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PubMed2026

The role of adjunctive aqueous suppressants for anti-vascular endothelial growth factor therapy: A systematic review.

Our goal is to determine whether adjunctive aqueous suppressants (topical β-blockers, carbonic anhydrase inhibitors, or oral acetazolamide) enhance outcomes of anti-vascular endothelial growth factor (anti-VEGF) therapy for diabetic macular edema (DME), retinal vein occlusion (RVO), and neovascular age-related macular degeneration (nAMD), focusing on retinal thickness, visual acuity, injection burden, intraocular pressure (IOP), and safety. DME, RVO, and nAMD are leading causes of vision loss treated with repeated intravitreal injections, yet many eyes show persistent fluid. Aqueous suppressants are inexpensive and widely available, with potential to prolong intravitreal drug residence and improve outcomes, but their clinical value remains uncertain. Following a registered protocol, we searched 4 databases (January, 2000 toMay, 2025) for randomized and comparative studies evaluating adjunct aqueous suppressants with anti-VEGF therapy. Primary outcome was change in retinal thickness; secondary outcomes included visual acuity, injection burden, IOP, and adverse events. Risk of bias was assessed and findings synthesized narratively. Twelve studies (7 randomized trials; 495 eyes) met inclusion criteria. In DME, 3 of 4 trials showed greater thickness reduction with adjunctive dorzolamide (±timolol), although visual gains were inconsistent. In RVO, 1 trial suggested transient anatomical benefit, whereas oral acetazolamide showed no added effect. In nAMD, adjunctive dorzolamide-timolol reduced residual fluid in refractory cases without visual or treatment-sparing benefit. Topical therapy produced modest IOP reductions without serious adverse events. Adjunct aqueous suppressants may provide limited short-term anatomical benefit, particularly in DME and refractory nAMD, but consistent functional or durability effects are not found in this study. Larger, longer-term randomized studies are needed.

Humans↗

PubMed2026

Uric Acid-to-HDL Cholesterol Ratio is Associated with Hepatic Steatosis but Not Fibrosis in Nonobese Adults: A NHANES 2017-2020 Study.

BACKGROUND: Although metabolic dysfunction-associated steatotic liver disease (MASLD) has traditionally been regarded as a disease closely related to obesity, its prevalence is gradually rising in nonobese populations. The uric acid-to-high-density lipoprotein cholesterol ratio (UHR) is a novel metabolic biomarker that has been shown to be associated with MASLD. However, its role in nonobese individuals remains unclear. This study aimed to investigate the association between UHR and nonobese MASLD. METHODS: Data from the 2017 to 2020 National Health and Nutrition Examination Survey (NHANES) were analyzed. UHR was calculated as the serum uric acid (UA) divided by the high-density lipoprotein cholesterol (HDL). Liver steatosis (using controlled attenuation parameters, CAP) and fibrosis (using liver stiffness measurement, LSM) were evaluated through vibration-controlled transient elastography (VCTE). Multivariate linear regression was employed to evaluate associations. Nonlinear relationships were examined using smoothed curve fitting. RESULTS: This analysis included 3573 participants (47.41% male; aged 20-80 years). Log2-UHR was positively associated with CAP (β = 9.96, 95% CI: 6.93-12.98, P < 0.001) and MASLD prevalence (OR = 1.64, 95% CI: 1.38-1.95, P < 0.001). Subgroup analyses revealed significant interactions by sex, age, ethnicity, and smoking status (all P for interaction < 0.05), with stronger associations in females, adults aged 40-59 years, individuals of other Hispanic ethnicity, and never-smokers. Moreover, the association between log2-UHR and CAP was linear and positive (P < 0.01). No significant association was found between log2-UHR and LSM (P > 0.05). CONCLUSIONS: UHR is independently associated with hepatic steatosis but not fibrosis in nonobese US adults, suggesting its potential utility as an early risk assessment to tool. Large scale prospective studies are needed in the future to further validate the conclusions of this study.

Humans↗

PubMed2026

Transcriptomic and RNAi analyses reveal chloride channel 3-associated osmoregulation in Litopenaeus vannamei under low-salinity stress.

Chloride channels and transporters are important for cellular volume regulation and salinity adaptation in euryhaline crustaceans, yet the intestinal transcriptional relationship between plasma-membrane and intracellular chloride pathways remains unclear in Litopenaeus vannamei. In this study, RNA interference of anoctamin 1 (ANO1) was combined with intestinal transcriptome sequencing under the production-relevant low-salinity condition of salinity 3. ANO1 silencing produced a focused transcriptional response, with 16 differentially expressed genes (DEGs) identified (11 upregulated and 5 downregulated). Functional enrichment indicated that these genes were associated with transporter activity, cytoskeletal organization, extracellular matrix-receptor interaction, membrane lipid metabolism, and vesicular processes. Notably, a transcript encoding chloride channel protein 3 (CLC-3) was significantly upregulated following ANO1 knockdown, suggesting a potential transcriptional relationship between ANO1 and CLC-3 in chloride homeostasis. Based on this finding, CLC-3 was selected for full-length cDNA cloning, sequence characterization, salinity-gradient expression analysis, and RNAi-based functional assessment. The cloned CLC-3 cDNA was 2883 bp in length and encoded an 850 amino acid protein containing a conserved voltage-gated chloride channel (Voltage-CLC) domain and two cystathionine β-synthase domains. Phylogenetic analysis placed LvCLC-3 within the intracellular CLC-c clade, and tissue distribution analysis showed the highest CLC-3 expression in the intestine. Intestinal CLC-3 expression responded nonlinearly to salinity variation, peaking at salinity 20. Under salinity 3, CLC-3 knockdown reduced ANO1, Na+/K+-ATPase alpha subunit, and Na+-K+-2Cl- cotransporter transcript levels, whereas glutamate-gated chloride channel expression increased. Mild hepatopancreatic structural alterations were also observed after CLC-3 knockdown. These findings suggest that CLC-3 is a salinity-responsive intracellular chloride-transporter candidate associated with intestinal ion-transport-related transcriptional responses after ANO1 suppression in L. vannamei, although the underlying physiological mechanism requires further validation.

Animals↗

PubMed2026

CoLchicine for Treatment of OsteoArthritis of the Knee (CLOAK): Clinical and biochemical outcomes from a three-month double-blind, placebo-controlled study.

OBJECTIVE: Knee osteoarthritis (KOA) causes pain and progressive disability, but pharmacologic treatments are limited. Colchicine inhibits inflammation that might modulate KOA, but efficacy trials have yielded mixed results. We tested whether colchicine, without concurrent NSAIDs, improved KOA pain, function, synovial effusion size, and OA-associated inflammatory serum biomarkers. METHODS: Participants with symptomatic KOA and radiographic Kellgren-Lawrence grades 2/3 were randomized to receive three months of daily colchicine or placebo in a double-blind manner, with no concurrent NSAID use. The primary outcome was between-group change in visual analog score (VAS) for index knee pain. Secondary outcomes included changes in Knee Osteoarthritis Outcome Scores (KOOS), size (depth in millimeters) of sonographically-identified effusions, acetaminophen use, and changes in OA-related serum biomarkers. RESULTS: From baseline to end of study of 120 enrolled participants, no significant differences were observed in improvement of VAS pain, KOOS scores or effusion size. Subsets of participants with more severe VAS pain, worse radiographic disease, or higher hsCRP or serum urate levels at baseline also showed no significant clinical benefit from colchicine compared to placebo. In contrast to the clinical outcomes, colchicine treatment was associated with significant or trending improvement in multiple OA-related serum biomarkers including hsCRP and β-NGF (p < 0.05) and PGE2, IL-1ra, IL-8, and VEGF (p < 0.16). CONCLUSION: This double-blind placebo-controlled trial of colchicine for KOA failed to demonstrate improvement in pain, function, or synovial effusion size in comparison to placebo at three months. Early improvement in OA-associated inflammatory biomarkers suggests a possible longer-term clinical benefit. Clinical Trials Registration No NCT03913442.

Humans↗

PubMed2026

Effect of flavored on!® nicotine pouch products on smoking behaviors: A sequential, multiple assignment, randomized controlled trial.

PURPOSE: To evaluate whether flavored versus unflavored nicotine pouch (NP) access affects cigarette reduction and smoke exposure among adults who smoke daily, and whether delayed flavor introduction affects these outcomes. METHODS: Adults who smoked ≥ 5 cigarettes/day (CPD) with interest in replacing cigarettes with NPs were enrolled in a remote, six-week, sequential multiple assignment randomized trial (n = 402 randomized; n = 400 analyzed). Participants were randomized to immediate access to seven NP flavors (Flavor), unflavored-only access for six weeks (Original), or unflavored-only for three weeks followed by flavor access (Delayed Flavor). Primary outcomes were ≥ 50% reduction in weekly mean expired-air carbon monoxide (CO) from baseline and mean CO at Week 6. Secondary outcomes included ≥ 50% CPD reduction, mean CPD, CO-verified 7-day abstinence, and incident smoke-free days. RESULTS: At Week 6, Flavor and Original did not differ in ≥ 50% CO reduction (14.3% vs 14.2%; IRR=1.0, 95% CI=0.6-1.8) or mean CO (18.3 vs 16.5 ppm; β=1.9, 95% CI=-1.3-5.0). CPD decreased across groups by Week 6, with no differences between Flavor and Original in ≥ 50% CPD reduction (50.3% vs 51.6%; IRR=1.0, 95% CI=0.8-1.2) or CO-verified abstinence (9.3% vs 8.9%; IRR=1.0, 95% CI=0.5-2.2). Flavor increased smoke-free days early, with attenuation over time. Among Week 3 non-responders, delayed flavor access increased ≥ 50% CPD reduction at Week 6 (33.3% vs 18.6%; IRR=1.8, 95% CI=1.0-3.2). CONCLUSIONS: NP access supported cigarette reduction regardless of flavor availability, but flavors may accelerate smoke-free days and improve response among individuals who do not reduce cigarette consumption with unflavored products alone.

Humans↗

PubMed2026

Novelty seeking and rapid symptom improvement across active and sham accelerated iTBS conditions: A pooled individual-patient data analysis.

INTRODUCTION: Major depressive disorder (MDD) is highly prevalent and often treatment-resistant. Accelerated intermittent theta burst stimulation (aiTBS) is a promising intervention for treatment-resistant depression (TRD), though outcomes vary. Personality traits have been examined in relation to rTMS outcomes, yet their role in aiTBS remains underexplored. This pooled individual-patient-data analysis of two randomized, sham-controlled trials examined associations between baseline Temperament and Character Inventory (TCI) traits and one-week symptom change, and whether they differed by condition. METHODS: The left dorsolateral prefrontal cortex was targeted for 20 sessions over 4 days. Personality was assessed with the TCI, depression severity with the 17-item Hamilton Depression Rating Scale (HDRS-17). TCI-symptom-change associations were examined with a robust linear mixed-effects model, adjusting for age, gender, repeated measurements, and study membership. RESULTS: 104 participants were included (M/F 45/59; mean age 40.9 ± 12.7; active/sham 50/54). The model yielded a Time × Novelty Seeking interaction (β = -1.70, p = 0.021): higher baseline Novelty Seeking was associated with faster symptom reduction, without a between-arm difference. However, the interaction did not survive Holm correction across 14 trait-interaction tests (adjusted p = 0.294) and is therefore exploratory. No other interaction reached the uncorrected threshold. CONCLUSIONS: Higher baseline Novelty Seeking showed a nominal association with faster symptom reduction, without a difference between active and sham conditions. Because it did not survive multiplicity correction and was not reproduced in within-arm analyses, it is preliminary and may reflect contextual or nonspecific processes. Independent replication is required before temperament assessment can be clinically informative.

Humans↗

PubMed2026

Regional genomic analysis of lineage distribution and transferable multidrug resistance among chicken-associated Salmonella Kentucky isolates in China.

Salmonella enterica serovar Kentucky is an important multidrug-resistant foodborne pathogen in the poultry meat supply chain. Although recent broader genomic studies have elucidated the population structure and epidemiological significance of major lineages in China (e.g., ST198 and ST314), the regional dynamics within local poultry supply chains remain insufficiently characterized. In this study, 31 chicken meat-derived isolates from Shanghai and 39 publicly available genomes from China were analyzed using antimicrobial susceptibility testing, whole-genome sequencing, phylogenetic analysis, conjugation experiments, and complete sequencing of representative plasmids. This enabled a systematic characterization of the molecular epidemiological features of the population and the mechanisms underlying resistance dissemination. Population genomic analysis revealed a lineage composition markedly different from the global epidemiological pattern: ST314 was the predominant sequence type among the Shanghai chicken-derived isolates (74.2%), whereas the internationally recognized high-risk clone ST198 accounted for only 25.8% of the local isolates. However, risk stratification analysis indicated that although ST198 was detected less frequently, it carried a significantly greater burden of acquired resistance genes and therefore represented a higher-risk resistant lineage. Functional and structural validation further elucidated the molecular basis of resistance dissemination within this high-risk lineage. Conjugation experiments confirmed the co-transfer of a multidrug resistance module carrying blaTEM-1 and blaCTX-M-267 to the recipient strain Escherichia coli J53. Complete plasmid analysis revealed that these two β-lactam resistance genes were co-localized on a 242-kb transferable plasmid flanked by Tn1331, Tn3, and multiple transposase-associated elements, thereby providing a structural basis for their horizontal transfer. This study provides important molecular epidemiological evidence for lineage-specific surveillance and risk-stratified control of resistant Salmonella in the poultry meat supply chain and further underscores the need for continuous monitoring of mobile genetic elements within a One Health framework.

Animals↗

PubMed2026

Transcriptomic responses of gill and intestinal tissues in Nile tilapia (Oreochromis niloticus) to bacterial infection following sequential nanoimmersion and hydrogel-based multivalent vaccination.

Bacterial pathogens, including Flavobacterium oreochromis, Aeromonas veronii, Streptococcus agalactiae, and Edwardsiella tarda, represent major infectious threats to Nile tilapia (Oreochromis niloticus). A multivalent vaccination strategy integrating cationic nanoemulsion immersion with oral hydrogel boosters was developed to investigate tissue-specific immune responses at the transcriptomic level. Gill tissues were collected following immersion challenge and intestinal tissues following intraperitoneal injection challenge, reflecting the physiologically relevant infection biology of each pathogen and the mechanistic rationale of each delivery platform. RNA sequencing (RNA-seq) generated high-quality datasets (mapping rate > 81.64%) with strong concordance to quantitative real-time PCR (qRT-PCR) validation (r = 0.83). Comparative transcriptomic analysis revealed distinct yet complementary immune signatures between tissues. Gill transcriptomes were enriched in phagosome, focal adhesion, extracellular matrix-receptor interaction (ECM-receptor interaction), and cytokine-cytokine receptor interaction pathways, accompanied by increased expression of major histocompatibility complex class I/II (MHC class I/II), mannose receptor, αVβ3 integrin, and calnexin, indicating innate activation, enhanced phagocytic capacity, epithelial barrier reinforcement, and adaptive immune coordination. Intestinal transcriptomes showed predominant enrichment of adaptive immune pathways, including the intestinal immune network for immunoglobulin (Ig) production, Forkhead box O (FoxO) signaling, and mitogen-activated protein kinase (MAPK) signaling, with increased expression of T-cell receptor (TCR), inducible T-cell co-stimulator ligand (ICOS-L), C-X-C chemokine receptor type 4 (CXCR4), and polymeric immunoglobulin receptor (pIgR), reflecting T and B cell coordination, lymphocyte trafficking, and mucosal immunoglobulin transport, alongside innate engagement through phagosome pathway enrichment. Shared upregulation of MHC class II, B-cell receptor (BCR) signaling, integrin alpha M (ITGAM), and immunoglobulin-associated components across both tissues suggests coordinated mucosal immune activation through a conserved immune module, warranting direct experimental validation. Collectively, these findings provide transcriptomic evidence that this vaccination strategy elicits an integrated, tissue-specialized immune response, advancing mechanistic understanding of gill and intestinal immunity in vaccine-induced protection of teleost fish.

Animals↗

PubMed2026

Hyper-oncotic albumin administration reduces mortality in acute Respiratory Distress Syndrome compared to crystalloid: a systematic review and meta-analysis.

BACKGROUND: To evaluate the association between albumin administration as volume replacement and mortality in adult ARDS patients, we performed this meta-analysis and trial sequential analysis (TSA). METHODS: We searched databases including PubMed, Science Direct, Scopus, Web of Science databases and Cochrane Central Register of Controlled Trials up to 12 December 2024. We screened trials that included adult ARDS patients and compared albumin with crystalloid. The 28-day mortality served as the primary endpoint, while the oxygenation change, the length of ICU stay and the length of hospital stay were designated as secondary outcomes. To clarify the differing concentrations of albumin, we formed two distinct subgroups: the hyper-oncotic albumin subgroup (≥20%) and the iso-oncotic albumin subgroup (4%∼5%). Statistical synthesis was performed with Cochrane Review Manager 5.4.1, employing random-effects models. To mitigate random errors, TSA was implemented with α = 0.05 and β = 0.20 parameters. RESULTS: The analysis incorporated 5 publications: 3 randomized controlled trials (RCTs) and 2 non-randomized studies (NRSs). Overall mortality was lower in the albumin group (33.2%, 97/292) than in the crystalloid group (44.9%, 133/296) (OR = 0.61, 95%CI 0.43-0.85, p = 0.004). RCTs (n = 204) showed no benefit (OR = 0.83, p = 0.54), but NRSs (n = 384) demonstrated reduced mortality (OR = 0.52, p = 0.002). Hyper-oncotic albumin was associated with lower mortality in NRSs (OR = 0.40, p = 0.02) but not in RCTs (OR = 0.74, p = 0.57). Iso-oncotic albumin showed no benefit (OR = 0.88, p = 0.72). Regarding the impact of albumin on oxygenation, significant improvements in oxygenation were observed only on the first (p = 0.05) and second days (p < 0.0001). The TSA indicated a continued need for high-quality RCTs. CONCLUSIONS: Our analysis suggests that hyper-oncotic albumin may reduce mortality and improve early oxygenation in ARDS patients compared to crystalloids. Larger RCTs are urgently needed to validate these findings and define their potential role in clinical management.

Humans↗

PubMed2026

Premenarche risk factors for future dysmenorrhoea: a prospective cohort study.

BACKGROUND: Dysmenorrhoea, or pain during menstruation, is common in adolescence and is often dismissed or left untreated. Dysmenorrhoea can interfere with daily functioning and can lead to other chronic pain conditions; however, little is known about the risk factors for dysmenorrhoea. We aimed to characterise premenarche risk factors for the presence and severity of future dysmenorrhoea. METHODS: In this prospective cohort study, we obtained data for female adolescents from the population-based Adolescent Brain Cognitive Development Study (USA) who were premenarchal at baseline (age 9-10 years) and had both reached menarche and completed the Menstrual Cycle Survey at 3-year follow-up (age 12-13 years). Parents or guardians provided sociodemographic information and completed the Child Behavior Checklist, the Sleep Disturbance Scale for Children, and the Pubertal Development Scale, which captured data on non-painful somatic symptoms, attention problems, anxiety, depression, sleep disturbances, and pubertal development at baseline. Our primary objective was to analyse associations between dysmenorrhoea at 3-year follow-up (status and severity) with select symptom domains (sleep problems, attention problems, somatic symptoms, anxious or depressive symptoms, and baseline pain status) at baseline. We also investigated associations between dysmenorrhoea and participant characteristics (pubertal status, race or ethnicity, and income-to-needs ratio) that underlie social determinants of health. Differences by race were tested using Fisher exact tests. Differences by ethnicity and baseline pain status were tested using χ2 tests. Differences in continuous variables were assessed using ANOVA. Wilcoxon-Rank Sum tests were used in analyses of sleep problems, attention problems, and somatic symptoms, and ANOVA was used for pubertal status and income-to-needs ratio. Multinomial logistic regression was used to test associations with dysmenorrhoea severity, and linear regression was used to test associations with dysmenorrhoea status and menstrual pain interference. FINDINGS: 2254 female adolescents were included in this study. 1299 (57·6%) participants developed dysmenorrhoea at age 12-13 years, and 247 (19·0% of those with dysmenorrhoea) reported severe dysmenorrhoea. Non-painful somatic symptoms were prospectively associated with future dysmenorrhoea (odds ratio [OR] 1·17 [95% CI 1·04-1·32]; p=0·0070), whereas anxiety or depression, sleep disturbances, and attention problems were not. Sleep disturbances were prospectively associated with menstrual pain interference (β coefficient 0·16 [95% CI 0·01-0·31]). Advanced pubertal status at ages 9-10 years was prospectively associated with risk of dysmenorrhoea 3 years later (OR 1·79 [95% CI 1·47-2·17]; p<0·0001), as was lower income-to-needs ratio (0·96 [0·93-1·00]; p=0·031). Black (1·38 [1·05-1·83]; p=0·024) and Hispanic (1·34 [1·03-1·68]; p=0·010) young females were at a significantly greater risk of experiencing dysmenorrhoea than were White and non-Hispanic young females, respectively. INTERPRETATION: Sociodemographic characteristics and clinical symptoms present before menarche might help to identify at-risk individuals for dysmenorrhoea before pain becomes a lifelong issue. FUNDING: The National Institute of Nursing Research, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Eunice Kennedy Shriver National Institute for Child Health and Human Development.

Humans↗

PubMed2026

Effects of CPAP on endothelial activation and fibrinolytic balance in coronary artery disease with obstructive sleep apnea: The RICCADSA randomized controlled trial.

BACKGROUND: Obstructive sleep apnea (OSA) promotes endothelial activation and a prothrombotic milieu through intermittent hypoxia, oxidative stress, and systemic inflammation, mechanisms closely linked to atherosclerosis progression. The vascular effects of continuous positive airway pressure (CPAP) therapy in patients with established coronary artery disease (CAD) remain incompletely understood. OBJECTIVE: To evaluate the longitudinal effects of CPAP treatment on endothelial adhesion molecules and fibrinolytic balance in patients with CAD and OSA. METHODS: In this randomized controlled analysis from the RICCADSA trial, 210 revascularized CAD patients with moderate-to-severe OSA were assigned to CPAP (n = 104) or no-CPAP (n = 106) and had available biomarker measurements at baseline and 12 months. Circulating intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) were assessed. Linear mixed-effects models were used to examine longitudinal changes and time-by-treatment interactions adjusted for cardiometabolic covariates. RESULTS: For ICAM-1, no significant time-by-treatment interaction was observed. For PAI-1, a borderline time-by-treatment interaction suggested a numerically smaller increase in the CPAP group compared with no-CPAP (p = 0.09). CPAP treatment was associated with a significantly greater reduction in VCAM-1 over time compared with no-CPAP (time-by-treatment interaction p = 0.045 in adjusted models). CONCLUSIONS: CPAP treatment was associated with selective modulation of vascular biomarkers in patients with CAD and OSA, characterized by attenuation of endothelial activation reflected by reduced VCAM-1 levels, while fibrinolytic imbalance appeared largely resistant to intervention. These findings support pathway-specific vascular responses to CPAP and provide mechanistic insight into residual atherosclerotic risk in this high-risk population.

Aged↗

PubMed2026

Risk of adverse events in elotuzumab-treated patients with multiple myeloma: a systematic review and meta-analysis.

BACKGROUND: Elotuzumab, an anti-SLAMF7 monoclonal antibody for multiple myeloma (MM), lacks a comprehensive safety profile from meta-analysis. METHODS: We systematically searched PubMed, Web of Science, EMBASE and CENTRAL through February 13, 2025 for randomized controlled trials (RCTs) evaluating elotuzumab in MM. Pooled relative risks(RRs) of adverse events observed in elotuzumab-containing regimens versus control therapies. RESULTS: 6 RCTs (N=1,736) were included. Elotuzumabsignificantly reduced incidence of neutropenia (RR = 0.86, 95% CI: 0.76-0.98), but increased risks of cough (RR = 1.41, 95% CI: 0.96-2.09), pneumonia (RR = 1.30, 95% CI: 1.07-1.59), diarrhea (RR = 1.16, 95% CI: 1.05-1.30), pyrexia (RR = 1.47, 95% CI: 1.10-1.96) and infections (RR = 1.09, 95% CI: 1.03-1.15). No significant differences were observed for anemia, thrombocytopenia, respiratory infections, nausea, appetite loss, back pain, muscle spasms, peripheral edema, insomnia, rash, pruritus, fatigue, or hypokalemia. For grade 3-4 events, elotuzumab was associated with higher risks of lymphopenia (RR = 1.86, 95% CI: 1.31-2.64, p = 0.0005, I2 = 9%), diarrhea (RR = 1.47, 95% CI: 1.00-2.17), pneumonia (RR = 1.57, 95% CI: 1.11-2.23), cataracts (RR = 2.87, 95% CI: 1.15-7.21) and infections (RR = 1.30, 95% CI: 1.04-1.62). CONCLUSION: Elotuzumab in MM appears safe but with a specific adverse events pattern : lower neutropenia, but higher respiratory, gastrointestinal, metabolic, and infectious events. Differences may be influenced by longer treatment and corticosteroid use; therefore, interpretation of outcomes such as hyperglycemia and cataracts requires particular caution.

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↗

PubMed2028

Parental son preference in childhood and sex differences in the risk of cardiovascular disease in middle-aged and older adults.

INTRODUCTION: Sex differences in cardiovascular disease (CVD) risk are examined through biological and clinical factors, with less attention to early-life social exposures. This study examined associations of childhood parental son preference with CVD risk, sex differences, and mediation by modifiable risk factors. METHODS: This cohort analysis included China Health and Retirement Longitudinal Study participants aged ≥45 years without baseline CVD. Parental son preference was assessed retrospectively in 2014; incident CVD was self-reported physician-diagnosed heart disease or stroke through 2020. Sampling-weighted, community-clustered Cox models estimated adjusted hazard ratios (aHRs) and 95% CIs. Sex was prespecified as an effect modifier; mediation by 13 risk factors used inverse-odds-ratio weighting. Data were collected from 2011 to 2020 and analyzed from 2025 to 2026. RESULTS: Among 8,079 participants (mean age, 57.5 years; 4,216 women [52.2%]), 1,820 (22.5%) reported parental son preference. Son preference was associated with higher CVD risk overall (aHR 1.23 [95% CI 1.04, 1.46]) and among women (aHR 1.25 [95% CI 1.03, 1.53]); among men, the estimate was 1.16 (95% CI 0.87, 1.56), with limited heterogeneity by sex (ratio of aHRs 1.06 [95% CI 0.72, 1.58]). Among women, risk was concentrated in the highest paternal (aHR 1.47 [95% CI 1.14, 1.90]) and maternal (aHR 1.50 [95% CI 1.12, 1.99]) preference categories. Modifiable risk factors mediated 5.8% (95% CI 1.9%, 9.7%) of the association among women, mainly through socioeconomic and psychosocial factors. CVD risk was highest with both son preference and high risk-factor burden overall (aHR 1.97 [95% CI 1.43, 2.73]) and among women (aHR 2.23 [95% CI 1.61, 3.10]). CONCLUSIONS: Parental son preference was associated with higher incident CVD risk, with the largest estimates in the highest paternal or maternal categories among women. Modifiable risk factors explained a modest proportion, supporting life-course cardiovascular prevention that considers sex-differentiated childhood environments alongside risk-factor modification.

cardiovascular disease↗

PubMed2026

Safety, tolerability, and efficacy of alixorexton, a selective orexin 2 receptor agonist for narcolepsy type 1 (Vibrance-1): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: The clinical potential of orexin 2 receptor (OX2R) agonism for improving measures of wakefulness and cataplexy in patients with narcolepsy type 1 has been described in a phase 2 study. Here, we aimed to evaluate the safety, tolerability, and efficacy of alixorexton, another oral OX2R agonist, in narcolepsy type 1. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, adult participants (aged 18-70 years) with narcolepsy type 1 were recruited from 46 hospitals and private research centres across the USA, Europe, and Australia. Participants were centrally randomly assigned (1:1:1:1) in blocks of four via an interactive response technology system stratified by region and baseline weekly cataplexy rate (WCR) to receive 4 mg, 6 mg, or 8 mg tablets of alixorexton or placebo once daily for 6 weeks, followed by an optional 7-week open-label extension. Participants had narcolepsy type 1, diagnosed per the International Classification of Sleep Disorders, Third Edition, and confirmed by overnight polysomnography and the Multiple Sleep Latency Test or cerebrospinal hypocretin-1 concentrations. The sponsor, assessors, investigators, and participants were masked during the randomised double-blind treatment period. Efficacy and safety assessments were conducted in participants who received at least one dose of study drug. The primary endpoint was change from baseline to week 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT). Safety endpoints included treatment-emergent adverse events. This trial was registered with ClinicalTrials.gov (NCT06358950) and is completed. FINDINGS: Between May 24, 2024, and May 5, 2025, 153 individuals were screened and 92 participants were randomly assigned to receive alixorexton 4 mg (n=23), 6 mg (n=22), 8 mg (n=24), or placebo (n=23). Mean age was 33·5 years (SD 12·1), 57 (62%) were women, and 35 (38%) were men. At week 6, the observed MSL on the MWT was 2·3 min (SD 2·7) for placebo, 24·0 min (8·7) for alixorexton 4 mg, 25·9 min (9·4) for 6 mg, and 28·2 min (11·4) for 8 mg. Alixorexton improved MSL on the MWT, with a least-squares mean placebo-corrected change from baseline of 22·2 min (95% CI 17·2-27·2) for alixorexton 4 mg, 24·1 min (19·0-29·1) for 6 mg, and 26·0 min (21·0-31·0) for 8 mg (adjusted p=0·0099 for 4 mg, adjusted p<0·0001 for 6 mg and 8 mg). Treatment-emergent adverse events occurring in at least 5% of participants given alixorexton and more frequently than those given placebo up to week 6 were pollakiuria (38 [55%]), insomnia (19 [28%]), salivary hypersecretion (17 [25%]), micturition urgency (ten [14%]), blurred vision (ten [14%]), and hyperhidrosis (five [7%]). INTERPRETATION: In this phase 2 trial, once-daily oral alixorexton provided clinically meaningful improvements at 6 weeks for participants with narcolepsy type 1, including in wakefulness, excessive daytime sleepiness, and cataplexy. The treatment was generally well tolerated, with adverse events consistent with the known on-target effects of OX2R agonists. Together, these findings support the further phase 3 evaluation of alixorexton as a potential therapeutic option for people with narcolepsy type 1. FUNDING: Alkermes.

Humans↗

PubMed2026

Donor Human Milk Utilization in a Level 1 Newborn Unit of a High-Volume Delivery Hospital: A Cautionary Tale.

INTRODUCTION: Donor human milk (DHM) is an alternative to formula for supplementation of breastfed newborns and has been associated with higher in-hospital exclusive breast milk feeding rates. Its use has increased substantially, most recently among term newborns, yet there is scarce data to describe patient characteristics and volumes administered. We aimed to characterize DHM utilization in our level 1 nursery. METHODS: We conducted a retrospective cross-sectional study of newborns discharged in 2022 from the level 1 nursery. Variables included sex, gestational age, birth weight, delivery type, hypoglycemia diagnosis, DHM volume, and length of stay. DHM use was compared across preferred language, race, ethnicity, and payer type using chi-square testing. RESULTS: A total of 10,432 discharges were reviewed-those transferred to Neonatal Intensive Care Unit (NICU) or another unit were excluded. Of 9,074 newborns receiving level 1 care, 1,094 (12.1%) received DHM. Newborns born between 35 and 37 weeks gestation, delivered by cesarean section, or diagnosed with hypoglycemia or small for gestational age were more likely to receive DHM (p < 0.05). DHM was also more common among newborns whose birth parent preferred the English language, identified as White or non-Hispanic, or had non-Medicaid insurance (p < 0.05). 6,552.6 ounces were consumed, with a total median of 3.9 ounces per newborn (dose range 2-50 mL). CONCLUSIONS: DHM use in the level 1 nursery varied by clinical and sociodemographic factors, revealing inequities. In addition, some doses exceeded recommended supplemental volumes. Future efforts should focus on ensuring equitable access to DHM, standardized dosing and discontinuation guidelines, and evaluation of impacts on exclusive breastfeeding rates.

Humans↗

PubMed2026

Long-term safety and efficacy of ponesimod, an oral S1P1 receptor modulator, in relapsing-remitting multiple sclerosis (RRMS): Results from randomized phase 2b core and extension studies spanning up to 13 years.

BACKGROUND: Ponesimod demonstrated efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) in 24-week phase-2 core study, further confirmed by an interim combined analysis of the core and open-label long-term extension (LTE) studies (NCT01093326; up to 8 years). Current study evaluated safety and efficacy of ponesimod using combined core and LTE studies data for up to 13 years. METHODS: Of 393 participants completing the core study, 353 (90%) entered LTE, having 3 treatment periods (TP). In TP1 (∼1.85 years), participants continued core treatment (ponesimod: 10, 20, or 40 mg QD) whereas placebo-treated participants were re-randomized (1:1:1) to respective ponesimod doses. In TP2 (TP2 and TP3 combined duration: ∼10.4 years), participants on 40 mg were re-randomized (1:1) to 10/20 mg, while others continued same dose; in TP3 all participants received 20 mg. Study outcomes included safety and efficacy (ARR, time-to 24-week confirmed-disability-accumulation [24-week CDA], total T1-weighted Gadolinium-enhanced (T1 Gd+) lesions, new/enlarging T2 lesions and Combined Unique Active Lesions [CUALs]). RESULTS: For 20 mg dose, total 92.4% participants experienced ≥1 TEAEs (73.1% mild/moderate severity) and 19 (13%) participants discontinued study. Mean (95% CI) ARR=0.14 (0.10-0.20); Kaplan-Meier estimate (95% CI) of confirmed relapse and 24-week CDA=52.5% (42.3-63.5) and 31.3% (22.6-42.3). Mean [SD] T1 Gd+ lesions decreased from ponesimod baseline (2.62 [7.06]) to 12.4 years (0.26 [1.48]), mean (95% CI) CUALs per participant/year=3.97 (2.75-5.73). CONCLUSION: Ponesimod treatment for up to 13 years was not associated with new safety concerns. Participants continued to experience low levels of disease activity consistently across clinical and MRI outcomes.

Humans↗

PubMed2026

Role of omentin-1 in the global proteome of porcine pituitary cells: insights into proliferation- and apoptosis-related processes.

The anterior pituitary integrates endocrine regulation, cellular growth, and adaptive responses. Adipokines, secreted mainly by adipose tissue, act as hormonal signals linking metabolism, inflammation, appetite, and reproduction. They regulate hypothalamic-pituitary-ovarian axis by modulating hormone secretion and intracellular signaling. The presence of adipokine receptors in anterior pituitary suggests local metabolic-endocrine interactions. Omentin-1, predominantly expressed in visceral adipose tissue, participates in glucose metabolism and ovarian steroid regulation. Recent findings indicate that omentin-1 modulates tropic hormones, their receptors, and adipokine balance in anterior pituitary cells. We hypothesized that omentin-1 affects protein expression and signaling pathways involved in pituitary cell proliferation and apoptosis. This study examined its effects in anterior pituitary cells from Large White and Meishan pigs. Proteomic analysis identified 230 candidate differentially abundant proteins after omentin-1 treatment: 30 downregulated and 3 upregulated in Large White pigs, and 107 downregulated and 90 upregulated in Meishan pigs, associated with enriched 116 Gene Ontology terms. Key proteins were associated with cell cycle, DNA replication, gene expression, and posttranscriptional/posttranslational regulation. Responses differed between breeds. CDK5RAP2 and SIX1 were linked to proliferative control in Large White pigs, whereas AKT1S1 and RHOA were among the proteins associated with the broader proteomic response observed in Meishan pigs. Meishan pigs showed dynamic apoptotic protein regulation, including HTRA2, PARP2, and DFFA. Complementary in vitro experiments demonstrated that omentin-1 downregulated cyclins and caspase-3, upregulated BCL2, increased BCL2/BAX ratio, and modulated ERK1/2, AKT, AMPKα, and STAT3 phosphorylation. Together, these findings suggest that omentin-1 modulates proteomic networks and intracellular signaling associated with anterior pituitary cell function during the mid-luteal phase of the estrous cycle.

Animals↗

Results for “TGF-&#x3b2;1”

Results for “TGF-β1”