Understanding Degradation Dynamics of Azomethine-containing Conjugated Polymers.

Understanding the influence of chemical environments on the degradation properties of conjugated polymers is an important task for the continued development of sustainable materials with potential utility in biomedical and optoelectronic applications. Azomethine-containing polymers were synthesized via palladium-catalyzed direct arylation polymerization (DArP) and used to study fundamental degradation trends upon exposure to acid. Shifts in the UV-vis absorbance spectra and the appearance/disappearance of aldehyde and imine diagnostic peaks within the 1H NMR spectra indicate that the polymers will degrade in the presence of acid. After degradation, the aldehyde starting material was recovered in high yields and was shown to maintain structural integrity when compared with commercial starting materials. Solution-degradation studies found that rates of degradation vary from 5 h to 90 s depending on the choice of solvent or acid used for hydrolysis. Additionally, the polymer was shown to degrade in the presence of perfluoroalkyl substances (PFASs), which makes them potentially useful as PFAS-sensitive sensors. Ultimately, this research provides strategies to control the degradation kinetics of azomethine-containing polymers through the manipulation of environmental factors and guides the continued development of azomethine-based materials.

Expanding Color Control of Anodically Coloring Electrochromes Based on Electron-Rich 1,4-Dihydropyrrolo[3,2-b]pyrroles.

Anodically coloring electrochromes have received attention in recent years as high-contrast alternatives to cathodically coloring electrochromes due to their superior optical contrast during electrochemical switching. While current systems represent significant progress for organic electrochromics, it is necessary to expand the structural diversity of these materials while simultaneously reducing the hazards associated with synthetic protocols. With these considerations in mind, a family of 1,4-dihydropyrrolo[3,2-b]pyrrole (DHPP) chromophores with varying functionalities along the 2,5-axis was envisioned to accomplish these goals. After predicting different absorbance traits as oxidized molecules with time-dependent density functional theory, DHPP chromophores with varying peripheral functionalities were synthesized in a single aerobic synthetic step via an iron-catalyzed multicomponent reaction and characterized as high-contrast chromophores. In solution, the DHPP chromophores absorb in the ultraviolet region of the electromagnetic spectrum, resulting in color-neutral L*a*b* color coordinates of ∼100, 0, 0. Upon chemical oxidation, each molecule transitions to absorb at various points across the visible spectrum based on the extent of electron-donating ability and can display five distinct colors. Importantly, the chromophores are redox-active and display switching capabilities with an applied electrochemical potential. In conjunction with building fundamental insights into molecular design of DHPP chromophores, the results and synthetic simplicity of DHPPs make them compelling materials for color-controlled high-contrast electrochromes.

Correction: Facing the escalating burden of dengue: Challenges and perspectives.

[This corrects the article DOI: 10.1371/journal.pgph.0002598.].

Placental Transcriptome Analysis in Connection with Low Litter Birth Weight Phenotype (LBWP) Sows.

It is possible to identify sub-populations of sows in every pig herd that consistently give birth to low birth weight (BW) piglets, irrespective of the litter size. A previous study from our group demonstrated that placental development is a main factor affecting the litter birth weight phenotype (LBWP) in sows, thereby impacting the BW of entire litters, but the biological and molecular pathways behind this phenomenon are largely unknown. The aim of this study was to investigate the differential gene expression in placental tissues at day 30 of gestation between low LBWP (LLBWP) vs. high LBWP (HLBWP) sows from a purebred Large White maternal line. Using mRNA sequencing, we found 45 differentially expressed genes (DEGs) in placental tissues of LLBWP and HLBWP sows. Furthermore, (GO) enrichment of upregulated DEGs predicted that there were two biological processes significantly related to cornification and regulation of cell population proliferation. To better understand the molecular interaction between cell proliferation and cornification, we conducted transcriptional factor binding site (TFBS) prediction analysis. The results indicated that a highly significant TFBS was located at the 5' upstream of all four upregulated genes (CDSN, DSG3, KLK14, KRT17), recognized by transcription factors EGR4 and FOSL1. Our findings provide novel insight into how transcriptional regulation of two different biological processes interact in placental tissues of LLBWP sows.

Sample Size Considerations for Fine-Tuning Large Language Models for Named Entity Recognition Tasks: Methodological Study.

BACKGROUND: Large language models (LLMs) have the potential to support promising new applications in health informatics. However, practical data on sample size considerations for fine-tuning LLMs to perform specific tasks in biomedical and health policy contexts are lacking. OBJECTIVE: This study aims to evaluate sample size and sample selection techniques for fine-tuning LLMs to support improved named entity recognition (NER) for a custom data set of conflicts of interest disclosure statements. METHODS: A random sample of 200 disclosure statements was prepared for annotation. All "PERSON" and "ORG" entities were identified by each of the 2 raters, and once appropriate agreement was established, the annotators independently annotated an additional 290 disclosure statements. From the 490 annotated documents, 2500 stratified random samples in different size ranges were drawn. The 2500 training set subsamples were used to fine-tune a selection of language models across 2 model architectures (Bidirectional Encoder Representations from Transformers [BERT] and Generative Pre-trained Transformer [GPT]) for improved NER, and multiple regression was used to assess the relationship between sample size (sentences), entity density (entities per sentence [EPS]), and trained model performance (F1-score). Additionally, single-predictor threshold regression models were used to evaluate the possibility of diminishing marginal returns from increased sample size or entity density. RESULTS: Fine-tuned models ranged in topline NER performance from F1-score=0.79 to F1-score=0.96 across architectures. Two-predictor multiple linear regression models were statistically significant with multiple R2 ranging from 0.6057 to 0.7896 (all P<.001). EPS and the number of sentences were significant predictors of F1-scores in all cases ( P<.001), except for the GPT-2_large model, where EPS was not a significant predictor (P=.184). Model thresholds indicate points of diminishing marginal return from increased training data set sample size measured by the number of sentences, with point estimates ranging from 439 sentences for RoBERTa_large to 527 sentences for GPT-2_large. Likewise, the threshold regression models indicate a diminishing marginal return for EPS with point estimates between 1.36 and 1.38. CONCLUSIONS: Relatively modest sample sizes can be used to fine-tune LLMs for NER tasks applied to biomedical text, and training data entity density should representatively approximate entity density in production data. Training data quality and a model architecture's intended use (text generation vs text processing or classification) may be as, or more, important as training data volume and model parameter size.

Dengue NS1 interaction with lipids alters its pathogenic effects on monocyte derived macrophages.

Background: While dengue NS1 antigen has been shown to be associated with disease pathogenesis in some studies, it has not been linked in other studies, with the reasons remaining unclear. NS1 antigen levels in acute dengue are often associated with increased disease severity, but there have been a wide variation in results based on past dengue infection and infecting dengue virus (DENV) serotype. As NS1 engages with many host lipids, we hypothesize that the type of NS1-lipid interactions alters its pathogenicity. Methods: Primary human monocyte derived macrophages (MDMs) were co-cultured with NS1 alone or with HDL, LDL, LPS and/or platelet activating factor (PAF) from individuals with a history of past dengue fever (DF=8) or dengue haemorrhagic fever (DHF=8). IL-1ß levels were measured in culture supernatants, and gene expression analysis carried out in MDMs. Monocyte subpopulations were assessed by flow cytometry. Hierarchical cluster analysis with Euclidean distance calculations were used to differentiate clusters. Differentially expressed variables were extracted and a classifier model was developed to differentiate between past DF and DHF. Results: Significantly higher levels of IL-1ß were seen in culture supernatants when NS1 was co-cultured with LDL (p=0.01), but with lower levels with HDL (p=0.05). MDMs of those past DHF produced more IL-1ß when NS1 with PAF (p=0.02). MDMs of individuals with past DHF, were significantly more likely to down-regulate RPLP2 gene expression when macrophages were co-cultured with either PAF alone, or NS1 combined with PAF, or NS1 combined with LDL. When NS1 was co-cultured with PAF, HDL or LDL two clusters were detected based on IL10 expression, but these did not differentiate those with past DF or DHF. Conclusions: As RPLP2 is important in DENV replication and in regulating cellular stress responses and immune responses and IL-10 is associated with severe disease, it would be important to further explore how differential expression of RPLP2 and IL-10 could lead to disease pathogenesis based on NS1 and lipid interactions.

Heightened Epstein-Barr virus immunity and potential cross-reactivities in multiple sclerosis.

BACKGROUND: Epstein-Barr virus (EBV) is a likely prerequisite for multiple sclerosis (MS) but the underlying mechanisms are unknown. We investigated antibody and T cell responses to EBV in persons with MS (pwMS), healthy EBV-seropositive controls (HC) and post-infectious mononucleosis (POST-IM) individuals up to 6 months after disease resolution. The ability of EBV-specific T cell responses to target antigens from the central nervous system (CNS) was also investigated. METHODS: Untreated persons with relapsing-remitting MS, POST-IM individuals and HC were, as far as possible, matched for gender, age and HLA-DRB1*15:01. EBV load was determined by qPCR, and IgG responses to key EBV antigens were determined by ELISA, immunofluorescence and Western blot, and tetanus toxoid antibody responses by multiplex bead array. EBV-specific T cell responses were determined ex vivo by intracellular cytokine staining (ICS) and cross-reactivity of in vitro-expanded responses probed against 9 novel Modified Vaccinia Ankara (MVA) viruses expressing candidate CNS autoantigens. RESULTS: EBV load in peripheral blood mononuclear cells (PBMC) was unchanged in pwMS compared to HC. Serologically, while tetanus toxoid responses were unchanged between groups, IgG responses to EBNA1 and virus capsid antigen (VCA) were significantly elevated (EBNA1 p = 0.0079, VCA p = 0.0298) but, importantly, IgG responses to EBNA2 and the EBNA3 family antigens were also more frequently detected in pwMS (EBNA2 p = 0.042 and EBNA3 p = 0.005). In ex vivo assays, T cell responses to autologous EBV-transformed B cells and to EBNA1 were largely unchanged numerically, but significantly increased IL-2 production was observed in response to certain stimuli in pwMS. EBV-specific polyclonal T cell lines from both MS and HC showed high levels of autoantigen recognition by ICS, and several neuronal proteins emerged as common targets including MOG, MBP, PLP and MOBP. DISCUSSION: Elevated serum EBV-specific antibody responses in the MS group were found to extend beyond EBNA1, suggesting a larger dysregulation of EBV-specific antibody responses than previously recognised. Differences in T cell responses to EBV were more difficult to discern, however stimulating EBV-expanded polyclonal T cell lines with 9 candidate CNS autoantigens revealed a high level of autoreactivity and indicate a far-reaching ability of the virus-induced T cell compartment to damage the CNS.

Fatality Rates After Infection With the Omicron Variant (B.1.1.529): How Deadly has it been? A Systematic Review and Meta-Analysis.

Background: Since late 2019, the global community has been gripped by the uncertainty surrounding the SARS-CoV-2 pandemic. In November 2021, the emergence of the Omicron variant in South Africa added a new dimension. This study aims to assess the disease's severity and determine the extent to which vaccinations contribute to reducing mortality rates. Methods: A systematic review and meta-analysis of the epidemiological implications of the omicron variant of SARS-CoV-2 were performed, incorporating an analysis of articles from November 2021that address mortality rates. Results: The analysis incorporated data from 3,214,869 patients infected with omicron, as presented in 270 articles. A total of 6,782 deaths from the virus were recorded (0.21%). In the analysed articles, the pooled mortality rate was 0.003 and the pooled in-house mortality rate was 0.036. Vaccination is an effective step in preventing death (odds ratio: 0.391, p < 0.01). Conclusion: The mortality rates for the omicron variant are lower than for the preceding delta variant. mRNA vaccination affords secure and effective protection against severe disease and death from omicron.

Is the rise in childhood obesity rates leading to an increase in hospitalizations due to dengue?

BACKGROUND: Obesity and diabetes are known risk factors for severe dengue. Therefore, we sought to investigate the association of obesity with increased risk of hospitalization, as there is limited information. METHODS AND FINDINGS: Children aged 10 to 18 years (n = 4782), were recruited from 9 districts in Sri Lanka using a stratified multi-stage cluster sampling method. Details of previous admissions to hospital due to dengue and anthropometric measurements were recorded and seropositivity rates for dengue were assessed. The body mass index (BMI) centile in children aged 10 to 18, was derived by plotting the values on the WHO BMI-for-age growth charts, to acquire the percentile ranking. RESULTS: Although the dengue seropositivity rates were similar in children of the different BMI centiles, 12/66 (18.2%) seropositive children with a BMI centile >97th, had been hospitalized for dengue, compared to 103/1086 (9.48%) of children with a BMI centile of <97th. The logistic regression model suggested that BMI centiles 50th to 85th (OR = 1.06, 95% CI, 1.00 to 1.11, p = 0.048) and BMI centile of >97th (OR 2.33, 95% CI, 1.47 to 3.67, p = 0.0003) was significantly associated with hospitalization when compared to children in other BMI categories. CONCLUSIONS: Obesity appears to be associated with an increased risk of hospitalization in dengue, which should be further investigated in longitudinal prospective studies. With the increase in obesity in many countries, it would be important to create awareness regarding obesity and risk of severe disease and hospitalization in dengue.

A DIO2 missense mutation and its impact on fetal response to PRRSV infection.

BACKGROUND: Porcine reproductive and respiratory syndrome virus 2 (PRRSV-2) infection during late gestation substantially lowers fetal viability and survival. In a previous genome-wide association study, a single nucleotide polymorphism on chromosome 7 was significantly associated with probability of fetuses being viable in response to maternal PRRSV-2 infection at 21 days post maternal inoculation. The iodothyronine deiodinase 2 (DIO2) gene, located ~ 14 Kilobase downstream of this SNP, was selected as a priority candidate related to fetal susceptibility following maternal PRRSV-2 infection. Our objectives were to identify mutation(s) within the porcine DIO2 gene and to determine if they were associated with fetal outcomes after PRRSV-2 challenge. Sequencing of the DIO2, genotyping identified variants, and association of DIO2 genotypes with fetal phenotypes including DIO2 mRNA levels, viability, survival, viral loads, cortisol and thyroid hormone levels, and growth measurements were conducted. RESULTS: A missense variant (p.Asn91Ser) was identified in the parental populations from two independent PRRSV-2 challenge trials. This variant was further genotyped to determine association with fetal PRRS outcomes. DIO2 mRNA levels in fetal heart and kidney differed by the genotypes of Asn91Ser substitution with significantly greater DIO2 mRNA expression in heterozygotes compared with wild-type homozygotes (P < 0.001 for heart, P = 0.002 for kidney). While Asn91Ser did not significantly alter fetal viability and growth measurements, interaction effects of the variant with fetal sex or trial were identified for fetal viability or crown rump length, respectively. However, this mutation was not related to dysregulation of the hypothalamic-pituitary-adrenal and thyroid axis, indicated by no differences in circulating cortisol, T4, and T3 levels in fetuses of the opposing genotypes following PRRSV-2 infection. CONCLUSIONS: The present study suggests that a complex relationship among DIO2 genotype, DIO2 expression, fetal sex, and fetal viability may exist during the course of fetal PRRSV infection. Our study also proposes the increase in cortisol levels, indicative of fetal stress response, may lead to fetal complications, such as fetal compromise, fetal death, or premature farrowing, during PRRSV infection.

Porous Metal Augments Have Comparable Outcomes to Other Constructs for Severe Acetabular Bone Loss at Mid-Term Follow-up.

BACKGROUND: Acetabular reconstruction options in the setting of severe bone loss remain limited, with few comparative studies published to date. The purpose of this study was to compare the outcomes of revision total hip arthroplasty (THA) for severe bone loss using porous metal augments to cup cage and triflange prostheses. METHODS: We reviewed a consecutive series of 180 patients who had Paprosky 3A or 3B acetabular defects and underwent revision THA. Patients treated with porous augments (n = 141) were compared with those who received cup cages or triflange constructs (n = 39). Failure of the acetabular construct was defined as undergoing acetabular revision surgery or radiographic evidence of loosening. RESULTS: There was no difference in acetabular component survivorship in patients undergoing revision THA with porous augments or a cage or triflange prosthesis (92.2 versus 87.2%, P = .470) at a mean follow-up of 6.6 ± 3.4 years. Overall, survivorship free from any revision surgery was comparable between the 2 groups (78.7 versus 79.5%, P = .720). There was also no difference in dislocation (5.7 versus 10.3%, P = .309) or periprosthetic joint infection rates (7.8 versus 10.3%, P = .623). In a subgroup analysis of patients who had pelvic discontinuity (n = 47), survivorship free from any revision surgery was comparable between the 2 groups (79.5 versus 72.2%, P = .543). CONCLUSIONS: Porous metal augments in the setting of severe acetabular bone loss demonstrated excellent survivorship at intermediate-term (mean 6.6 years follow-up, even in cases of pelvic discontinuity, with comparable outcomes to cup cages and triflanges. Instability and infection remain major causes of failure in this patient population, and long-term follow-up is needed.

Increased Risk of Postoperative Complications in Patients Who Have Obstructive Sleep Apnea Undergoing Total Joint Arthroplasty: A Systematic Review and Meta-Analysis.

BACKGROUND: Obstructive sleep apnea (OSA) has been linked to multiple adverse health outcomes and postoperative complications. Despite the high prevalence of OSA in patients undergoing total joint arthroplasty (TJA), few studies have evaluated the postoperative course of OSA patients after joint arthroplasty surgery. METHODS: PubMed (MEDLINE) and Scopus (EMBASE, MEDLINE, and COMPENDEX) were used to conduct a systematic review of articles from inception to July 2023. Primary studies comparing postoperative outcomes following TJA between patients who had and did not have OSA were included. Postoperative medical complications, utilization of critical care, hospital stay, and mortality data were extracted. Descriptive statistics and random-effects meta-analysis models were used to analyze the available data. Included studies were evaluated for methodological risks of bias using the risk of bias in non-randomized studies of interventions. This review was registered on the International Prospective Register of Systematic Reviews (ID: CRD42023447610). RESULTS: There were 7 studies with a total of 20,977 patients (9,425 hip; 11,137 knee; 415 hip or knee) that were included. Pulmonary complications were most frequently studied, followed by thromboembolic events. Cardiac, gastrointestinal, hematologic, genitourinary, and delirium events were also reported across studies. Meta-analysis revealed that OSA patients had 4-fold increased odds of overall medical complications (OR [odds ratio], 4.23; 95% confidence interval (CI), 2.97 to 6.04; P < .001; I2 = 0%), 4-fold increased odds of pulmonary complications (OR, 4.31; 95% CI, 2.82 to 6.60; P < .001; I2 = 0%), 2-fold increased odds of thromboembolic complications (OR, 1.92; 95% CI, 1.22 to 3.03; P = .005; I2 = 9%), and 4-fold increased odds of delirium (OR, 3.94; 95% CI, 1.72 to 9.04; P = .001; I2 = 0%). CONCLUSIONS: A significant association was found between OSA and overall medical, pulmonary, and thromboembolic complications. These patients also had a higher incidence of postoperative delirium. The present findings underscore the need for comprehensive perioperative strategies to mitigate these risks in OSA patients who elect to undergo TJA.

Weighing the Impact: The Influence of Body Mass Index on Facility Costs in Total Joint Arthroplasty.

BACKGROUND: Using time-driven activity-based costing (TDABC), a novel cost calculation method that more accurately reflects true resource utilization in health care, we sought to compare the total facility costs across different body mass index (BMI) groups following total joint arthroplasty (TJA). METHODS: The study consisted of 13,806 TJAs (7,340 total knee arthroplasties [TKAs] and 6,466 total hip arthroplasties [THAs]) performed between 2019 and 2023. The TDABC data from an analytics platform was employed to depict total facility costs, comprising personnel and supply costs. For the analysis, patients were stratified into four BMI categories: <30, 30 to <35, 35 to <40, and ≥40. Multivariable regression was used to determine the independent effect of BMI on facility costs. RESULTS: When indexed to patients who had BMI <30, elevated BMI categories (30 to <35, 35 to <40, and ≥40) were associated with higher total personnel costs (TKA 1.03x versus 1.07x versus 1.13x, P < .001; THA 1.00x versus 1.08x versus 1.08x, P < .001), and total supply costs (TKA 1.01x versus 1.04x versus 1.04x, P < .001; THA 1.01x versus 1.02x versus 1.03x, P = .007). Total facility costs in TJAs were significantly greater in higher BMI categories (TKA 1.02x versus 1.05x versus 1.08x, P < .001; THA 1.01x versus 1.05x versus 1.05x, P < .001). Notably, when incorporating adjustments for demographics and comorbidities, BMI values of 35, 40, and 45 relative to BMI of 25, exhibit a significant association with a 2, 3, and 5% increase in total facility cost for TKAs and a 3, 5, and 7% increase for THAs. CONCLUSIONS: Using TDABC methodology, this study found that overall facility costs of TJAs increase with BMI. The present study provides patient-level cost insights, indicating the potential need for reassessment of physician compensation models in this population. Further studies may facilitate the development of risk-adjusted procedural codes and compensation models for public and private payors. LEVEL OF EVIDENCE: Level IV, economic and decision analyses.

Direct and indirect costs of paediatric asthma in the UK: a cost analysis.

OBJECTIVE: To estimate the cost of paediatric asthma from a UK National Health Service (NHS) and societal perspective and explore determinants of these costs. DESIGN: Cost analysis based on data from a large clinical trial between 2017 and 2019. Case report forms recorded healthcare resource use and productivity losses attributable to asthma over a 12-month period. These were combined with national unit cost data to generate estimates of health service and indirect costs. SETTING: Asthma clinics in primary and secondary care in England and Scotland. MAIN OUTCOME MEASURES: Cost per asthma attack stratified by highest level of care received. Total annual health service and indirect costs. Modelled effect of sex, age, severity, number of attacks and adherence on total annual costs. RESULTS: Of 506 children included in the analysis, 252 experienced at least one attack. The mean (SD) cost per attack was £297 (806) (median £46, IQR 40-138) and the mean total annual cost to the NHS was £1086 (2504) (median £462, IQR 296-731). On average, children missed 6 days of school and their carers missed 13 hours of paid work, contributing to a mean annual indirect cost of £412 (879) (median £30, IQR 0-477). Health service costs increased significantly with number of attacks and participant age (>11 years). Indirect costs increased with asthma severity and number of attacks but were found to be lower in older children. CONCLUSIONS: Paediatric asthma imparts a significant economic burden on the health service, families and society. Efforts to improve asthma control may generate significant cost savings. TRIAL REGISTRATION NUMBER: ISRCTN 67875351.

Serum and Synovial Markers in the Diagnosis of Periprosthetic Joint Infection of the Hip, Knee, and Shoulder: An Algorithmic Approach.

➤ No single test has demonstrated absolute accuracy for the diagnosis of periprosthetic joint infection (PJI).➤ Physicians rely on a combination of serological tests, synovial markers, and clinical findings plus clinical judgment to help to guide preoperative decision-making.➤ Several organizations have proposed criteria for the diagnosis of hip or knee PJI on which we now rely.➤ Given that shoulder arthroplasty has only recently become popular, it is possible that a shoulder-specific definition of PJI will be introduced in the coming years.➤ Although a number of serum and synovial markers have demonstrated high accuracy for the diagnosis of PJI of the hip and knee, further research is needed in order to identify markers that may be more suitable for the diagnosis of shoulder PJI and for the potential development and identification of specific serological tests as screening tools for PJI.

Low-level elevations in high-sensitivity cardiac troponin predict obstructive coronary artery disease and revascularisation in rural patients with non-ST-elevation myocardial infarction referred for coronary angiography.

Rural patients with non-ST-elevation myocardial infarction (NSTEMI) are transferred to metropolitan hospitals for invasive coronary angiography (ICA). Yet, many do not have obstructive coronary artery disease (CAD). In this analysis of rural Western Australian patients transferred for ICA for NSTEMI, low-level elevations in high-sensitivity cardiac troponin (≤5× upper reference limit) were associated with less obstructive CAD and revascularisation. Along with other factors, this may help identify rural patients not requiring transfer for ICA.

Rationale and design of the early valve replacement in severe asymptomatic aortic stenosis trial.

BACKGROUND: Aortic valve replacement in asymptomatic severe aortic stenosis is controversial. The Early valve replacement in severe ASYmptomatic Aortic Stenosis (EASY-AS) trial aims to determine whether early aortic valve replacement improves clinical outcomes, quality of life and cost-effectiveness compared to a guideline recommended strategy of 'watchful waiting'. METHODS: In a pragmatic international, open parallel group randomized controlled trial (NCT04204915), 2844 patients with severe aortic stenosis will be randomized 1:1 to either a strategy of early (surgical or transcatheter) aortic valve replacement or aortic valve replacement only if symptoms or impaired left ventricular function develop, or other cardiac surgery becomes nessessary. Exclusion criteria include other severe valvular disease, planned cardiac surgery, ejection fraction <50%, previous aortic valve replacement or life expectancy <2 years. The primary outcome is a composite of cardiovascular mortality or heart failure hospitalization. The primary analysis will be undertaken when 663 primary events have accrued, providing 90% power to detect a reduction in the primary endpoint from 27.7% to 21.6% (hazard ratio 0.75). Secondary endpoints include disability-free survival, days alive and out of hospital, major adverse cardiovascular events and quality of life. RESULTS: Recruitment commenced in March 2020 and is open in the UK, Australia, New Zealand, and Serbia. Feasibility requirements were met in July 2022, and the main phase opened in October 2022, with additional international centers in set-up. CONCLUSIONS: The EASY-AS trial will establish whether a strategy of early aortic valve replacement in asymptomatic patients with severe aortic stenosis reduces cardiovascular mortality or heart failure hospitalization and improves other important outcomes.