SEARCH · Search PubMed

Results for “pituitary dysfunction”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

151 records · Page 5Linked to original sources

PubMed2026

Comparative safety of lipid-lowering drugs alone or in combination: insights from a systematic review and network meta-analysis.

BACKGROUND AND AIMS: Although the safety profile of lipid-lowering therapies (LLTs) is known, there are no comprehensive comparative assessments. We aimed to compare the risk of muscle-related events, diabetes, liver dysfunction, and cognitive disorders among LLTs through a network meta-analysis. METHODS AND RESULTS: Databases were searched from inception to May 2025. Eligible studies included adult patients, using statins, ezetimibe, PCSK9 monoclonal antibodies (PCSK9mAbs), inclisiran, bempedoic acid, or their combinations as intervention, reporting the information about any of the selected adverse events, a total sample size of ≥200 subjects, and had ≥1 month of intervention. Pooled estimates were assessed by fixed effects model within a frequentist setting. Pooled relative risks (RR) and their 95% confidence interval were estimated. A total of 303,397 subjects from 153 RCTs were included. Bempedoic acid ranked the lowest risk of myalgia (vs PCSK9mAbs, RR 0.80 [0.69, 0.93]). PCSK9mAbs were associated with lower incidence of creatine kinase (CK) elevation, diabetes, and liver dysfunction comparing to statins (statins vs PCSK9mAbs, RR 1.44 [1.14, 1.81], RR 1.13 [1.05, 1.22], and RR 1.38 [1.17, 1.62], respectively). In terms of muscle-related events and cognitive disorders, no significant risk differences were found among treatments and their combinations. CONCLUSIONS: PCSK9mAbs appear to have a more favourable safety profile regarding the risk of CK elevation, diabetes, and liver dysfunction. Bempedoic acid seem to be a better choice for subjects with high risk of myalgia. This information can be valuable when selecting therapy for specific patient subgroups at higher risk of certain adverse events.

Humans↗

PubMed2026

Micro- and nanoplastics-induced neurotoxicity: a CNS-centered, evidence-graded adverse outcome pathway framework based on systematic weight-of-evidence assessment.

Micro- and nanoplastics (MPs/NPs) are ubiquitous anthropogenic particulate pollutants posing emerging threats to human neurological health. Severe heterogeneity in particle physicochemical properties, environmental aging status, exposure paradigms and experimental platforms has created persistent mechanistic uncertainties in MP/NP neurotoxicology, hindering reliable hazard characterization and risk translation. Here, we systematically consolidate empirical toxicological evidence and construct a dedicated central nervous system (CNS)-targeted adverse outcome pathway (AOP) network integrated with rigorous weight-of-evidence (WoE) grading to elucidate the hierarchical, particle-specific toxic cascades underlying MP/NP-induced neural injury. Our synthesis overturns the conventional linear toxicity paradigm, demonstrating that MPs/NPs trigger neurotoxicity via a complex multi-input mechanistic network. We definitively establish oxidative stress as a robust early convergent key event-rather than a universal molecular initiating event-orchestrating ROS overproduction, lipid peroxidation, mitochondrial dysfunction, and neuroinflammation to propagate neuronal damage. This core module is driven by five distinct particulate upstream triggers: particle-biomolecule interfacial perturbation, corona-facilitated cellular internalization, plastic-associated chemical leaching, aging-derived free radical reactivity, and gut-borne systemic neurotoxic signaling. Downstream pathogenic outcomes encompass glial overactivation, neurotransmitter dyshomeostasis, autophagy-lysosome dysfunction, metabolic reprogramming, regulated neuronal cell death, and behavioral impairments. Tiered WoE analysis confirms strong validation for early oxidative/inflammatory cascades, moderate support for gut-brain axis crosstalk and intracellular trafficking disruption, and nascent evidence for synaptic dysfunction and neurodegeneration-linked proteostatic defects. Extrapolation to human health risk remains constrained by the frequent use of high-dose exposure paradigms, limited validated data on internal dosimetry in the human brain, discrepancies between effective concentrations in experimental models and environmentally relevant human tissue burdens, and insufficient causal validation of distal adverse outcomes. We highlight key research priorities including aged mixed-particle exposure systems, leachate-controlled assays, quantitative internal dose evaluation, and mechanistic intervention verification. This evidence-stratified AOP framework resolves longstanding mechanistic ambiguities in particulate neurotoxicity, providing a standardized, causality-based foundation for future mechanistic exploration and health risk assessment of global plastic pollution.

Adverse outcome pathway↗

PubMed2026

Stratified medicine with eplerenone for myocardial infarction or injury and no obstructive coronary arteries: A registry-based basket trial.

BACKGROUND: Myocardial Infarction with No Obstructive Coronary Arteries (MINOCA) or Nonischemic Myocardial Injury affects approximately 1 in 9 patients presenting with acute coronary syndrome, yet evidence-based therapies are lacking. Coronary microvascular dysfunction is implicated in the pathogenesis of suspected MINOCA, but its prevalence, prognostic implications and treatment are uncertain. The objectives are, first, to assess the prevalence of coronary microvascular dysfunction in patients with suspected MINOCA and, second, to implement endotype-informed stratified medicine involving patients with coronary microvascular dysfunction to treatment with eplerenone, a cardio- and vasculo-protective mineralocorticoid receptor antagonist. METHODS: This is a prospective, registry-based, multicenter, diagnostic study and nested, randomized, controlled, open-label, blinded-endpoint (PROBE) basket trial. Up to 400 patients with clinically suspected MINOCA and one or more cardiovascular risk factors will be enrolled into a registry-based diagnostic study. Coronary microvascular function will be assessed during invasive angiography using thermodilution. Patients with an index of coronary microvascular resistance (IMR) ≥ 25 will be randomized 1:1 to eplerenone (25-50 mg daily for 6 months) or standard care without eplerenone (control group) (n = 150 randomized). Final endotypes will be centrally adjudicated by a panel of blinded cardiologists. The primary outcome of the diagnostic study is the proportion of patients with IMR ≥ 25 during index coronary angiography. Secondary outcomes include coronary flow reserve, cardiovascular MRI parameters, patient-reported outcome measures, biomarkers of myocardial fibrosis and vascular inflammation, health outcomes and health economic assessments. The primary outcome of the randomized trial is the within-individual change in NT-proBNP at baseline, 1 month, and 6 months, based on intention-to-treat. Secondary outcomes include mechanistic blood biomarkers and patient-reported outcome measures. VALUE: This registry-based randomized trial will provide novel evidence on endotype-informed secondary prevention therapy with eplerenone for suspected MINOCA.

Humans↗

PubMed2026

Multi-omics reveals that burdock seed aglycone alleviates renal fibrosis by restoring mitochondrial oxidative phosphorylation function.

Renal fibrosis (RF), a common pathological process driving chronic kidney disease (CKD) progression to end-stage renal failure, is closely associated with oxidative phosphorylation (OXPHOS). Arctigenin (ATG), the main active component of burdock seed, exhibits anti-inflammatory and anti-fibrotic activities, but its mechanisms in RF treatment remain unclear. Here, we performed integrated transcriptomic and proteomic analyses to identify key targets and pathways of ATG in a unilateral ureteral obstruction-induced rat RF model. Multi-omics enrichment analysis revealed that NDUFS8 and NDUFS2 were the core targets of ATG, with the OXPHOS pathway as the central intersecting pathway. Our results suggest that ATG exerts anti-renal fibrosis effects by targeting the OXPHOS pathway to inhibit excessive reactive oxygen species production and oxidative stress. SIGNIFICANCE: Chronic kidney disease (CKD) continues to impose an escalating global health and socioeconomic burden, while renal fibrosis (RF), as the convergent pathological endpoint of virtually all progressive nephropathies, remains the principal determinant of irreversible renal failure and adverse clinical outcomes. Despite extensive efforts to develop antifibrotic therapies, effective clinical interventions remain elusive, largely due to the complex and multifactorial nature of RF pathogenesis. In this study, we employed an integrated multi-omics framework encompassing transcriptomics, proteomics, and metabolomics to systematically decipher the antifibrotic mechanism of arctigenin (ATG), a bioactive natural compound derived from traditional Chinese medicine. Our findings identify mitochondrial oxidative phosphorylation as the pivotal regulatory axis underlying the renoprotective effects of ATG and further establish key catalytic subunits of mitochondrial complex I as its direct molecular targets. Mechanistically, ATG not only restores complex I activity and reprograms mitochondrial energy metabolism but also preserves the intracellular stability and localization of these subunits, thereby preventing their aberrant release-mediated inflammatory activation and disrupting the self-perpetuating cycle linking metabolic dysfunction, inflammation, and fibrosis progression. Beyond revealing a previously unrecognized dual mechanism integrating metabolic and inflammatory regulation, this study provides compelling evidence that mitochondrial dysfunction is not merely a secondary consequence of tissue injury but a fundamental driver of fibrotic remodeling. Importantly, our work highlights the translational potential of natural product-based mitochondrial interventions for CKD treatment and supports a broader conceptual shift toward metabolism-centered therapeutic strategies for chronic fibrotic diseases. Given the central role of mitochondrial dysfunction across multiple organs, these findings may also have far-reaching implications for the treatment of systemic fibrosis-related disorders beyond the kidney.

Animals↗

PubMed2026

From pathobiology to prescribing in obesity-driven HFpEF: A systematic review and practical therapeutic framework.

Heart failure with preserved ejection fraction (HFpEF) is increasingly driven by obesity and cardiometabolic dysfunction. In this phenotype, the dominant biology extends beyond congestion alone and includes visceral and epicardial adiposity, systemic inflammation, impaired myocardial energetics, endothelial dysfunction, and exertional elevation in filling pressures. We performed a PRISMA-compliant systematic review with structured narrative evidence synthesis to evaluate pharmacological therapy in obesity-driven HFpEF, searching PubMed/MEDLINE, Scopus, Web of Science Core Collection, ClinicalTrials.gov, and WHO ICTRP through December 2025. Eighteen reports were included in the final qualitative synthesis. The available evidence supports sodium-glucose cotransporter 2 inhibitors as the pharmacological foundation because they provide the most mature outcome data across the preserved ejection fraction spectrum. Semaglutide improves symptoms, physical limitations, exercise capacity, and body weight in dedicated obesity-related HFpEF trials, whereas tirzepatide extends this signal by improving clinical status and reducing worsening heart failure events. Finerenone broadens the therapeutic platform in HF with mildly reduced or preserved ejection fraction, although obesity-specific data remain indirect. Conventional neurohormonal therapies retain a selective role, but they are not the principal biological match for this phenotype. Obesity-driven HFpEF should therefore be managed as a cardiometabolic syndrome with heart failure expression, using a phenotype-based sequence that links diagnosis, decongestion, SGLT2 inhibition, obesity-directed therapy, and selective adjunctive intensification.

Humans↗

PubMed2026

Synaptic vesicle glycoprotein 2A PET imaging in parkinsonian α-synucleinopathies: a systematic review.

Synaptic dysfunction is increasingly recognized as an early and biologically relevant component of α-synucleinopathies. However, conventional imaging biomarkers mainly assess dopaminergic dysfunction, glucose metabolism, or structural damage rather than presynaptic density itself. Synaptic vesicle glycoprotein 2A (SV2A) PET enables in vivo assessment of presynaptic terminal integrity and may provide complementary information in Parkinson's disease (PD), Parkinson's disease dementia/dementia with Lewy bodies (PDD/DLB), and multiple system atrophy (MSA). This systematic review synthesized the available evidence on SV2A-targeted PET in parkinsonian α-synucleinopathies, focusing on regional imaging patterns, clinical associations, longitudinal findings, and methodological determinants of interpretation. Seventeen reports were included. In PD, the most recurrent finding was reduced SV2A binding in the substantia nigra, although additional involvement of brainstem, caudate, striatal, thalamic, raphe, or cortical regions was reported in selected cohorts. In PDD/DLB, abnormalities appeared broader and more cortical, with evidence of association between cortical SV2A binding and cognitive performance. In MSA, one study suggested a distinct infratentorial and cerebellar pattern with potential relevance for phenotypic stratification. SV2A PET is a promising research biomarker for biological characterization of synucleinopathies. However, the field remains limited by small cohorts, methodological heterogeneity, variable quantification strategies, limited longitudinal evidence, and potential cohort overlap. Multicentre validation and harmonized protocols are required before clinical translation.

Humans↗

PubMed2026

Nutrition and Diet-Related Training and Curriculum in the US Predoctoral Dental Programs.

PURPOSE: Nutrition and diet are vital for oral and systemic health. It is unclear how well US predoctoral dental programs prepare students in nutrition screening and counseling. This study analyzed US dental school curricula on these topics. METHODS: A cross-sectional online survey was sent to the publicly available email addresses of 67 of 72 academic dental deans at US Commission on Dental Accreditation-accredited dental schools. Items assessed availability, modes and hours of instruction, curricular topics, clinical integration, and instructors. Descriptive statistics summarized responses. RESULTS: A total of 21 academic deans responded, for an overall response rate of 29%. Most (85%) of responding academic dental deans reported that nutrition and diet education was mandatory, with none treating it as optional. Of these schools, 83% offered both classroom and clinical training, while 17% provided only didactic teaching. Didactic hours varied; 42% reported 10 or fewer hours. Foundational nutrition topics were common, although dietary guidelines such as MyPlate were reported less often (66%). Oral health-related nutrition content was broadly covered, with all respondents reporting instruction related to caries, erosion, periodontal disease, and oral dysfunction. Counseling content was less consistent, particularly public health nutrition (67%) and the impact of oral dysfunction on diet and nutrition (72%). CONCLUSION(S): Most responding academic dental deans report including nutrition and diet education in their curricula. However, it remains uncertain whether these topics are incorporated at schools that did not participate in the survey. Variability in curricular time, counseling, and teaching highlights the need for clearer competencies and more clinical training. Improving this could better prepare future dentists for common dietary risks affecting oral and systemic health.

dental caries↗

PubMed2026

Predictive value of anal sphincter electromyography for sacral neuromodulation test-phase outcomes.

BACKGROUND: Sacral neuromodulation (SNM) is an established therapy for refractory pelvic organ dysfunction. Anal sphincter electromyography (EMG) is commonly used preoperatively to assess sacral and peripheral nerve integrity. However, the prognostic significance of chronic neurogenic EMG changes for SNM outcomes remains unclear. OBJECTIVE: To evaluate whether chronic neurogenic changes on preoperative anal sphincter EMG predict the outcome of the SNM test phase. METHODS: We retrospectively analysed 62 consecutive patients with bladder and/or bowel dysfunction or pelvic pain who were candidates for SNM treatment and who underwent preoperative anal sphincter EMG. EMG findings were classified as normal or showing chronic neurogenic changes. SNM test-phase success was defined as a ≥50% improvement of symptoms at 24 days. Outcomes were compared between EMG groups. RESULTS: Of the 62 patients (49 women, 13 men), 30 (48%) had normal EMG findings and 32 (52%) showed chronic neurogenic changes. Overall, the SNM test phase was successful in 47 patients (76%). Success rates were similar in patients with normal EMG (72%) and neurogenic EMG changes (79%), with no statistically significant difference (p = 0.878). Sex-stratified analyses revealed no significant association between EMG findings and test-phase success in women or men. CONCLUSIONS: Chronic neurogenic changes on anal sphincter EMG do not predict SNM test-phase outcomes. These findings suggest that abnormal sphincter EMG results should not be used as a standalone criterion to exclude patients from SNM therapy. SIGNIFICANCE: Signs of neurogenic damage on anal sphincter EMG are not an indicator of reduced neuromodulatory capacity or diminished clinical response to SNM.

Humans↗

PubMed2026

Simultaneously PYCR-1 and ALH-6 inhibition exacerbates 6-PPD quinone toxicity via disrupting proline and glutamate metabolisms and activating insulin signals in Caenorhabditis elegans.

Glutamate synthesized from the proline can serve as a precursor for key intermediate metabolites of citric acid cycle. Recently, we observed reduced glutamate content and expression of alh-6 controlling glutamate synthesis by 6-PPD quinone (6-PPDQ) in Caenorhabditis elegans. However, possible effect of 6-PPDQ on proline synthesis and the association with 6-PPDQ toxicity induction remain unclear. After 0.1-10 μg/L 6-PPDQ exposure, proline content was further reduced, and expression of pycr-1 governing proline biosynthesis was decreased. In 6-PPDQ exposed nematodes, RNA interference (RNAi) of pycr-1 decreased α-ketoglutarate content, enhanced mitochondrial dysfunction, reduced nicotinamide adenine dinucleotide (NADH) and reduced flavine adenine dinucleotide (FADH₂) contents, inhibited mitochondrial complex I/II activities, and decreased expressions of gas-1 and mev-1. Moreover, compared to single RNAi, double RNAi of pycr-1 and alh-6 exacerbated the 6-PPDQ toxicity in reducing α-ketoglutarate, NADH, and FADH₂ contents, and suppressing mitochondrial complex I/II activities and gas-1 and mev-1 expressions. Additionally, double RNAi of pycr-1 and alh-6 intensified toxicity of 6-PPDQ on longevity and caused upregulation of insulin ligand and receptor genes and downregulation of daf-16 and its targeted genes in 6-PPDQ exposed nematodes. Furthermore, after 6-PPDQ exposure, daf-16 RNAi suppressed pycr-1 and alh-6 expressions, suggesting formation of a regulatory feedback loop between pycr-1/alh-6 and daf-16. Our findings highlight involvement of disrupted proline and glutamate metabolisms in 6-PPDQ-induced mitochondrial dysfunction and reduced longevity.

Animals↗

PubMed2026

Form and function of actin impacts actin health and aging.

The actin cytoskeleton is a fundamental and highly conserved structure that functions in diverse cellular processes, yet its direct contribution to organismal aging remains unclear. Here, we systematically interrogated how genetic and pharmacologic perturbations of actin structure and function influence lifespan and various hallmarks of aging in Caenorhabditis elegans. Whole-animal and tissue-specific knockdown of actin and key actin-binding proteins (ABPs)-arx-2 (Arp2/3), unc-60 (cofilin), and lev-11 (tropomyosin)-led to premature disruption of filament organization, reduced lifespan, and tissue-specific physiological defects. Actin dysfunction also displayed a more "aged" transcriptome using previously validated transcriptomics clocks, and broadly exacerbated many age-associated phenotypes, including mitochondrial dysfunction, lipid dysregulation, loss of proteostasis, impaired autophagy, and intestinal barrier failure. Pharmacological destabilization with Latrunculin A mirrored genetic knockdowns, while mild stabilization with Jasplakinolide modestly extended lifespan, emphasizing that optimal and finely tuned actin function is critical for healthy aging. Finally, analysis of human genome-wide association data revealed that common ACTB polymorphisms correlate with differences in age-related decline in gait speed, suggesting some links between aging and actin across organisms. Taken together, our results provide a comprehensive and publicly accessible resource that maps, for the first time, how changes in actin integrity correlate with diverse aging phenotypes across tissues. This descriptive framework is intended to enable future mechanistic discovery by offering a deep, unbiased dataset that can be integrated with emerging studies to define how actin dynamics can potentially influence aging.

actin↗

PubMed2026

Wearable Sleep Monitoring in Pediatric Acute Lymphoblastic Leukemia: Associations With Subjective Sleep Ratings and Neurocognitive Functioning.

BACKGROUND: Sleep disturbances are associated with increased fatigue, reduced quality of life, and neurocognitive dysfunction and have emerged as a common complication among pediatric cancer survivors. Sleep disturbances are particularly concerning given their potential to exacerbate existing neurocognitive impacts of cancer treatments. This pilot study examined the feasibility and acceptability of a home-wearable EEG-based sleep device (Sleep ProfilerTM) for acute lymphoblastic leukemia (ALL) survivors as well as associations between specific sleep parameters and neurocognitive functioning. PROCEDURE: Children (ages 8-12; M = 10 years, SD = 1.6; N = 23) >6 months post-treatment for ALL were enrolled at clinical visits and wore the Sleep ProfilerTM for two consecutive nights at home, followed by neurocognitive testing of attention, inhibitory control, working memory, and processing speed. Parents completed subjective measures of child sleep, anxiety, depression, and acceptability. Feasibility reflected the percentage of children wearing the device at least one night and the percentage of nights with good EEG quality data. RESULTS: All participants wore the device both nights, with 84% meeting the threshold for good quality measurement. Few children met recommended quantity and quality sleep thresholds based on objective measurement, including 5 patients with elevated snoring levels; 43.5% of subjective ratings fell above the threshold for sleep disturbance. Greater sleep latency was associated with worse inhibitory control (r = -0.42, p = 0.046), and total sleep time was positively associated with inhibitory control and attention. CONCLUSIONS: Findings confirm the feasibility and acceptability of home EEG sleep monitoring in school-age survivors, and associations of sleep latency and snoring with reduced neurocognitive functioning may offer modifiable risk factors for aspects of neuropsychological dysfunction common in pediatric survivorship. CLINICAL TRIAL REGISTRATION: At the time this study was conducted, we were not required to register the study on ClinicalTrials.gov. It was a single-institution feasibility study without intervention, which was not considered a clinical trial.

Humans↗

PubMed2026

ADAM10's combined influence on the diagnostic usefulness of IL 22, IL 10, IL-17 A, and IL-17D in autism spectrum disorders: Predicted role on gut leakiness as co-morbidity.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with increasing global prevalence but a lack of reliable diagnostic biomarkers. Emerging evidence suggests that immune dysregulation, gut-brain axis dysfunction, and increased intestinal permeability play key roles in ASD pathophysiology. This study investigated the combined diagnostic value of ADAM10 and cytokines (IL-10, IL-22, IL-17 A, and IL-17D). Multivariable logistic regression produces an improved ROC curve that improves diagnostic accuracy over individual markers by combining numerous predictors into a single risk score (linear predictor). The technique, which frequently raises individual marker AUCs, entails modelling a binary result, calculating the probability, and visualizing ROC based on the projected probabilities. In this case-control study, plasma levels of ADAM10, IL-10, IL-22, IL-17 A, and IL-17D were measured in 37 male children with ASD and 37 age-matched controls. Group comparisons, correlation analyses, and receiver operating characteristic (ROC) curve analyses, including combined ROC models, were performed. ADAM10, IL-22, and IL-17 A levels were significantly reduced in children with ASD compared to controls, whereas IL-10 and IL-17D showed no significant differences. ADAM10, IL-17 A, and IL-22 demonstrated good diagnostic performance, with AUC values of 0.886, 0.855, and 0.812, respectively. In contrast, IL-10 and IL-17D showed poor discriminatory ability, with AUC values of 0.524 and 0.599, respectively. Combined ROC analysis markedly improved diagnostic accuracy, with all panels including ADAM10 achieving AUC values above 0.90, and some reaching as high as 0.988, with high sensitivity and specificity. The combination of ADAM10 with selected cytokines significantly enhances diagnostic performance compared to individual markers, supporting a link between immune dysregulation, barrier dysfunction, and gut permeability in ASD.

Humans↗

PubMed2026

Corneal Epithelial Alterations Associated With Cyclin-Dependent Kinase 4/6 Inhibitor Therapy in Hormone Receptor-Positive Breast Cancer.

IMPORTANCE: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are standard therapy for hormone receptor-positive (HR+), HER2-negative breast cancer. By blocking the G1/S cell-cycle transition, these agents may impair renewal of the corneal epithelium. No controlled study has systematically evaluated corneal epithelial changes in patients receiving CDK4/6 inhibitors. OBJECTIVE: To determine whether CDK4/6 inhibitor-based therapy is associated with cornealepithelial alterations independent of aromatase inhibitor exposure and tear film dysfunction. DESIGN, SETTING, AND PARTICIPANTS: Retrospective comparative cross-sectional study at a tertiary ophthalmology center. A total of 132 women were enrolled: 45 receiving a CDK4/6 inhibitor plus an aromatase inhibitor (CDKAI group), 44 receiving aromatase inhibitor monotherapy (AI group), and 43 age-matched postmenopausal controls without systemic oncologic therapy. EXPOSURES: CDK4/6 inhibitor (ribociclib, palbociclib, or abemaciclib) combined with an aromatase inhibitor; aromatase inhibitor alone; or no systemic oncologic therapy. MAIN OUTCOMES AND MEASURES: Prevalence and severity of punctate epitheliopathy and vortex keratopathy, assessed by a masked ophthalmologist. Secondary outcomes included Schirmer I test, tear film break-up time, and Ocular Surface Disease Index (OSDI). RESULTS: PE was present in 44.4% of eyes in the CDKAI group vs 4.7% in the AI group and 2.3% in controls (χ² = 34.31; P < .001). All moderate (13.3%) and severe/complicated (8.9%) PE cases occurred exclusively in the CDKAI group. Vortex keratopathy was observed in 13.3% of CDKAI patients and in none of the other groups (P = .025). Schirmer values, tear film break-up time, and OSDI scores did not differ among groups (all P > .05). Within the CDKAI group, PE was not associated with treatment duration (P = .963) or tear film parameters. CONCLUSIONS AND RELEVANCE: In this comparative study, CDK4/6 inhibitor-based therapy was associated with significantly higher prevalence and severity of PE and vortex keratopathy, independent of aromatase inhibitor exposure and in the absence of measurable tear film dysfunction. These findings suggest a direct cytostatic effect on the corneal epithelium. Symptom scores were low, although OSDI interpretation was limited by incomplete responses. Proactive corneal surface evaluation with fluorescein staining may be warranted during CDK4/6 inhibitor treatment.

Humans↗

PubMed2026

Phase IIB, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Intravenous Defibrotide for the Prevention and Treatment of Respiratory Distress and Cytokine Release Syndrome in COVID-19.

INTRODUCTION: Endothelial dysfunction is key in COVID-19 pathogenesis. This randomized, double-blind phase IIb trial investigated continuous intravenous infusion of defibrotide in patients hospitalized with SARS-CoV-2 infection and respiratory failure. METHODS: One-hundred and fifty patients were randomized (2:1) to defibrotide or placebo, stratified by disease severity (WHO COVID-19 severity scale 4/5 vs. 6). The primary endpoint was clinical improvement time (days from first improvement through Day 30). RESULTS: Median clinical improvement time was not significantly different with defibrotide versus placebo (15.0 [IQR: 0-24] vs. 20.0 [IQR: 9-25] days; p = 0.10). Day-30 (23.0% vs. 22.0%) and Day-60 (26.0% vs. 22.0%) mortality, reduction in mean fraction of inspired oxygen during treatment, and median duration of hospitalization did not differ with defibrotide versus placebo. Defibrotide demonstrated favorable safety, with no differences versus placebo in serious adverse events (34.0% vs. 36.0%), hypotension (16.0% vs. 12.0%), or hemorrhage (13.0% vs. 8.0%). Exploratory pre-specified biomarker analyses showed greater early d-dimer reduction and lymphocyte recovery with defibrotide, although these results require validation. CONCLUSION: Continuous intravenous infusion of defibrotide was safe but did not improve clinical outcomes in severe COVID-19. Further analyses will explore mechanistic actions and pharmacokinetics of defibrotide and the pathophysiology of endothelial dysfunction in COVID-19. TRIAL REGISTRATION: EudraCT identifier: 2020-001409-21. CLINICALTRIALS: gov identifier: NCT04348383.

Adult↗

PubMed2026

GATA2 deficiency: enhancer deregulation, immune surveillance failure, and clonal evolution.

Germline mutations in GATA2 cause a syndromic inborn error of immunity characterized by cytopenia, infections, immune dysregulation, and a marked predisposition to myelodysplastic syndrome and acute myeloid leukemia. Initially defined by the DCML phenotype-dendritic cell, monocyte, B- and NK-cell deficiency-GATA2 deficiency is now recognized as a disorder of global immune-hematopoietic homeostasis. Recent multi-omics and experimental models reveal enhancer-driven inflammatory rewiring, IRF8-dependent lineage imbalance, and premature hematopoietic aging. In parallel, adaptive immune defects, including impaired B- and T-cell development and function, contribute to defective immune surveillance. These alterations not only explain susceptibility to infection but also shape clonal evolution and malignant transformation. Clinically, improved risk stratification and transplant outcomes underscore the importance of early recognition and monitoring of immune dysfunction. GATA2 deficiency thus represents a paradigm linking immune dysregulation, inflammatory stress, and cancer predisposition.

Humans↗

PubMed2026

Balanced Fluid or 0.9% Saline in Children Treated for Septic Shock.

BACKGROUND: Whether treatment with balanced crystalloid fluid leads to better outcomes than 0.9% saline in children treated for septic shock is debated. METHODS: In this pragmatic clinical trial conducted at 47 emergency departments in five countries, patients (2 months to <18 years of age) with suspected septic shock and abnormal perfusion were randomly assigned to receive fluid resuscitation with either balanced fluid or 0.9% saline for up to 48 hours. The primary outcome was a major adverse kidney event (a composite of death, new renal-replacement therapy, or persistent kidney dysfunction) at 30 days after enrollment or hospital discharge, whichever occurred first. RESULTS: Of 9041 enrolled patients, 277 (6.1%) in the balanced-fluid group and 282 (6.2%) in the 0.9%-saline group withdrew from the trial, leaving 4235 and 4247 patients, respectively, for analysis. A primary-outcome event occurred in 137 patients (3.4%) in the balanced-fluid group and in 124 (3.0%) in the 0.9%-saline group (difference, 0.4 percentage points; 95% confidence interval [CI], -0.5 to 1.3; risk ratio, 1.10; 95% CI, 0.88 to 1.40; P = 0.85). The median number of hospital-free days during 28 days after enrollment was 23 (interquartile range, 19 to 25) in both groups. Hyperchloremia occurred in 868 patients (31.4%) in the balanced-fluid group and in 1383 (49.0%) in the 0.9%-saline group; hypernatremia in 52 (1.8%) and 89 (3.1%), respectively; and hyperlactatemia in 260 (19.8%) and 228 (16.7%). No differences in other safety outcomes or adverse events were seen. CONCLUSIONS: Among children treated for septic shock, no significant difference was seen in the incidence of death, new renal-replacement therapy, or persistent kidney dysfunction when fluid resuscitation was administered with balanced fluid as compared with 0.9% saline. (Funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; PRoMPT BOLUS ClinicalTrials.gov number, NCT04102371.).

Adolescent↗

PubMed2026

Mechanisms of Hematopoietic Stem Cell Aging and Emerging Rejuvenation Strategies.

Hematopoietic stem cell (HSCs) aging is a complex biological process driven by both cell-intrinsic alterations and extrinsic cues from the bone marrow niche. Understanding these mechanisms is critical for developing therapies against aging-related hematopoietic disorders. This review synthesizes recent advances in the molecular mechanisms underlying HSCs aging, including microenvironmental aging, genomic instability, epigenetic dysregulation, mitochondrial dysfunction, and aberrant nuclear mechanotransduction. We summarize that the functional decline of HSCs during aging drives a compensatory expansion of the phenotypically defined stem cell pool, leading to an aberrant increase in cell number. We also highlight aging-associated HSCs heterogeneity, including CD150high and P-selectin-positive subsets that enrich for myeloid-biased or functionally compromised HSCs states while emphasizing that surface phenotype alone may not fully indicate functional rejuvenation. Finally, we discuss emerging rejuvenation strategies-including targeting myeloid-biased HSCs, modulating inflammatory pathways, and implementing epigenetic or metabolic interventions-supported by cutting-edge technologies such as single-cell multi-omics, gene editing, and computational modeling. These approaches hold promise for counteracting age-related hematopoietic decline and restoring immune competence.

Humans↗

PubMed2026

Single nucleus multiomics reveals an early inflammatory response to high-fat diet in mouse islets.

In periods of sustained hyper-nutrition, pancreatic β-cells undergo functional compensation through transcriptional upregulation of gene programs driving insulin secretion. This adaptation is essential for maintaining systemic glucose homeostasis and metabolic health. Using single nuclei multiomics, we have mapped the early transcriptional adaptive mechanisms in murine islets of Langerhans exposed to high-fat diet (HFD) for 1 and 3 wk. We show that β-cells exhibit the largest transcriptional response to HFD, characterized by early activation of pro-inflammatory eRegulons and down-regulation of β-cell identity genes, particularly in a distinct subset of β-cells. These observations extend to humans, where the prevalence of an β-cells with a high inflammatory signature is increased in diabetes. Collectively, these observations point to cellular crosstalk through pro-inflammatory signaling as a central and early driver of β-cell dysfunction that limits the compensatory capacity of β-cells, which is closely linked to the development of diabetes.

Animals↗