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Over the past three decades, adenosine signalling has emerged as a fundamental regulatory system controlling immune responses, tissue homeostasis, metabolism, and repair processes. The identification of four adenosine receptor subtypes and the development of selective agonists and antagonists generated substantial enthusiasm for therapeutic targeting across a broad spectrum of inflammatory, autoimmune, metabolic, and neoplastic diseases. However, despite compelling preclinical evidence, the clinical translation of adenosine-based therapies has often yielded inconsistent or disappointing results. Increasing evidence suggests that these limitations may not primarily reflect inadequate pharmacological tools, but rather an incomplete understanding of the remarkable spatial, temporal, and cellular heterogeneity of adenosine signalling in human disease. Advances in immunology, systems biology, single-cell technologies, spatial transcriptomics, metabolomics, and artificial intelligence are revealing highly diverse purinergic landscapes across tissues and patient populations. These findings challenge the traditional "one receptor-one disease" paradigm and support a transition toward precision medicine approaches capable of identifying disease-specific and patient-specific purinergic signatures. In this commentary, we discuss how the field is moving beyond classical receptor pharmacology toward biomarker-driven patient stratification. We propose that the next generation of purinergic therapeutics will depend not only on improved drugs but also on the ability to define when, where, and in whom adenosine signalling should be manipulated. Such a shift may ultimately represent the long-awaited bridge between decades of successful experimental research and meaningful clinical implementation.

Acute respiratory infections caused by influenza, respiratory syncytial virus (RSV), and SARS-CoV-2 remain a major public health challenge in Europe. Although surveillance systems for these pathogens are well established, the past 2 decades have seen a rapid diversification of data streams supporting surveillance and research. This expanding data landscape, combined with fragmentation across institutions, sectors, and countries, may limit timely evidence synthesis and effective public health decision-making. This scoping review aimed to identify and characterize data sources used for surveillance and research on influenza, RSV, and SARS-CoV-2 in Europe over the past 20 years, and to examine their evolution over time, their alignment with research objectives, and geographic variation in data availability and use. We conducted a scoping review using an objective-driven analytical framework. Empirical reports published between January 2005 and September 2025 were identified in MEDLINE, Web of Science, and Embase. Eligible reports focused on influenza, RSV, or SARS-CoV-2 and included data from 12 European countries. Clinical and interventional studies were excluded. Reports were classified according to 4 research objectives: epidemiological monitoring, evaluation of interventions, assessment of disease burden and health outcomes, and analyses of population adherence and trust toward public health measures. Data sources were grouped into 9 categories, including surveillance systems, electronic health records (EHRs), registries, claims, surveys, digital, environmental, integrated datasets, and others. A total of 2564 empirical reports were included. Over time, respiratory virus research relied on an increasingly diverse set of data streams. While surveillance systems remained central, particularly for epidemiological monitoring, their relative dominance declined. From 2020 onward, there was a marked expansion in the use of EHRs, registries, claims data, digital sources, and linked or integrated datasets, alongside increased use of open-access data. Data source use varied by research objective: surveillance data predominated in monitoring and intervention evaluation; EHRs in studies of risk factors and treatment effectiveness; surveys in seroprevalence and public trust analyses; and claims data in assessments of economic burden. Substantial geographic disparities were observed. Northern European countries more frequently used linked and multisource datasets, whereas Southern Europe relied more often on open-access or single-source data. This scoping review provides a multipathogen, cross-country mapping of data sources for respiratory virus surveillance and research in Europe over 2 decades, applying an innovative objective-driven framework. Unlike prior reviews focused on single pathogens or data types, it offers a consolidated, comparative perspective based on 2564 reports to inform public health decision-making. The COVID-19 pandemic accelerated innovation in data generation and access, but progress remained largely centered on SARS-CoV-2, while structural fragmentation continues to limit timely, integrated data across Europe. Strengthening preparedness will require interoperable infrastructures, federated analysis platforms, sustainable funding for surveillance innovations, and cross-sectoral data sharing.

BackgroundMaternal mortality in the United States has doubled over the last two decades, primarily due to cardiovascular disease, with more than half of deaths occurring postpartum. Despite national calls to action, attendance at postpartum clinic visits remains low. The role of alternative care delivery strategies, such as home visiting, remains insufficiently studied.ObjectiveTo describe postpartum clinic visit attendance among participants in a large national home visiting program, identify sociodemographic and clinical factors associated with attendance, and examine how timing and duration of enrollment relate to postpartum follow-up.DesignWe conducted a retrospective cohort study of pregnancy episodes among mothers enrolled in the Parents as Teachers (PAT) national home visiting program between July 2016 and September 2024.MethodsThe primary outcome was documented attendance at a postpartum clinic visit within 12 weeks of delivery. Descriptive analyses estimated overall attendance rates and characterized variation by pregnancy risk status, geography, calendar year, and sequential pregnancies. Multilevel logistic regression with random intercepts for participant and site was used to account for repeated pregnancies and clustering. Sensitivity analyses included all pregnancies, including those exiting home visiting prior to 12 weeks postpartum.ResultsAmong 46,899 pregnancy episodes from 39,498 participants, median maternal age was 27 years (IQR 18-36). Overall, 30.1% (95% CI 29.6-30.5) attended a postpartum clinic visit within 12 weeks, including 33.2% (95% CI 32.3-34.1) among high-risk pregnancies. Attendance was lower among Black (adjusted OR 0.80 [95% CI 0.75-0.86]), American Indian/Alaska Native (0.61 [0.55-0.68]), rural participants (0.77 [0.73-0.82]), and participants who primarily used the emergency room or urgent care for medical care before pregnancy (0.78 [0.72-0.85]). Attendance washigher among recent immigrants (1.17 [1.05-1.30]), women with high-risk pregnancies (1.13 [1.06, 1.20]),and those enrolled prenatally (1.93 [1.84-2.04]).ConclusionsPostpartum clinic attendance was low in this national home visiting cohort. Prenatal and sustained engagement in home visiting were associated with higher odds of attendance. Home visiting is a potential complementary care model to extend early care beyond clinical settings and promote sustained engagement in clinical follow-up.

Engineering proteins for therapeutic applications is a field that has seen substantial growth in the past two decades, but challenges remain. A major deficiency in current strategies is the lack of a means to efficiently screen for binding to key epitopes to yield a desired function. To meet this challenge, we designed a tethered yeast surface display construct that leverages high local concentrations by tethering a candidate protein binder to a target protein of interest (POI) via a flexible peptide linker. These high local concentrations enable screening of epitope-specific binders based on decreased signal due to inhibitory function when the construct is assayed alongside a competitive POI binder. We demonstrate that epitope-specific screening and enrichment is possible based on fluorescent output and study key optimization parameters. We anticipate this technique will accelerate binder development by reducing the need for downstream low throughput epitope mapping of isolated proteins.

The Na-K-2Cl cotransporter isoform 1 (NKCC1) regulates cell volume and ionic distribution, thereby also controlling the efficacy of neuronal GABAergic inhibition. enhanced activity of the NKCC1 chloride importer and high Cl. levels has been reported in a long list of disorders, including epilepsies, brain trauma, peripheral and central cancers, spinal cord injury or chronic pain, and cerebrovascular infarcts, indicating that NKCC1 inhibitors might constitute promising therapeutic avenues. Synthetized four decades ago, bumetanide constitutes the only agent that is widely used in animal models and human trials, limiting the possibility to assign some NKCC1 inhibitors specifically to treat some disorders. Here, we have synthetized many novel NKCC1 inhibitors to augment the range of molecules that can be tested in animal models and pre-IND tests. We used modifications of the bumetanide parent molecule by modifying two sites with alterations that have not been envisaged before. Specifically, we incorporated carboxylic acid bioisosteres and sulfonimidamides or sulfoximines moieties. Their efficacy was evaluated against NKCC1, NKCC2, and KCC2 using human cell lines. The synthesis of the new inhibitors and the structure-activity relationship (SAR) are described. Some molecules are superior to bumetanide as NKCC1 inhibitors, which widens the family of NKCC1 inhibitors and paves the way for more efficient agents. Our aims here are solely chemical, namely, describing the possible targets of the bumetanide molecule that can be changed using novel approaches. In the future, we and others will test these molecules in animal models and clinical trials to validate the use of some of them in treating a variety of disorders.

Over the past two decades, concerns have arisen about the distinction between health span and lifespan, highlighting that longevity does not necessarily equate to good health, a concept often referred to as "healthy longevity." While various strategies have been explored to promote healthy aging and achieve healthy longevity, it remains uncertain which practices are most effective. To identify the existing and emerging practices and interventions that promote healthy longevity, identify the key components of these practices and interventions, and to consider how stakeholders contribute to these practices and interventions. Design: A scoping review of literature Methods: Arksey & O'malley's six-stage framework was used to conduct and guide reporting. The Joanna Briggs Institute Population-Concept-Context framework was used to define eligibility criteria and select studies that report practices/interventions aimed at achieving long health span or promoting healthy longevity carried out in community. Data were manually extracted by two independent reviewers to detail the characteristics of these practices and interventions, guide the data charting process and narrative synthesis. Data Sources: Six databases (PubMed, Web of Science, Embase, Scopus, CINAHL, and Google Scholar) were searched for academic papers published between January 2010 and February 2025. Twenty-one studies met the inclusion criteria. Studies, mostly published after 2020, were predominantly conducted in high income settings (81.0%) across North America, Europe, and Asia. Four study types were identified: interventional (33%), intervention development (19%), association (24%), and descriptive (24%). Interventional. Intervention development studies primarily described multi component programmes targeting individual and social determinants of health and generally reported beneficial effects on physical, cognitive, and psychosocial outcomes. Association studies linked micro , meso , and macro level factors (e.g. nutrition, household expenditure, housing quality, health insurance, public financing policy) to healthy longevity indicators. Descriptive studies highlighted themes cross micro and meso level, such as finance, physical activity, mental and spiritual health, digital literacy, independent living, safety, social support, and healthcare support. The identified community-based strategies, practices, and policies which extend health span represent the joint effort of multiple stakeholders and disciplines. The implementation of these practices and policies are worthy to be supported. More studies in diverse socioeconomic contexts are needed.

Edible salt is an essential component of the human diet and a critical vehicle for iodine fortification, yet it can also serve as a pathway for chronic dietary exposure to toxic heavy metals. Despite decades of research documenting metal contamination in salt, the sources of contamination, particularly the potential role of mine blasting, remain inadequately characterized, and the efficacy of conventional purification methods has been overestimated. This systematic review aimed to synthesize available evidence on heavy metal contamination in edible salt across four interconnected dimensions: (1) documented sources of contamination, while also highlighting empirically untested hypotheses regarding potential extraction‑related contamination pathways (e.g., mining operations) as priorities for future investigation; (2) limitations of conventional purification methods in achieving complete metal removal; (3) human exposure levels and associated health risks; and (4) existing regulatory frameworks and their shortcomings. A systematic search of PubMed, Scopus, and Web of Science was conducted for original research articles published between January 2016 and June 2026 reporting quantitative measurements of heavy metals in edible salt. Of the 16 studies initially meeting the broad eligibility criteria, 12 provided robust quantitative data on heavy metal concentrations with associated health risk or purification assessments and formed the core evidence base (Table 1). The remaining 4 studies were predominantly method‑development or qualitative classification papers and are summarized separately in Supplementary Table S2. Lead (Pb) was the most frequently reported toxic metal, with concentrations ranging from 0.001 mg/kg in Lake Urmia salt to 18.43 mg/kg in contaminated Pakistani sea salt. Cadmium (Cd) reached 6.08 mg/kg in Ghanaian market salts, and mercury (Hg) reached 15.3 mg/kg in Pakistani sea salt, 153 times the Codex limit. Conventional purification methods substantially reduced heavy metal concentrations, but did not completely eliminate them. Health risk assessments diverged sharply: salts from clean environments posed negligible risks, while contaminated salts exhibited hazard indices exceeding 20 and carcinogenic risks above the USEPA threshold. Importantly, no study investigated the contribution of mine blasting with explosives to salt contamination, a significant research gap. Regulatory standards were inconsistent across jurisdictions, with no limits specified for chromium, nickel, cobalt, aluminum, or antimony. Heavy metal contamination of edible salt is a global phenomenon, with the highest levels found in salts from polluted harvesting sites. Conventional purification methods can substantially reduce heavy metal contamination, often by over 90%, but they do not necessarily eliminate it entirely. Current regulatory frameworks exhibit important inconsistencies and coverage gaps, particularly for several trace metals that are not specifically addressed in existing standards. The absence of direct evidence regarding contamination pathways associated with mining operations highlights an important knowledge gap that warrants future investigation. Strengthened regulatory standards, may help improve food safety oversight and reduce consumer exposure.

Gonorrhea is a preventable and treatable infection caused by Neisseria gonorrhoeae, remaining a major public health concern because of antibiotic-resistant strains. A milestone was reached with zoliflodacin, the first therapeutic in its class in nearly 2 decades. Zoliflodacin is a first-in-class spiropyrimidinetrione antibacterial agent that targets type II topoisomerases DNA gyrase and topoisomerase IV enzymes essential for DNA synthesis. Its primary target is the GyrB subunit of DNA gyrase, rather than the GyrA or ParC subunits affected by fluoroquinolones. The area under the concentration-time curve/minimum inhibitory concentration is the primary pharmacokinetics and pharmacodynamics index associated with bacterial killing. Zoliflodacin binds approximately 83% to plasma proteins, undergoes extensive metabolism through cytochrome P450-mediated and non-P450-mediated pathways, has a low urinary excretion with a major fecal route elimination pathway, and an elimination half-life of around 5-6 hours. Zoliflodacin demonstrated positive results for the treatment of uncomplicated urogenital gonorrhea in phase 2 and subsequently phase 3 trials. In a phase 2, multicenter, open-label RCT, the efficacy and safety of zoliflodacin was compared with ceftriaxone. Cure rates for urogenital infections were 96% (55/57) (2 g), 96% (54/56) (3 g), and 100% (28/28) (ceftriaxone). In a phase 3, multinational, open-label, noninferiority RCT, participants were randomly assigned (2:1) to receive a single 3 g oral dose of zoliflodacin or a single dose of 500 mg intramuscular injection of ceftriaxone plus 1 g oral azithromycin. The primary end point for microbiological cure was achieved in 90.9% (460/506) of patients on zoliflodacin compared with 96.2% (229/238) of the comparator, demonstrating noninferiority and good tolerability. Oral zoliflodacin represents a novel option for the treatment of uncomplicated urogenital gonorrhea, including antibiotic-resistant strains, providing an important alternative therapy.

In recent decades, extensive research has focused on developing titania for photocatalysis, photovoltaics, and energy storage. Metal doping, electronic structure modification, and morphological design are effective strategies to enhance the performance of titania for these applications. In this study, we report the fabrication of hybrid nanostructures of gold nanoparticles (AuNPs) anchored on reduced dendritic fibrous nanotitania (R-DFNT) (Au/R-DFNT) via a chemical reduction method. The hierarchical structure of R-DFNT not only facilitates rapid mass transport but also maximizes the exposure of abundant defect species as nucleation sites for anchoring gold nucleation, resulting in well-dispersed AuNPs on R-DFNT. The photocatalytic performance of Au/R-DFNT nanocomposites is evaluated through the photodegradation of ciprofloxacin (CP). The optimized Au/R-DFNT sample exhibits outstanding photocatalytic activity towards CP degradation, with a kinetic rate constant of 0.0111 min-1, which is 2.3, 25.5, and 4.1 times higher than those of pristine R-DFNT, reduced commercial P25, and the AuNPs/reduced-P25 nanocomposite, respectively. The superior photocatalytic efficiency of Au/R-DFNT is mainly attributed to its dendritic fibrous morphology, the abundance of exposed defect sites, and the well-formed gold-titania heterojunction, which facilitates charge-transfer and prolongs the lifetime of charge carriers.

Homologous recombination deficiency (HRD) is an actionable vulnerability found in a substantial fraction of human cancers, yet current HRD-directed therapies are limited by toxicity, incomplete responses, and acquired resistance. Many DNA-damaging agents were developed before DNA repair biomarkers were available, suggesting that abandoned agents may harbor previously unrecognized genotype-selective activity. Here, through a focused screen of DNA-damaging agents in isogenic homologous recombination-proficient and -deficient models, we identify CB1954, a decades-old nitrobenzamide aziridine prodrug, as highly selective for BRCA2-deficient tumor cells. CB1954 forms DNA interstrand crosslinks independent of HR status, but selectively induces DNA-damage signaling, apoptosis, and loss of clonogenic survival in HR-deficient cells. Targeted DDR CRISPR screening and isogenic validation define a distinct repair dependency for the Fanconi anemia and homologous recombination pathways, with limited dependence on mismatch repair or nucleotide excision repair. Genetic and pharmacologic perturbation of NQO2, the bioactivating enzyme for CB1954, reveals a bifurcated mechanism in which NQO2-dependent activation selectively contributes to HRD cytotoxicity, while aziridine-dependent lesions likely account for residual activity in HR-proficient cells. CB1954 exhibits favorable preclinical pharmacokinetic properties and genotype-dependent antitumor activity in BRCA2-deficient xenografts. These findings reposition CB1954 as a historically overlooked HRD-selective agent and demonstrate that biomarker-guided profiling of DNA-damaging agents can uncover new opportunities for precision oncology.

The History of Medicine Library at the Royal Australasian College of Physicians is now one of the leading comprehensive research collections on the history of medicine of Australasia. This is a far cry from the founding fellows' original proposition in 1938, when they felt the need for a 'scientific library' to ensure the academic standards of their fledgling college. The present library has been made possible by donations from many personal and corporate collections. The first was a gift from the Royal College of Physicians of London in 1954, which redirected the focus to the history of medicine, followed in 1978 by the first munificent gift from Sir Edward Ford of his personal collection of Australiana. In the concluding decades of the 20th century, the value of all traditional history of medicine libraries worldwide was brought into question. Our library has survived the threat of dispersal on several occasions. The library and the extensive heritage collection of archives, artefacts, artwork and an image library have adapted to the challenges of the digital age, with greater visibility and accessibility through digital platforms. Our library, with its own unique history, has never looked so vibrant.

Congenital aerodigestive fistulae (ADF) represent extremely rare developmental malformations derived from disrupted embryological separation of the primitive foregut, which can be classified by lesion location into tracheoesophageal fistulae, bronchoesophageal fistulae (BEF), and other subtypes. While typically diagnosed in neonates, isolated BEF without esophageal atresia ("H-type") may remain undetected for decades, presenting in adulthood with chronic, stereotyped symptoms. Endoscopic interventions for congenital BEF remain poorly characterized, with limited evidence regarding patient selection and technique optimization. A 58-year-old man presented with a 40-year history of persistent, swallowing-induced cough, accompanied by expectoration of white mucoid sputum. Initial chest computed tomography at an outside hospital identified a left lower lobe mass suspicious of lung cancer complicated by obstructive pneumonia. Bronchoscopy confirmed an esophageal-left main bronchial fistula, and endobronchial ultrasound-guided biopsy demonstrated acute and chronic inflammation with fibrous hyperplasia. Repeat imaging at our institution demonstrated a direct, upward fistulous tract between the mid-esophagus and left main bronchus, consistent with Braimbridge and Keith Type II congenital BEF. A multidisciplinary consensus deemed surgical repair high-risk with uncertain efficacy, and the patient declined operative intervention. Combined bronchoscopy and esophagoscopy under general anesthesia confirmed a 2-mm fistula orifice 2 cm below the left main carina. The fistula was successfully closed using argon plasma coagulation-mediated de-epithelialization followed by over-the-scope clip (OTSC) deployment, with immediate resolution of swallowing-induced cough. At the 10-month follow-up, esophagography showed no contrast extravasation, computed tomography confirmed no persistent fistulous communication, and esophagoscopy demonstrated granulation tissue with white scarring and no identifiable fistula orifice. This case illustrates the potential for extraordinarily delayed presentation of congenital BEF in adulthood and highlights the importance of maintaining a high index of suspicion for this rare anomaly in patients with chronic, liquid-induced paroxysmal cough. Combined endoscopic de-epithelialization and OTSC closure appears to be an effective, minimally invasive alternative to surgical repair in eligible patients with congenital BEF. More clinical studies are warranted to develop consensus-based guidelines for the management of benign ADF.

Sulfate-reducing bacteria (SRB) are widespread in marine and terrestrial environments, where they often form syntrophic associations with bacteria, archaea, and eukaryotes. Among the most intimate of these are multipartite symbioses in gutless marine oligochaete worms, which host SRB and sulfur-oxidizing endosymbionts that engage in a syntrophic exchange of sulfur compounds. Despite decades of research on free-living SRB, the metabolic traits that enable SRB to persist in symbiosis, and how these differ across hosts and environments, remain poorly understood. We show that a globally distributed clade of symbiotic SRB, which we named Candidatus Desulfoconcordia, has a conserved core metabolism that diverges from free-living relatives. Using comparative genomics and metaproteomics, we reveal that these endosymbionts retain key traits of SRB such as sulfate reduction, complete oxidation of acetate to CO2, amino acid degradation for nitrogen acquisition, and transport of essential nutrients. However, they exhibit a more oxygen-tolerant metabolism and lack typical nutrient-scavenging mechanisms of free-living SRB. One trait, the glyoxylate bypass, was consistently expressed in situ and may serve both in reactive oxygen species defence and in biomass generation. The expression of oxygen-tolerant pathways, coupled with the loss of nutrient-scavenging functions, indicate specialization to a host-associated, redox-fluctuating environment distinct from that of free-living SRB. The symbiont genomes are also larger than those of free-living relatives, contrasting with genome reduction in many endosymbionts and reinforcing the importance of metabolic versatility. Our findings provide a framework for understanding how metabolic flexibility enables SRB to persist in long-term multipartite symbioses across diverse marine ecosystems.

Pulmonary alveolar proteinosis (PAP) is a rare lung disease caused by impaired surfactant clearance resulting in lipoproteinaceous material accumulation in the alveoli often causing progressive dyspnea and respiratory failure. Autoimmune PAP (aPAP), accounting for ~90% of cases with a prevalence of 6.7-6.9 per million, disrupts granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling via neutralizing autoantibodies. This article explores the role of GM-CSF in the pathogenesis and treatment of PAP. GM-CSF autoantibodies block signaling essential for alveolar macrophage function. Therapeutic whole lung lavage (WLL) remains the gold standard of treatment for PAP. While WLL is an effective and safe treatment, and can indeed complement GM-CSF therapy, it is labor intensive and often requires repeated procedures. GM-CSF augmentation represents a new era of therapeutic advancement targeting the pathogenesis of PAP to ensure sustained, efficacious results. Inhaled GM-CSF shows superior efficacy over subcutaneous treatment. Trials through recent decades including IMPALA-2 show improvements in symptoms physiology, radiology with a favorable safety profile. These studies have helped inform the much-needed European Respiratory Society guidelines for the diagnosis and management of PAP in 2024. Despite our greater understanding of this ultra-rare disease, further studies are required to explore the mechanistic and logistical aspects of treatment with GM-CSF. We explore some of these aspects in our expert opinion section.

We present the Encyclopedia of DNA Elements (ENCODE), a reference map of the genomic basis of gene regulation. A product of more than two decades of systematic interrogation of genome function, ENCODE encompasses more than 16,000 genome-wide experiments, predominantly in primary cells and tissues, focused on three core layers of genome function. First, ENCODE now provides a catalog of gene regulatory elements. The catalog is based on a foundation of 5.3 million DNase I hypersensitive sites that delineate essentially all chromatin-accessible regulatory DNA in the human genome, as well as extensive maps of chromatin states, transcription factor occupancy, and nascent transcription, and systematic predictions of the functional consequences of non-coding genetic variants on regulatory element activity. Second, ENCODE expands the catalog of genes and transcripts, which now includes nearly 18,000 novel human long noncoding RNA genes, nearly 150,000 novel transcript isoforms, and genome-wide maps of transcript stability across cell types and time. Third, ENCODE now maps physical and functional interactions among regulatory elements and genes across more than 100 human tissues and cell lines at up to 10 bp resolution. Those studies reveal a vast network of interactions among millions of loop anchors across and links those interactions to gene expression. Through parallel studies in mice, ENCODE also provides extensive maps of gene regulatory elements, transcripts, and their interactions across the mouse postnatal development. Together, the Encyclopedia of DNA Elements provides a foundational framework for genome-focused studies of human and mouse biology.

In evolutionary terms, chemical senses are the oldest sensory modality and play key roles in ecological functions such as orientation, foraging, and socio-sexual communication. Chemical perception encompasses olfaction, taste, and chemesthesis, and has been widely studied across vertebrates. However, these senses remain poorly documented in marine mammals, particularly cetaceans. The transition from land to water profoundly reshaped cetacean sensory systems, and for decades they were considered incapable of chemoreception, implying a complete regression. Recent studies challenge this view, suggesting a more complex and incomplete regression. In this review, we synthesize current knowledge from different perspectives, using an integrative framework. First, we examine the anatomical basis of chemoreception, identifying relevant structures enabling this process and their development across early life stages. Second, we explore genetic and molecular foundations, focusing on genes underlying the development and function of chemical receptors. Third, we review behavioural evidence, highlighting experimental studies on cetacean responses to chemical cues in ecological contexts such as predator-prey interactions, foraging, and social behaviour. This approach allows us to characterize and quantify chemosensory regression in cetaceans and confirms divergent evolutionary trajectories between odontocetes and mysticetes. We also identify key unresolved questions: (1) cetaceans appear to use social chemical signals, but the mechanisms remain unknown; (2) reliance on taste is still debated, with conflicting findings; (3) the ontogeny of chemical senses remains poorly understood; and (4) alternative chemical modalities such as chemesthesis have been largely overlooked despite hypothesis on their potential ecological importance.

Geroscience clinical trials need biomarker surrogate endpoints for healthspan. Leading candidates are omics-based composites developed from machine learning analysis of aging phenotypes including calendar age, survival, functional capacity, and Pace of Aging. Existing Pace of Aging biomarkers were developed in the Dunedin Longitudinal Study, limiting inference about strengths/weaknesses of the method as distinct from the Study, a unique single-year birth cohort followed through midlife with near-perfect retention and uniform measurement of multi-organ-system function across two decades of follow-up. We adapted our Pace of Aging method for mixed-age cohorts with variable follow-up of organ-function measures and applied it to develop a novel DNA methylation biomarker of Pace of Aging in data from the Framingham Heart Study Offspring Cohort, FraminghamPACE. Validation analyses across four independent cohorts and one clinical trial establish advantages for the Pace of Aging method in developing biomarkers that are both predictive of healthspan and responsive to geroprotective intervention.