistant epilepsy. So, a comprehensive review of exciting literature is important to see the pooled effect. Previous systematic review and meta‐analysis papers were mostly randomized control trial type with specific diseases. The use of a wider variety of study designs than only randomized controlled trials is important. So, we included retrospective and prospective cohort studies in addition to randomized control trials. This enables a more thorough assessment of the connection between quality of life, cognitive function, and vagus nerve stimulation. In addition, the paper looks at a wide range of disease kinds and patterns. We have established a uniform and comprehensive approach throughout the selected studies by mandating the inclusion of all three crucial parameters: vagus nerve stimulation, cognitive function, and quality of life. Plain Language Summary This systematic review examined 392 relevant studies on vagus nerve stimulation (VNS) therapy, with participants ranging from 11 to 33 years old and follow‐up durations of 6–36 months. Eleven studies were included, and the mean response rate after VNS therapy was 56.94%, ranging from 48.90% to 83.00%. The review also reported on quality of life and cognitive function, and seizure severity frequency result from several studies.

Abstract Objective The purpose of this study is to analyze composition of HMS (homemade CBD), NLS (non‐licensed commercial products), and bioequivalent CBD (BES) collected from Chilean patients that voluntary accepted to analyze the “CBD‐substance.” Methods Samples were collected through an open invitation for different patients to anonymously and free of charge participate in the analysis of CBD oil. The analysis of the active principle was performed using High‐Resolution Liquid Chromatography (HPLC). Results A total of 35 samples were collected between March 2020 and September 2021, including two BES, six NLS, and 27 HMS products. The BES had an average CBD concentration of 89.15 mg/mL and an average THC concentration of 0.015 mg/mL, which complied with the maximum THC levels required by regulatory authorities (

Abstract Background Skeletal muscle is a highly plastic tissue crucial for many functions associated with whole‐body health across the life course. Magnetic resonance imaging (MRI) is the current gold standard for measuring skeletal muscle size. However, MRI is expensive, and access to facilities is often limited. B‐mode ultrasonography (U/S) has been proposed as a potential alternative to MRI for the assessment of muscle size. However, to date, no work has explored the utility of U/S to assess disuse muscle atrophy (DMA) across muscles with different atrophy susceptibility profiles, an omission which may limit the clinical application of previous work. Methods To address this significant knowledge gap, 10 young men (22 ± years, 24.1 ± 2.3 kg/m2) underwent 15‐day unilateral leg immobilization using a knee‐brace and air boot. Cross‐sectional area (CSA) and muscle thickness (MT) of the tibialis anterior (TA) and medial gastrocnemius (MG) were assessed via U/S before and after immobilization, with CSA and muscle volume assessed via MRI. Results With both muscles combined, there were good correlations between each U/S and MRI measure, both before (e.g., CSAMRI vs. MTU/S and CSAU/S: r = 0.88 and 0.94, respectively, both P

Abstract Background ADCK genes encode aarF domain‐containing mitochondrial kinases involved in coenzyme Q (CoQ) biosynthesis and regulation. Haploinsufficiency of ADCK2 in humans leads to adult‐onset physical incapacity with reduced mitochondrial CoQ levels in skeletal muscle, resulting in mitochondrial myopathy and alterations in fatty acid β‐oxidation. The sole current treatment for CoQ deficiencies is oral administration of CoQ10, which causes only partial recovery with postnatal treatment, underscoring the importance of early diagnosis for successful intervention. Methods We used Adck2 heterozygous mice to examine the influence of this gene on muscle structure, function and regeneration throughout development, growth and ageing. This investigation involved techniques including immunohistochemistry, analysis of CoQ levels, mitochondrial respiratory content, muscle transcriptome analysis and functional tests. Results We demonstrated that Adck2 heterozygous mice exhibit defects from embryonic development, particularly in skeletal muscle (1102 genes deregulated). Adck2 heterozygous embryos were 7% smaller in size and displayed signs of delayed development. Prenatal administration of CoQ10 could mitigate these embryonic defects. Heterozygous Adck2 mice also showed a decrease in myogenic cell differentiation, with more severe consequences in ‘aged’ mice (41.63% smaller) (P

Training programs focused on developing the next generation of scholars with expertise in HIV and mental health are crucial for advancing health equity and cultivating a diverse workforce by supporting individuals with lived experience and a strong commitment to serving underserved communities. However, disparities persist in the workforce, particularly in the inclusion of professionals typically underrepresented in research. The aim of this commentary is to explore the strengths and challenges of a NIMH-funded training program (T32), Culturally focused HIV Advancements through the Next Generation for Equity (CHANGE), at the University of Miami, with the goal of providing a series of general recommendations. The program excels in leveraging Miami’s unique context, recruiting a cohort of trainees committed to addressing HIV and mental health inequities, delivering a tailored curriculum, and providing strong leadership and mentorship networks to trainees. Additional opportunities for training programs that attract minoritized scholars to realize their vision include further increasing underrepresented scholars in health research, expanding federal funding and institutional investment in training programs, continuing to combat systemic inequities, fostering culturally-sensitive mentorship training, and building upon existing resources to provide trauma-informed support that acknowledges and addresses the unique, intersectional, and historical trauma experienced by trainees. We close with calls to action spanning institutional, community, and policy levels, urging scientists and decision-makers to actively address disparities in diversifying the HIV workforce, fostering equity, and creating inclusive training environments.

Epithelial-mesenchymal transition (EMT) plays important roles in tumour progression and is orchestrated by dynamic changes in gene expression. While it is well established that post-transcriptional regulation plays a significant role in EMT, the extent of alternative polyadenylation (APA) during EMT has not yet been explored. Using 3’ end anchored RNA sequencing, we mapped the alternative polyadenylation (APA) landscape following Transforming Growth Factor (TGF)-β-mediated induction of EMT in human mammary epithelial cells and found APA generally causes 3’UTR lengthening during this cell state transition. Investigation of potential mediators of APA indicated the RNA-binding protein Quaking (QKI), a splicing factor induced during EMT, regulates a subset of events including the length of its own transcript. Analysis of QKI crosslinked immunoprecipitation (CLIP)-sequencing data identified the binding of QKI within 3’ untranslated regions (UTRs) was enriched near cleavage and polyadenylation sites. Following QKI knockdown, APA of many transcripts is altered to produce predominantly shorter 3’UTRs associated with reduced gene expression. These findings reveal the changes in APA that occur during EMT and identify a potential role for QKI in this process.

Abstract Aims Heart failure (HF) is a highly prevalent and progressive condition associated with significant morbidity and mortality rates. Acute decompensated HF precipitates millions of hospitalizations each year. Despite therapeutic advances, the overall prognosis of HF is poor. The varying clinical courses and outcomes of patients with this disease may be due to region‐specific gaps and since most HF studies are conducted in developed countries, the participation of Latin American and Caribbean countries is low. Considering this, the American Registry of Ambulatory and Acute Decompensated Heart Failure (AMERICCAASS) aims to characterize the population with ambulatory and acute decompensated HF in the American continent and to determine rehospitalization and survival outcomes during the 12 months of follow‐up. Methods and results AMERICCAASS Registry is an observational, prospective, and hospital‐based registry recruiting patients with ambulatory or acute decompensated HF. The registry plans to include between two and four institutions per country from at least 20 countries in the Americas, and at least 60 patients recruited from each participant institution regardless of their ambulatory or acutely decompensated condition. Ambulatory patients with confirmed HF diagnosis or inpatients presenting with acute decompensated HF will be included. Follow‐up will be performed at 12 months in ambulatory patients or 1, 6, and 12 months after hospital discharge in acutely decompensated HF patients. This ongoing study began on 1 April 2022, with recruitment scheduled to end on 30 November 2023, and follow‐up on 31 January 2025. Ethics approval was obtained from the Biomedical Research Ethics Committee of Fundación Valle del Lili. Data collected in the AMERICCAASS registry is being stored on the electronic platform REDCap (Research Electronic Data Capture), which allows different forms for patient groups to enable unbiased analyses. For quantitative variables comparison, we will use the Student's t‐test or non‐parametric tests accordingly. Categorical variables will be presented as proportions, and groups will be compared with Fisher's exact test. The significance level will be

Abstract Aims LMNA‐related dilated cardiomyopathy (DCM) is a rare disease with an incompletely defined phenotype. The phase 3 REALM‐DCM trial evaluated a potential disease‐modifying therapy for LMNA‐related DCM but was terminated due to futility without safety concern. This study utilized pooled data from REALM‐DCM to descriptively characterize the phenotype and progression of LMNA‐related DCM in a contemporary cohort of patients using common heart failure (HF) measures. Methods REALM‐DCM enrolled patients with stable LMNA‐related DCM, an implanted cardioverter defibrillator or cardiac resynchronization therapy defibrillator, and New York Heart Association (NYHA) Class II/III HF symptoms. Results Between 2018 and 2022, 77 patients took part in REALM‐DCM. The median patient age was 53 years (range: 23–72), and 57% were male. Overall, 88% of patients had a pathogenic or likely pathogenic LMNA variant, and 12% had a variant of uncertain significance with a concordant phenotype. Among patients with confirmed sequencing, 55% had a missense variant. Atrial fibrillation was present in 60% of patients; 79% of all patients had NYHA Class II and 21% had NYHA Class III HF symptoms at baseline. Median (range) left ventricular ejection fraction (LVEF), 6 min walk test (6MWT) distance, Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ‐OS) score and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) concentration at baseline were 42% (23–62), 403 m (173–481), 67 (18–97) and 866 pg/mL (57–5248), respectively. LVEF, 6MWT distance and KCCQ‐OS score were numerically lower in patients who had NYHA Class III versus II symptoms at baseline (LVEF: 38% vs. 43%; 6MWT distance: 326 vs. 413 m; and KCCQ‐OS score: 43 vs. 70), whereas NT‐proBNP concentration was higher (1216 vs. 799 pg/mL). Median follow‐up was 73 weeks (range: 0.4–218; 73 in NYHA Class II and 75 in NYHA Class III). Patients displayed variable change from baseline in 6MWT, KCCQ‐OS and NT‐proBNP values during follow‐up. Overall, 25% of patients experienced ventricular tachycardia, and 8% had ventricular fibrillation. Ten (13%) patients met the composite endpoint of worsening HF (adjudicated HF‐related hospitalization or urgent care visit) or all‐cause death; six had NYHA Class II and four had NYHA Class III at baseline. All‐cause mortality occurred in 6 (8%) patients; three had NYHA Class II and three had NYHA Class III symptoms at baseline. Conclusions Findings confirm the significant morbidity and mortality associated with LMNA‐related DCM despite the standard of care management. Typical measures of HF, including 6MWT distance, KCCQ‐OS score and NT‐proBNP concentration, were variable but correlated with NYHA class. An unmet treatment need remains among patients with LMNA‐related DCM. NCT03439514.

The World Health Organization documented 247 million reported malaria cases worldwide resulting in 619,000 fatalities in 2021. More than 70% of these deaths are attributed to Children under five years of age and sub-Saharan Africa is the region in which the highest number of deaths occur. The Plasmodium falciparum parasite is the deadliest form of malaria, and treating falciparum infection is becoming more challenging due to the emergence of drug-resistant parasites, causing a decrease in the efficiency of antimalarial medications. Artemisinin combination therapy is now considered the gold standard for malaria treatment; however, this method is at risk due to parasites exhibiting delayed clearance to artemisinin and resistance to partner drugs such as lumefantrine, amodiaquine, mefloquine, piperaquine, and sulfadoxine/pyrimethamine. This review assessed drug targets in Plasmodium falciparum for the development of novel antimalarials. Over Eighty-five papers on malaria, Plasmodium falciparum protein targets, and protein inhibitors were gathered from Google Scholar, ProQuest, PubMed, and Science Direct, between 2012 and 2023. Only articles with comparable keywords on malaria drug targets concentrating on enzyme proteins, carrier molecules present in Plasmodium falciparum, and their inhibitors were retrieved for review, while articles within that range that did not provide definite data were excluded. Most recently, inhibitors of dihydroorotate dehydrogenase (DHODH), artefenomel (OZ439), and ferroquine have been reported and are being explored in combination with other partner medications to work against different stages of plasmodium parasite. In identifying target proteins for drug development, essentiality and vulnerability throughout the life cycle of the parasite, its druggability, and the availability of target-based assays are critical factors. The use of modern proteomics and cellular proteins from database search which assists in parasite proliferation delivers optimal information on the new generation of lead compounds. In addition, advances in in silico methods enable the identification of protein targets for drug development.

Groundwater is the most important source of freshwater across the world. However, its quality is deteriorating over time due to anthropogenic and natural factors. Koga irrigation scheme is one of the most intensively irrigated areas causing groundwater deterioration. Nonetheless, groundwater quality used for drinking purpose was not properly assessed. Hence, this study was intended to evaluate the groundwater quality used for drinking purposes using GIS-based WQI method. This method considers twelve water quality parameters (Turbidity, TDS, pH, Nitrate, Sulfate, phosphate, Ammonium, Copper, Iron, Fluoride Electric conductivity and thermotolerant coliform). Besides, geostatistical and spatial analyses were used to assess their spatial pattern. Accordingly, the concentration of nitrate, ammonia, turbidity, pH value, and thermotolerant coliform were not within WHO standard. Furthermore, about 64.4% and 35.6% of the irrigation scheme maintain good and poor groundwater quality, respectively. Yet, the area requires further investigation through including additional parameters, and identifying pollution hotspot areas.

Summary: Introduction: Radiotherapy is a challenge in autologous breast reconstruction because of its impact on cutaneous and vascular systems. Hyperbaric oxygen therapy (HBOT) is a recognized treatment of radiation-related complications. We aimed to assess the impact of perioperative HBOT on irradiated breast microvascular reconstructive outcomes. Method: We reviewed the medical charts of patients who received radiotherapy and then underwent secondary free autologous breast reconstruction at our institution. Data on demographics, HBOT protocol, intervention characteristics and post-operative complications were collected. Outcomes of the irradiated patients were then compared between the HBOT and non-HBOT groups. Results: Fourteen patients were included (11 unilateral and 2 bilateral deep inferior epigastric artery perforator flaps and 1 free transverse rectus abdominis muscle flap). Seven patients received HBOT and 7 did not. In the non-HBOT group, there were 1 Clavien–Dindo grade II, 1 Clavien–Dindo grade IIIa and 2 Clavien–Dindo grade IIIb post-operative complications. In the HBOT group, there were 3 Clavien–Dindo grade I, 1 Clavien–Dindo grade IIIa and 2 Clavien–Dindo grade IIIb post-operative complications. The mean operative time was 452.3 minutes (SD ±62.4 minutes) for unilateral cases without HBOT and 457.8 minutes (SD ±102.1 minutes) with HBOT (p=0.913). Mean ischaemia time per flap without HBOT was 109.4 minutes (SD ±51.8 minutes) versus 80.1 minutes (SD ±37.7 minutes) in the HBOT group (p=0.249). Conclusion: This study provides insights into the potential of HBOT treatment in preparing patients with irradiated breast cancer for secondary autologous reconstruction.

Abstract Background Unicompartmental knee arthroplasty (UKA) is a surgical procedure for managing osteoarthritis of one joint compartment, most commonly the medial side. This systematic review investigates the causes of UKA revision. The outcomes of interest were establishing the revision rate, time to revision, and the most common causes of revision in the long- and midterm follow-up. Methods This study was conducted according to the 2020 PRISMA statement. In October 2024, the following databases were accessed: PubMed, Web of Science, Google Scholar, and Embase. All the clinical studies investigating the rate and causes of revision in UKA were accessed. Only studies with a minimum of 10 years of follow-up were considered. Results Data from 56 studies (13,540 patients) were collected. Of them, 65.6% were women. The mean length of the follow-up was 13.1 ± 3.0 years. The mean age of the patients was 65.6 ± 5.6 years, and the mean BMI was 28.5 ± 2.2 kg/m2. Revisions were performed in 8.8% (2641 of 30,140) of implanted UKAs. The mean time to revision was 6.5 ± 2.6 (range, 2.5 to 13.0) years. Conclusion 8.8% (2641 of 30,140) of UKAs were revised at a mean time of 6.5 ± 2.6 years. Level of evidence Level IV, systematic review.

Abstract We construct and discuss generic N $$ \mathcal{N} $$ = 1 and N $$ \mathcal{N} $$ = 2 Carroll dilaton supergravity in two dimensions. We apply our general results to the supersymmetric Carroll-Jackiw-Teitelboim model, including a discussion of specific boundary conditions. For N $$ \mathcal{N} $$ = 2 Carroll dilaton supergravity, we find two versions, dubbed “democratic” and “despotic”.

Abstract For almost two decades now, scientists have increasingly focused on the occurrence of microplastic particles (MPs) in the environment and their impact on environmental and human health. Currently, the variety of analytical methods used in microplastic research result in data of different quality. This largely hampers comparability between data sets and consequently prevents a reliable risk assessment. In this context, the lack of suitable reference microplastic particles (RMPs) that can be added as an internal standard in an exactly known number further prevents quality assessment of, and harmonization in terms of comparability between different analytical methods. Although this challenge has been widely recognized, the availability of RMPs is currently limited to commercially available particles in the form of micro-beads or -fragments (powders). Manual addition of such RMPs to samples in a precisely defined number as an internal standard is inefficient and the alternative use of MP suspensions does not allow for the addition of an exactly defined particle number. The optimum solution to solve this issue would be RMPs embedded in an easy-to-use soluble matrix in exact numbers. This would allow for evaluating analytical quality during microplastic analysis as well as establishing harmonization in terms of comparability between different methods. In the present study we focused on the development of such RMPs. We used computerized numerical controlled (CNC) milling to produce small diameter plastic columns followed by gelatine embedment and subsequent cryosectioning. This results in gelatin slices containing an exactly defined number of RMPs with well-defined size, shape and polymer type / chemical composition that can be added to a sample easily with the dissolution of the gelatine. We successfully produced square shaped RMPs in a size range of 125–1000 μm of five different polymers. The overall size-deviation of the RMPs never exceeded ± 11.2% from the mean value of a set of particles. The highest percentage mass-deviation was 25.5% from the mean value of a set of 125 × 125 × 20 μm polystyrene (PS) RMPs. Our approach allows for the production of RMPs tailored to specific needs of all different analytical methods used in current microplastic research. Beyond analytical method validation, these RMPs furthermore open possibilities for experiments on MPs in different fields.

Abstract Nuclear atypia is a hallmark of cancer. A recent model posits that excess surface area, visible as folds/wrinkles in the lamina of a rounded nucleus, allows the nucleus to take on diverse shapes with little mechanical resistance. Whether this model is applicable to normal and cancer nuclei in human tissues is unclear. We image nuclear lamins in patient tissues and find: (a) nuclear laminar wrinkles are present in control and cancer tissue but are obscured in hematoxylin and eosin (H&E) images, (b) nuclei rarely have a smooth lamina, and (c) wrinkled nuclei assume diverse shapes. Deep learning reveals the presence of extreme nuclear laminar wrinkling in cancer tissues, which is confirmed by Fourier analysis. These data support a model in which excess surface area in the nuclear lamina enables nuclear shape diversity in vivo. Extreme laminar wrinkling is a marker of cancer, and imaging the lamina may benefit cancer diagnosis.

Abstract Background: Mesenchymal stem cells (MSCs) derived from gestational tissues offer a promising avenue for prenatal intervention in congenital malformations although their application is hampered by concerns related to cellular plasticity and the need for invasive, high-risk surgical procedures. Here, we present naturally occurring exosomes (EXOs) isolated from amniotic fluid-derived MSCs (AF-MSCs) and their mimetic analogs (MIMs) as viable, reproducible, and stable alternatives. These nanovesicles present a minimally invasive therapeutic option, addressing the limitations of MSC-based treatments while retaining therapeutic efficacy. Methods: MIMs were generated from AF-MSCs by combining sequential filtration steps through filter membranes with different porosity and size exclusion chromatography columns. A physicochemical, structural, and molecular comparison was conducted with exosomes (EXOs) released from the same batch of cells. Additionally, their distribution patterns in female mice were evaluated following in vivo administration, along with an assessment of their safety profile throughout gestation in a mouse strain predisposed to neural tube defects (NTDs). The possibility to exploit both formulations as mRNA-therapeutics was explored by evaluating cell uptake in two different cell types(fibroblasts, and macrophages) and mRNA functionality overtime in an in vitro experimental setting as well as in an ex vivo, whole embryo culture using pregnant C57BL6 dams. Results: Molecular and physiochemical characterization showed no differences between EXOs and MIMs, with MIMs determining a threefold greater yield. Biodistribution patterns following intraperitoneal administration were comparable between the two particle types, with the uterus being among targeted organs. No toxic effects were observed in the dams during gestation, nor were there any malformations or significant differences in the number of viable versus dead fetuses detected. MIMs delivered a more intense and prolonged expression of mRNA encoding for green fluorescent protein in macrophages and fibroblasts. An ex-vivo whole embryo culture demonstrated that MIMs mainly accumulate at the level of the yolk sac, while EXOs reach the embryo. Conclusions: The present data confirms the potential application of EXOs and MIMs as suitable tools for prevention and treatment of NTDs and proposes MIMs as prospective vehicles to prevent congenital malformations caused by in utero exposure to drugs.

Abstract Background Aim of this questionnaire-based cross-sectional study was to compare self-efficacy, social support, oral hygiene-related self-efficacy (OHRSE) and oral health-related quality of life (OHRQoL) between patients under chronic hemodialysis (HD) and patients after kidney transplantation (KTx) as well as a healthy comparison group (HC). Methods Patients under HD were recruited during their routine outpatient dialysis therapy, KTx patients during their maintenance appointment and HC patients during their regular dental check-up in the dental clinic. General self-efficacy, the OHRSE, social support (F-SozU-K14) and the OHRQoL (OHIP-G5) were assessed by specific validated questionnaires. The survey was performed by one experienced dentist. Results 44 HD, 40 KTx and 45 HC patients were included, between which the age and gender distribution was comparable (p > 0.05). With a median of 1.5 [IQR: 0–3], HD patients showed higher OHIP-G5 than the participants in KTx group (p

Abstract This research performs an ex-ante assessment of the 19 high potential areas for offshore wind energy (HPA-OWE) allocated in four maritime spatial planning subdivisions of Spain. A 39 geo-statistical criteria pool was developed and categorized into five planning tiers (coexistence, socio-ecological, spatial-efficiency, energy-equity, technical/technological). An ensemble of three multi-criteria decision analysis (MCDA) techniques coupled with a Monte Carlo method based on a large, uniform number of randomly distributed criteria weights is applied for more robust priority rankings of HPA-OWE. The co-existence tier indicates that HPA-OWE should be prioritized in the North Atlantic and in the Levantine–Balearic planning subdivision. The application of machine learning on the MCDA results identified criteria that most influence the rank of each HPA-OWE at planning subdivision. The outcomes highlight the need to include place-based data to better take into account spatial inequalities in coastal regions and re-balance them with socio-economic and energetically privileged coastal territories.

Abstract Background A new transitional housing program was established in Sudbury, Ontario, Canada, in response to the escalating global prevalence of substance use and homelessness, and the specific challenges faced in Northern Ontario. This protocol outlines a comprehensive program evaluation to assess its impact on patient outcomes, healthcare utilization, and client perspectives. Methods We will conduct a parallel mixed-method study that includes the analysis of single-center-level administrative health data and primary data collection. This includes a longitudinal observational study (target n = 1,200), pre- and post-admission quantitative interviews (target n = 40), and qualitative interviews (target n = 40). We will implement a participatory approach to this evaluation collaborating with people who use substances, frontline staff, and decision-makers. Data analysis methods include a range of statistical techniques, including logistic regression models, Cox proportional hazards models, Kaplan-Meier curves, Generalized Estimating Equations, and thematic qualitative analysis, ensuring a robust evaluation of patient outcomes and healthcare utilization. Discussion This protocol underpins a comprehensive assessment aimed at providing insights into the program’s effectiveness in addressing substance use-related challenges, reducing healthcare disparities, and improving patient outcomes, such as stable housing and increased social capital. All study procedures adhere to the ethical principles outlined in the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. Findings will be disseminated progressively through established committees and working groups and subsequently published in peer-reviewed journals. Anticipated outcomes include informing evidence-based healthcare decision-making and driving improvements in addiction treatment practices within healthcare settings.

Abstract Road construction involves activities that emit pollutants, including particulate matter, which harms humans. This study determined and compared particulate matter (PM1.0, PM2.5 and PM10) levels and air quality index (AQI) at unpaved roads, asphalt overlay, chip-sealed and asphalt-producing sites in Ghana and the health risks posed by their exposure. It was conducted in the Ashanti and Ahafo Regions, Ghana and was cross-sectional using the low-cost sensor, PCE-RCM16. Data collection took place, January-May, 2020. The asphalt-producing, asphalt overlay, chip-sealed and unpaved road sites had mean PM10 concentrations of 12.7-fold, 7.4-fold, 6.1-fold and 2.6-fold respectively of the 2021 World Health Organisation (WHO) air quality guideline (AQG) daily limit, 45 μg m−3. The mean PM2.5 concentrations were 30.4-fold, 17.2-fold, 14.1-fold and 6.1-fold greater than the daily AQG limit, 15 μg m−3 respectively. The mean PM1.0 values were of grave concern. Using the AQI, the asphalt-producing and asphalt overlay sites were considered “hazardous”, chip-sealed site was “very unhealthy” and the unpaved sites were “unhealthy for sensitive groups”. Type of activity influenced pollution levels (p

Abstract Condensate ring formation can be used as a benchmark in welding processes to assess the efficiency and quality of the weld. Condensate formation is critical as the resulting condensate settles into the powder thereby altering the quality of unconsolidated powder. This study investigates the intricate relationship between alloy composition, vapor pressure, and condensate ring thickness as seen in a two-dimensional micrograph. To study the process, laser spot welding was performed on 9 different alloys, and the inner spot weld diameter along with the condensate ring formation was studied. Leveraging machine learning models, experimental observations, and molecular dynamics simulations, we explore the fundamental factors governing condensate ring formation. The models, adept at predicting weld spot diameter and condensate ring thickness, identify laser power as a primary determinant for weld spot diameter followed by physical properties like hardness and density. Conversely, for condensate ring thickness, vapor pressure and melting point descriptors consistently emerge as paramount, as validated across all models. Molecular dynamics simulations on Ni-Cr alloys elucidate the vaporization dynamics, confirming the role of vapor pressure in governing surface vaporization. Our findings underscore the pivotal influence of vapor pressure and melting point descriptors in condensate ring formation. The convergence of machine learning predictions and simulation insights elucidates the dominance of these descriptors, offering crucial insights into alloy design strategies to minimize condensate ring formation in laser welding processes.

Abstract Cranial sex estimation often relies on visual assessments made by a forensic anthropologist following published standards. However, these methods are prone to human bias and may be less accurate when applied to populations other than those for which they were originally developed with. This study explores an automatic deep learning (DL) framework to enhance sex estimation accuracy and reduce bias. Utilising 200 cranial CT scans of Indonesian individuals, various DL network configurations were evaluated against a human observer. The most accurate DL network, which learned to estimate sex and cranial traits as an auxiliary task, achieved a classification accuracy of 97%, outperforming the human observer at 82%. Grad-CAM visualisations indicated that the DL model appears to focus on certain cranial traits, while also considering overall size and shape. This study demonstrates the potential of using DL to assist forensic anthropologists in providing more accurate and less biased estimations of skeletal sex.

Abstract River systems once safeguarded from water development are being developed. This includes intermittent rivers that annually dry to a series of pools. Describing fish species relationships between abundance and pool depth can help managers set water-take rules that protect fish in dry-season pools. We sampled fish in main-channel and floodplain pools that spanned a gradient of depths and overcame sampling challenges by accounting for interacting effects of species mean length, environmental attributes, and sampling attributes on fish capture probabilities. Fish abundance-depth relationships varied systematically with species mean length, mesohabitat type (main channel, floodplain), water turbidity, and structural complexity, highlighting system complexity and the potential generality of abundance-depth relationships. Similarly, fish length moderated the effects of environmental attributes on capture probability for all sampling methods. We evaluated impacts of hypothetical water-take regulations on fish species’ distributions. Results suggested that water-take rules prohibiting draining of main-channel pools below 1.65 m and reducing floodplain pools by no more than 14% minimises impacts to species’ distributions, promoting conservation of the fish community. Additionally, our approach demonstrates the capacity of species length for predicting distributional and sampling patterns of fish species.

Abstract Histological assessment is essential for the diagnosis and management of celiac disease. Current scoring systems, including modified Marsh (Marsh–Oberhuber) score, lack inter-pathologist agreement. To address this unmet need, we aimed to develop a fully automated, quantitative approach for histology characterisation of celiac disease. Convolutional neural network models were trained using pathologist annotations of hematoxylin and eosin-stained biopsies of celiac disease mucosa and normal duodenum to identify cells, tissue and artifact regions. Biopsies of duodenal mucosa of varying celiac disease severity, and normal duodenum were collected from a large central laboratory. Celiac disease slides (N = 318) were split into training (n = 230; 72.3%), validation (n = 60; 18.9%) and test (n = 28; 8.8%) datasets. Normal duodenum slides (N = 58) were similarly divided into training (n = 40; 69.0%), validation (n = 12; 20.7%) and test (n = 6; 10.3%) datasets. Human interpretable features were extracted and the strength of their correlation with Marsh scores were calculated using Spearman rank correlations. Our model identified cells, tissue regions and artifacts, including distinguishing intraepithelial lymphocytes and differentiating villous epithelium from crypt epithelium. Proportional area measurements representing villous atrophy negatively correlated with Marsh scores (r = − 0.79), while measurements indicative of crypt hyperplasia positively correlated (r = 0.71). Furthermore, features distinguishing celiac disease from normal duodenum were identified. Our novel model provides an explainable and fully automated approach for histology characterisation of celiac disease that correlates with modified Marsh scores, potentially facilitating diagnosis, prognosis, clinical trials and treatment response monitoring.

Abstract The retinal pigment epithelium (RPE) is vital for the healthy function of the retina. Cellular level changes in the RPE are not visualized with current clinical techniques due to a lack of spatial resolution. Fluorescence adaptive optics scanning light ophthalmoscopy (AOSLO) can image RPE cells by utilizing their intrinsic autofluorescence (AF). The RPE AF has been imaged with only a few discrete excitation and emission bands and the multi-spectral AF has not been interrogated systematically at the level of single cells. In this study, we imaged 16 healthy eyes (ages 20-75) with AOSLO to investigate the multi-spectral AF as a function of age and wavelength with excitation from 650 - 805 nm. Quantitative analysis showed that 720 nm light produced images with the highest SNR (65.0 dB). Spatial AF variability showed a trend to increase with aging, suggesting increased heterogeneity in RPE AF with age. Spatial variability in the multi-spectral fluorescence of RPE cells with age may be a consequence of normal age-related loss of RPE cells. Multi-spectral fluorescence AOSLO provides new insight into aging related changes to RPE cells and may be a useful tool for studying diseases that affect the RPE, such as age-related macular degeneration (AMD).

Abstract Equations of State model relations between thermodynamic variables and are ubiquitous in scientific modelling, appearing in modern day applications ranging from Astrophysics to Climate Science. The three desired properties of a general Equation of State model are adherence to the Laws of Thermodynamics, incorporation of phase transitions, and multiscale accuracy. Analytic models that adhere to all three are hard to develop and cumbersome to work with, often resulting in sacrificing one of these elements for the sake of efficiency. In this work, two deep-learning methods are proposed that provably satisfy the first and second conditions on a large-enough region of thermodynamic variable space. The first is based on learning the generating function (thermodynamic potential) while the second is based on structure-preserving, symplectic neural networks, respectively allowing modifications near or on phase transition regions. They can be used either “from scratch” to learn a full Equation of State, or in conjunction with a pre-existing consistent model, functioning as a modification that better adheres to experimental data. We formulate the theory and provide several computational examples to justify both approaches, highlighting their advantages and shortcomings.

Abstract Wildlife diseases are major players in local and global extinctions. Effective disease surveillance, management and conservation strategies require accurate estimates of pathogen prevalence. Yet pathogen detection in wild animals remains challenging. Current gold standards often require samples collected through veterinary examination, but this method is costly, intensive, invasive, and requires specialised staff and equipment. Collection of non-invasive samples, such as scats, is an effective monitoring tool which can be deployed at large scale, as scats contain DNA of both host and pathogens. The koala (Phascolarctos cinereus) is listed as ‘endangered’ under the EPBC Act 1999, with chlamydial disease representing a major threat. Here, we present a new approach that combines restriction-enzyme associated sequencing and targeted-sequence-capture genotyping, namely DArTcap, to detect Chlamydia pecorum in koala scats. We found this method has similar accuracy to current gold standards (qPCR of swab samples), with a sensitivity of 91.7% and a specificity of 100%. This method can be incorporated into existing koala genetic studies using marker panels, where population attributes can be estimated alongside C. pecorum presence, using the same scat samples, with the option to add further markers of interest. Such a one-stop-shop panel would considerably reduce processing times and cost.