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Pulmonary arterial hypertension (PAH) is a rare, progressive condition associated with high per-patient treatment costs and substantial clinical burden. Interpreting cost-effectiveness evidence for rare diseases remains challenging when uniform thresholds are applied across conditions that differ markedly in prevalence and scale of healthcare production. The aim of this study was to estimate a prevalence-adjusted effective cost-effectiveness threshold for PAH and illustrate how disease prevalence and production scale influence the interpretation of cost-effectiveness evidence under a fixed health care budget. We applied a previously developed prevalence-adjusted cost-effectiveness threshold framework, referred to as a generalized dynamic prevalence (GeDP) approach, to PAH using nationally representative disease prevalence data from the Medical Expenditure Panel Survey. A flexible statistical transformation was used to accommodate the highly right skewed distribution of disease prevalence and to estimate the relationship between prevalence and effective thresholds. The analysis was anchored to an empirically estimated US health opportunity cost benchmark and applied to PAH, with comparisons to selected common and rare diseases. Illustrative scenarios examined how effective thresholds evolve under changes in disease prevalence over time. Effective cost-effectiveness thresholds increased as disease prevalence declined, reflecting production-side scale effects rather than differences in societal preferences. For PAH (prevalence ≈ 0.013%), the prevalence-adjusted effective threshold was estimated at US$582,270 per QALY (95% CI 581,319-583,163), representing more than a five-fold increase relative to the reference opportunity-cost benchmark of US$104,000 per QALY applied to highly prevalent conditions. Dynamic scenarios showed that effective cost-effectiveness thresholds decline as prevalence changes over time, with larger adjustments observed for initially rare conditions. Applying a uniform cost-effectiveness threshold across diseases implicitly assumes homogeneous production conditions and opportunity costs. Prevalence-adjusted effective thresholds derived under the GeDP framework provide a quantitative, descriptive approach for contextualizing cost-effectiveness evidence for rare diseases such as PAH without redefining societal willingness to pay or prescribing decision rules. This approach can complement existing pharmacoeconomic evaluations by improving transparency around the role of prevalence and scale in shaping opportunity costs.

Diseases caused by Flaviviridae viruses exert profound global health and economic burdens due to their high incidence and associated mortality. Infection by the Flaviviridae family often leads to severe acute or chronic illnesses, including hemorrhagic systemic diseases caused by dengue virus (DENV) and yellow fever virus, neurological complications associated with West Nile virus and Zika virus (ZIKV) infection, as well as liver damage and hepatocellular carcinoma resulting from hepatitis C virus (HCV) infection. Accumulating evidence indicates that a hallmark of Flaviviridae infection is to hijack calcium (Ca2+) signaling of the host cells, consequently facilitating viral entry, RNA replication, viral assembly, and release. Transient receptor potential (TRP) channels, a superfamily of nonselective cation channels, are central regulators of intracellular Ca2+ homeostasis. Recent studies reveal that TRP channels are closely involved in Flaviviridae infection. This comprehensive review synthesizes current findings on the role of TRP channels (e.g. TRPC, TRPV, TRPA, TRPM, and TRPML) in the pathogenesis of Flaviviridae viruses such as DENV, ZIKV, HCV, and Japanese encephalitis virus. Moreover, this review summarizes virus-TRP channel interaction mechanisms and discusses the potential of targeting TRP channels for host-directed antiviral therapies. This review aims to establish a conceptual framework for understanding TRP channel biology in Flaviviridae infection and to guide future research on antiviral strategies. Future directions should highlight the potential utility of TRP channel research for advancing anti-Flaviviridae therapies and clarifying their underlying mechanisms.

This study aims to investigate the role of biliary microbiota (defined as the microbial community colonizing the biliary tract, including the gallbladder, intrahepatic and extrahepatic bile ducts) in the pathogenesis of cholelithiasis (CHOL) and cholangiocarcinoma (CCA), with a focus on the associations between microbial communities and these biliary diseases. We conducted a comprehensive bioinformatics analysis using high-throughput sequencing data obtained from the Sequence Read Archive (SRA) database to characterize the composition of microbial communities in patients with CCA and CHOL. We performed operational taxonomic unit (OTU) clustering, statistical analyses and Mendelian randomization (MR) to elucidate the causal relationships between specific bacterial strains and disease outcomes. Our findings revealed differences in the relative abundance of specific microbial taxa among research groups. The CCA + CHOL group exhibited a significant increase in the abundance of Fusobacteria, particularly Fusobacterium, compared to the Control or CCA group. This suggests a potential pathogenic role for these microorganisms in CHOL formation. Additionally, the CCA group demonstrated a higher diversity index, indicating that increased microbial diversity may contribute to the progression of the disease. MR analysis identified nominally significant statistical associations between specific bacterial strains. However, the presence of pleiotropy in some analyses necessitates caution when interpreting causal relationships. Our study highlights the complex interplay between biliary microbiota and the pathogenesis of CHOL and CCA. Modulating biliary microbiota may represent a promising therapeutic strategy for managing these diseases. Future research should focus on the functional roles of specific taxa in bile metabolism and immune modulation, ultimately improving our understanding of biliary health and disease management.

Cutaneous manifestations can indicate various systemic diseases, including rheumatological, metabolic, endocrinological, infectious, gastrointestinal, and oncological disorders. The study aimed to examine the demographic, clinical, and laboratory characteristics as well as the final diagnoses of pediatric patients who presented with a rash complaint at a rheumatology clinic. This was a retrospective, cross-sectional, and descriptive study conducted at the pediatric rheumatology department of the center. The medical records of patients aged 0-18 years who presented with a rash as one of the initial complaints at the pediatric rheumatology clinic between January 2017 and December 2023 were reviewed. Data on demographics, clinical presentation, laboratory results, and final diagnosis were analyzed. A total of 307 patients were included, including 166 women (54%). Of these, 255 (83%) were diagnosed with rheumatic disease. The most common rash type was petechiae/purpura (63.5%), followed by maculopapular rash (10%), urticarial rash (10.7%), and others. The most frequent rheumatic diagnosis was immunoglobulin A vasculitis. Other diagnoses include juvenile dermatomyositis, systemic lupus erythematosus, Kawasaki disease, and multisystem inflammatory syndrome in children. Skin manifestations often present as the initial complaint in pediatric rheumatic diseases. A thorough cutaneous examination is crucial for identifying the underlying systemic conditions and guiding appropriate management.

Lameness grading in cattle facilitates the diagnosis of musculoskeletal disorders and provides information regarding the disease severity in terms of animal welfare and transportability of the animal. Therefore, this study investigated the relationship between the degree of lameness and the severity of musculoskeletal disorders in cattle. The degree of lameness in 545 cattle with different orthopaedic disorders was analysed retrospectively. The categories age, type of lameness, anatomical localisation of the lesions, involvement of soft tissues, bones, joints, and other synovial structures, severity of infection, and claw involvement were generated. The categories were correlated with the degree of lameness, and both were correlated with the prognosis. Calves were more severely lame than older cattle (4/5 versus 3/5). Lameness originating from lesions at the carpus and tarsus or distally from these areas mostly led to supporting-leg lameness (87,5 % and 85,7 % or 95,7 %). Diseases localised proximal to the carpal and tarsal joints caused mixed lameness in 81,3 % of cases and supporting-leg lameness in 12,5 %; swinging-leg lameness was rare (6,3 %) The median degree of mixed lameness (3,5/5) exceeded that of supporting-leg lameness (3/5). Cattle with stifle (3,5/5) or elbow disorders (4/5) had significantly higher degrees of lameness compared with cattle with lameness attributable to other causes. Likewise, lameness caused by joint disease (3,5/5) was generally more severe than lameness caused by other disorders. Superficially infected musculoskeletal disorders and uncomplicated claw diseases were associated with milder lameness (both 3/5) than those with deep infection and complicated claw disorders (3/5 and 3,5/5). Cattle that recovered and were discharged had less severe lameness (2,5/5) than those that were slaughtered (3/5), and the latter had less severe lameness than those that were euthanised (3,5/5). The correlation between the severity of an orthopaedic disorder and the degree of lameness in cattle is consistent with clinical experience. This investigation allowed us to substantiate several relationships between the investigated variables and the degree of lameness. Our findings allowed the severity of a musculoskeletal disorder to be tentatively diagnosed and the affected anatomical structure to be identified based on the degree and type of lameness. This, in turn, may improve diagnostic capability and formulation of the prognosis, as well as the assessment of the fitness for transport of cattle with orthopaedic disorders. Die Lahmheitsgraduierung dient der Diagnostik von Erkrankungen des Bewegungsapparates, aber auch der Einschätzung der Schwere einer Erkrankung hinsichtlich Tierwohl und Transportfähigkeit. In der hier vor- legten Arbeit sollte deswegen untersucht werden, wie der Lahmheitsgrad mit der Schwere der Erkrankung des Bewegungsapparates zusammenhängt. Der Lahmheitsgrad von 545 Rindern mit verschiedenen orthopädischen Erkrankungen wurde retrospektiv untersucht. Zur Auswertung wurden die Kategorien Lebensalter, Lahmheitsart, Lokalisation der Lahmheitsursache, sowie die Beteiligung von Weichteilen, Knochen, Gelenken oder anderen synovialen Strukturen, der Infektionsgrad und gesondert die Klauenkrankheiten gebildet. Diese Kategorien wurden mit dem Lahmheitsgrad und beide mit der Prognose in Beziehung gesetzt. Kälber waren stärker lahm als ältere Rinder (4/5 versus 3/5). Erkrankungen, die am Karpus und Tarsus oder distal davon lokalisiert waren, äusserten sich mehrheitlich in Stützbeinlahmheiten (87,5 % und 85,7 % oder 95,7 %). Proximal der Fusswurzelgelenke lokalisierte Erkrankungen riefen zu 81,3 % gemischte Lahmheiten und zu 12,5 % Stützbeinlahmheiten hervor; Hangbeinlahmheiten waren selten (6,3 %). Gemischte Lahmheiten (3,5/5) hatten einen höheren medianen Lahmheitsgrad als Stützbeinlahmheiten (3/5). Erkrankungen von Knie (3,5/5) und Ellbogen (4/5) verursachten signifikant schwerere Lahmheiten als die der Restgesamtheit. Gelenkerkrankungen waren mit höheren Lahmheitsgraden (3,5/5) assoziiert. Oberflächlich infizierte Gliedmassenerkrankungen und unkomplizierte Klauen­erkrankungen führten zu leichteren Lahmheiten (beide 2/5) als tief infizierte Gliedmassenerkrankungen und komplizierte Klauenerkrankungen (3/5 resp. 3,5/5). Die als geheilt entlassenen Tiere waren weniger stark lahm (2,5/5) als die später geschlachteten (3/5) und diese wiederum weniger stark lahm als die euthanasierten Tiere (3,5/5). Dass ein Zusammenhang zwischen der Schwere einer orthopädischen Erkrankung und dem Lahmheitsgrad besteht, entspricht der klinischen Erfahrung. Mit der hier vorgelegten Dokumentation konnten viele Zusammenhänge belegt werden. Aufgrund dessen ist es möglich, von Lahmheitsgrad und -art auf den Schweregrad der Erkrankung und in einigen Fällen auf bestimmte betroffene Gewebe zu schliessen. Dadurch können Diagnose- und Prognosestellung sowie die Einschätzung der Transportfähigkeit von Tieren mit orthopädischen Erkrankungen verbessert werden. Boiteries sévères chez les bovins associées à des troubles orthopédiques graves et à un mauvais pronostic. L’évaluation du degré de boiterie chez les bovins facilite le diagnostic des troubles musculo-squelettiques et fournit des informations sur la gravité de la maladie en termes de bien-être animal et de transportabilité de l’animal. Cette étude a donc examiné la relation entre le degré de boiterie et la gravité des troubles musculo-squelettiques chez les bovins. Le degré de boiterie chez 545 bovins atteints de différents troubles orthopédiques a été analysé rétrospectivement. Les catégories suivantes ont été créées : âge, type de boiterie, localisation anatomique des lésions, atteinte des tissus mous, des os, des articulations et d’autres structures synoviales, gravité de l’infection et atteinte des onglons. Ces catégories ont été corrélées au degré de boiterie, et les deux ont été corrélés au pronostic. Les veaux étaient plus gravement boiteux que les bovins plus âgés (4/5 contre 3/5). La boiterie provenant de lésions au niveau du carpe et du tarse ou distalement par rapport à ces zones entraînait principalement une boiterie d’appui (87,5 % et 85,7 % ou 95,7 %). Les maladies localisées à proximité des articulations carpiennes et tarsiennes ont provoqué une boiterie mixte dans 81,3 % des cas et une boiterie d’appui dans 12,5 % des cas ; la boiterie de soutien était rare (6,3 %). Le degré médian de boiterie mixte (3,5/5) dépassait celui de la boiterie d’appui (3/5). Les bovins présentant des troubles du grasset (3,5/5) ou du coude (4/5) avaient des degrés de boiterie significativement plus élevés que les bovins présentant une boiterie attribuable à d’autres causes. De même, les boiteries causées par une affection articulaire (3,5/5) étaient généralement plus graves que celles causées par d’autres troubles. Les troubles musculo-squelettiques infectés superficiellement et les maladies des onglons sans complication étaient associés à une boiterie plus légère (3/5 dans les deux cas) que ceux présentant une infection profonde et des lésions des onglons compliqués (3/5 et 3,5/5). Les bovins qui se sont rétablis et ont été rendus à leurs propriétaires présentaient une boiterie moins grave (2,5/5) que ceux qui ont été abattus (3/5), et ces derniers présentaient une boiterie moins grave que ceux qui ont été euthanasiés (3,5/5). La corrélation entre la gravité d’un trouble orthopédique et le degré de boiterie chez les bovins est conforme à l’expérience clinique. Cette étude nous a permis de mettre en évidence plusieurs relations entre les variables étudiées et le degré de boiterie. Nos résultats ont permis de diagnostiquer provisoirement la gravité d’un trouble musculo-squelettiques et d’identifier la structure anatomique touchée en fonction du degré et du type de boiterie. Cela pourrait améliorer la capacité de diagnostic et la formulation du pronostic ainsi que l’évaluation de l’aptitude au transport des bovins atteints de troubles orthopédiques. La classificazione del grado di zoppia nei bovini rappresenta uno strumento fondamentale per la diagnosi dei disturbi dell’apparato muscoloscheletrico e fornisce indicazioni rilevanti sulla gravità della malattia, sia in termini di benessere animale sia di idoneità al trasporto. Il presente studio ha quindi analizzato la relazione tra il grado di zoppia e la severità delle patologie muscoloscheletriche nei bovini. Sono stati valutati retrospettivamente 545 bovini affetti da differenti patologie ortopediche. Sono state considerate le seguenti categorie: età, tipo di zoppia, localizzazione anatomica delle lesioni, coinvolgimento di tessuti molli, ossa, articolazioni e altre strutture sinoviali, gravità dell’infezione e interessamento degli unghioni. Tali variabili sono state correlate con il grado di zoppia e con la prognosi. I vitelli presentavano una zoppia più grave rispetto ai bovini adulti (4/5 contro 3/5). Le lesioni localizzate a livello del carpo e del tarso o distalmente a tali regioni determinavano prevalentemente una zoppia di appoggio (87,5 %, 85,7 % e 95,7 %). Le patologie situate prossimalmente alle articolazioni carpali e tarsali causavano una zoppia mista nell’81,3 % dei casi e una zoppia di appoggio nel 12,5 %; la zoppia di oscillazione risultava rara (6,3 %). Il grado mediano della zoppia mista (3,5/5) era superiore a quello della zoppia di appoggio (3/5). Le patologie del ginocchio (3,5/5) o del gomito (4/5) presentavano gradi di zoppia significativamente più elevati rispetto agli animali con zoppia dovuta ad altre cause. Analogamente, le zoppie secondarie a patologie articolari (3,5/5) risultavano generalmente più severe rispetto a quelle associate ad altri disturbi. Le affezioni muscoloscheletriche con infezione superficiale e le patologie ungueali non complicate erano correlate a gradi di zoppia più lievi (3/5) rispetto ai casi con infezioni profonde o patologie ungueali complicate (3/5 e 3,5/5). Dal punto di vista prognostico, gli animali guariti e dimessi presentavano un grado di zoppia inferiore (2,5/5) rispetto a quelli inviati alla macellazione (3/5), mentre questi ultimi mostravano una zoppia meno grave rispetto agli animali sottoposti a eutanasia (3,5/5). La correlazione tra la severità della patologia ortopedica e il grado di zoppia riscontrata in questo studio è coerente con l’esperienza clinica. L’analisi ha permesso di documentare in modo sistematico diverse associazioni tra le variabili esaminate e il grado di zoppia. I risultati suggeriscono che, sulla base del tipo e dell’intensità della zoppia, sia possibile formulare un’ipotesi preliminare sulla gravità del disturbo muscoloscheletrico e sulla struttura anatomica coinvolta. Ciò può contribuire a migliorare la capacità diagnostica, la definizione della prognosi e la valutazione dell’idoneità al trasporto dei bovini affetti da patologie ortopediche.

Inflammatory arthritis (IA) is a group of autoimmune diseases characterised by joint inflammation and progressive damage, thus impairing the patient's quality of life. The JAK/STAT pathway inhibitor Tofacitinib has been successfully introduced into the clinic to treat patients with IA, however its direct effect on T cell responses is widely unknown. This study aims to assess the effect of Tofacitinib on T cell activation, polyfunctionality, proliferation and metabolism. The effect of Tofacitinib on T cells from peripheral blood, synovial fluid and synovial tissue was evaluated with multidimensional flow cytometric analysis. T cell proliferation was assessed by flow cytometry and T cell metabolism was examined by qPCR and Seahorse XF analyser. To investigate the effect of Tofacitinib on T cell polarisation, na&#xef;ve T cells were differentiated into Th1, Th2 and Th17 with specific cytokine cocktails. Soluble mediators were evaluated by MSD multiplex analysis. Tofacitinib significantly inhibited T helper cell activation as evidenced by a marked reduction in the frequency of PD-1/CD69/CD25-positive cells (p&#x2009;<&#x2009;0.01). Reduced activation was consistent with impairment of pathogenic polyfunctionality of peripheral blood and synovial tissue-derived T cells. The impact of Tofacitinib on T cell plasticity was further substantiated by reduced T cell polarisation towards Th1 (p&#x2009;<&#x2009;0.05), Th2 (p&#x2009;<&#x2009;0.05), Th17 (p&#x2009;<&#x2009;0.05) and a reduction in genes associated with T cell functions. The attenuation of pathogenic T cell responses is linked to metabolic adaptation, with Tofacitinib leading to a switch in metabolic capacity, mainly ascribed to the CD4-CD8+ T cell compartment. Tofacitinib strongly alters T cell responses and potentially limits T cell pathogenicity by decreasing their activation, polyfunctionality, differentiation, and metabolic potential in both the circulation and the joints of patients with inflammatory arthritis.

Aging is a complex biological process characterized by progressive functional decline across tissues and increased susceptibility to age-related diseases, with oxidative stress being a key contributing factor. Glycine-Histidine-Lysine (GHK), a naturally occurring tripeptide present in human plasma and urine, possesses potent antioxidant properties; however, its broader anti-aging potential remains inadequately explored. In this study, we employed&#xa0;the model organism Caenorhabditis elegans to systematically investigate the anti-aging effects of GHK-Cu (GHK complexed with copper) and elucidate its underlying molecular mechanisms. Our results demonstrated that GHK-Cu significantly extended&#xa0;lifespan of C. elegans and ameliorated mutiple aging-related phenotypes, including enhanced resistance to oxidative and thermal stress, improved motility, pharyngeal pumping, defecation rhythm, and reduced lipofuscin/lipid accumulation. Mechanistically, GHK-Cu preserved mitochondrial function by increasing mitochondrial membrane potential, alleviating age-related mitochondrial network fragmentation, shifting mitochondrial dynamics toward fusion via regulating drp-1 and fzo-1 expression, and promoting ATP biosynthesis. Meanwhile, GHK-Cu activating DAF-16 and SKN-1 pathway, and upregulating&#xa0;sod-3,&#xa0;gst-4,&#xa0;gcs-1, lys-7 and lys-8. This study provides the first mechanistic evidence that GHK-Cu delays aging through coordinated regulation of mitochondrial function and activation of both DAF-16 and SKN-1 pathways. Our findings identify novel molecular targets for developing anti-aging interventions and underscore the potential of GHK-Cu's as a multifaceted geroprotective compound.

The aim of this study is to describe the evolution of cefoperazone-sulbactam consumption in Romania between 2011 and 2024. The use of this fixed-dose combination is not recommended by the World Health Organisation as it may result in selection of antimicrobial resistance. This retrospective study analyzed the data on antibiotic consumption collected by the National Center for Surveillance and Control of Communicable Diseases which is based on data provided by the National Health Insurance Fund and the IQVIA-Multinational Integrated Data Analysis System. Antibiotic sales were converted into defined daily doses (DDDs) per 1,000 inhabitants per day. The consumption of cefoperazone-sulbactam in Romania between 2011 and 2024 ranged from 0.016 to 0.021 DDD per 1000 inhabitants per day, with an average of 0.019 DDD per 1000 inhabitants per day. When adjusted for population, the RO1 macroregion registered the highest average consumption (0.033 DDDs per 1000 inhabitants per day). One-way ANOVA on DDD per 1,000 inhabitants per day data suggested that there were no statistically significant differences between macroregions (F = 2.78, p = 0.054). Although differences are observed in the mean values, they can be explained by counties with abnormally high consumption. Educational and training activities focused on the outlier counties are necessary to raise awareness about the risk of increased selection of antimicrobial resistance. In line with the rejection of the reclassification proposal of cefoperazone-sulbactam in the updated 2025 WHO AWaRe classification of antibiotics, new government policies to ensure the discontinuation of cefoperazone-sulbactam use in Romania are needed.

Maternal adult congenital heart disease (ACHD) has been associated with increased offspring congenital heart disease (CHD), but evidence from resource-limited regions remains scarce. The association between maternal acquired heart disease (AHD) and offspring CHD is unknown. To quantify the overall and subtype-specific CHD risk in offspring associated with maternal ACHD and AHD, examine the association of maternal ACHD and AHD with outcomes in offspring with CHD, and identify maternal factors that may modify the associations between maternal cardiac diseases and offspring CHD risk. This prospective birth cohort study enrolled pregnant women receiving prenatal care between August 1, 2011, and December 31, 2021, at a major cardiac referral center in China. Participants included pregnant women with ACHD, with AHD, or without cardiac disease and were followed up through delivery; their offspring were followed up until 1 year of age. All follow-ups were completed by December 15, 2023. Data were analyzed from April 1, 2024, through April 31, 2025. Maternal ACHD and AHD, confirmed via the center's electronic medical records. The main outcome was offspring CHD, which was diagnosed using echocardiography. Log-binomial regression was used to estimate relative risks (risk ratios [RRs]) and 95% CIs. Adverse outcomes were compared using pairwise tests. Stratification analyses identified potential effect modifiers. A total of 14&#x202f;336 pregnant women with 15&#x202f;677 offspring (8480 males [54.1%]) were included. The mean (SD) maternal age and gestational age at enrollment were 31.4 (4.5) years and 16.4 (6.4) weeks, respectively. Both maternal ACHD and AHD were associated with higher CHD risk in offspring (RR, 1.71 [95% CI, 1.26-2.31] and 1.38 [95% CI, 1.02-1.87], respectively). Minor CHDs, particularly septal defects, were the subtypes with the greatest magnitude of associations with maternal ACHD (RR, 2.95; 95% CI, 1.97-4.43) and AHD (RR, 2.28; 95% CI, 1.50-3.45). Right ventricular outflow tract obstruction (RR, 6.17; 95% CI, 3.59-10.60) and valvular heart disease (RR, 1.65; 95% CI, 1.11-2.45) were the key contributors to offspring CHD risk. Preterm birth had higher rates among offspring with CHD and mothers with ACHD as well as offspring with CHD and mothers without ACHD compared with offspring without CHD and mothers without cardiac disease (12 of 39 [30.8%] and 121 of 780 [15.5%] vs 1287 of 14&#x202f;088 [9.1%]; all P&#x2009;<&#x2009;.001). Higher rates of chromosomal (5 of 39 [12.8%] and 38 of 780 [4.9%] vs 75 of 14&#x202f;088 [0.5%]; all P&#x2009;<&#x2009;.001) and genetic aberrations (3 of 39 [7.7%] and 16 of 780 [2.1%] vs 57/14&#x202f;088 [0.4%]; all P&#x2009;<&#x2009;.001) were found among offspring with CHD and mothers with AHD as well as offspring with CHD and mothers without AHCD compared with offspring without CHD and mothers without cardiac disease. Associations between maternal cardiac disease and offspring CHD were robust in primiparous women (ACHD: RR, 2.15 [95% CI, 1.48-3.11], P for interaction < .001; AHD: RR, 1.73 [95% CI, 1.17-2.56], P for interaction = .02) and those with periconceptional exposure to hazardous substances (ACHD: RR, 2.22 [95% CI, 1.56-3.16], P for interaction < .001; AHD: RR, 1.57 [95% CI, 1.05-2.36], P for interaction = .02). In this cohort study, maternal ACHD and AHD were associated with increased risks and adverse outcomes of offspring CHD. Targeted modification of identified maternal factors could help mitigate offspring CHD risk in this high-risk population.

Mucolipidosis type III (ML-III) alpha/beta and gamma are uncommon lysosomal storage diseases caused by a partial deficiency of the N-acetylglucosaminyl-1-phosphotransferase enzyme. Biallelic mutations in the GNPTAB gene are responsible for ML-III alpha/beta, whereas mutations in GNPTG lead to ML-III gamma. This study aims to thoroughly investigate the clinical manifestations and diagnostic clues of ML-III, with the goal of preventing misdiagnosis and delays in diagnosis. A retrospective review was conducted of all patients referred to the Pediatric Metabolism Department between 2010 and 2022 due to joint stiffness and/or pain, with a total of 192 patients evaluated during this period. The clinical, laboratory, radiological, and genetic data of patients diagnosed with ML-III were reviewed in detail. Six patients (3.1%) from the cohort of 192 were diagnosed with ML-III. The median age of these patients at symptom onset was 2.75 years (min-max: 1.2-11.5 years). The initial finding of all patients was stiffness of finger joints. Five patients were misdiagnosed before admission, and the median age at diagnosis was 12 years (min-max: 5-35 years). The median delay in diagnosis was 6.5 years (min-max: 3-24 years). Neither ML-III alpha/beta nor ML-III gamma patients had psychomotor retardation. The patients' ages ranged from 8.6 to 38 years. The ML-III's clinical findings can lead to misdiagnoses, such as rheumatological disorders. Heightened awareness could prompt earlier detection, underlining the importance of thorough evaluations for all patients with joint-related presentations.

The Naples Prognostic Score (NPS) has demonstrated prognostic value in oncology and certain chronic diseases. Its utility in cardio-renal-metabolic multimorbidity (CRMM) remains unexplored. This study aims to evaluate the association between NPS and all-cause mortality in individuals with CRMM. We analyzed data from the National Health and Nutrition Examination Survey (1999-2018) comprising 3,602 adults with CRMM. The NPS was derived from serum albumin, total cholesterol (TC), neutrophil-to-lymphocyte ratio (NLR), and lymphocyte-to-monocyte ratio (LMR). Weighted Cox proportional hazards models and restricted cubic spline (RCS) analysis were used to evaluate associations between NPS and all-cause mortality. Over a median follow-up of 79 months, 1,621 (41.4%) deaths occurred. After comprehensive adjustment for potential confounders, each 1-point increase in NPS was associated with a 24.6% higher risk of all-cause mortality (HR 1.246, 95% CI 1.150-1.350, P < 0.0001). The HRs for all-cause mortality was 1.133 (95 % CI: 0.846-1.518, P = 0.401) in the medium NPS group and 1.721 (95 % CI: 1.248-2.375, P = 0.0009) in the high NPS group, as compared with the low NPS group. RCS analysis indicated a nonlinear relationship between NPS and all-cause mortality among participants with CRMM (Pnonlinear=0.014). Weighted quantile sum regression analysis identified NLR as the primary contributor to mortality risk (weight: 0.612 at 2 years, 0.580 at 5 years), followed by TC. This study identified a positive, nonlinear association between NPS and all-cause mortality in CRMM individuals. The NPS integrates inflammatory, metabolic, and nutritional biomarkers into a practical prognostic tool that may enhance risk stratification and guide personalized management in multimorbidity.

N6-methyladenosine (m6A) and 5-methylcytosine (m5C) are dynamic and reversible RNA modifications that play important roles in cardiovascular diseases (CVDs). By regulating RNA stability, splicing, transport, translation, and degradation, m6A and m5C shape key pathological processes including endothelial dysfunction, inflammation, apoptosis, fibrosis, impaired contractility, and metabolic remodeling. Core regulators, including METTL3, METTL14, fat mass and obesity-associated protein (FTO), AlkB homolog 5 (ALKBH5), and YTH family proteins for m6A, as well as NSUN2, DNMT2, TET2, and ALYREF YBX1 for m5C related pathways, display disease stage specific and cell type-specific patterns across atherosclerosis, ischemic cardiomyopathy, heart failure, myocarditis, cardiomyopathy, and rheumatic heart disease, highlighting their potential as diagnostic and prognostic biomarkers. Therapeutically, pharmacological modulation of writers and erasers, adeno-associated virus-based gene delivery, and stem cell-based strategies show encouraging preclinical efficacy, while lifestyle interventions such as exercise may optimize the cardiac RNA methylation landscape. In addition, emerging RNA methylation marks, including N&#xb9;-methyladenosine (m1A),7-methylguanosine (m7G), N&#x2076;,2'-O-dimethyladenosine (m6Am), and oxidative cytosine derivatives such as 5-hydroxymethylcytosine (hm5C) and 5-formylcytosine (f5C), further expand the RNA modification landscape of cardiovascular remodeling by linking cap-dependent translation, mitochondrial protein synthesis, and stress adaptation. However, major challenges remain, including resolving RNA methylation dynamics at single-nucleotide and single-cell resolution, integrating RNA methylation with other regulatory layers, and achieving precise cardiac delivery with durable safety. With advances in multi-omics, spatial mapping, nanomedicine, and translational research, targeting RNA methylation offers a promising paradigm for improved diagnosis, risk stratification, and personalized therapy in cardiovascular disease.

Driven by recent advances in artificial intelligence, particularly in medicine, audio-based voice and speech biomarkers are increasingly investigated for various medical applications as a complementary or even alternative modality to traditional medical devices. The adoption of deep learning techniques in recent literature is motivated by their superior performance compared to classical machine learning (ML) methods. However, ethical and regulatory concerns regarding the black-box nature of these models have limited their integration into clinical workflows. Consequently, Explainable AI (XAI) has recently been employed to address this issue by generating explanations for opaque model outputs. Ideally, medical XAI systems aim to provide human-understandable, clinically grounded explanations essential for enhanced AI trustworthiness and, thereby, facilitated adoption into real-world clinical settings. We conduct a systematic literature review of XAI methods applied for explaining deep learning techniques in audio-based voice and speech clinical applications. Our aim is to identify what XAI methods have been used to explain the decisions of deep learning voice and speech AI systems in healthcare, as well as XAI-informed insights. Additionally, we aim to contextualize these findings with respect to clinical applicability and stakeholder relevance. Lastly, we identify opportunities and recommendations for future clinical audio XAI design. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Six electronic databases (IEEE Xplore, ACM Digital Library, Scopus, PubMed, Web of Science, and Nature) were systematically searched for articles published between January 2015 and February 2025. Eligible studies applied explainability or interpretability methods to deep learning models for voice or speech audio in healthcare contexts. Risk of bias was assessed using PROBAST+AI. Results were thematically synthesized across explainability categories, input representations, clinical domains, validation strategies, and stakeholder considerations. Thirty studies met the inclusion criteria. These studies employed a range of explainability approaches, including gradient-based methods, perturbation-based techniques, surrogate model-based methods, model-internal representation analyses, concept-based detectors, and attention-based explanations. Applications spanned diverse clinical domains, including voice disorders, neurodegenerative diseases, psychiatric conditions, and traumatic brain injury. Overall, results indicate that most studies relied primarily on qualitative interpretation of explainability outputs, with limited quantitative validation of explanation consistency across external datasets. Furthermore, none of the included studies explicitly conducted human-in-the-loop evaluations with relevant stakeholders, highlighting a substantial gap in stakeholder alignment. Current XAI practices in clinical voice and speech analysis are limited by insufficient validation, lack of domain-specific design, and misalignment with clinical stakeholder needs. This review highlights opportunities for developing validated, audio-aware, and stakeholder-centered XAI approaches to support trustworthy clinical deployment. Interpretation of these findings should consider limitations related to single-reviewer study selection, potential high-risk of bias in model development and evaluation, and the repeated use of benchmark datasets across reviewed studies.

Drug overdose is a leading cause of death among US veterans with homeless experience. Medications for opioid use disorder (MOUD) reduce overdose and all-cause mortality, yet receipt remains low among veterans with homeless experience. Identifying factors associated with MOUD receipt in Department of Veterans Affairs (VA) permanent supportive housing (PSH) can inform strategies to support MOUD implementation and advance health equity. To identify demographic, clinical, and service-related factors associated with MOUD receipt among veterans with homeless experience with opioid use disorder (OUD) in the Housing and Urban Development-VA Supportive Housing (HUD-VASH) program. This cohort study used linked national VA administrative and electronic health record data. US veterans with OUD entering HUD-VASH between October 1, 2017, and September 30, 2021, were followed up for 12 months after move-in. Eligible participants were diagnosed with OUD as defined by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision criteria within 5 years before or 1 year after move-in. Sequential logistic regression models examined associations between demographic, clinical, and service utilization factors and MOUD receipt. Statistical analyses were conducted between May 2025 and February 2026. Demographic, clinical, and service-related factors. Receipt of MOUD (buprenorphine, methadone, or extended-release naltrexone) within 12 months after HUD VASH move-in. Among 10&#x202f;110 veterans with OUD, the mean (SD) age was 53.2 (12.0) years (9297 male [92%]; 3211 Black [32%], 606 Hispanic [6%], 5537 White [55%]); 1685 veterans (17%) received MOUD. Older age (age 55 to 64 years: adjusted odds ratio [AOR], 0.52 [0.42-0.64]) and non-Hispanic Black race (AOR, 0.47 [95% CI, 0.40-0.55]) were associated with lower odds of MOUD receipt, while depression (AOR, 1.24 [95% CI, 1.05-1.46]) and greater behavioral health engagement was associated with higher odds of receipt. Having 1 or more instances of inpatient hospitalization was associated with lower odds of MOUD receipt (AOR, 0.74 [95% CI, 0.64-0.87]). In this cohort study of veterans with homeless experience with OUD, 1 in 6 veterans received MOUD within a year of entering PSH. Lower rates of MOUD receipt among older veterans and veterans from racial minority groups highlighted persistent inequities, regardless of housing status.

The study examines how magnesium compounds, especially Magnesium-L-Threonate (MLT) and Magnesium-Acetyl-Taurate (MAT), affect neurophysiological functions in adult Wistar rats. Magnesium is essential for many cellular processes in the brain & peripheral system, such as neurotransmitter regulation, muscle function, and energy metabolism. Tissue Mg&#xb2;&#x207a; levels were defined as the primary endpoint of the study, as they directly reflect the central objective of evaluating magnesium-based interventions. All other outcomes, including behavioral, biochemical, and molecular parameters, were considered secondary endpoints. This research aimed to compare the brain effectiveness of MLT (115&#xa0;mg/kg and 450&#xa0;mg/kg) and MAT (150&#xa0;mg/kg and 500&#xa0;mg/kg) in raising magnesium levels in biological samples like blood plasma, cerebrospinal fluid (CSF), muscles and brain tissues. The aim is to examine the effect of Magnesium compounds (MLT, MAT & combination treatment) on modulation and alterations in all the biological markers for neuroinflammation, synaptic plasticity, neurotransmission balance, oxidative stress & mitochondrial functioning. MAT showed better Mg2+, resulting in more notable improvements in cognitive functions, neuromuscular strength, and motor coordination compared to MLT. Behavioral tests indicated that MAT and the combined therapy of MLT and MAT significantly improved spatial learning, memory, and anxiety-related behaviors. These improvements correlated with increased expression of key proteins, including brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), Nrf2, HO-1, cAMP, and synaptic proteins such as synaptophysin and PSD-95, which are crucial for synaptic plasticity and cognition. Additionally, MAT treatment was associated with alteration inantioxidant markers, including superoxide dismutase (SOD), glutathione (GSH), catalase, and coenzyme Q10 (CoQ10), indicating better cellular defense against oxidative stress. Moreover, the upregulation of Mitochondrial ETC complexes by MAT and the combination therapy of MLT and MAT suggest improved mitochondrial function inside cells. Levels of Threonate, Taurine, and Mg2+ were also significantly higher in the MAT, MLT, and combined treatment groups. Neurotransmitters such as Dopamine, GABA & Glutamate, as well as complete blood count, have also been estimated. Morphological and histological analyses showed that MAT and the combination therapy significantly enhanced neuronal myelination and structural integrity across various brain regions. These results suggest that MAT & MLT&#x2009;+&#x2009;MAT could serve as a promising neurotherapeutic agent due to its ability to improve better magnesium bioavailability, stimulate neurogenesis, enhance cognitive functions & overall brain functioning. Future research should focus on refining methods for higher-brain bioavailable magnesium salt supplementation and investigating the combined effects of such magnesium salts with other neuroprotective compounds for treating cognitive decline, neurodegenerative diseases & other neurological conditions.

The Wnt signaling pathway antagonist SFRP1 is frequently silenced by promoter DNA hypermethylation in colorectal cancer (CRC). MBD2, a DNA methylation reader, is known to contribute to SFRP1 epigenetic silencing. Previous work showed that MBD2 critically suppresses SFRP1 expression without altering promoter methylation, though the underlying mechanism remained unclear. Elucidating how DNA methylation silences tumor suppressor genes, such as SFRP1, could reveal novel therapeutic targets with significant clinical potential. MBD2 was inhibited in CRC models using either siRNA or a small molecule inhibitor (KCC07). The effects on SFRP1 and &#x3b2;-catenin expression, Wnt pathway activity, cell proliferation, and apoptosis were assessed. Tumor growth was also evaluated in vivo. Mechanistic studies investigated the role of MBD2 in mediating MED19 binding to the SFRP1 promoter and its impact on RNA polymerase II CTD-S7 phosphorylation. The IC50 of KCC07 was 23.25&#x2009;&#x3bc;M in SW480 cells, 26.83&#x2009;&#x3bc;M in HCT116 cells, and 39.66&#x2009;&#x3bc;M in NCM460 cells. Inhibition of MBD2, either genetically or pharmacologically with KCC07, upregulated SFRP1 expression, downregulated &#x3b2;-catenin, and suppressed the Wnt pathway. KCC07 treatment also inhibited CRC cell proliferation, promoted apoptosis, and suppressed tumor growth in vivo. Mechanistically, MBD2 was found to silence SFRP1 by blocking MED19 binding to its promoter, which subsequently reduced RNA polymerase II CTD-S7 phosphorylation and impaired transcription. This study reveals a novel mechanism whereby DNA methylation suppresses gene expression via MBD2, independent of changes in methylation status, by disrupting MED19 binding and subsequent transcription. Targeting MBD2 represents a promising therapeutic strategy for colorectal cancer.

Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder primarily affecting the gastrointestinal tract. The pathogenesis arises from complex interactions among genetic predisposition, immune dysregulation, and gut microbiota alterations. Recent advances in molecular biology, genomics, and microbiome research have identified novel therapeutic targets, enabling the development of innovative treatment strategies. Natural products derived from plants offer bioactive compounds with anti-inflammatory, antioxidant, and immunomodulatory properties, gaining attention for IBD symptom management. Conventional therapeutic management includes aminosalicylates, immunomodulators, corticosteroids, and biologics; however, 30-50% of patients show inadequate response, and oral drug delivery faces challenges due to gastrointestinal environmental heterogeneity. Recent years have witnessed substantial advances in nanoparticle-based drug delivery systems for IBD, offering improved targeting capabilities, enhanced therapeutic efficacy, and better tolerability through stimuli-responsive platforms (ROS-sensitive, pH-responsive) and active targeting strategies. Nanoparticle-mediated gene therapy, including siRNA, miRNA, and emerging CRISPR-based approaches, represents a paradigm-shifting strategy for modulating aberrant gene expression in IBD. This comprehensive review synthesizes the current understanding of IBD pathophysiology, evaluates both conventional and emerging therapeutic approaches, and provides critical analysis of advanced nanoparticle delivery systems and gene-based therapeutic strategies.

Atopic dermatitis is a chronic immune-inflammatory skin disease that significantly impairs quality of life, with itch representing a key, but not exclusive, contributor to this burden. We aimed to evaluate itch relief and quality-of-life improvements with abrocitinib or dupilumab for 16 weeks alongside topical therapy in patients with moderate-to-severe atopic dermatitis. This post hoc analysis included pooled data from patients who received abrocitinib (200 mg/day) or dupilumab (300 mg/every 2 weeks) in phase III JADE COMPARE and JADE DARE. Assessments included proportions of patients achieving a &#x2265; 4-point improvement from baseline in Peak Pruritus Numerical Rating Scale (PP-NRS4), itch-free state (PP-NRS 0/1) by baseline itch severity, and proportions of patients with residual itch achieving Dermatology Life Quality Index score of 0/1 (DLQI 0/1), total Patient-Oriented Eczema Measure (POEM) score &#x2264; 2, SCORing Atopic Dermatitis (SCORAD) sleep loss visual analog scale score of 0/1 (SCORAD&#xa0;sleep loss visual analog scale 0/1), and POEM sleep item score of 0 (POEM sleep 0). Among 1196 patients (abrocitinib, n = 588; dupilumab, n = 608), those with greater baseline itch severity experienced greater atopic dermatitis severity and worse quality of life than patients with less severe itch. At week 16, numerically more patients achieved PP-NRS4 (67% vs 63%) and PP-NRS 0/1 (36% vs 27%) with abrocitinib versus dupilumab, respectively, regardless of baseline itch severity, although 95% confidence intervals overlapped for both measures. Median time to achieve PP-NRS4 (11 vs 29 days) and PP-NRS 0/1 (57 vs 139 days) was shorter with abrocitinib versus dupilumab, respectively. Numerically greater proportions of patients achieving PP-NRS 0/1 also achieved DLQI 0/1, POEM &#x2264; 2, SCORAD sleep loss visual analog scale 0/1, or POEM sleep 0 than patients with residual itch (PP-NRS &#x2265; 2). In this post hoc pooled analysis of the JADE COMPARE and JADE DARE trials, the proportion of patients with moderate-to-severe atopic dermatitis achieving clinically meaningful itch responses, including an itch-free state, was generally higher with abrocitinib compared with dupilumab. Median time to achievement of both PP-NRS4 and an itch-free state was shorter with abrocitinib than with dupilumab. Patients who achieved an itch-free state experienced greater improvements in quality of life and sleep compared with patients with residual itch. JADE COMPARE (NCT03720470; registration date: 2018/10/24); JADE DARE (NCT04345367; registration date: 2020/04/10).

Children are extremely vulnerable to climate-related environmental impacts and air pollution due to both biological and behavioral factors. Despite the emerging evidence of the increasing effects of climate change on the world and on children's health, policies to drive change and halt the effects are lacking. Climate change is causing Europe to heat up faster than other continents. Here, we assessed the evidence-based effects of climate change and air pollution on child health in Europe.&#xa0;A scoping review was performed to map the impact of climate-related exposures on the health of children in Europe. A literature search was conducted in three bibliographic databases (PubMed, Embase.com, and Cochrane Database of Systematic Reviews/Cochrane Central Register of Controlled Trials), for studies published between January 1, 2014, and November 11, 2024. Studies were included if they met the following criteria: original studies performed in Europe, addressing climate-related exposures (i.e., the effects of air pollution, heat stress and/or wildfires) on clinical outcomes in neonates, infants, and children (<18 years).&#xa0;The literature search generated a total of 3838 unique articles; upon screening, 73 articles were included in this scoping review. Most studies were conducted in South and West Europe. Climate-related exposures were linked to negative neonatal outcomes, increased risk of respiratory and allergic disease, adverse neurological development, and&#xa0;a higher incidence&#xa0;of metabolic conditions in children. Most studies assessed the impact of air pollution (mainly particulate matter with a diameter smaller than 2.5 micrometers PM2.5 and PM10 exposure); few studies assessed other climate-related outcomes such as heat stress or wildfires. &#xa0;Climate change is an active driver of pediatric morbidity in Europe, posing urgent respiratory, neurological, and perinatal risks amplified by social inequality. Protecting future generations demands a paradigm shift in healthcare that moves beyond treating acute symptoms to addressing upstream environmental drivers, including the integration of environmental exposure data into clinical practice. &#x2022; Children are biologically vulnerable to environmental hazards and more prone to climate-related exposures. &#x2022; Europe is warming up faster than other continents; therefore, children in Europe are at increased risk of climate-related adverse health outcomes. &#x2022; This scoping review confirms climate change may lead to increased pediatric morbidity in Europe, linking air pollution, heat stress, and wildfires to perinatal, respiratory, metabolic, and neurological risks. &#x2022; European studies regarding climate change and children's health have mainly focused on the impact of air pollution, but hardly focused on the impact of heat stress,&#xa0;highlighting the need for broader research and a coordinated pan-European change in political interventions tackling climate change.