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Age-related differences in semen quality in Holstein-Friesian bulls: a paired within-bull comparison of early and mature reproductive stages.

Genomic selection has changed dairy cattle breeding by increasing the use of young bulls for artificial insemination and shortening the reproductive lifespan of sires. Under these conditions, semen quality at the beginning of commercial use has become an important practical issue. Semen samples from 39 fertile Holstein-Friesian bulls used for commercial AI were collected between 2013 and 2016, during the introduction of genomic selection in Poland. This paired within-bull study compared semen collected from the same bulls at an early reproductive stage (13-20 months; young bulls, YB) and at full maturity (5-6 years; mature bulls, MB). The evaluation included conventional ejaculate traits, CASA-derived motility and kinematic descriptors, mtDNA copy number, and mitochondrial content per sperm cell. Importantly, all ejaculates met the quality requirements for commercial insemination. Ejaculate volume, sperm concentration, mitochondrial DNA copy number, and mitochondrial content did not differ significantly between age groups. The CASA-derived sperm movement profile, in contrast, differed with age. Semen from young bulls showed a higher proportion of progressively motile spermatozoa, whereas semen from mature bulls showed higher velocity-related parameters, including VSL, VCL, and STR. These findings indicate that bull age mainly affected sperm movement characteristics rather than semen output or mitochondrial content. Overall, the results support the use of young bulls in artificial insemination programs and show that age-related differences in semen quality are expressed mainly through changes in the post-thaw sperm motility and kinematic profile.

Animals

New Horizons in the Development of Treatments for Substance Use Disorders.

Substance use disorders (SUDs) are a major public health problem in the United States and cause substantial morbidity and mortality. There are meaningful gaps in the available SUD treatment options, and the development of new therapies is urgently needed. While medications with U.S. Food and Drug Administration approval are available for alcohol, nicotine, and opioid use disorders, there are no approved pharmacotherapies for cannabis, cocaine, or methamphetamine use disorders. Behavioral treatments for SUDs have significant limitations in effectiveness and accessibility, and there is a need for the development of both new behavioral treatment options and new models of treatment delivery. The next generation of treatments for SUDs will likely come from a diverse set of interventions, including new drug classes, new technologies, and new methods of delivery.

Humans

Asthma Exacerbation Risk and School Asthma Readiness.

OBJECTIVES: School-based asthma management is a key facet of child asthma care. We aimed to describe the proportion of students whose schools have child-specific components of asthma care, derive a composite metric of these components ("school asthma readiness"), and assess its association with asthma exacerbations (asthma risk) in the preceding year. METHODS: Within a nested cohort of children enrolled in a larger randomized clinical trial, we assessed the baseline proportion of children whose school had elements of necessary asthma care. We then derived a "school asthma readiness" composite and used ordinal logistic regression to model the association between number of asthma exacerbations in the preceding year and the composite, accounting for demographic, clinical, and school characteristics. RESULTS: Of 202 participants aged 5 to 13 years, most identified as Black (95%) and non-Hispanic (98%), and most participants (73%) had an emergency department visit for asthma in the year before enrollment. Most students' schools (79%) had awareness of the child's asthma diagnosis, whereas fewer had reliever medications and valved holding chambers (both 31%) and asthma care plans (7%). Asthma exacerbations in the prior year were associated with a significantly higher school asthma readiness in bivariate (odds ratio [OR], 1.44 [95% CI, 1.14-1.82]; P = .002) and multivariable analysis (OR, 1.31 [95% CI, 1.02-1.7]; P = .037). CONCLUSIONS: A minority of children attended schools that were equipped to manage asthma symptoms. More past exacerbations were associated with higher school readiness, suggesting that more work is needed to support proactive asthma care in schools.

Humans

Comprehensive identification of carboxylic acids by using bromine isotope-based chemical isotope labelling and structure-guided molecular network.

Carboxylic acids (CAs) are important contributors to the flavor quality of sauce-flavor Chinese Baijiu, yet their comprehensive analysis remains challenging due to poor ionization efficiency, weak chromatographic retention, and limited annotation capability. Herein, we developed a workflow for the high-coverage discovery and annotation of CAs in Baijiu by coupling chemical isotope labeling-liquid chromatography-mass spectrometry with a structure-guided molecular network strategy (SGMNS). A bromine-containing derivatization reagent, 1-(3-aminopropyl)-3-bromoquinolin-1-ium bromide (APBQ), was designed and synthesized to exploit the natural isotope distribution of bromine and characteristic MS/MS fragmentation behavior. Following APBQ derivatization, the target CAs showed superior chromatographic retention and favorable analytical performance. Based on isotopic peak pairing in MS1 and diagnostic fragment validation in MS2, 372 potential CA derivatives were discovered from pooled Baijiu samples and 355 of them were validated by diagnostic fragments in MS2 spectra. To address the scarcity of derivatized spectral libraries, SGMNS was employed for annotation using a background network constructed from APBQ-labeled candidates derived from the Expanded Chinese Baijiu Compound Database. The developed method was further applied to profile Baijiu samples, revealing pronounced differences in CA composition across the seven fermentation rounds. Notably, rounds 3 to 5 exhibited the largest numbers of differential CAs. This study provided an effective analytical strategy for large-scale CA profiling, offering new insight into the chemical basis of flavor formation during multi-round fermentation of sauce-flavor Baijiu.

Isotope Labeling

Nitrogen sources and concentrations shape algal odor compounds: Key drivers of β-cyclocitral and β-ionone in water bodies of the lower Yangtze River.

Taste and odor (T&O) compounds derived from cyanobacterial blooms pose escalating threats to freshwater security worldwide, yet the drivers of specific T&O metabolites remain poorly constrained. Here, we investigated the dual effects of nitrogen (N) sources and concentrations on the production of β-cyclocitral and β-ionone, two algal-derived T&O compounds, through integrated field surveys (54 sites across lakes and rivers) in the eutrophic lower Yangtze River, China, and laboratory cultivation of typical cyanobacteria (Microcystis aeruginosa and Pseudanabaena cinerea). Our field data revealed that the concentrations of β-cyclocitral and β-ionone in lakes and rivers were not significantly different, but increased with the trophic level index. Redundancy analysis and Mantel analysis showed that Microcystis and Pseudanabaena were potentially dominant contributors to β-cyclocitral and β-ionone in the water column. Structural equation modeling and variation partitioning analysis showed that enhanced nitrate (NO3--N) significantly promoted the production of these compounds. Laboratory experiments demonstrated that inorganic N (NaNO₃) maximized total T&O yields by promoting algal biomass, whereas organic N (urea and glutamic acid) elevated the T&O production per unit biomass by 1.5- to 9.5-fold. Notably, Pseudanabaena exhibited a 2.3-fold higher β-ionone yield than Microcystis, with greater sensitivity to N concentrations. Our study highlights the critical role of nitrogen pollution, both source and concentration, in the production of T&O compounds by phytoplankton and provides reference data for managing T&O issues in rivers and shallow lakes.

Norisoprenoids

Clinical and endocrine correlates of genetic etiologies in severe hypospadias: Study from 34 patients.

OBJECTIVE: Hypospadias is a prevalent congenital anomaly (0.3%-1.0%); however, severe hypospadias (defined as proximal cases with the meatus at the penoscrotal junction, scrotum, or perineum) is a rare and clinically challenging entity with a multifactorial etiology. This study aimed to characterize the interrelationships among the clinical, endocrine, and genetic profiles in children with severe hypospadias. MATERIALS AND METHODS: We conducted a comprehensive analysis of 34 male patients with severe hypospadias. Preoperative hormone levels were measured using two methods: chemiluminescent immunoassay for luteinizing hormone and follicle-stimulating hormone, and liquid chromatography-tandem mass spectrometry for testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), 17α-hydroxyprogesterone (17α-OHP), and other steroids. Genetic analysis was conducted via whole exome sequencing. RESULTS: The diagnostic yield of clinically relevant genetic variants (including pathogenic and likely pathogenic, and variants of uncertain significance) in our cohort was 41.2% (14/34) of patients. Patients carrying these variants exhibited a more complex phenotypic profile compared to non-carriers, including a significantly higher rate of patients with ≥3 associated malformations and a greater prevalence of cryptorchidism. Furthermore, the group with clinically relevant variants showed selective elevations in adrenal-derived precursors, specifically 17α-OHP and DHEA. Correlation analysis revealed significant positive associations of both 17α-OHP levels and the T/DHT ratio with the number of associated malformations. CONCLUSION: This study reveals significant genetic heterogeneity in patients with severe hypospadias. Those carrying genetic variants was associated with more severe clinical phenotypes, while certain endocrine variations, including the elevation of adrenal-derived hormones, were also observed in this cohort.

Humans

Treatment of Hot Flashes in Men With Prostate Cancer Undergoing Androgen Deprivation Therapy.

BACKGROUND: Hot flashes are common and often debilitating side effects of castration therapy; a cornerstone in the treatment of metastatic prostate cancer (PCa) as well as in localized or locally advanced PCa when combined with radiotherapy. The evidence for relieving vasomotor symptoms is limited. This systematic review presents both pharmacological and non-pharmacological interventions for treating hot flashes in men with PCa undergoing castration therapy, primarily androgen deprivation therapy (ADT). METHODS: a systematic literature search was conducted in PubMed using ("hot flash*" OR "hot flush*" OR "vasomotor*") AND ("prostate") as keywords. Studies with intervention for hot flashes due to castration therapy, estimation of treatment response (e.g., reduction in frequency or impact on quality of life) and patients with PCa (any stage) were eligible. RESULTS: Of 469 papers, 35 were included in the review. The included studies evaluated cyproterone acetate, estrogen or estrogen derivatives, progesterone derivatives, selective serotonin reuptake inhibitors (SSRIs), gabapentin, oxybutynin, and clonidine, as well as non-pharmacological interventions such as acupuncture, cognitive behavioral therapy (CBT), and dietary supplements (e.g., Dong Quai/Angelica Sinensis, Serelys Homme, soy protein, and Salvia officinalis). Across all blinded pharmacological interventions, the relative reduction in hot flash frequency ranged from -21% to -84%, and the placebo effect was between -19% and -30%. CONCLUSION: Hormonal agents such as cyproterone acetate and estrogen appear to be the most effective treatments, although they are associated with side effects. Non-pharmacological options like acupuncture and CBT may offer some benefit, while dietary supplements seem to be ineffective. Future studies are needed also to evaluate newer treatments, such as fezolinetant, in this patient population.

Humans

Orchard netting impacts on biodiversity leading to cascading effects at the ecosystem level.

Agriculture must ensure food production without further compromising the ecosystem functions upon which it depends. Agricultural practices should therefore avoid harming farmland biodiversity, especially of taxa that supply the key ecosystem services (e.g. pollination, pest control and nutrient uptake) that ultimately support crop production. Orchards are among the largest permanent plantations worldwide and are increasingly characterised by the spread of plastic nets used to protect fruits/nuts from either abiotic (anti-hail, anti-rain, shade nets) or biotic (exclusion nets) hazards. Despite having received little attention to date, these nets may impact natural communities, acting both as physical barriers and as drivers of habitat changes to which biota must respond. Species-level responses to netting depend on the organism's ability to enter the netted environment and successfully exploit available resources. Net-mediated ecological filtering and plastic behavioural responses may alter species interactions, leading to cascading ecological impacts that may create species-poorer 'netted communities' with simplified ecological networks. Such changes may erode biological control potential, other ecosystem functions, and overall system stability. We conducted a systematic review on the effects of protection nets on biota, and reported novel empirical evidence on anti-hail nets' impacts on communities of orchard-dwelling birds, flower-visiting insects, and rodents. In total, we identified 48 studies from the literature, however this literature was strongly biased towards apple orchards, western countries, and pest taxa. Net deployment was highly effective in deterring target pest species, in some cases regardless of their original function, as even weather-protection nets limited pest populations. Side effects on non-target taxa were also often reported, such as decreases in pollinators and natural enemies, and/or increases in secondary pests or microbial diseases. However, most assessments largely disregarded non-pest taxa and the broader ecological consequences of netting. The few studies that addressed the effects of nets at the guild/community level, including our empirical study, confirmed that orchard netting resulted in species-poor assemblages, with possible ecosystem-level consequences. We propose that future assessments should pay more attention to the indirect effects of netting on non-target taxa, and on the supply of crop-supporting ecosystem services mediated by wild species occurring in agroecosystems. Due to the trade-offs between these services and net-mediated crop protection, integrated alternatives should be tested to improve the environmental sustainability of food production and biodiversity conservation in farmed landscapes.

Biodiversity

The gut microbiota-obesity axis in the pathogenesis and prognosis of breast cancer.

BACKGROUND: Breast cancer (BC) remains a major global health concern, accounting for 11.7% of all cancer cases and ranking as the second leading cause of female cancer-related deaths worldwide. Increasing evidence highlights the interplay between gut microbiota (GM) dysbiosis and obesity-associated metabolic dysfunction in BC progression. This review aims to elucidate the role of GM in obese patients with BC. METHODS: A systematic literature search was conducted in PubMed and Web of Science databases for publications from July 2015 to January 2025. Search terms combined BC, GM, obesity, dysbiosis, immunity, and microbiome. Article selection prioritized studies investigating microbial alterations in BC patients, mechanistic links between obesity and cancer progression, and GM-targeted interventions. Both original studies and authoritative reviews were included, supplemented by manual reference screening. DISCUSSION: Obesity may trigger systemic inflammation, altered adipokine secretion, and disrupted steroid hormone metabolism via gut-derived β-glucuronidase activity, thereby exacerbating BC occurrence and recurrence. GM dysbiosis-driven metabolites such as branched-chain amino acids (BCAAs) and short-chain fatty acids (SCFAs) can activate oncogenic signaling pathways and immunosuppressive myeloid-derived suppressor cells (MDSCs), fostering tumor immune evasion. Conversely, dietary interventions, probiotics, and fecal microbiota transplantation (FMT) can alleviate dysbiosis, strengthen gut barriers, and restore anti-tumor immunity, improving chemotherapy response and reducing recurrence. However, challenges persist in deciphering BC subtype-related microbial signatures and optimizing microbiota-targeted therapies. CONCLUSION: Future longitudinal studies are needed to clarify causal relationships, validate microbial biomarkers, and translate preclinical findings into clinical applications. Addressing the gut-breast axis may offer transformative potential for precision oncology in obesity-driven BC.

Humans

Redox Rewiring in Nicotine-Driven Gastric Carcinogenesis: Uncovering ROS-Dependent Oncogenic Circuits.

SIGNIFICANCE: Nicotine from tobacco products, secondhand smoke, and emerging delivery systems remains a major but underappreciated driver of gastric carcinogenesis (GC). Although reactive oxygen species (ROS) have long been implicated in tumor biology, current models incompletely explain how chronic nicotine selectively reprograms gastric epithelial signaling. This review advances the concept of redox rewiring, whereby nicotine establishes a persistent oxidative state that orchestrates multiple oncogenic programs via spatially compartmentalized NOX signaling. RECENT ADVANCES: We synthesize evidence for a unified model wherein nicotine activates nAChR/β-AR signaling, Ca2+ influx, PKC, and compartmentalized NOX-derived ROS to generate distinct oncogenic outputs. Beyond the established NOX/ROS/NF-κB/MAPK-driven IL-8 and MMP-9 axes, we integrate emerging evidence into three interconnected modules governing EMT/metastasis (ABL1/STAT3/COX-2/periostin), survival/chemoresistance (ERK/GLI1/Bcl-2), and invasion/immune evasion (miR-21/PDCD4). Collectively, these circuits suggest that ROS function not merely as damaging byproducts but as spatially organized signaling mediators dictating tumor behavior. CRITICAL ISSUES: A major challenge is distinguishing established mechanisms from incompletely validated models. The three proposed axes are testable hypotheses requiring experimental validation. Most data derive from in vitro studies with nonphysiologic nicotine concentrations, and artifacts from nonspecific ROS probes are common. Compensatory pathway activation and multi-target effects of natural products remain underexplored. FUTURE DIRECTIONS: We outline a precision-redox oncology roadmap linking pathway-specific biomarkers, mechanistically matched natural products, and biomarker-enriched trials. Priorities include genetic validation of the three axes, time-resolved ROS imaging, and pulsed natural product regimens. By reframing nicotine-driven GC as adaptive redox network remodeling, this review provides a framework for prevention, stratification, and next-generation therapy. Antioxid. Redox Signal. 00, 000-000.

gastric cancer

Comparison of posterior cellular bonegraft options for single-level lumbar spinal fusion: a randomized trial.

BACKGROUND: Iliac bone autograft (IBG) is osteoinductive/osteogenic/osteoconductive but requires an additional harvesting procedure with known morbidities. Bone morphogenic protein (BMP) is osteoinductive and effective in obtaining fusion but is used off label for posterior fusion, has multiple side effects, and is expensive. Stem cell bone products, both auto- and allograft are attractive osteoinductive alternatives that avoid morbidity related to the graft donor site and may have a better safety profile than BMP. Morcelized allograft bone is osteoconductive but not osteoinductive or osteogenic. PURPOSE: Evaluate and compare the effectiveness of 6 types of viable or osteoinductive bone graft material in obtaining a solid posterior spinal fusion (PSF) for single level anterior/posterior lumbar spinal fusion. The bone grafts were IBG, BMP, autogenous stem cells (MSC) from concentrated bone marrow aspirate (BMA), allograft MSC from bone marrow, adipose tissue, or amniotic fluid, combined with inert cancellous allograft (Allo). STUDY DESIGN/SETTING: Prospective, single-blinded randomized study of 6 cohorts and inert historical control. PATIENT SAMPLE: Elective anterior-posterior lumbar spinal fusion of 175 patients. OUTCOME MEASURES: Assessments included pre and postoperative back and leg pain (VAS) scores, pain drawing, disability (ODI) scores, pain medication usage, and 1-year postoperative thin-cut CT scans (read by blinded radiologists). METHODS: Patients who were surgical candidates for a 1-level anterior/posterior lumbar fusion were randomized to 1 of 6 types of posterior bone graft alternatives: IBG, BMP, BMA, allograft MSC derived from bone marrow combined with morcelized Allo (cAlloBone), adipose derived MSC combined with morcelized Allo (cAlloFat), or amnion derived MSC combined with morcelized Allo (cAlloAm). Historical Allo patients served as a negative control group. Each group (n 27) had prospective outcomes and were followed for a minimum of 2 years. Fusion rate and outcomes were compared and referenced to Allo group. RESULTS: All but 5 patients had a solid ASF. The posterior fusion rates were 98% for IBG, 94% for BMP, 85% for BMA, 67% for cAlloBone, 64% for cAlloFat, 62% for cAlloAm, and 50% for Allo. Outcomes were significantly improved for all measures for all groups and there was no difference between groups except cAlloFat had slightly greater improvement in back pain in the 7-12 month follow-up period. BMP was the most expensive graft material; cellular allografts had a high-cost relative to fusion rate. CONCLUSIONS: For single level ASF/PSF, the PSF fusion rate was significantly greater for IBG and BMP followed by BMA. Various allograft MSC bone graft options resulted in lower fusion rates but may be greater than Allo. Outcomes were uniformly improved regardless of the type of graft used or the fusion status of the posterior fusion as long as the interbody fusion was solid. If bone graft cost savings is a consideration for PSF, then IBG has the greatest radiographic value, and Allo the greatest clinical value as long as the anterior interbody fusion is solid.

Humans

Microbial signal profiles and organism-level concordance between plasma metagenomic sequencing and blood culture in suspected bloodstream infection.

Plasma metagenomic next-generation sequencing (mNGS) and blood culture detect different components of the microbial signal and frequently produce discordant organism reports. We characterized microbial signal class, report-derived burden, organism-level concordance, and independent clinical attribution in a retrospective, single-center, episode-level cohort. Among 329 episodes with evaluable plasma mNGS reports, 315 had blood culture performed; 232 were mNGS positive/culture negative and 53 were positive by both methods. In the 232 discordant episodes, the recorded routine-care diagnosis classified 124 as bloodstream infection (BSI) and 108 as non-BSI. Nonviral signals were present in 78.2% and 42.6%, respectively (P&#x2009;<&#x2009;0.001), and median maximum report-derived sequence counts were 98.5 and 11.5 (P&#x2009;<&#x2009;0.001). Two laboratory physicians then independently reviewed source records using structured criteria while masked to the recorded BSI label and mNGS organism and sequence-count information. Initial agreement for the five-category BSI assessment was 97.6% (Cohen's kappa, 0.960). Within the mNGS-positive/culture-negative subgroup, adjudicated BSI likelihood showed a modest ordinal association with report burden (Spearman rho&#x2009;=&#x2009;0.190; P&#x2009;=&#x2009;0.004), while mNGS organisms were considered supported in 1 episode, plausible in 158, unlikely or contaminant in 72, and unresolved in 1. Among 53 dual-positive episodes, 33 (62.3%) shared at least one species, but only 5 (9.4%) had complete species-set concordance. Plasma mNGS and blood culture therefore frequently generated non-equivalent organism sets. Signal class and report burden contributed graded contextual evidence, but organism-level attribution required clinical review and orthogonal microbiology rather than binary positivity alone.

Humans

Artificial intelligence for anticancer drug discovery from natural products of macroalgae and sponges: A systematic review.

Marine natural products (MNPs) from macroalgae and marine sponges have inspired clinically important anticancer agents, including the cytarabine pharmacophore and the eribulin scaffold, while cyanobacterial dolastatin chemistry supplies the auristatin payloads of several marine-inspired antibody-drug conjugates (ADCs) such as brentuximab vedotin. Artificial intelligence (AI) methods, encompassing both classical machine learning (ML) with hand-engineered features and modern deep learning (DL) with many-layered neural networks, are increasingly supporting key decisions in natural-product anticancer drug discovery, including bioactivity prediction, target identification, absorption, distribution, metabolism, excretion and toxicity (ADMET) filtering, generative analogue design, and the selection of preclinical candidates. DL architectures relevant to this field include graph neural networks, transformer-based molecular generators, diffusion models for protein-ligand docking, and convolutional networks for mass spectrometry, while classical ML contributes interpretable fingerprint-based bioactivity models and molecular networking for dereplication. This review follows a systematic literature review methodology to organize the landscape of AI methods now applied to MNP anticancer discovery, distinguishing ML and DL approaches where relevant, situating them within the chemical context of macroalgal and sponge-derived oncology leads, and critically examining published case studies, including validation level (computational, in vitro, in vivo, clinical). The principal bottleneck for medical translation has shifted partly from algorithmic capability toward data infrastructure and experimental validation. Sparse, heterogeneous, and taxonomically biased bioactivity records limit what current models can learn and reduce the reliability of AI-prioritized candidates entering the preclinical pipeline. A roadmap is proposed that prioritizes open MNP-specific benchmarks, symbiont-aware modeling, and active learning loops with synthesizability and ADMET constraints. These AI workflows may accelerate the prioritization of marine-derived anticancer leads and support earlier, more evidence-based translational decisions in oncology drug development.

Biological Products

Fatty acids and breast cancer: Epidemiology, subtype-specific metabolism, immune regulation, and clinical translation.

Fatty acids (FAs) are bioactive dietary and metabolic molecules that participate in membrane architecture, energy homeostasis, inflammatory signaling, gene regulation and immune function, all of which intersect with breast cancer (BC) risk, progression and treatment response. In this narrative review we integrate epidemiological, clinical, translational and mechanistic evidence on the role of FAs in BC. Saturated, monounsaturated, trans- and polyunsaturated FAs (PUFAs) are treated as distinct biological exposures rather than interchangeable measures of total fat intake. Similarly, evidence from dietary assessment, circulating biomarkers, erythrocyte membrane composition, adipose tissue stores and tumor lipid signatures is interpreted separately, because each captures exposure and biology at a different level. BC subtypes differ in FA synthesis, uptake, oxidation, storage and remodeling: luminal tumors are frequently linked to hormone-regulated lipogenesis, human epidermal growth factor receptor 2 (HER2)-positive tumors to growth-factor-driven lipid metabolism, and triple-negative tumors to exogenous FA uptake, inflammatory lipid mediators and ferroptosis-related vulnerabilities. FA-derived mediators also shape immune-cell polarization, cytokine signaling and the tumor microenvironment, and dietary FAs may reshape the gut microbiota; the fiber-derived short-chain FAs it produces, distinct from dietary FAs, likewise help regulate immune and inflammatory tone. Clinical data suggest possible roles for fat-quality modification and selected n-3 PUFA interventions, but findings are heterogeneous and not yet sufficient to support routine biomarker-guided precision onco-nutrition. Candidate biomarkers, such as erythrocyte n-6:n-3 composition, require prospective validation before clinical implementation. FA biology thus represents a modifiable but complex axis in BC prevention, tumor biology and supportive care.

Humans

Beyond multidimensionality: a systematic review of recurrent frailty archetypes in community-dwelling older adults.

BACKGROUND: Frailty is a clinically heterogeneous geriatric syndrome commonly summarised using physical or multidomain severity scores. Whether person-centred analyses identify recurring within-frailty configurations has not been systematically examined in community-dwelling older adults. METHODS: We searched PubMed, Embase, MEDLINE, and CINAHL (January 2000-November 2025) for cross-sectional studies using latent class, latent profile, or analogous clustering methods to derive frailty subgroups. Quality was assessed using the AHRQ checklist and a purpose-built appraisal of person-centred model reporting. Study-derived classes were mapped in duplicate to a structured archetype framework developed through comparison of class-defining features across studies. RESULTS: Fourteen reports representing 12 independent datasets from eight countries were included. Six configurations were identified: minimally impaired reference, mobility-physical, nutritional-metabolic, cognitive-predominant, combined cognitive-physical, and psychosocial/mood-predominant. Convergence was measurement-dependent. The reference and mobility-physical configurations recurred across physical-only and multidomain indicator sets, while the combined cognitive-physical configuration appeared across several multidomain frameworks but required cognition to be measured. The remaining configurations emerged only when their defining domains were included. Evidence of prognostic value beyond aggregate frailty severity came from one deficit-index study. Collapsing shared-provenance reports and excluding the boundary-eligible study did not alter recurrence; excluding the Croatian dataset left five configurations recurrent, with the cognitive-predominant configuration supported by one independent dataset. CONCLUSIONS: Person-centred analyses identify recurring within-frailty configurations, but their apparent stability is partly measurement-dependent. A five-configuration core persisted after exclusion of the Croatian dataset, whereas the cognitive-predominant configuration remained weakly replicated. Harmonised indicators and rigorous external validation are needed before clinical application.

Humans

Current Diagnostic Pathways for Rheumatoid Arthritis-Associated Interstitial Lung Disease Result in Substantial Underdiagnosis and Excess Mortality: A Multicenter Norwegian Quality Assurance Audit.

OBJECTIVE: Recent guidelines suggest risk-stratified screening for rheumatoid arthritis-associated interstitial lung disease (RA-ILD). However, the diagnostic gap between current routine care and this screening approach remains unquantified. We assessed currently detected RA-ILD in Norway, benchmarking findings against recent screening-based estimates of the true disease burden. METHODS: This 10-year quality assurance audit across six centers covered 43% of the Norwegian population. RA-ILD cases identified via ICD-10 codes were confirmed by manual chart review. Prevalence was calculated relative to a registry-derived total RA background population and benchmarked against a 10% expected target derived from recent prospective studies. Mortality was compared to a 3:1 frequency-matched RA control group using Cox proportional hazards regression. RESULTS: Among 17,305 RA patients, 188 (1.1%) had verified ILD; when benchmarked against an expected 10% prevalence, this indicates an 89% diagnostic gap in routine clinical care. Mean age at ILD detection was 67.5 years. Most cases (93.6%) possessed &#x2265;2 established risk factors for RA-ILD: 93.6% were seropositive, 76.1% had smoking histories, while RA onset age &#x2265;60 and persistently increased inflammatory laboratory markers were present in over half of patients. RA-ILD was associated with significantly increased mortality; 66 (4.1/100 person-years) deaths occurred in the RA-ILD group vs. 120 (2.3/100 person-years) among RA controls (HR 1.77; 95% CI: 1.31-2.39, p<0.001). CONCLUSION: When comparing to prevalence expectations, current routine care may leave a substantial proportion of cases undetected, primarily capturing a high-risk phenotype with excess mortality. Systematic, risk-stratified screening is needed to bridge this diagnostic gap, aiming to enable earlier intervention.

Interstitial lung disease

Coordinated use of three homocysteine methyltransferases supports l-methionine biosynthesis and environmental adaptation among plant-associated bacteria.

Plant pathogens colonize multiple plant-associated habitats throughout their life cycle, encountering distinct nutrient conditions and microbial communities. l-methionine is required for bacterial growth and environmental adaptation. However, how plant pathogens coordinate l-methionine biosynthetic pathways to adapt to different plant-associated environments remains poorly understood. Here, using the plant pathogen Xanthomonas campestris pv. campestris strain XC1 as a model, we show that three homocysteine methyltransferase pathways allow XC1 to catalyze the final step of l-methionine biosynthesis using different methyl donors and cofactors under different environmental conditions. Bioinformatic and transcriptional analyses identified three homocysteine methyltransferase-associated operons in XC1, mesMXD, mmuPM, and metHRHaHb, corresponding to the MesD-, MmuM-, and MetHaHb-dependent pathways, respectively. MesD uses an endogenously synthesized methyl donor and functions as the dominant homocysteine methyltransferase under l-methionine-limiting conditions, supporting bacterial growth, intracellular l-methionine accumulation, and full virulence. Furthermore, MmuM enables XC1 to use plant-derived S-methylmethionine for l-methionine biosynthesis, whereas MetHaHb enables XC1 to use vitamin B12 supplied by a neighboring bacterium for l-methionine biosynthesis in co-culture. Expression analyses showed that mesMXD was the only homocysteine methyltransferase-associated operon that responded to l-methionine availability, and its expression also decreased when S-methylmethionine- or vitamin B12-dependent pathways supported l-methionine biosynthesis. Comparative genomic analysis further showed that the three-homocysteine methyltransferase configuration is conserved in Xanthomonas and is also present in other plant-associated bacteria. Together, these findings show that a plant pathogen can coordinate endogenous, plant-derived, and microbially supported homocysteine methyltransferase pathways to maintain l-methionine biosynthesis, providing a metabolic strategy for adaptation to plant-associated environments.

Methionine

Muscle Massage Adding Capacitive Resistive Electric Transfer Therapy in Active or Sham Condition for Post-Exercise Recovery in Athletes: A Crossover Clinical Trial.

The increasing demands of elite sports reduce recovery time, impair performance, and increase injury risk. Efficient lactate transport is essential for postexercise recovery. Capacitive resistive electric transfer (CRET) therapy enhances deep tissue heating, induces vasodilation, and promotes circulation. To evaluate whether adding active CRET to a standardized muscle recovery massage, compared with the same massage plus sham CRET, influences indicators of muscle recovery following a maximal anaerobic effort test. A randomized, single-blind, sham-controlled, and crossover clinical trial was conducted in 25 athletes. Participants completed four visits and, after the maximal power and anaerobic capacity test (Wingate test), received a standardized muscle recovery massage combined with either active CRET or sham CRET. Blood lactate levels, muscle oxygenation, muscle thickness, echogenicity, knee extension force, and muscle activity were assessed before and after the test, after treatment, and 24&#xa0;hours later. Compared with massage plus sham CRET, massage plus active CRET was associated with lower blood lactate concentration at 60&#xa0;min postexercise (p&#xa0;=&#xa0;0.029). Ultrasound-derived muscle thickness and echogenicity also differed between conditions at several time points (p&#xa0;<&#xa0;0.05). However, no significant differences were observed in Wingate test performance, force, muscle activity, and oxygenation between conditions. In athletes performing repeated Wingate exercise, adding active CRET to massage was associated with lower blood lactate concentration at 60&#xa0;min postexercise and with differences in ultrasound-derived muscle thickness and echogenicity compared with sham CRET plus massage. However, these between-condition differences were not accompanied by clear short-term functional recovery benefits. TRIAL REGISTRATION: NCT06906146.

Humans