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PubMed2026

Low-Dose Perineural Dexamethasone Enhances Analgesia After Pediatric Hand Surgery Without Elevating Systemic Stress Markers: A Randomized Controlled Trial.

BACKGROUND: Supraclavicular brachial plexus block is a widely used technique for upper limb surgery in children. Although perineural dexamethasone has demonstrated efficacy in prolonging analgesia in adults, data on its optimal dosing and systemic safety in pediatric patients are limited. This study aimed to evaluate whether low-dose perineural dexamethasone can prolong postoperative analgesia without increasing systemic stress markers in young children undergoing hand or wrist surgery. METHODS: In this triple-blinded, randomized controlled trial (ClinicalTrials.gov Identifier: NCT06086392), 90 children aged 3 months to 6 years undergoing elective upper extremity surgery were assigned to receive supraclavicular brachial plexus block with 0.2% ropivacaine combined with either normal saline (control), dexamethasone 0.05 mg/kg, or dexamethasone 0.1 mg/kg. The primary outcome was time from arrival in the postanesthesia care unit to first administration of rescue opioid analgesia. Secondary outcomes included total opioid consumption, postoperative pain intensity using the FLACC scale, blood glucose levels, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and time to motor recovery. RESULTS: Both dexamethasone groups demonstrated significantly prolonged time to first opioid use compared with the control group (mean±SD: 19.4±2.2 h in the 0.1 mg/kg group, 16.0±1.9 h in the 0.05 mg/kg group, and 8.5±1.3 h in controls; P <0.0001). Total opioid consumption was significantly reduced in the dexamethasone groups. Postoperative pain scores were lower in both intervention groups, especially during the first 12 hours. No significant differences were found among groups in blood glucose, inflammatory markers, or incidence of nerve deficits. Motor recovery was delayed in the dexamethasone groups but did not interfere with early mobilization. CONCLUSIONS: Low-dose perineural dexamethasone (0.05 to 0.1 mg/kg) safely and effectively prolongs postoperative analgesia and reduces opioid needs in children undergoing upper limb surgery, without causing systemic metabolic or inflammatory disturbances. The 0.05 mg/kg dose may offer a more favorable balance between analgesic efficacy and motor recovery time. LEVEL OF EVIDENCE: Level I-randomized controlled trial.

Humans↗

PubMed2026

Electro-clinical efficacy and safety of midazolam in neonatal seizures: a systematic review with individual level exploratory analysis of gestational age-related treatment response.

UNLABELLED: Neonatal seizures are the most common neurological emergency during the neonatal period and are associated with increased mortality and adverse neurodevelopmental outcomes. Despite current recommendations supporting phenobarbital as first-line therapy, seizure control remains suboptimal in a large proportion of neonates, prompting the use of second-line antiseizure medications. Midazolam is increasingly administered in refractory neonatal seizures but evidence regarding its electro-clinical efficacy and safety remains limited and heterogeneous. To systematically review the available evidence on the electro-clinical efficacy and safety of midazolam in neonatal seizures and to perform an exploratory individual-level analysis investigating the association between gestational age and treatment response. A systematic review was conducted according to PRISMA 2020 guidelines. Studies including neonates with EEG- or aEEG-confirmed seizures treated with midazolam were included. Binary logistic regression was performed to assess the individual-level association between gestational age and treatment response. Eleven studies involving 146 neonates treated with midazolam were included. Electro-clinical response was observed in 101/146 neonates (69.2%), while seizure cessation was achieved in 61/146 neonates (41.8%). In an exploratory complete-case logistic regression analysis, higher gestational age appeared to be associated with a greater probability of electro-clinical response. The predicted probability curve crossed the 50% response probability at approximately 36.5 weeks of gestation. Hypotension was the most frequently reported adverse event, while respiratory depression, sedation-related effects, and transient EEG/aEEG suppression were reported less frequently. CONCLUSIONS: Midazolam may have a role as an add-on antiseizure medication in neonatal seizures, particularly in refractory cases. However, the evidence remains limited by heterogeneity in study design, EEG monitoring strategies, outcome definitions, and incomplete individual-level data. The observed association between gestational age and response is hypothesis-generating and requires prospective validation. WHAT IS KNOWN: • Phenobarbital often provides incomplete seizure control in neonates, making second-line antiseizure therapies necessary in refractory cases. • Evidence supporting midazolam for neonatal seizures remains limited and heterogeneous. WHAT IS NEW: • This systematic review summarizes the electro-clinical efficacy and safety of midazolam and includes an exploratory patient-level analysis suggesting that higher gestational age may be associated with improved treatment response. • These findings support further prospective studies on developmental determinants of response to GABAergic therapy.

Humans↗

PubMed2026

Feasibility of implementation, diagnostic accuracy, and end-user impact of an electronic health record (EHR)-based ureteral stent tracking tool in a pediatric population.

INTRODUCTION & OBJECTIVES: Ureteral stent tracking systems have reduced stent retention in adults, but their accuracy and impact in pediatrics have been minimally explored. With low event rates in children, such tools may yield high false positives, raising questions on balancing event prevention with provider burden. We aimed to evaluate the feasibility, diagnostic accuracy, and end-user impact of an Electronic Surveillance Tool for Evaluating Nephroureteral stent Tracking (eSTENT) at our institution. STUDY DESIGN: eSTENT, implemented in 1/2024, flags ureteral stents at risk for retention based on implant documentation, expected explant date, and explant documentation. Monthly reports are generated for stents missing explant documentation. We retrospectively evaluated the diagnostic performance of eSTENT from 1/2024-8/2025 at our pediatric hospital. A usability survey including a validated 1-7 implementation score (higher = easier implementation) was distributed to pediatric urologists and operating room nurses. RESULTS: Of 172 cases with ureteral stent placement, eSTENT flagged 28 events (16%) in 24 patients. Of these, 26 represented documentation gaps where explant had been appropriate. Two flags had no documentation of explant, representing near miss events that were identified. No retained stents occurred, consistent with high sensitivity and modest specificity. There were no flags in the last 6 months of the study period. Survey response rate was 100% for surgeons and 55% for nurses. Before eSTENT, stents were not routinely tracked. All surgeons and 93% of nurses reported no added burden, despite occasional misidentification of retained stents. Three surgeons found eSTENT beneficial, four were neutral, and free-text responses generally cited eSTENT's "fail safe" nature as positive. Nurses suggested improvements, including user support and integrated documentation reminders. The average implementation score among both groups was 6/7, indicating easy adoption. DISCUSSION: While the impact of stent tracking tools in adult literature has been positive, our study emphasizes the feasibility of broader adoption at a pediatric hospital. Integration of eSTENT may avoid the potentially devastating consequences of a retained stent. Prioritizing sensitivity over specificity appears acceptable for a "never event" in patient safety. Our study is limited by the retrospective nature of data collection and survey bias. CONCLUSIONS: Though no stents were retained in the study period, eSTENT appropriately flagged two cases without added burden to most end-users. Further optimization is warranted, but adoption in pediatric centers may enhance care reliability.

Humans↗

PubMed2026

Effect of brewers' yeast or beta-glucan derived from Saccharomyces cerevisiae on breast milk supply following preterm birth: the BLOOM randomised controlled trial.

OBJECTIVE: Breast milk is the optimal source of nutrition for preterm infants; however, low breast milk production is common following a preterm birth. This study aimed to determine if taking brewers' yeast or beta-glucan improves daily expressed breast milk volume. DESIGN: Randomised, blinded, parallel, placebo-controlled trial. SETTING: Three Australian tertiary-level neonatal units. PATIENTS: Mothers with a singleton or twin pregnancy who gave birth at <34 weeks' gestation. INTERVENTIONS: Mothers were randomised within 72 hours of birth into three parallel groups in a 1:1:1 ratio to receive either brewers' yeast, beta-glucan or placebo capsules for 7 days. MAIN OUTCOME MEASURE: Total expressed breast milk volume over a 24-hour period on day 7 of intervention. RESULTS: A total of 105 mothers underwent randomisation between August 2022 and April 2024 (36 brewers' yeast, 35 beta-glucan and 34 placebo). The adjusted mean difference in daily expressed breast milk volume was 94 mL/day (95% CI -51 mL/day to 239 mL/day) between the brewers' yeast and placebo groups and -25 mL/day (95% CI -173 mL/day to 123 mL/day) between the beta-glucan and placebo groups. Maternal side effects were similar across groups. CONCLUSION: We found no clear effect of short-term administration of brewers' yeast or beta-glucan on breast-milk production following preterm birth; both interventions were well tolerated. Given the small sample size, these findings do not rule out the possibility of a clinically meaningful benefit of brewers' yeast and suggest further research with a larger sample size may be warranted to clarify the potential clinical impact. TRIAL REGISTRATION NUMBER: ACTRN12622000968774.

Intensive Care Units, Neonatal↗

PubMed2026

Quality of life and gender identity in females with congenital adrenal hyperplasia after genital restoration surgery: A single-center experience.

BACKGROUND: Legislation restricting surgical interventions in children with differences of sex development (DSD) has intensified debate about female genital restoration surgery (FGRS) in patients with congenital adrenal hyperplasia (CAH). Long-term patient-reported outcomes are needed regarding the optimal timing of surgery. OBJECTIVE: We aimed to assess health-related quality of life (HRQoL), gender identity, and family satisfaction regarding surgical timing and outcome in females with CAH following genital restoration surgery. STUDY DESIGN: Cross-sectional survey of CAH patients who underwent surgery between January 2007 to December 2016 at our institution. Validated instruments (KINDL questionnaire for HRQoL, Utrecht Gender Dysphoria Scale, UGDS) and structured telephone interviews were employed. RESULTS: Data on HRQoL was available for 25 patients (self- and/or parent-reported) out of 56 eligible patients (45% response rate). Median age at first surgery was 6 months (range: 3-137 months). Patients' age at time of participation ranged from 2 to 28 years. All had 21-hydroxylase deficiency (92% salt-wasting form) with Prader grades ranging from II-V. Wound dehiscence requiring secondary suturing occurred in 15% of patients with primary surgery at our center, while only one (4%) patient developed vaginal stenosis after early primary vaginoplasty. Two additional patients (8%) with prior outside surgery required vaginal revision after FGRS at age 12. HRQoL scores were comparable to healthy reference populations across most age groups. Children aged 3-6 and adolescents and young adults showed no significant difference from reference values, while children aged 7-13 showed a slight elevation. None of five patients ≥14 years demonstrated gender dysphoria (all UGDS scores <40, threshold ≥40). 14 patients and families were also interviewed by telephone. All preferred early surgical timing. No family expressed regret about the decision or preferred delayed surgery. DISCUSSION: This study provides validated intermediate-term patient- and parent-reported outcomes after FGRS in CAH. Key limitations include the small sample size, single-center design, and young age of most patients. Selection bias may exist, though participating families included those who underwent revision surgery. The absence of a non-operated comparison group reflects current clinical reality, as nearly all CAH patients with urogenital sinus underwent surgical correction. CONCLUSIONS: Females with CAH reported normal HRQoL and a comfortable female gender identity after early FGRS. The patients and their families expressed a preference for early surgery. However, there is need for longer-term follow-up to assess sexual function and reproductive outcomes as well comparison of outcomes with a non-operated group.

Humans↗

PubMed2026

Vitamin D Deficiency During Pregnancy Is Associated With Greater LDL-C Increase, Elevated β-Hydroxybutyrate and Altered Neonatal Metabolic Markers-A Secondary, Pooled Analysis of the Randomized, Controlled Vitamin D and Lifestyle for Gestational Diabetes Prevention Trial (DALI).

INTRODUCTION: Vitamin D (vitD) plays a role in metabolic regulation, including lipid metabolism and insulin sensitivity. During pregnancy, profound physiological changes in lipid handling and ketogenesis occur to support fetal development. However, the extent to which maternal vitamin D status influences these metabolic adaptations and fetal metabolic markers remains unclear. METHODS: In this secondary analysis, we examined lipid distribution throughout pregnancy-from before 20 weeks' gestation to delivery-in women with overweight or obesity, stratified by vitamin D status (deficiency, insufficiency, or sufficiency), assessing both maternal and cord blood. Main inclusion criteria were: age > =18 years, singleton pregnancy, < 20 weeks' gestation, BMI ≥ 29 kg/m2. Women with GDM < 20 weeks' gestation were excluded. In total, 962 pregnant women were divided into vitD deficient (< 30 nmol/L, n = 102), insufficient (30-50 nmol/L, n = 222) and sufficient (> 50 nmol/L, n = 638) groups. VitD levels and lipid concentrations were assessed at < 20, 24-28 and 35-37 weeks' gestation and in cord blood. RESULTS: Compared with vitD sufficient women, women with vitD deficiency had significantly larger increases in LDL-C throughout pregnancy and ß-OH-butyrate at 24-28 weeks' gestation, in adjusted analysis. VitD in cord blood was highest in offspring of mothers with vitD sufficiency. In cord blood, significantly higher ß-OH-butyrate was observed with vitD deficiency; lipid concentrations were similar between groups. CONCLUSIONS: Early vitamin D deficiency before 20 weeks of gestation was associated with altered metabolic trajectories during pregnancy, including greater increases in LDL cholesterol and ketone body concentrations in women with overweight or obesity, as well as higher cord blood ketone levels in their offspring. These findings suggest that early maternal vitamin D status may influence maternal and fetal metabolic adaptations, although causal relationships and clinical implications require further investigation. TRIAL REGISTRATION: Trial registered at ISRCTN registry (https://doi.org/10.1186/ISRCTN70595832) trial number ISRCTN70595832. Registration date 02/12/2011.

Humans↗

PubMed2026

Pain outcomes of pediatric circumcision patients following administration of pre-operative ketorolac: A randomized clinical trial.

INTRODUCTION: Circumcision is a common surgical intervention, and pain is the most common complaint. Poorly managed pain can increase morbidity and reduce patient and parent satisfaction. Ketorolac, a non-steroidal anti-inflammatory drug (NSAID), provides analgesia and may be effective in reducing pain after circumcision in pediatric patients. STUDY OBJECTIVES: The primary objective was to determine the effect of pre-operative intravenous ketorolac versus normal saline placebo on parental perception of postoperative pain at 24 h. We also explored the effect of ketorolac on postoperative pain scores, incidence of bleeding, incidence of vomiting, and analgesic use. MATERIALS AND METHODS: A prospective, randomized, single-blinded trial was conducted at a single tertiary children's hospital. Patients aged 1-17 presenting for circumcision were included and randomized to either normal saline injectate or ketorolac (0.5 mg/kg, maximum 30 mg). Postoperative delirium and pain scores were recorded in the post-anesthetic care unit. Parents completed the parents' postoperative pain measure (PPPM) at 24 h. The CONSORT criteria and checklist were used to guide reporting of this randomized controlled trial. RESULTS: A total of 100 participants were included. 50 participants were in each group. Mean (SD) PPPM score 24 h after normal saline and ketorolac was 6.1 (3.4) and 5.5 (3.3), respectively for a mean difference of -0.55 points [95% CI: -1.9 to 0.83; p = 0.427]. The mean (95% CI) fixed effect size of ketorolac on post anesthetic care unit reported Face, Leg, Activity, Cry, Consolability score was -0.17 (-0.77 to 0.43, p = 0.585) points, while the mean (95% CI) effect size of ketorolac on numerical rating scale was -1.2 (-2.2 to -0.18, p = 0.026) points. DISCUSSION: Pre-operative intravenous ketorolac, compared to normal saline placebo, did not result in a difference in parental perception of postoperative pain at 24 h after circumcision surgery. As part of exploratory analyses, those receiving ketorolac had modestly lower mean immediate postoperative pain scores, likely not of clinical importance. Ketorolac has often been avoided due to concerns of increased bleeding risk, however it is important to consider that there is no substantial evidence to support this. This is the first study to our knowledge evaluating the effect of ketorolac in pediatric circumcision patients. While the PPPM score is a family centered outcome, it is an indirect measurement of pediatric pain. CONCLUSIONS: Pre-operative intravenous ketorolac was not associated with lower parental reported pain scores at 24 h compared to normal saline placebo after pediatric circumcision surgery. CLINICAL TRIAL REGISTRATION: NCT02973958.

Humans↗

PubMed2026

Single-center experience with isolated male epispadias: Outcomes of Thiersch-Duplay and modified Cantwell-Ransley repairs by anatomical subtype.

BACKGROUND: Isolated male epispadias (IME) is a rare congenital malformation. Surgical repair aims to improve urinary function, correct penile curvature, reconstruct the urethra and glans, and preserve future sexual function. Because available series are small, the influence of anatomical subtype and operative technique on outcome remains incompletely defined. OBJECTIVE: To report single-center outcomes of Thiersch-Duplay and modified Cantwell-Ransley repairs for IME, with attention to anatomical subtype, complications, and age-appropriate continence outcomes. METHODS: We retrospectively reviewed boys with IME who underwent primary urethral reconstruction in my hospital, Capital Medical University, from May 2005 to June 2024. Data were locked on 30 June 2024. Primary outcomes were postoperative complications graded by the Clavien-Dindo system and urinary continence at last follow-up in patients aged 5 years or older. Secondary outcomes included improvement of preoperative incontinence, ICIQ score, subsequent bladder neck reconstruction, penile appearance/residual curvature when documented, and patient/parent-reported sexual function. RESULTS: Sixty-seven patients were included: 35 underwent modified Cantwell-Ransley repair and 32 underwent Thiersch-Duplay repair. The cohort included 26 glanular (38.8%), 23 penile (34.3%), and 18 penopubic (26.9%) cases. Median age at surgery was 28 months in both groups. Median age at last follow-up was 92.8 months (IQR 63.9-108.4) after modified Cantwell-Ransley repair and 137.9 months (IQR 77.9-172.6) after Thiersch-Duplay repair (P = 0.011). Procedure distribution differed by meatal location (P = 0.036), although penopubic cases were treated with both procedures. Total complications occurred in 5/35 and 5/32 patients, respectively. Formal continence analysis included 26 modified Cantwell-Ransley patients and 27 Thiersch-Duplay patients aged 5 years or older. Postoperative urinary incontinence persisted in 14/26 (53.8%) and 12/27 (44.4%), respectively. Among age-eligible patients with preoperative incontinence, any improvement was documented in 13/20 (65.0%) and 14/17 (82.4%), and complete remission occurred in 6/20 (30.0%) and 5/17 (29.4%), respectively. Three patients, all with penopubic epispadias treated with Thiersch-Duplay repair, subsequently underwent bladder neck reconstruction for persistent incontinence. Erectile function data were available in 37/67 patients (55.2%). CONCLUSIONS: In this large single-center retrospective cohort, Thiersch-Duplay and modified Cantwell-Ransley repairs had comparable overall complication rates. Continence and reoperation patterns were strongly influenced by anatomical subtype, with penopubic epispadias representing the highest-risk group. These findings support individualized, anatomy-conscious operative planning and prospective evaluation of standardized selection criteria, rather than a single prescriptive algorithm. CLINICAL/TRANSLATIONAL IMPLICATION: This series supports standardized reporting of anatomical subtype, age-appropriate continence outcomes, and graded complications when counseling families and comparing outcomes across centers. LEVEL OF EVIDENCE: Level III.

Humans↗

PubMed2026

Height variation independent of known genetic variants and health in later life: a cohort study.

BACKGROUND: Adult-attained height is associated with later-life health, but it reflects both genetic and nongenetic influences. The health implications of height variation not explained by known common height-associated genetic variants remain unclear. OBJECTIVES: This study aimed to examine associations of residual height (height variation independent of known genetic variants) with multiple disease incidence and all-cause mortality in later life. METHODS: In this cohort study of 407,366 adults of European ancestry (aged 40-70 y) in the United Kingdom Biobank (2006-2010), sex- and age-specific genetically predicted height was estimated from 9863 height-associated variants, adjusted for 30 principal components of ancestry. Residual height was calculated as the difference between observed and genetically predicted height. Plasma proteomics (2054 proteins; Olink Explore) were profiled. Deaths and 49 incident diseases were ascertained through national registries. Multivariable Cox models estimated associations of residual height and related proteins with disease incidence and mortality. RESULTS: Higher residual height [mean (standard deviation, SD), 0.0 (4.8)] was associated with more favorable self-reported preadulthood exposures (e.g., later birth years, no maternal smoking around birth, being breastfed as an infant, no adoption experience, and lower childhood adversity scores) and lower hazard ratios (HRs) of 32 out of 49 diseases (median follow-up = ∼12.5 y). Using participants with residual height within ±0.5 SDs from the mean as reference, those with residual height < -2 SDs had higher adjusted HRs of mortality [1.61; 95% confidence interval (CI): 1.50, 1.72], multimorbidity (1.28; 95% CI: 1.12, 1.46), cardiovascular disease (1.45; 95% CI: 1.32, 1.60), psychiatric/neurological disease (1.38; 95% CI: 1.28, 1.48), and other disease categories (e.g., diabetes, digestive, and musculoskeletal diseases). In contrast, higher genetically predicted height was associated with a higher incidence of 19 diseases, including subtypes of cancer, non-atherosclerotic cardiovascular diseases, and musculoskeletal diseases, as well as higher all-cause mortality. We identified 806 plasma proteins related to inflammation, immune response, and autophagy via tumor necrosis factor, Nuclear factor-kappa B, phosphoinositide-3 kinase/protein kinase B, and Janus kinase/signal transducer and activator of transcription signaling pathways, which were associated with residual height and multiple diseases and mortality. CONCLUSIONS: Higher residual height is associated with lower disease incidence and mortality, with associations that are distinct from those for genetically predicted height.

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

Biochemical Insights Into the Conserved Interactions of NMD Factors From Budding Yeast to Humans.

Nonsense-mediated mRNA decay (NMD) is one of the most extensively studied pathways of cytoplasmic mRNA degradation. It plays a critical role in diverse cellular processes by eliminating aberrant transcripts containing premature stop codons and by regulating the stability of physiological mRNAs. NMD factors were initially identified through genetic screens in S. cerevisiae (UPF1, 2, 3) and C. elegans (SMG-1, SMG5-7). Subsequent biochemical and genetic studies revealed the composition of NMD complexes and identified additional factors. A major protein hub for NMD is Upf1, an ATP-dependent RNA helicase that is part of two mutually exclusive NMD assemblies, the Upf1-Upf2-Upf3 complex and the Upf1-decapping complex, which contains the decapping enzyme and its co-factors. Here, we discuss recent findings, primarily from budding yeast, on the protein-protein interactions driving NMD complexes dynamics and their similarities to human NMD. Together, the N-terminal cysteine and histidine rich (CH) and helicase domains (HD) of Upf1 act as a hub for binding multiple partners. Upf1 is required for binding to NMD substrates and for the initiation of RNA degradation through decapping (yeast) or endonucleolytic hydrolysis (humans). We focus on the interplay between Upf2, Dcp2 and Nmd4 (yeast SMG6), which ensures the mutually exclusive formation of Upf1-bound subcomplexes modulating Upf1's affinity for RNA. Thus, the study of NMD factors interactions in different organisms sheds new light on the remarkable conservation of NMD molecular mechanisms.

Nonsense Mediated mRNA Decay↗

PubMed2026

Mitigating pH-induced instability in deruxtecan-based ADCs: an onboard-mixing icIEF approach for robust charge heterogeneity characterization.

Accurate charge variant analysis of antibody-drug conjugates (ADCs) is essential for understanding product heterogeneity and ensuring quality control. However, Deruxtecan (DXd)-based ADCs present a unique analytical challenge due to the intrinsic instability of the payload, where the lactone ring readily undergoes hydrolysis under alkaline conditions, resulting in time-dependent shifts in charge distribution during imaged capillary isoelectric focusing (icIEF). In this study, we describe the development of an onboard-mixing icIEF method designed to minimize pH-induced degradation during sample preparation. By separating ADC samples from carrier ampholytes (CAs) prior to injection and enabling real-time mixing within the instrument, this approach effectively suppresses premature lactone ring opening and stabilizes charge variant profiles. Comparative studies between conventional premixing and onboard-mixing approach demonstrated that the latter significantly enhances reproducibility, particularly for acidic variants that are highly sensitive to structural conversion. Comprehensive method validation confirmed excellent precision, linearity, and sensitivity, with consistent performance across run-to-run and intra-day analyses. The results underscore the importance of controlling microenvironmental pH exposure in the analysis of chemically instable ADCs. The proposed onboard-mixing strategy provides a robust and efficient solution for icIEF-based characterization, reducing analytical artifacts while simplifying method development. This approach is broadly applicable to ADCs and other biotherapeutics containing pH-sensitive functional groups.

Hydrogen-Ion Concentration↗

PubMed2026

Transcriptome analysis of the pectoral fin degeneration in half-smooth tongue sole (Cynoglossus semilaevis).

Appendage degeneration is a notable morphological feature of some teleosts with specialized benthic lifestyles. The half-smooth tongue sole (Cynoglossus semilaevis) undergoes severe pectoral fin regression during metamorphosis. However, the molecular basis underlying rapid pectoral fin degeneration remains unclear. Here, we performed time-series transcriptome sequencing on pectoral fins at pre-metamorphosis, metamorphosis peak and post-metamorphosis to characterize the molecular changes associated with pectoral fin degeneration. Transcriptional dynamics and functional enrichment showed that no significant enrichment of classical apoptosis-related transcriptional pathways was detected during pectoral fin degeneration. Instead, sustained downregulation of twist1b, identified as a transcriptomic candidate, together with significant upregulation of ssh1, coupled with enrichment of lysosome and ubiquitin-proteasome system (UPS) pathways, suggested enhanced tissue remodeling during pectoral fin degeneration. Temporal expression clustering revealed heterochronic misalignment in the developmental gene expression: upstream initiator tbx5 was upregulated at early metamorphosis, while downstream maintenance signal fgf10 decreased synchronously. Distal patterning gene hoxd12a exhibited premature expression and rapid decay, losing sustained late-phase expression. Moreover, transient elevation of gli3 during metamorphosis may contribute to restricted distal fin growth. We conclude that pectoral fin degeneration in C. semilaevis is associated with heterochronic disruption of developmental signaling and extensive tissue remodeling. This study provides transcriptomic insights into pectoral fin degeneration in tongue soles and establishes a basis for future functional studies of appendage reduction in teleosts.

Animals↗

PubMed2026

Artificial Intelligence for Diagnosis, Risk Stratification, and Prognosis of Neuroblastoma - A Systematic Review and Meta-Analysis.

PURPOSE: To synthesizes evidence on artificial intelligence (AI) performance in neuroblastoma (NB) diagnosis, risk stratification, prognosis, and genomic characterization. MATERIALS AND METHODS: A systematic review and meta-analysis was conducted following PRISMA 2020 guidelines (PROSPERO: CRD42024539475) across five databases. Meta-analyses used random-effects models with logit-transformed Area Under the Curve (AUCs) and cluster-robust standard errors. AI models were classified as Machine Learning Models (MLM) or Hybrid Nomograms (HN) based on their construction methodology. RESULTS: Of 3,742 articles identified, 53 were included. MLMs demonstrated higher point estimates than radiologists in differential diagnosis (AUC: 0.87 vs. 0.83), though this difference was not statistically significant and carried substantial uncertainty. HNs achieved stronger performance in risk stratification (AUC: 0.87). AI-derived nomograms (AUC: 0.9) and gene signatures (AUC: 0.8) outperformed conventional prognostic markers descriptively. Chemotherapy response prediction remained below clinical utility thresholds across all model types. Only 33.9% of models reported calibration and 24.5% underwent external validation. CONCLUSIONS: AI demonstrates proof-of-concept across multiple NB clinical domains. However, clinical adoption remains premature given persistent gaps in external validation, calibration, dataset size, and pediatric-specific model development. Future studies should test these models prospectively in multicenter pediatric cohorts, ideally through COG or SIOPEN, using shared definitions for diagnosis, risk group, treatment response, and survival outcomes.

Humans↗

PubMed2026

Ibuprofen versus acetaminophen for acute mild-to-moderate pain management in pediatric populations: a systematic review and meta-analysis of their efficacy.

UNLABELLED: Ibuprofen and acetaminophen are the most widely used analgesics in pediatric practice for the management of acute mild-to-moderate pain. Despite their widespread use, the comparative analgesic efficacy of these two agents in children remains a subject of ongoing debate, with existing evidence largely derived from heterogeneous clinical settings and small individual trials. Therefore, this study aimed to systematically review and meta-analyze randomized controlled trials comparing the analgesic efficacy of ibuprofen versus acetaminophen in pediatric populations with acute mild-to-moderate pain. A systematic literature search was conducted up to May 2026 in PubMed, Scopus, and Web of Science. The review was conducted and reported in accordance with the PRISMA-Children and Adolescents (PRISMA-C) 2026 reporting guideline. Eligible studies were randomized controlled trials comparing ibuprofen with acetaminophen in children and adolescents (defined as individuals aged 0 to < 18 years) with acute pain, reporting at least one extractable efficacy outcome. Continuous outcomes were synthesized as standardized mean differences (Hedges' g) using random-effects models; dichotomous outcomes were pooled as risk ratios (RRs) with 95% confidence intervals. Risk of bias was assessed using the Cochrane RoB 2 tool and certainty of evidence was evaluated using the GRADE framework. Eight randomized controlled trials enrolling 1325 participants were included. Three pediatric trials contributed to the primary continuous pain outcome meta-analysis (n = 196 analyzable participants), yielding a pooled SMD of - 0.28 (95% CI - 0.57 to 0.00; p = 0.052; I2 = 0%), indicating a small effect favoring ibuprofen that did not reach conventional statistical significance. Given the small number of contributing studies (k = 3), the I2 statistic should be interpreted with caution as it has limited power to detect heterogeneity in this context. For the dichotomous pain freedom outcome (2 trials, n = 114), no significant difference was observed (pooled RR 1.03, 95% CI 0.53-1.99; p = 0.93; I2 = 0%). A prespecified sensitivity analysis including an adult soft-tissue injury trial attenuated the pooled effect toward the null (SMD - 0.15, 95% CI - 0.38 to 0.09; p = 0.23; I2 = 36.6%). Narrative synthesis of additional studies generally demonstrated comparable analgesic efficacy between the two agents across postoperative and outpatient pediatric settings. The overall certainty of evidence was rated as low for both primary outcomes, primarily due to imprecision and indirectness. CONCLUSION: Current evidence from randomized controlled trials does not demonstrate a superiority of ibuprofen over acetaminophen for acute mild-to-moderate pain management in children. Both agents appear to provide clinically meaningful analgesia across heterogeneous pediatric pain settings. The clinical choice between agents should be guided by individual patient factors, including contraindications to NSAIDs, the inflammatory nature of the pain etiology, and patient-specific characteristics. The low certainty of evidence underscores the need for adequately powered, methodologically rigorous trials to definitively establish the comparative efficacy of these two analgesics in the pediatric population. WHAT IS KNOWN: • Ibuprofen and acetaminophen are the two most widely used non-opioid analgesics for acute mild-to-moderate pain in children, and both are recommended as first-line agents by major international guidelines. • Prior meta-analyses in mixed pediatric-adult populations have suggested a modest analgesic advantage of ibuprofen over acetaminophen, but pediatric-specific evidence has remained limited and methodologically heterogeneous. WHAT IS NEW: • This systematic review and meta-analysis, restricted to randomized controlled trials in pediatric populations, found that ibuprofen showed a small effect favoring pain reduction compared with acetaminophen (SMD - 0.28, p = 0.052), although this did not reach conventional statistical significance. • The analgesic advantage of ibuprofen may be more pronounced in pain etiologies with a significant inflammatory component (e.g., fractures). At the same time, both agents appear broadly equivalent in most other acute pediatric pain settings, supporting individualized analgesic selection based on clinical context and patient-specific factors.

Humans↗

PubMed2026

Active Site Assembly by SMG5 as a Mechanism for SMG6 Endonuclease Licencing in Nonsense-mediated mRNA Decay.

Nonsense-mediated mRNA decay (NMD) is a conserved eukaryotic surveillance pathway that eliminates transcripts containing premature termination codons (PTCs). Substantial progress has been made in defining the transcript features that mark aberrant translation termination for NMD activation, yet key mechanistic steps remain incompletely understood - including how recruitment of the central NMD factor UPF1 is coupled to the downstream effector phase in which targeted mRNAs are nucleolytically degraded. In metazoans, NMD employs an endonucleolytic route mediated by SMG6, a PIN-domain nuclease, alongside SMG5 and SMG7, which act downstream of PTC recognition. SMG5 has recently been proposed to licence SMG6 activity, yet the molecular basis of this licencing has remained elusive. Here, we combine AlphaFold structural predictions with biochemical assays to investigate interactions among human SMG5, SMG6, and SMG7. Structural models predict a high-confidence interface between SMG5 and SMG6 PIN domains that forms a composite active site: a conserved SMG5 aspartate (D893) complements the SMG6 acidic triad to reinstate the canonical tetrad required for PIN-domain catalysis. In vitro, SMG6 alone exhibits weak endonucleolytic activity, which is enhanced ∼10-fold by the SMG5 PIN domain. Mutational analyses confirm that conserved residues from both proteins are essential for this composite configuration. Our findings reveal that the SMG5 PIN domain, previously considered catalytically inert, plays a critical role in activating SMG6 by completing its active site. This work provides mechanistic insight into the SMG5-dependent licencing step and uncovers a composite PIN nuclease architecture at the heart of the metazoan NMD effector phase.

Nonsense Mediated mRNA Decay↗

PubMed2026

ALG-020572, an Antisense Oligonucleotide for the Treatment of Chronic Hepatitis B Virus Infection Discontinued for Drug-Induced Liver Injury.

Current treatment options for chronic HBV infection are suboptimal in that they fail to suppress HBsAg levels. ALG-020572 is an antisense oligonucleotide designed to reduce viral protein synthesis through degradation of HBV mRNA. ALG-020572-401 was a double-blind, randomized, placebo-controlled trial consisting of two parts. Part 1 (single-ascending doses) evaluated the pharmacokinetics, safety and tolerability of single doses of ALG-020572 or placebo in healthy participants. In Part 2 (multiple dosing), participants with non-cirrhotic HBeAg-negative, virologically suppressed chronic HBV infection were administered up to 7 doses of ALG-020572 to evaluate safety, pharmacokinetics and antiviral activity. In Part 1, 32 participants were randomized to ALG 020572 or placebo. Single doses of ALG-020572 up to 480 mg were well tolerated. The most common treatment-emergent adverse event reported was injection site reaction. ALG-020572 was rapidly absorbed and plasma exposures increased with dose. In Part 2, 8 participants with non-cirrhotic HBeAg-negative virologically suppressed chronic hepatitis B infection were enrolled and received up to 7 doses of ALG-020572. The study was prematurely discontinued after 4 participants experienced significant alanine aminotransferase elevations that were subsequently attributed to drug-induced liver injury. Single doses of ALG-020572 demonstrated a favourable pharmacokinetic and safety profile in healthy participants. Unexpectedly, ALG-020572 was poorly tolerated in participants with chronic HBV infection, resulting in the early termination of the study and further development of ALG-020572 due to idiosyncratic drug-induced liver injury, suggesting caution is required in the development of this class of drugs. Trial Registration: Registered at clinicaltrials.gov: NCT0500102.

Adult↗

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↗