Fluid overload (FO) is associated with poor clinical outcomes among critically ill children. The objective of this trial was to assess the impact of a protocolized restrictive maintenance fluid strategy on FO among mechanically ventilated children. This open-label randomized controlled trial was conducted in the pediatric intensive care unit (PICU) of a tertiary care hospital in North India over 13 months (November 2023-November 2024). Hemodynamically stable mechanically ventilated children were randomized to protocolized restrictive (n = 64) (40-50% of maintenance fluids with diuretic infusion if FO% > 10%); and liberal/usual (n = 66) (70-80% of maintenance fluid) groups. The primary outcome was the proportion of children with cumulative FO% > 10% through day 5. Secondary outcomes were daily cumulative FO%; inferior vena cava variability index (∆IVC) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at 48 h; safety parameters (requirement of fluid boluses or vasoactive drugs); 28-day ventilator and PICU-free days (VFDs and PFDs), and mortality. Significantly fewer children in the protocolized restrictive group had cumulative FO% > 10% than in the liberal/usual group (22% vs. 47%, p = 0.003). Also, the restrictive group had significantly lower daily cumulative FO% on the first 5 days. ∆IVC and NT-proBNP levels at 48 h, as well as safety parameters, were similar between the two groups. Protocolized restrictive and liberal/usual groups had similar VFDs [20 (8-24) vs. 16 (0-23), p = 0.076], PFDs [16 (3-21) vs. 13 (0-19), p = 0.071], and mortality (14% vs. 24%, p = 0.14).  A protocolized restrictive maintenance fluid strategy resulted in significantly lower FO among hemodynamically stable, mechanically ventilated children without a measurable impact on short-term clinical outcomes. • Fluid overload (FO) is associated with poor clinical outcomes among critically ill mechanically ventilated children. • Among hemodynamically stable, mechanically ventilated children, a restrictive maintenance fluid strategy may be a useful intervention to limit FO and improve clinical outcomes in LMICs.
Iron(III) and copper(II) ions are ubiquitous in the environment, posing potential risks to the environment and human health, which urgently demands rapid detection methods. In this study, a ratiometric fluorescent probe was developed by integrating biomass-based carbon dots with rhodamine B (RhB) for the rapid and accurate detection of Fe³⁺ and Cu²⁺. Under normal conditions, the strong coordination ability of Fe³⁺ and Cu²⁺ enables them to rapidly occupy the active sites on the surface of carbon dots (CDs), resulting in rapid fluorescence changes. RhB provides a stable reference signal and achieves self-calibrated dual-emission output, thereby reducing matrix and environmental interferences. To address the coexistence of Fe³⁺ and Cu²⁺ in practical detection, ethylenediaminetetraacetic acid (EDTA) was introduced as a selective masking agent, which preferentially forms a stable complex with Fe³⁺. This reduces the signal interference of Fe³⁺ in low-concentration systems and realizes highly selective detection of Cu²⁺. In the detection of Cu²⁺ in actual water samples, the probe exhibits high sensitivity (4.91 µM) and favorable accuracy with recoveries ranging from 97.3% to 99.5%, demonstrating strong reliability in complex samples. This study not only provides a green and sensitive method for Cu²⁺ detection, but also presents an effective strategy for resolving specific detection issues in complex matrices using classical masking agents.
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Vascular endothelial growth factor (VEGF) is widely used in regenerative medicine and therapeutic research. However, the purification of recombinant VEGF largely relies on affinity chromatography, which requires expensive chromatographic columns, specialized equipment, and multistep processing. These column-based workflows increase operational complexity and cost, particularly for large-scale production. Therefore, the development of an alternative purification strategy to conventional chromatography-based purification for VEGF is needed. In this study, we developed a chromatography-free VEGF purification strategy using an anti-VEGF-scFv-calsequestrin (CSQ) fusion protein that enables calcium-dependent affinity precipitation. The fusion protein retained strong binding affinity for VEGF (Kd = 1.1 nM) while exhibiting rapid and reversible Ca2⁺-dependent polymerization. Upon CaCl₂ addition, the anti-VEGF-scFv-CSQ-VEGF complex rapidly formed aggregates, enabling efficient separation of VEGF from impurities. Using this strategy, VEGF was purified within 30 min with a purity of 94% and a yield of 93%. SEC-HPLC analysis confirmed a purity of 94.3%, and host cell protein contamination was reduced from 1.44 × 104 ppm to 774 ppm. The fusion protein also maintained stable purification performance over five repeated cycles, with VEGF recovery consistently maintained above 85%. These findings demonstrate that the scFv-CSQ fusion protein enables rapid separation of VEGF through calcium-dependent polymerization. This column-free mechanism reduces operational cost and technical complexity, highlighting its potential as an alternative to conventional chromatography-based purification.
To determine the prevalence and clinical relevance of carotid atherosclerosis in patients undergoing surgery for degenerative cervical myelopathy (DCM). Specifically, to identify clinical and radiographic predictors of carotid plaque, to develop and internal-temporal validate a nomogram to guide selective preoperative carotid ultrasound screening, and to explore the association between carotid disease and both neurological recovery and global patient-reported outcome. We conducted a single-center retrospective prognostic cohort study of 160 consecutive patients who underwent cervical decompression for DCM between January 2017 and February 2023, all with ≥ 2 years of follow-up. Patients treated from 2017 to 2021 (n = 104) formed the development cohort, and those treated from 2021 to 2023 (n = 56) constituted a temporally distinct internal-temporal validation cohort from the same institution. Preoperative carotid ultrasonography classified patients by (1) presence of carotid plaque and (2) carotid stenosis severity (none/mild vs. moderate/severe, ≥ 50%). Clinical, biochemical, radiographic, and outcome measures-including mJOA recovery rate and modified Macnab criteria (excellent/good vs. fair/poor)-were compared between groups. In the development cohort, variables with p < 0.05 in univariable analyses entered multivariable logistic regression to identify independent predictors of carotid plaque and construct a nomogram. Model performance was assessed by the area under the receiver operating characteristic curve (AUC), calibration plots, and decision curve analysis (DCA) in both cohorts. Bootstrap-based internal validation with 1,000 resamples was additionally performed for the final prediction model in the development cohort. Overall, 94 of 160 patients (58.8%) had carotid plaque and 39 (24.4%) had moderate/severe carotid stenosis. In the development cohort, the plaque group was older, had higher body mass index (BMI), more vertigo and hypertension, greater C2-C7 Cobb angle (CL), more moderate/severe stenosis, and a lower proportion of excellent/good outcomes by modified Macnab criteria than the normal group (p < 0.05). Multivariable analysis identified age, BMI, vertigo, and CL as independent predictors of carotid plaque; each 1-year increase in age increased the odds of plaque by 13.7% (odds ratio 1.137, p < 0.001). These four variables were incorporated into a nomogram. The model showed good discrimination in the development cohort (apparent AUC 0.863; optimism-corrected AUC 0.838) and internal-temporal validation cohort (AUC 0.892), with acceptable calibration. DCA in both cohorts demonstrated greater net benefit for nomogram-guided selective screening than for "screen-all" or "screen-none" strategies across a clinically relevant range of threshold probabilities. Carotid atherosclerotic plaque is common in patients undergoing surgery for DCM and is independently associated with age, BMI, vertigo, and increased cervical lordosis. These findings do not support mandatory preoperative carotid ultrasound screening for all DCM patients. A nomogram-based selective screening strategy using these four readily available variables may provide a practical framework for risk stratification, but its clinical utility should be interpreted cautiously pending stronger outcome-based evidence and external validation.
To evaluate the efficacy and prognostic factors of haploidentical haematopoietic stem cell transplantation (haplo-HSCT) for paroxysmal nocturnal haemoglobinuria (PNH). We retrospectively analyzed 36 PNH patients (2 classic PNH, 34 AA-PNH syndrome) undergoing haplo-HSCT (G-CSF/ATG-based protocol) from June 2013 to December 2024, with BU/CY/ATG (n = 28) or BU/CYlow/FLU/ATG (n = 8) conditioning and uniform GVHD prophylaxis. The overall myeloid engraftment rate was 100% (median + 12 d) and platelet engraftment rate 95.5% (median + 13 d). Competing risk analysis showed 42.7% acute GVHD (26.7% grade II-IV, 5.3% grade III-IV); 27.3% chronic GVHD (15.2% mild, 12.1% moderate-severe) among 33 evaluable patients. With a median follow-up of 57 months, the 5-year overall survival rate was 88.6 ± 5.4%. All 32 monitored patients achieved PNH clone clearance (median 3 months), 33 had normalized blood counts, and 3 died of infection, organ hemorrhage or pulmonary embolism. Haplo-HSCT yields favorable outcomes and is a curative therapy for PNH, serving as a valuable option for severe bone marrow failure patients, with G-CSF/ATG-based haplo-HSCT as a promising alternative strategy.
Ventriculovesical (VV) shunting is an uncommon salvage option for cerebrospinal fluid (CSF) diversion in pediatric patients with complex hydrocephalus when conventional distal shunts are no longer viable. Evidence regarding appropriate patient selection, urological safety, and long-term durability of this technique remains limited. This study aimed to evaluate the clinical outcomes and urological safety for VV shunting in children with neurogenic bladder, with particular attention to urodynamic factors that may influence shunt performance. A retrospective case series was conducted including pediatric patients who underwent VV-shunt placement after failure or contraindication of conventional CSF-diversion routes. Demographic characteristics, neurological diagnoses, bladder dynamics, prior shunt history, and clinical outcomes were reviewed. All patients had underlying neurogenic bladder managed with clean intermittent catheterization. Ten patients underwent VV shunt placement at a median age of 7 years (range 2-13 years). Median follow-up duration was 18.5 months (range 10-42 months). Hydrocephalus control was maintained in nine patients (90%) during follow-up. Distal shunt migration requiring revision occurred in two patients (20%). In one patient, persistent inability to achieve adequate bladder pressure control necessitated conversion to a ventriculo-gallbladder shunt following a period of external ventricular drainage. No intraoperative complications occurred, and no febrile urinary tract infections or bladder stone formation were observed during follow-up. VV shunting may represent a viable salvage option for CSF diversion in carefully selected pediatric patients with complex hydrocephalus and neurogenic bladder. Adequate bladder pressure control appears to be a critical determinant of shunt durability, whereas persistently high-pressure bladders may predispose to distal shunt-related complications. These findings highlight the importance of urodynamic assessment and integrated uro-neurosurgical evaluation when considering VV shunting as an alternative CSF diversion strategy and may assist neurosurgeons in identifying appropriate candidates when conventional distal sites are exhausted.
Leptomeningeal metastasis from a solid tumor carries a dismal prognosis with median survival of 3 to 5 months after diagnosis and treatment with external beam radiation therapy. It targets the whole-brain or the entire central nervous system depending on disease extent, and is the current standard therapeutic approach, however, its effectiveness is limited by insufficient cytotoxicity and severe off target radiotoxicity. Radiopharmaceutical therapy is a promising strategy to deliver therapeutic radiation doses directly to the leptomeningeal space while minimizing damage to the normal central nervous system tissue. In this study, the tumor targeting alkylphosphocholine (NM600) was radiolabeled with 177Lu for SPECT/CT imaging and 225Ac for therapeutic efficacy in the context of solid tumor leptomeningeal metastasis. In in-vitro experiments 225Ac-NM600 induced significantly greater apoptosis, reduced colony formation, and increased expression of DNA damage markers, compared to 177Lu or external beam radiation. In-vivo therapeutic and toxicity profiles were assessed in leptomeningeal metastasis models of triple negative breast cancer and non-small cell lung cancer in NSG mice. Intrathecal administration of 177Lu- or 225Ac-NM600 demonstrated excellent tumor targeting with minimal off target effect, confirmed by SPECT/CT imaging and ex vivo biodistribution. 225Ac-NM600 was well tolerated, inhibited tumor growth, and significantly improved overall survival in both models. Moreover, central nervous system radiotoxicity was markedly lower with 225Ac-NM600 RPT compared to external beam radiation therapy. Compared with whole brain external beam radiation therapy, 225Ac-NM600 provides superior anti-tumor efficacy and reduced off target toxicity supporting its further evaluation in clinical trial. When cancer spreads to the lining around the brain and spinal cord, most patients survive only three to five months with standard radiation therapy. We tested a new drug, ²²⁵Ac-NM600, injected directly into the spinal fluid, that seeks out and destroys cancer cells while sparing healthy tissue. In mice with aggressive breast and lung cancers that had spread to the brain, the drug outperformed standard radiation by killing cancer more effectively, causing less brain damage, and significantly extending survival. These results suggest this treatment is promising enough to now be tested in humans.
This study introduces highly sensitive, functionalized dialdehyde fullerene-like carbon nanostructures (DAFs) as a versatile platform for chemical sensing. The DAFs were synthesized through an effective functionalization strategy, confirmed by Fourier-Transform Infrared Spectroscopy (FTIR), which introduced key dialdehyde groups necessary for multi-modal detection. Transmission Electron Microscopy (TEM) validated a critical morphological evolution from small carbon dots (CDs) to larger, fullerene-shaped DAFs, providing a new electronic and structural foundation for sensing. The DAFs demonstrate dual sensing capabilities for both pH and non-polar organic vapors, specifically explosive cyclohexane (LEL ≈ 13000 ppm). The DAFs sensor's Limit of Detection (LOD) of 137.34 ppm is strategically justified by this hazard, as it provides an early, high-reliability safety warning significantly below the 10% LEL industrial safety threshold of 1300 ppm. Density Functional Theory (DFT) calculations elucidated the mechanism of gas detection, confirming that the interaction with non-polar cyclohexane fundamentally alters the electronic structure of the DAFs, causing the dipole moment (µ) to increase significantly from 5.060 Debye to 8.203 Debye, which underlies the observed fluorescence enhancement. Experimentally, the DAFs function as an effective pH probe, exhibiting a distinctive "turn-on" fluorescence response at alkaline pH 12 due to the deprotonation of surface functional groups. Crucially, the material operates as a simple, naked-eye visual sensor for cyclohexane, quantified by a clear shift in CIE chromaticity coordinates from (0.193, 0.422) to (0.209, 0.473) upon gas exposure. This work provides a deep, integrated theoretical and experimental understanding of functionalized carbon nanostructures for industrial safety and general environmental applications.
Echocardiography with point-of-care ultrasound (POCUS) must support clinical decision-making under tight bedside time and operator-effort constraints. We introduce a personalized, budget-constrained data acquisition strategy in which a reinforcement learning agent, given a partially observed multi-view study, selects the next view to acquire or terminates acquisition to support heart failure (HF) assessment. Upon termination, a diagnostic model jointly predicts aortic stenosis (AS) severity and left ventricular ejection fraction (LVEF), two key HF biomarkers, and outputs calibrated uncertainty, enabling an explicit trade-off between diagnostic performance and acquisition cost. We model bedside POCUS as a sequential, cost-constrained acquisition problem in which an RL agent retrospectively selects among five predefined standard views, each represented by one clip with equal acquisition cost, or terminates acquisition. Upon termination, a shared multi-view transformer performs multi-task inference with two heads, ordinal AS classification and LVEF regression, and outputs Gaussian predictive distributions yielding ordinal probabilities over AS classes and EF thresholds. These probabilities drive a reward that balances expected diagnostic benefit against acquisition cost (e.g., number of acquired views), producing patient-specific acquisition pathways rather than a fixed protocol. The video selector is trained with online RL, updating on-policy in a partial-observation simulator built from complete multi-view POCUS studies. The dataset comprises 12,180 patient-level studies, split into training/validation/test sets (70/15/15). On the 1820 test studies, our method matches full-study performance while using 32 % fewer videos, achieving 77.2 % mean balanced accuracy across AS severity classification and LVEF estimation, demonstrating robust multi-task performance under acquisition budgets. In this constrained retrospective setting, patient-tailored view selection preserves decision quality while reducing the number of acquired views, supporting adaptive acquisition policies. The framework is extensible to additional cardiac endpoints and warrants prospective evaluation in live bedside POCUS. The code is available at https://github.com/Armin-Saadat/Double-Precise.
Cognitive Training (CT) is proposed to improve cancer-related cognitive impairment (CRCI), but its effect on objective cognition remains unclear. This systematic review and meta-analysis (PROSPERO ID: CRD42023426761) aimed to examine the efficacy of CT on objective CRCI using neuropsychological tests categorised into cognitive domains following international classifications. Secondary objectives were to assess CT effects on self-reported variables. A systematic search was conducted in PubMed, PsycINFO and Cochrane Library (last search in May 2024). Controlled trials performing CT and reporting neuropsychological outcomes were included. Risk of bias was assessed with RoB-2 and certainty of evidence with the GRADE approach. Hedges' g at post-intervention was the primary outcome of the multivariate meta-analysis, calculated as the standardized mean difference between groups at post-intervention. Hedges´ g at pre-intervention was included as a fixed covariate. Fifteen studies were included in the systematic review and 12 in the meta-analysis (control group n = 507; intervention group n = 578). The meta-analysis showed a small, significant effect of CT on executive functioning (Hedges' g = 0.15, 95% CI [0.00, 0.29], p = .047). This result warrants cautious interpretation due to low-quality evidence. No significant effects were found in other cognitive domains or self-reported indices. Although these results contrast with previous meta-analyses, this study includes a larger dataset, enhancing the robustness of the results, and introduces a novel analysis strategy by grouping neuropsychological tests according to international classifications. In conclusion, CT shows a small benefit for executive functioning in CRCI, but high-quality studies are needed to confirm its efficacy.
Pseudomonas aeruginosa is a prevalent multidrug-resistant pathogen responsible for severe infections. Rapid, ultrasensitive, and selective detection of this bacterium is essential for effective clinical diagnostics and infection control. Here, we report a novel dual-mode biosensing platform based on two-dimensional metal-organic framework-stabilized iron nanoclusters (MOF-Fe NCs) for the simultaneous electrochemical and colorimetric detection of P. aeruginosa. The MOF-Fe NCs display synergistic properties, including exceptional electrocatalytic activity and robust peroxidase-like (POD-like) behavior. Specific capture of the target bacteria by a surface-immobilized F23 aptamer modulates electrochemical signaling and suppresses the POD-like activity for colorimetric readout. The dual-mode bioassay achieves a broad detection range from 101 to 108 CFU/mL, with detection limits of 1.7 CFU/mL (electrochemical) and 1.0 CFU/mL (colorimetric), and demonstrates high selectivity against other bacterial species. This work provides a robust, self-validating sensing strategy with significant potential for point-of-care diagnostics and real-time infection monitoring.
Jehova's Witnesses refuse the administration of allogenic blood products for religious reasons. This stance represents a special challenge for the perioperative management and requires individualized ethically sensitive and medically founded strategies. In this respect patient blood management (PBM) provides a structured and evidence-based approach for optimization of the preoperative, intraoperative and postoperative care. Description of the current medical, ethical and legal procedure for the management of patients who refuse blood transfusions exemplified by Jehova's Witnesses and presentation of a standardized clarification model. Narrative overview of current recommendations and guidelines on preoperative treatment of anemia, intraoperative coagulation treatment, autotransfusion and the legal framework of action. In addition, a questionnaire on differentiated clarification developed at the University of Bonn is presented. A timely structured management of anemia, the application of viscoelastic point of care diagnostics and the differentiated use of autologous procedures, such as mechanical autotransfusion, enable a safe perioperative treatment even in cases of refusal of allogenic blood transfusion. Legal aspects underline the binding to patient advance directives, particularly in adults able to provide informed consent. For children, the child's welfare is prioritized in emergency cases. The clarification form presented reduces uncertainties and strengthens the interdisciplinary decision making. An individualized PBM concept represents an effective and ethically tenable strategy for the perioperative treatment of patients who refuse blood transfusions. It combines medical safety with respecting patient autonomy. HINTERGRUND: Zeugen Jehovas lehnen aus religiösen Gründen die Gabe allogener Blutprodukte ab. Diese Haltung stellt eine besondere Herausforderung für das perioperative Management dar und erfordert individualisierte, ethisch sensible sowie medizinisch fundierte Strategien. Das Patient Blood Management (PBM) bietet hierbei einen strukturierten, evidenzbasierten Ansatz zur Optimierung der prä-, intra- und postoperativen Versorgung. Darstellung des aktuellen medizinischen, ethischen und rechtlichen Vorgehens beim Management transfusionsverweigernder Patient:innen am Beispiel der Zeugen Jehovas sowie Vorstellung eines standardisierten Aufklärungsmodells. Narrative Übersicht aktueller Empfehlungen und Leitlinien zu präoperativer Anämiebehandlung, intraoperativer Gerinnungstherapie, Autotransfusion und juristischem Handlungsrahmen. Ergänzend wird ein am Universitätsklinikum Bonn entwickelter Fragebogen zur differenzierten Aufklärung vorgestellt. Ein frühzeitiges, strukturiertes Anämiemanagement, die Anwendung viskoelastischer Point-of-Care-Diagnostik sowie der differenzierte Einsatz autologer Verfahren wie der maschinellen Autotransfusion ermöglichen auch bei Ablehnung allogener Transfusionen eine sichere perioperative Versorgung. Juristische Aspekte unterstreichen die Bindung an Patientenverfügungen, insbesondere bei einwilligungsfähigen Erwachsenen. Bei Kindern hat das Kindeswohl im Notfall Vorrang. Der vorgestellte Aufklärungsbogen reduziert Unsicherheiten und stärkt die interdisziplinäre Entscheidungsfindung. Ein individualisiertes PBM-Konzept stellt eine effektive und ethisch vertretbare Strategie dar zur perioperativen Versorgung von Patient:innen, die Bluttransfusionen ablehnen. Es vereint medizinische Sicherheit mit Achtung der Patientenautonomie.
MLL-rearranged acute myeloid leukemia (AML) is a high-risk hematological malignancy driven by aberrant epigenetic regulation. MLL fusion proteins recruit the DOT1L methyltransferase, causing dysregulated histone H3K79 methylation and sustained leukemogenic gene expression (HOXA10, MLLT10), while BCL-2 overexpression contributes to apoptosis resistance. This study evaluated the synergistic efficacy of combining the DOT1L inhibitor EPZ004777 with the BCL-2 inhibitor ABT-737. THP-1 cells were treated with EPZ004777 and ABT-737 alone or in combination. Cell proliferation, apoptosis, H3K79 methylation, target gene expression, and PI3K/AKT signaling were assessed. An in vivo xenograft mouse model (C-NKG mice) validated therapeutic effects. Combined treatment exhibited potent synergistic cytotoxicity. Dual inhibition reduced H3K79 di- and tri-methylation, downregulated HOXA10 and MLLT10, and blocked PI3K/AKT phosphorylation. In vivo, combination therapy prolonged survival, restored bone marrow function, and alleviated organ infiltration. These findings demonstrate that dual targeting of DOT1L and BCL-2 exerts synergistic anti-leukemic activity via PI3K/AKT suppression in MLL-rearranged AML, providing a pharmacological rationale for this innovative combination strategy.
Ependymoma (EPN) is the third most common pediatric brain tumor with no targeted therapies available to patients. In supratentorial ependymoma, the most frequent driver alteration is a gene fusion between ZFTA and RELA (denoted ZR), leads to constitutive localization of ZR in the nucleus. Because ZR is not currently druggable, we tested whether ZR expression leads to aberrant protein interactions that could represent therapeutic vulnerabilities. Using CRISPR-Cas9 pooled screening, we identified many novel druggable ZR interacting proteins including XPO1, CARM1, SMARCA4, and CDK1. We focused on the nuclear export protein (XPO1), given the ability of most XPO1 inhibitors (i.e. Selinexor) to cross the blood brain barrier, FDA approval, and documented safety profiles in children. We found that specific nuclear ZR levels are needed for cell proliferation and are regulated by XPO1. Increased ZR accumulation in the nucleus does not increase oncogenic gene expression but drives tumor cells out of cell cycle, as compared to a defective ZR DNA binding mutant. Treatment of ZR driven patient-derived mouse models with Selinexor impairs cell growth and extends survival of animals in vivo. The combination of Selinexor treatment with Gemcitabine and Ribociclib (used in a clinical trial for relapsed EPN at St Jude Children's Research Hospital (SJDAWN)) further extends mouse survival. Our findings demonstrate that ZR interacting proteins constitute therapeutic leads, and that XPO1 is critical for titrating 'goldilocks' levels of ZR nuclear expression. We identify a novel combination therapy of Selinexor, Gemcitabine, and Ribociclib that may be immediately translated into clinical trials for EPN patients that are currently without targeted treatments. XPO1 inhibition is an effective therapeutic strategy against ZFTA-RELA ependymoma.
Ferroptosis contributes to myocardial infarction (MI) pathogenesis. However, the role of nuclear receptor subfamily 1 group D member 2 (NR1D2) in MI-associated ferroptosis and its potential interaction with nuclear factor erythroid 2-related factor 2 (Nrf2) pathway remains unclear. We sought to determine whether NR1D2 regulates ferroptosis in MI through the Nrf2 pathway and to evaluate the therapeutic potential of NR1D2 knockdown. Bioinformatic analyses of GEO datasets identified NR1D2 as a key ferroptosis-related gene in MI. In vitro, NR1D2 expression was silenced in HL-1 cardiomyocytes subjected to hypoxia/reoxygenation (H/R) injury. Nrf2 inhibitor ML385 was used to verify pathway involvement. A mouse model of MI was established, and cardiac function was assessed following NR1D2 knockdown with or without ML385 co-treatment. NR1D2 expression was significantly upregulated in MI. Its knockdown in H/R-injured cardiomyocytes reduced cell death, inflammation, and ferroptosis, as indicated by decreased Fe²⁺ and malondialdehyde levels and elevated GSH/GSSG ratio. These protective effects were abolished by ML385, confirming Nrf2 dependence. Mechanistically, NR1D2 knockdown activated the Nrf2/HO-1 signaling axis, leading to the upregulation of downstream effectors glutathione peroxidase 4and SLC7A11. In MI mice, NR1D2 knockdown improved cardiac function (increased EF and FS), decreased infarct size, and inhibited ferroptosis-effects that were also negated by ML385. NR1D2 aggravates MI injury by suppressing the Nrf2 pathway and promoting ferroptosis. Targeting NR1D2 activates Nrf2 signaling and alleviates ferroptotic damage, revealing a novel regulatory mechanism and identifying NR1D2 as a promising therapeutic target for MI. A heart attack occurs when blood flow to the heart is blocked, causing heart muscle cells to die. We studied a specific type of cell death, ferroptosis, which is dependent on iron and worsens heart attack damage. Although ferroptosis is known to be important, how it is regulated remains unclear. Our data on heart attack identified NR1D2 as a protein that was significantly increased after a heart attack. To assess its importance, we reduced NR1D2 levels in isolated heart cells and in mice experiencing a heart attack. We discovered that lowering NR1D2 provided strong protection by reducing cell death and harmful inflammation and, crucially, preventing ferroptosis. We then sought to clarify the underlying mechanism. The protective effects of lowering NR1D2 were associated with activation of a well-known cellular defense pathway regulated by a protein called Nrf2. When we blocked the Nrf2 pathway, the benefits of reducing NR1D2 disappeared, confirming that NR1D2 acts by suppressing this natural protective system. In summary, our findings show that the NR1D2 protein aggravates heart attack injury by blocking the protective Nrf2 pathway and promoting ferroptosis. This suggests that therapies designed to target NR1D2 may offer a novel strategy to limit tissue damage and improve patient recovery after a heart attack.
Localized chemotherapy offers a promising strategy to improve therapeutic efficacy while minimizing the systemic toxicity of conventional cancer treatment, particularly following tumor resection. Electrospun nanofibers are well suited for this purpose due to their high porosity, extracellular matrix-mimicking architecture, and capacity for localized drug release. In this study, electrospun nanofibers based on PCL and PLGA were developed for localized cancer therapy. Three distinct nanofibrous architectures were fabricated: PCL nanofibers, PCL-PLGA blended nanofibers, and PCL-PLGA multilayered (tetra-layered) nanofibers, and their encapsulation efficiency was determined by high-performance liquid chromatography (HPLC). Scanning electron microscopy confirmed uniform, bead-free nanofibrous morphologies, while Fourier transform infrared spectroscopy and thermal analyses verified effective polymer blending, molecular interaction, drug incorporation, and enhanced thermal stability. The incorporation of PLGA altered the degradation rate and surface wettability of the nanofibers, enabling modulation of drug release behavior. Biological evaluations demonstrated acceptable hemocompatibility, favorable interactions with RAW 264.7 macrophages, and high cytocompatibility across all formulations. Importantly, nanofiber architecture significantly influenced release profiles (curcumin dye as a model), with multilayered or blend nanofibers exhibiting reduced burst release and prolonged drug delivery compared to single-polymer systems. In addition, proliferation clonogenicity and western blotting assays confirm their corresponding high cytotoxic responses (docetaxel as a model). Overall, this work demonstrates that architectural and compositional engineering of PCL-PLGA electrospun nanofibers provides a robust and adaptable platform for localized, sustained cancer therapy.
Mass terror attacks can psychologically impact entire societies. This study examined the relationship between social inclusion and posttraumatic growth (PTG) among a population experiencing national trauma and explored mediating roles of optimism and self-efficacy. A structured questionnaire was administered to 500 adults in Israel following the October 7, 2023, Hamas terrorist attack. A serial mediation model found that perceived social inclusion was positively associated with PTG, and optimism and self-efficacy acted as sequential mediators. Specifically, individuals who felt more socially included reported greater optimism, which was associated with greater self-efficacy and greater PTG. These results support the social contextual framework and highlight the importance of fostering social inclusion and psychological resources during national crises. Strengthening social inclusion may be a key strategy for promoting resilience and PTG following collective traumatic events. (PsycInfo Database Record (c) 2026 APA, all rights reserved).
Excessive exercise can induce metabolic disturbances that precede overt clinical disease. As the central metabolic organ, the liver plays a pivotal role in systemic metabolic adaptations to exercise, although its dynamic metabolic response remains poorly characterized. Characterizing hepatic metabolic shifts could advance early diagnostic and preventive strategies. Single exhaustive exercise (SEE) is an acute, short-duration, high exercise load, often used to model a single bout of supra-physiological exertion, whereas repeated exhaustive exercise (REE) models the cumulative physiological stress induced by consecutive exhaustive exercise sessions. This study systematically delineates temporal metabolic alterations in murine liver following SEE and REE. C57BL/6J mice were subjected to a single bout of exhaustive exercise or daily REE regimens for 7 consecutive days. Liver tissues and serum samples were collected at predetermined intervals (0, 1, 6, 12, 24, 48 h post-exercise) for comprehensive analysis, including untargeted metabolomics, histopathological evaluation, and quantification of liver injury biomarkers. SEE provoked transient metabolic perturbations that resolved within 24 h, whereas REE induced progressive metabolic remodeling, particularly involving amino acid metabolism. Both exercise modalities caused histologically confirmed hepatic injury, and the biomarkers for liver injury were elevated at an early stage but recovered within 24 h. Multivariate analysis identified "steroid hormone biosynthesis" and "taurine/hypotaurine metabolism" as key modules correlating with injury severity. Time-series analysis showed that most injury-related metabolites in the SEE group returned to baseline, whereas those in the REE group remained elevated through 48 h, suggesting sustained metabolic alterations within the observation window, which may reflect delayed recovery and/or adaptive metabolic remodeling in response to repeated exhaustive exercise. Our findings reveal distinct patterns of hepatic metabolic alteration: acute exhaustive exercise triggers self-limited metabolic adjustments, whereas repeated exhaustive exercise induces more sustained metabolic remodeling. These results underscore the importance of personalized exercise regimens and suggest that modulation of specific metabolic pathways may represent a potential strategy for mitigating exercise-induced hepatic stress.
The optimal treatment strategy for elderly patients with aneurysmal subarachnoid hemorrhage (aSAH) remains uncertain. While endovascular coiling and surgical clipping are both established interventions, age-related physiological vulnerability and comorbidity burden may alter the risk-benefit profile. We performed a systematic review and meta-analysis to compare outcomes between these two modalities in elderly patients with aSAH. Searches of PubMed, Embase, Scopus, and Cochrane CENTRAL were conducted from inception to 20th July 2025. The definition of elderly patients aged ≥ 60 years was adopted as per the World Health Organization. Primary outcomes were favorable functional outcome (modified Rankin Scale [mRS] 0-2) and mortality. Secondary outcomes were delayed cerebral ischemia (DCI), delayed hydrocephalus and rebleed. Twenty studies (2 randomized controlled trials, 18 observational) were included. A total of 44,526 patients were included with 24,724 aneurysms clipped and 19,802 coiled. The mean age was 72.1 years in the coiling cohort and 72.8 years in the clipping cohort. Aneurysm location was anterior in 94% of cases. Hypertension was more prevalent in the coiling cohort (OR 1.25, 95% CI 1.03-1.51; p = 0.024). There was no association between poor-grade WFNS score 4-5 and treatment modality (OR = 0.89, 95% CI: 0.62-1.27; p = 0.471). There was no significant difference between coiling and clipping in achieving favorable outcomes (OR 1.07, 95% CI 0.75-1.52; p = 0.712) or mortality (OR 0.89, 95% CI 0.64-1.23; p = 0.471). Rates of delayed cerebral ischemia, hydrocephalus, and rebleeding were also comparable. Current evidence, derived from mainly observational studies, does not suggest difference in functional outcomes nor mortality between endovascular coiling and surgical clipping in elderly patients with aSAH. However, significant selection bias, variability in age definitions and the lack of randomized comparisons should be considered when interpreting these findings.