Search Results (3,726)

Wastewater-based epidemiology (WBE) is a rapidly evolving discipline that employs the analysis of human excreted biomarkers in untreated, community wastewater to provide near real-time population-level health assessments. While its popularity to support public health decision-making and intervention grew during the COVID-19 pandemic, understanding its utility and acceptability in healthcare is currently underexplored. This study aimed to generate evidence to support the integration of WBE into the healthcare setting via an educational webinar with the following objectives: (i) assess change in perspectives of WBE via surveys, (ii) understand major applications of interest and applicability to healthcare, and (iii) capture perspectives on its utility in this context. Comparative findings indicated an overall increase in support of WBE (95% to 100%), a reduction in concerns regarding data accuracy (40% to 25%), and an increase in support for the use of WBE to influence public policy (65% to 75%). Follow-up, open-ended survey responses indicated the workshop was an effective method to educate on WBE and its wide variety of applications. Overall, this pilot study revealed there is merit in further investigating the utility of integrating WBE data into the healthcare setting, as its integration demonstrates high levels of potential acceptability in clinical practice. Future work that reaches a wider audience and tests specific educational interventions is needed to further confirm utility, determine best educational outreach methods, and explore relevant and useful applications in the healthcare setting. Full article

The cardiovascular actions of testosterone remain controversial, particularly regarding the safety of testosterone replacement therapy (TTh) in hypogonadal men. We investigated the effects of sustained supraphysiological testosterone exposure on aortic atherogenesis and cardiac remodelling in the testicular feminised (Tfm) mouse, a model of functional androgen receptor (AR) deficiency. Male Tfm mice and AR-intact XY littermate controls were fed a cholesterol-enriched diet for 28 weeks and received fortnightly intramuscular injections of saline or supraphysiological testosterone, alone or in combination with fulvestrant (oestrogen receptor antagonist) or anastrozole (aromatase inhibitor). Aortic lipid deposition was quantified by Oil Red O staining, while cardiac remodelling was assessed by heart weight, cardiomyocyte cross-sectional area and myocardial gene expression. Supraphysiological testosterone significantly reduced aortic fatty streak formation in Tfm mice compared with saline-treated controls (1.25 ± 0.36% vs. 2.85 ± 0.37%, p < 0.01), an effect preserved following fulvestrant or anastrozole treatment, consistent with mechanisms that do not require classical AR or oestrogen receptor signalling. No additional reduction in aortic lipid deposition was observed in AR-intact XY littermates. In contrast, supraphysiological testosterone increased heart weight, cardiomyocyte size and expression of hypertrophic markers exclusively in XY mice, with no evidence of cardiac remodelling in Tfm mice. Collectively, these findings demonstrate divergent tissue-specific cardiovascular actions of testosterone, whereby supraphysiological exposure promotes AR-dependent cardiac remodelling without conferring additional vascular benefit, supporting maintenance of physiological testosterone concentrations during TTh. Full article

A series of novel substituted derivatives of the closo-decaborate anion [B₁₀H₁₀]²⁻ bearing alkoxy spacer chains of varying length derived from ring-opened crown ethers (12-crown-4, 15-crown-5, and 18-crown-6) with pendant L-amino acid methyl ester residues (L-tryptophan and L-histidine) have been synthesized. The synthetic approach involved the nucleophilic ring-opening of oxonium crown ether derivatives of the closo-decaborate anion followed by coupling with amino acid methyl esters via mixed anhydride activation. The obtained compounds were characterized by multinuclear NMR spectroscopy (¹H, ¹¹B, ¹³C), IR spectroscopy, elemental analysis, and electrospray ionization mass spectrometry (ESI-MS). The compounds were obtained as sodium salts and evaluated for their in vitro cytotoxic and antiviral properties against the influenza A virus strain A/Moscow/78/2020 (H1N1)pdm09, which contains the S31N mutation conferring resistance to adamantane-class drugs. Cytotoxicity was assessed on MDCK cells, and antiviral activity was determined by cell ELISA. The results revealed a clear structure–activity relationship: the length of the alkoxy spacer chain significantly influenced both antiviral activity and selectivity. The shortest spacer (derived from 12-crown-4) proved to be optimal, while elongation of the chain led to a decrease in antiviral potency. The compound containing a 12-crown-4-derived spacer and a tryptophan methyl ester residue exhibited the highest selectivity index (SI = 155) with low cytotoxicity (CC₅₀ = 155 µg/mL) and high antiviral activity (IC₅₀ = 1.0 µg/mL). Tryptophan-containing derivatives consistently outperformed their histidine analogues, confirming the key role of the indole side chain in antiviral activity. Overall, the closo-decaborate platform with crown ether-derived spacers and amino acid ester pendant groups represents a promising scaffold for the development of low-toxicity, highly selective inhibitors of influenza A virus replication. The compound with the 12-crown-4-derived spacer and a tryptophan methyl ester residue merits further investigation as the most promising among the synthesized samples. Full article

In the post-pandemic era, identifying children who are most susceptible to severe illness and COVID-19-related mortality is essential for guiding public health policies. This study examined the risk factors for COVID-19-related severe illness and mortality from 2023 to mid-2025. We conducted a population-based cohort study using nationwide Brazilian data from patients aged <18 years with laboratory-confirmed SARS-CoV-2 infection between January 2023 and June 2025. The primary outcomes were COVID-19-related severity and death. Separate binary multivariable logistic regression models were developed for each of the outcomes. Among 465,689 children, 1.3% (n = 5963) developed severe illness, and 0.18% (n = 847) died. Factors associated with an increased risk of severe illness included age < 2 years, presence of comorbidities, Indigenous ethnicity, and lack of vaccination. Neurological disorders conferred the highest risk among the clinical conditions (adjusted odds ratio [aOR] = 34.1; 95% CI: 27.9–41.8). Regional differences were also observed; the North and Northeast regions showed higher mortality (aOR = 2.3; 95% CI: 1.8–3.0) than the Central-West region. Compared with White ethnicity, non-White ethnicities had higher mortality: Indigenous (aOR = 23.5; 95% CI: 13.5–39.3), Black (aOR = 1.95; 95% CI: 1.29–2.92), and Brown (aOR = 1.43; 95% CI: 1.18–1.73) ethnicities. Lack of any vaccine dose was associated with a significantly increased risk of severe illness (aOR = 1.39; 95% CI: 1.15–1.67. p < 0.001) and death (aOR = 2.1; 95% CI: 1.3–3.5; p < 0.001). In the post-pandemic era, younger age, comorbidities, sociodemographic disparities, and lack of vaccination were associated with an increased risk of severe illness and COVID-19-related death in the pediatric population. Full article

Lyme borreliosis (LB) is a tick-borne disease caused by a diverse and expanding group of spirochetes characterized by complex biology and advanced immune evasion mechanisms. It presents a wide range of clinical symptoms affecting multiple organ systems and can lead to persistent complications. The pathogenesis of LB remains incompletely understood, and diagnosis typically relies on serologic assays to detect antibodies against LB. However, the standard two-tiered testing (STTT) algorithm is limited by cross-reactivity, low sensitivity, and delayed results, hindering timely and accurate diagnosis. Although molecular tests are considered the gold standard, their reliance on centralized laboratories can delay critical treatment decisions. This underscores the urgent need for rapid, reliable diagnostic tools, particularly for use at the point of hospital admission. Point-of-care serological and direct antigen testing can provide actionable information, supporting decentralized healthcare systems in diagnosing complex diseases, such as LB. In this study, we developed two fluorescent polarization immunoassays (FPIAs) using IgM and IgG LB-specific synthetic epitopes/peptides to evaluate their diagnostic potential. These FPIAs showed high sensitivity and specificity in detecting IgM or IgG anti-LB antibodies in patient sera within minutes. The fluorescently labeled synthetic peptides produced significant polarization differences between infected and healthy samples, allowing clear discrimination. The FPIA-LB functions as a one-step assay, eliminating the need for secondary antibodies or complex protocols. This work highlights the FPIA technique as a robust, rapid, and efficient tool for LB diagnosis, offering a promising advance in improving early detection and patient outcomes, which could save lives and reduce long-term health complications. Full article

Background/Objectives: Mindfulness-based interventions (MBIs) have gained increasing attention in sport psychology due to their potential to enhance psychological well-being and performance-related outcomes among athletes. Despite various systematic reviews and meta-analyses examining mindfulness in athletic contexts, broader scoping evidence mapping randomised controlled trials (RCTs) of MBIs targeting psychological well-being among athletes remains limited. This scoping review aims to map and synthesise empirical evidence from RCTs examining MBIs and psychological outcomes among athletes, identify methodological and conceptual gaps, and guide future systematic reviews and meta-analytic investigations. Methods: The review followed the Joanna Briggs Institute (JBI) methodology for scoping reviews and was reported according to the PRISMA-ScR guidelines. Searches were conducted across Scopus, Web of Science, and PubMed, initially in March 2026 and updated in April 2026. Data were extracted on study characteristics, participant demographics, intervention features, comparator conditions, outcome measures, and key findings. Results: A total of 17 studies met the inclusion criteria and were included in the review. The included studies generally reported beneficial effects of MBIs across psychological well-being, emotion regulation, cognitive functioning, and sport-related psychological outcomes among athletes. Beneficial effects were reported for several outcomes, including mindfulness, mental toughness, emotional intelligence, mental well-being, flow state, self-compassion, psychological flexibility, emotional regulation, attention, life satisfaction, and grit. Reductions in psychological distress, particularly anxiety and stress, were also reported in several studies, although findings for anxiety were not consistent across trials. Findings were mixed for some other outcomes, including self-esteem, acceptance, and depression. Improvements were additionally reported in social relationships, pleasure regulation, and overall psychological functioning. Conclusions: The findings suggest that MBIs may offer beneficial effects across multiple dimensions of psychological functioning among athletes, although effects were not uniform across outcomes or interventions. These findings indicate the potential utility of structured MBI programmes within athlete support settings, particularly when delivered by or in collaboration with sport psychologists and mental performance consultants, while highlighting the need for further well-designed RCTs to clarify intervention-specific effects and longer-term outcomes. Full article

This study presents a comparative in vitro evaluation of 24 natural sesquiterpene γ-lactones and selected semisynthetic derivatives against three trypanosomatid parasites responsible for neglected tropical diseases: Trypanosoma brucei brucei, Trypanosoma cruzi, and Leishmania amazonensis. The compounds were screened for antiparasitic activity across different parasite life stages, and their cytotoxicity was assessed in mammalian cells. Several compounds demonstrated high inhibitory activity (>95%) at 10 µg/mL, including estafiatin (1), grossheimin (4), cynaropicrin (5), argolide (2) derivatives, and arglabin (23). However, a marked decrease in activity was observed at lower concentrations and in intracellular parasite models, particularly for T. cruzi and L. amazonensis amastigotes. Among the tested compounds, dihydroargolide (3) and pulchellin C (19) exhibited comparatively lower cytotoxicity and were further evaluated, yielding IC₅₀ values of 10.51 ± 1.72 µg/mL and 2.51 ± 1.13 µg/mL against T. b. brucei, respectively. Against L. amazonensis promastigotes, estafiatin (1), 8α-chloroacetoxygrossheimin (12), and arglabin (23) showed IC₅₀ values of 0.16 ± 0.13, 0.35 ± 0.18, and 0.58 ± 0.11 µg/mL, respectively, although their selectivity indices remained limited. Comparative analysis of the dataset indicates that specific structural elements, such as the α-methylene-γ-lactone moiety and selected substituents (e.g., epoxy and acetyl groups), may influence antiparasitic activity in a species-dependent manner. At the same time, the generally low selectivity indices and reduced activity in intracellular models highlight important limitations of these compounds as direct drug leads. Overall, this work provides a systematic comparative dataset and identifies preliminary structure–activity trends that may guide further chemical optimization of sesquiterpene γ-lactones as antiparasitic hit compounds. Full article

Many people are affected by difficult-to-understand clinical phenomena associated with acute SARS-CoV-2 infection and by post-acute sequelae of COVID-19 (PASC, or long COVID, LC). The mechanisms responsible for the clinical phenomena have not been well established. The host cell receptor for SARS-CoV-2 is human angiotensin-converting enzyme 2 (ACE2), which binds the SARS-CoV-2 spike protein receptor-binding domain (RBD) to initiate infection. We hypothesized that some people may produce anti-RBD antibodies that sufficiently resemble ACE2 structure to have ACE2-like catalytic activity after infection, and such antibodies are hypothesized to contribute to disease pathogenesis. Our previous studies showed that ACE2-like catalytic activity was associated with immunoglobulin in some acute and convalescent COVID-19 patients. ACE2-like catalytic activity correlated with blood pressure changes following a moderate exercise challenge in people convalescing from COVID-19. To further establish that ACE2-like catalytic activity could be attributed to antibodies, we screened human monoclonal antibodies (mAbs) against SARS-CoV-2 spike protein from three different research centers and others purchased from a commercial source for ACE2-like catalytic activity. We identified four human monoclonal antibodies with ACE2-like catalytic activity. The ACE2-like catalytic activity of these mAbs was not inhibited by MLN-4760, a compound that inhibits native human ACE2 catalytic activity, nor by EDTA, unlike native ACE2, a zinc metalloprotease, but was inhibited by an overlapping pool of spike peptides. Enzyme kinetic studies showed that the mAbs had substantially lower Vmax and K_m values than native ACE2, consistent with the characteristics of other catalytic antibodies. The data therefore suggested that the antibodies cleave ACE2 substrate via a mechanism different from native ACE2. The identification of specific mAbs with ACE2-like catalytic activity supports the hypothesis that antibodies induced by SARS-CoV-2 infection could help mediate the pathogenesis of COVID-19 and LC, and, more generally, the hypothesis that catalytic antibodies induced by infectious agents can contribute to disease pathogenesis. Full article

Background/Objectives: Hexavalent chromium [Cr(VI)] is a toxic metal that enters the environment due to natural and anthropogenic processes. The liver is a major target organ of Cr(VI) exposure through drinking water, resulting in an increased risk of exposed individuals developing chronic liver diseases and cancers. Cr(VI) exposure is also associated with neurological dysfunction. Essential metal dyshomeostasis is a well-characterized biomarker of liver and neurological diseases, but the role Cr(VI) plays in altering essential metal levels in both organs is poorly understood. Methods: Male and female Hartley guinea pigs were exposed to 0 or 5 mg Cr(VI)/L in drinking water for 90 days. Chromium accumulation and essential metal levels in the liver, blood and brain were analyzed using inductively coupled plasma mass spectrometry. Results: Chromium significantly accumulated in a sex-dependent manner in the livers and blood of guinea pigs given 5 mg Cr(VI)/L in their drinking water, with sex- and region-specific chromium deposition observed in the brain. The livers and blood of female guinea pigs were more vulnerable to Cr(VI) exposure, as evident in the significant chromium accumulation and dyshomeostasis of several essential metals, including hepatic magnesium, zinc and potassium. Conversely, male guinea pigs were more vulnerable to Cr(VI)-induced essential metal dyshomeostasis in the brain, with significant changes in molybdenum and cobalt in nearly half of the 11 brain regions assessed. Conclusions: This study begins the process of establishing a novel model to study Cr(VI)-induced hepatotoxicity, neurotoxicity and organ crosstalk. Overall, Cr(VI) induced sex-dependent essential metal dyshomeostasis in the liver and blood, along with sex- and region-specific essential metal dyshomeostasis in the brain. These results suggest essential metal dyshomeostasis may play an important role in Cr(VI)-induced liver and neurodegenerative diseases, and these effects should guide future mechanistic investigations. Full article

Background/Objectives: Renal mass biopsy (biopsy) is increasingly incorporated into the evaluation of localized renal masses, yet its role in guiding management remains variable among clinical practices. We evaluated the clinical association of biopsy using a simplified classification system categorizing biopsy results as Biopsy Actionable for Immediate Treatment (BAIT) or Biopsy Actionable for Active Surveillance (BAAS)—assessing how biopsy-derived histology influences real-world management. Methods: We identified all patients undergoing biopsy for a renal mass measuring 2–7 cm at a single academic center between 2010 and 2025. After excluding nondiagnostic biopsies, repeat biopsies, and biopsies performed for metastatic diagnosis, 1395 patients formed the analytic cohort. Histologic subtypes and initial treatment were evaluated. Multivariable logistic regression assessed predictors of (1) radical versus partial nephrectomy, (2) surgery versus thermal ablation, and (3) active surveillance versus intervention, adjusting for tumor diameter, age, and BAIT/BAAS status. Results: Of 1395 patients, 1119 (80.2%) had BAIT pathology and 276 (19.8%) had BAAS pathology. Initial management included surgery (36.3%), thermal ablation (36.3%), active surveillance (24.2%), no treatment (1.7%), and radiation (1.5%). BAAS pathology was strongly associated with the selection of active surveillance (OR 21.80, p < 0.001). Larger tumor diameter was the principal driver of radical nephrectomy (OR 2.04/cm, p < 0.001) and of choosing surgery over ablation (OR 2.05/cm, p < 0.001). Younger age was associated with selection of surgery over ablation (OR 0.93/year, p < 0.001). Biopsy histology showed a stronger association with surveillance selection than either tumor diameter or age. Conclusions: Biopsy provides actionable diagnostic information for patients with 2–7 cm renal masses, identifying benign or indolent pathology in nearly one in five patients. BAIT/BAAS categorization was strongly associated with the selection of active surveillance for renal masses. Full article

Mesophotic coral reef ecosystems (MCEs) support unique biodiversity and can act as refuges for species that also occur on heavily impacted shallow coral reefs. However, we still know relatively little about the physical and environmental structure of MCEs and the species that characterise them, especially within the Western Indian Ocean. To address this gap, we surveyed fish and macrobenthic assemblages between 10 and 100 m depth at three islands of the Comoros Archipelago using Baited Remote Underwater Video Systems (BRUVS). We also recorded temperature and photosynthetically active radiation (PAR) using a Conductivity–Temperature–Depth (CTD) probe. The structure of the fish assemblages was influenced by substrate type, relief and depth. More diverse fish assemblages were found on higher relief reefs, while low-diversity fish assemblages were associated with shallow sand and deeper low-relief sand/reef mosaic habitats. The reef fish assemblages delineated into three groups, corresponding to three depth zones: the photic zone (12–45 m), upper-mesophotic zone (45–62 m) and lower-mesophotic zone (63–98 m). The upper–lower mesophotic break aligned with the theoretical bottom of the euphotic zone at PAR1%_surface. Macrobenthic assemblages comprised scleractinian corals on photic reefs, which transitioned at PAR3.5%_surface to assemblages of non-light-dependent Octocorallia (soft corals and fans), Gorgonia (sea whips) and Antipatharia (black corals) on the mesophotic reefs. Scleractinian corals were found deeper in Comoros, which may confer greater resilience to climate change. The photic and lower-mesophotic reefs supported unique fish assemblages of depth specialist species, while the upper-mesophotic zone appeared to be a transition zone for fish assemblages. The presence of numerous large depth-generalist fishery species at depths > 50 m suggests that the mesophotic zone may be providing a depth refuge for fishery species that are overfished on shallow reefs. Our findings highlight potential resilience in the coral reef ecosystems of Comoros and illustrate the importance of mesophotic coral reefs in conservation planning. Full article

Mitochondrial dysfunction, including impaired respiration and increased reactive oxygen species (ROS), is an early feature of Alzheimer’s disease (AD) models. Electron transport chain supercomplexes (mSCs) regulate respiratory efficiency and ROS generation, yet genetic determinants of mSC organization in AD models remain underappreciated. Cox7a2l is known to promote CIII₂/CIV association and CIV incorporation into mSCs. We examined the commonly used mixed-background B6;129S 3xTg-AD mice and B6129SF2/J controls aged 12–15 months, as well as specific rat AD models for changes in mSC organization using blue and clear native-PAGE and DIA-MS. BN and CN-PAGE revealed a marked shift toward larger mSC assemblies in 3xTg-AD mice and a distinct ~650 kDa assembly of complex III absent from controls. Gene sequencing showed that 3xTg-AD mice retained the full-length Cox7a2l variant similar to 129S strains, whereas controls predominantly carried a shortened C57BL/6-associated variant. DIA-MS identified greatly increased Cox7a2l in differential mSC bands. Similar changes were found in 3xTg-AD heart tissue. In contrast, AD rat models and their controls, all expressing full-length Cox7a2l, did not exhibit comparable mSC differences. These findings suggest Cox7a2l genotype as a determinant of mSC organization and highlight the need to account for genetic background when interpreting mSC-dependent mitochondrial phenotypes in mixed-background 3xTg-AD studies. This distinction is essential for accurately separating strain-dependent effects from AD-associated mitochondrial changes. Full article

Sulfated polysaccharides from red seaweeds are emerging as versatile bioactive macromolecules. Here, we report that funoran-type galactans from Gelidiopsis variabilis (GV) function as immunometabolic reprogrammers, orchestrating inflammation resolution through targeted remodeling of amino acid and fatty acid metabolism in macrophages, potentially via receptor-mediated pathways. Cold and hot water extraction yielded structurally distinct fractions (360–3006 kDa) characterized by NMR as sulfated galactans with κ-carrageenan motifs and variable sulfation (6.6–21.5%). In RAW264.7 macrophages, fractions GV-1A and GV-2A induced an anti-inflammatory metabolic state characterized by arginine accumulation (from 4.61% to 7.06% of the total amino acid pool), reduced ornithine levels, and complete the elimination of pro-inflammatory myristate (14:0), while upregulating phagocytosis (149% of control). In a carrageenan-induced paw edema model, GV-1A and GV-2A dose-dependently upregulated pro-resolution markers (IL-10, IL-4, TGF-β1, Arg1, HO-1), outperforming the standard drug meloxicam. While the in vitro arginine accumulation suggests functional arginase inhibition, the in vivo Arg1 upregulation reflects a transcriptional response in a complex tissue environment. We propose that these findings collectively support a ‘resolution-phase metabolic phenotype’, a working model whereby GV polysaccharides reprogram macrophage metabolism toward inflammation resolution through context-dependent mechanisms. These findings establish G. variabilis polysaccharides as metabolically active immunomodulators that promote inflammation resolution, with the potential for applications in inflammatory diseases and as a pharmaceutical platform for drug development. Full article

Background/Objectives: Skin yellowness measured using reflectance spectroscopy can be used as a proxy for ‘skin carotenoid’ concentration and as a valid estimate of fruit and vegetable intake. However, the association between different ethnic backgrounds, age, sex and self-reported skin colour on skin yellowness is yet to be explored. Methods: This exploratory cross-sectional study used a convenience sample to assess the relationship between skin yellowness (b*), measured using skin reflectance spectroscopy, and fruit and vegetable intakes across different age groups, sex, self-reported Caucasian and Asian ethnicities and self-reported skin colour. Recruited adults were aged ≥18 years who self-reported as Caucasian or of Asian ethnicity (N = 137). Data were collected on skin L*, a*, b* colours using skin reflectance spectroscopy, height, weight, body composition, waist circumference, demographic variables (e.g., age, sex, self-reported skin colour), and dietary intake measured using the online Australian Eating Survey^® (AES^®). Multiple linear regression models were used to investigate factors associated with the dependent variable, skin yellowness (b*). Results: Participants were on average 38.6 (SD = 17.7) years of age, self-reported as female (61%), Caucasian (77%) and met the recommended fruit intake of two serves/day (mean = 2.1, SD = 1.5) but not the recommended vegetable intake of five to six serves per day (mean = 4.4, SD = 3.1). There were significant associations between skin yellowness (b*) and several independent variables, including combined fruit and vegetable intake, total carotenoid intake, body fat percentage and self-reported skin colour. Conclusions: This study adds additional support for using skin yellowness as a proxy for fruit and vegetable intake when adjusting for self-reported skin colour, age and sex. Full article

Over the past decade, advances in sequencing technologies and computational pipelines enabled the development of personalized cancer vaccines (PCVs). Current PCV strategies primarily target cancer neoantigens generated by non-synonymous DNA mutations, which can result in altered amino acid sequences capable of eliciting tumor-specific immune responses. More recently, a distinct class of tumor-specific antigens (TSA), termed noncanonical or cryptic antigens, has emerged as an additional source of immunogenic targets. Unlike canonical neoantigens, noncanonical antigens typically cannot be identified by tumor/normal whole-exome sequencing, as they do not arise from classical DNA mutations. Instead, they are often associated with less well recognized and/or aberrant processes in the pathways from DNA to human leukocyte antigen (HLA)-presented peptides. Examples include transposable elements, circular RNA, translation of alternative open reading frames and/or long non-coding RNA, among others. Emerging evidence suggests that noncanonical antigens represent a substantial portion of the tumor-specific immunopeptidome and, similar to canonical neoantigens, are absent during thymic selection and can evade central tolerance and elicit T cell responses. Technological advances have increasingly facilitated the identification of noncanonical antigens. Long-read RNA sequencing reveals noncanonical transcripts by improving transcriptome assembly, while ribosome profiling provides genome-wide maps of actively translated regions, facilitating the discovery of peptides from aberrant translation events. Specialized molecular approaches enable enrichment and sequencing of circular RNAs, and immunopeptidomics using mass spectrometry allows for direct characterization of HLA-presented peptides. Together, these technological advances have led to an increasing interest in prioritizing and targeting noncanonical antigens in the next generation of PCVs. This review provides an overview of the diverse origins of TSAs beyond classical neoantigens and discusses emerging approaches that may enable the integration of these antigens in future clinical trials. Full article