This study investigated whether blood oxygenation in a membrane oxygenator can be regulated by modulating the gas-blood pressure difference. This study combined theoretical analysis, reduced computational simulation, and exploratory in vivo animal testing. A conceptual three-compartment framework based on Dalton's law, Fick's law, Henry's law, and the Hill equation was used to organize the main oxygen transfer pathway from the gas phase to plasma and red blood cells. For numerical analysis, this conceptual framework was reduced to a steady-state lumped oxygen balance model to assess how outlet blood oxygenation varies with gas-blood pressure difference and gas-to-blood flow ratio. Key trends were further examined in a rabbit ECMO circuit under different gas-side and blood-side operating pressures. The reduced simulations showed that post-oxygenator blood oxygen partial pressure depended strongly on both gas-blood pressure difference and gas-to-blood flow ratio. Under ambient air, simulated outlet P O 2 values above 120 mmHg were achievable within the practical range studied. In the animal experiments, at a gas-to-blood flow ratio of about 2:1, less favorable gas-blood pressure difference conditions were associated with a marked decrease in post-oxygenator arterial P O 2 , whereas at about 1:1, the oxygenation effect remained limited. A direct baseline model-experiment comparison showed trend-level agreement but also quantitative underestimation by the reduced model. Theoretical analysis, reduced simulation, and exploratory animal results support the feasibility of pressure difference-based oxygenation control in membrane oxygenators. Substantial oxygenation may be achieved with ambient air when the gas-to-blood flow ratio is adequate. The present model should be interpreted as a trend-level reduced mechanistic framework rather than a quantitatively validated subject-specific predictor. Future work should include absolute pressure-based analysis, explicit carbon dioxide transport modeling, parameter identification using larger datasets, and larger-scale in vivo evaluation.
Carbon monoxide (CO) poisoning is a leading cause of toxic exposure-related morbidity and mortality worldwide. Although hyperbaric oxygen therapy increases CO elimination, its clinical use is limited by accessibility, side effects, and inconclusive long-term efficacy. We developed a cEHT system - a device for continuous extracorporeal hyperoxygenation therapy that enhances CO removal from blood without exposing patients to systemic hyperbaric conditions. The system was tested in vitro and in vivo in a porcine CO poisoning model. Carboxyhemoglobin (COHb) half-life, hemodynamics, hemolysis, and tissue hypoxia were evaluated. In vivo, the cEHT system significantly reduced COHb half-life by 53% compared to ventilation with 100% oxygen alone (27.0 ± 0.3 min vs. 57.6 ± 12.5 min; p = 0.01). Hemodynamic parameters, pulmonary artery pressure, and plasma-free Hb remained stable during treatment. Histological analyses showed reduced ischemic injury in heart and brain tissues in the cEHT group in contrast to the control group. The cEHT system enables effective and hemodynamically stable extracorporeal CO elimination. It may offer a promising therapy for CO poisoning when a pressure chamber is not promptly available. Further studies are needed to optimize system performance and assess clinical translation.
Heart failure with reduced ejection fraction carries a poor prognosis. Although guideline-directed medical therapy reduces morbidity and mortality, its real-world utilization is low. Accordingly, we conducted an open-label randomized trial (POLY-HF) at two centers enrolling a predominantly underserved population to test whether a polypill strategy improves cardiac function in heart failure. Adults with heart failure and left ventricular ejection fraction ≤40% were randomized to a once-daily polypill containing metoprolol succinate (25/50/100/150 mg), spironolactone 12.5 mg and empagliflozin 10 mg, or rapid uptitration of individual guideline-directed medical therapy medications ('enhanced usual care'). Participants also continued treatment with a renin-angiotensin system inhibitor or sacubitril/valsartan as a separate pill. The primary endpoint was ejection fraction as assessed by cardiac magnetic resonance imaging at 6 months. Secondary endpoints included clinical outcomes and adherence. We randomized 212 patients (median age 54 years, 22% female, 54% Black). Follow-up magnetic resonance imaging data were available for 187 (88%) participants who were included in the modified intention-to-treat analysis. Polypill treatment was associated with greater improvement in ejection fraction compared to enhanced usual care (between-group difference, 3.3 percentage points, 95% confidence interval, 0.2-6.4; P = 0.039), meeting the primary outcome. Individuals randomized to the polypill also had a 60% lower rate of heart failure hospitalizations or emergency department visits (adjusted rate ratio, 0.40; 95% confidence interval, 0.18-0.88; P = 0.024). Adherence, assessed by blood concentrations of metoprolol and spironolactone, was higher with polypill treatment than with enhanced usual care (79% versus 54%, P = 0.001). The polypill was well tolerated, with fewer adverse events with polypill treatment as compared to enhanced usual care. A polypill for heart failure was associated with a significant improvement in cardiac function as compared with enhanced usual care. ClinicalTrials.gov registration: NCT04633005 .
We read with great interest the article by Bruno and D'Antimi titled "Early Protein Supplementation Enhances Wound Healing and Reduces Complications Following Abdominoplasty: A Controlled Study in Non-bariatric Patients" (Aesthetic Plastic Surgery, 2026) [1]. The authors should be praised for doing a well-planned study on a topic that is very important in clinical practice but has not gotten enough attention in aesthetic surgery. Their results provide encouraging insights regarding the function of protein supplementation. Nonetheless, various methodological and interpretative concerns overlooked by the authors necessitate thorough examination to guarantee accurate interpretation and subsequent application.No Level Assigned This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
In this study, a PtNi nanocomposite supported on reduced graphene oxide (rGO) was synthesized via a chemical reduction method, and its electrocatalytic performance for the electrochemical oxidation of sodium borohydride (NaBH₄) was investigated. The structural and morphological properties of the synthesized PtNi@rGO nanocomposite were characterized in detail using FTIR, XRD, TEM, and SEM-EDX analyses. The characterization results demonstrated that the PtNi alloy nanoparticles were successfully immobilized on the rGO surface and were homogeneously distributed in the 20-50 nm size range. Electrochemical performance studies were conducted using the cyclic voltammetry method in a solution containing 1 M NaOH and 0.1 M NaBH₄. The results revealed that the PtNi@rGO electrocatalyst achieved a maximum current density of 19.57 mA cm⁻², while under the same conditions, the PtNi and Pt electrodes exhibited values of 17.19 and 6.53 mA cm⁻², respectively. Furthermore, the determined initial potential of 0.13 V for PtNi@rGO indicated a faster reaction kinetics compared to the PtNi (0.17 V) and Pt (0.22 V) electrodes. Analyses conducted at different scan rates demonstrated that the reaction proceeded in a kinetically controlled manner and that the rGO support significantly improved charge transfer processes. Long-term stability tests have demonstrated that the developed nanocomposite maintains its electrocatalytic performance. The results indicate that the PtNi@rGO nanocomposite is a stable and promising electrocatalyst with high activity for hydrogen production via the electrooxidation of NaBH₄.
Globally, pine forest ecosystems are under increased threat of foliar fungal pathogens. This includes brown spot needle blight (BSNB), caused by Lecanosticta acicola. High disease severity of BSNB has been observed in loblolly pine plantations across the Southeastern U.S., causing substantial declines in productivity. Because foliar disease outcomes depend on phyllosphere community interactions, shifts in community composition under climate variation may influence outbreak potential of L. acicola. To investigate these interactions, fungal communities in first- and second-year symptomatic and asymptomatic needle tissue were examined over two years across six loblolly pine plantations in central Louisiana. L. acicola was consistently enriched in symptomatic needles and emerged as a strong indicator of disease, including increasing crown dieback, particularly in first-year needles. Disease progression was associated with reduced fungal diversity and pronounced shifts in community composition, consistent with microbiome dysbiosis. Additional fungi, including Lophodermium and Soleella, were enriched in symptomatic needles, likely representing opportunistic associates with a potential role in disease. There were distinct differences in the relationship with climate variables for symptomatic and asymptomatic communities. Symptomatic communities were associated with higher humidity, higher minimum temperatures, and reduced solar radiation, whereas asymptomatic communities were correlated with warmer, drier conditions. Our findings demonstrate that BSNB severity reflects both L. acicola infection and broader needle fungal community disruption, with first-year needles being especially vulnerable. These results underscore the need to integrate microbial community dynamics and climate into disease monitoring and management, as increasing humidity, warmer nights, and more variable precipitation likely elevate fungal pathogen risk.
Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid decline in glomerular filtration function caused by multiple factors. Factors such as stones and tumors can lead to AKI following renal obstruction. Renal tubular epithelial cell injury is a key component of the pathophysiological mechanism of ischemic acute kidney injury after obstruction.Oxygen-glucose deprivation (OGD) in HK-2 cells and a mouse model of unilateral ureteral ligation (UUO) were used to investigate the role of Claudin-2 in renal tubular epithelial cell apoptosis in ischemia-induced AKI. In animal experiments, the expression of Claudin-2 protein was decreased, while Bax and Caspase-3 expression were increased, and Bcl-2 expression was decreased in the renal tissue of UUO mice. Similarly, after OGD treatment, Claudin-2 protein expression was decreased, Bax and Caspase-3 expression were increased, and Bcl-2 expression was decreased. Upregulation of Claudin-2 protein expression through lentivirus transfection in OGD-treated HK-2 cells reduced the decline in cell viability and the proportion of apoptotic cells. Additionally, upregulation of Claudin-2 protein expression reduced OGD-induced Caspase-3 expression, while the Bax/Bcl-2 ratio showed no significant change. The expression of Claudin-2 is decreased during acute obstructive kidney injury, which contributes to changes in Caspase-3 apoptotic protein and activates cell apoptosis,while the Bax/Bcl-2 ratio showed no significant change.Claudin-2 protein likely modulates apoptosis through a caspase-3-dependent pathway independent of the Bax/Bcl-2 ratio.
Bidirectional DC-DC converters are widely used in electric vehicle (EV) powertrains. The adoption of digital control in such converters introduces inherent delays, particularly computational and PWM delays, which influence system stability and dynamic performance. Various delay mitigation techniques have been proposed; however, their impact on the frequency-domain characteristics and transient performance of bidirectional DC-DC converters has not been analyzed. This paper presents a delay-aware frequency-domain analysis of a digitally controlled bidirectional DC-DC converter, relating sampling strategies to effective control delay and corresponding stability margins. An advanced multi-sampling PWM technique incorporating sample-shift is implemented in this topology, and a comparison is carried out with single sampling and conventional multi-sampling. The frequency-domain results show that, in buck mode, the proposed approach improves the phase margin from 60.89° to 68.64° and the gain margin from 35.52 dB to 42.87 dB. Time-domain results support these observations, the settling time is reduced from 0.059 s to 0.038 s, and the steady-state error during input voltage disturbances is reduced from 7.73 V to 4.26 V in buck mode. Similarly, in boost mode, the response time to the reference step change improves from 0.00789 s to 0.00688 s, and the settling time is reduced from 0.0747 s to 0.0732 s. Experimental validation supports the effectiveness of the proposed approach.
Carriers of CYP2C19 loss-of-function (LOF) alleles have reduced clopidogrel bioactivation, higher on-treatment platelet reactivity, and more recurrent ischaemic events. Smoking may enhance clopidogrel responsiveness. We evaluated whether smoking modifies the impact of LOF alleles on clopidogrel effectiveness after acute ischaemic stroke. This is a post-hoc analysis of the PLATELET trial (ClinicalTrials.gov NCT04072705), a prospective, observational study enrolling participants from September 2019 to March 2023. Patients receiving clopidogrel were classified as current or non-current smokers and stratified by CYP2C19 genotype (carriers of LOF alleles vs. non-carriers). The primary outcome was a 6-month composite of ischaemic or haemorrhagic stroke, myocardial infarction, or cardiovascular death. Secondary outcomes included ischaemic stroke, transient ischaemic attack, coronary revascularization, early neurological deterioration and a good functional outcome, defined as modified Rankin Scale (mRS) score 0-2 at 3 months. Safety outcomes were major bleeding and mortality. Among 2,910 participants, the primary outcome occurred in 4.8% of non-current smokers and 4.2% of current smokers. In current smokers, events were lower in non-carriers than carriers (0.6% vs 6.5%), but not in non-current smokers (4.4% vs. 5.0%). In multivariable analysis, non-carriers had a lower risk than carriers of LOF alleles only among current smokers (adjusted hazard ratio [aHR], 0.13; 95% CI; 0.02-0.70). Among the secondary outcomes, only ischaemic stroke showed lower incidence in non-carriers within the current smoking group (0.3% vs. 2.8%), with a significantly reduced risk (aHR, 0.15; 95% CI 0.03-0.85). Safety outcomes did not differ by genotype in either group. The benefit of clopidogrel was confined to current smokers who were non-carriers, with comparable safety. Combining smoking status with CYP 2C19 genotyping may help personalize antiplatelet therapy.
Tungsten disulfide (WS2) nanoparticles are widely considered as promising solid lubricant additives for boundary/mixed lubrication. However, the consistent mechanism linking macroscopic tribotests to atomistic behavior remains elusive. We investigated WS2-dispersed polyalphaolefin (PAO 6) lubrication using ball-on-disk experiments, post-test surface analysis, and nonequilibrium molecular dynamics (MD) simulations. The addition of WS2 markedly reduced and stabilized friction, with the average coefficient of friction (COF) decreasing from 0.146 to 0.055, and mitigated wear, with the measured wear volume decreasing from 0.019 to 0.011 mm3 (≈ 42.1% reduction). X-ray photoelectron spectroscopy of the worn surface displayed W 4f and S 2p signals, consistent with WS2-derived species remaining within the wear track after sliding. MD simulations provided a mechanism-level atomistic interpretation consistent with this macroscopic friction trend: the WS2-containing interface exhibited a lower interfacial shear response than the PAO-only interface (time-averaged COF: ≈10.9% reduction from 0.46 to 0.41), while interfacial energetics indicated weaker PAO coupling with WS2 than with Fe (- 101.42 vs. -244.51 eV). This weaker PAO-WS2 coupling suggests that WS2-derived interfacial species may reduce effective PAO-Fe coupling and facilitate lower-shear interfacial accommodation, which is consistent with the experimentally observed friction stabilization and wear reduction. Representative MD configurations also displayed Fe atom detachment in the PAO-Fe model but not prominently in the WS2-mediated case.
Delays in diagnostic confirmation remain common in young children with autism spectrum disorder (ASD). These delays are particularly concerning for children with severe symptoms and elevated support needs, for whom early identification is especially important. There is therefore a need for objective and feasible approaches to assist early identification prior to specialist evaluation. Eye-tracking is a non-invasive method for quantifying gaze-fixation patterns associated with ASD. The present study examined whether gaze-fixation indices derived from the Gazefinder eye-tracking system can identify a clinically defined severe ASD subgroup within a real-world clinical population. The analysis included 442 children aged 2-6 years referred to a child psychiatry outpatient clinic who underwent Gazefinder assessment. Based on Childhood Autism Rating Scale (CARS) scores, children were classified into a Severe ASD group (n = 42) and an Other group (Non-ASD and Mild-to-moderate ASD; n = 400). Gaze fixation rates on predefined regions of interest were compared, and discriminative performance was evaluated using receiver operating characteristic analyses. Children in the Severe ASD group exhibited reduced fixation on the mouth region in dynamic facial stimuli and reduced fixation on people relative to geometry. A composite criterion derived from four gaze-fixation indices yielded a sensitivity of 85.7% and a specificity of 55.3% for discriminating Severe ASD. These findings suggest that Gazefinder-based measures may provide adjunctive information to support screening and referral-related decision-making for clinically defined severe ASD in young children.
Training in neurosurgery is increasingly challenged by the complexity of cranial anatomy, the rarity of certain pathologies, ethical constraints on cadaveric dissection, and limited operative exposure. Advances in three-dimensional (3D) printing have enabled the development of patient-specific anatomical models derived from computed tomography and magnetic resonance imaging, offering realistic, reproducible platforms for surgical training and preoperative planning. This chapter reviews contemporary applications of 3D-printed, hybrid, and multimodal simulation models in neurosurgical education, with particular emphasis on complex craniofacial and encephalocele procedures. Through illustrative case reports-including frontoethmoidal and transsphenoidal meningoencephaloceles, metopic craniosynostosis, and late encephalocele correction-the chapter demonstrates how multimaterial 3D-printing, hybrid silicone-resin constructs, and integration with augmented and mixed reality can enhance spatial understanding, tactile feedback, and procedural rehearsal. Evidence from these cases indicates that patient-specific simulation can alter surgical strategy, reduce operative time and blood loss, and improve multidisciplinary communication. Educational benefits extend beyond surgeons to trainees and allied health professionals, supporting structured skill acquisition and competency-based assessment. The chapter also discusses the relevance of low-cost 3D-printing solutions for low- and middle-income countries, highlighting open-source software and affordable fabrication techniques as tools to reduce global disparities in neurosurgical care. Limitations related to cost, material fidelity, imaging quality, and technical expertise are addressed, alongside future directions for research and curriculum integration. Overall, 3D-printed and hybrid simulation models represent a transformative approach to neurosurgical training and patient-specific surgical planning, with significant implications for education, safety, and global health equity.
Risk stratification in non-ischemic cardiomyopathies (NICM) remains challenging despite guideline-based phenotypic classification using multimodal diagnostics including endomyocardial biopsy (EMB). We aimed to identify EMB-derived histological and molecular markers that improve phenotypic characterization and long-term risk stratification in patients with NICM. In this prospective cohort study, 703 consecutive patients with symptomatic NICM underwent standardized multimodal evaluation, including clinical assessment, cardiac imaging, and endomyocardial biopsy. Biopsy specimens were analyzed using histology, immunohistochemistry, and targeted myocardial mRNA profiling. Associations between endomyocardial markers, and fibroinflammatory remodeling, imaging parameters, and molecular signatures were assessed cross-sectionally. Long-term prognostic relevance was evaluated using survival and multivariable prediction analyses during follow-up of up to fifteen years for all-cause mortality, cardiovascular mortality, implantable cardioverter-defibrillator (ICD) implantation, and appropriate ICD discharge. Elevated myocardial Gremlin-1 expression was associated with increased fibrosis, adverse cardiac remodelling, reduced left ventricular function, and enrichment of pro-fibrotic and inflammatory mRNA signalling pathways. Myocardial and circulating Gremlin-1 expression was independently associated with all-cause and cardiovascular mortality, and ICD implantation and discharge. Machine learning-based phenotyping using histological EMB data identified Gremlin-1 as a key predictive feature of poor prognosis. Incorporation of Gremlin-1 into predictive models significantly improved long-term cardiovascular risk stratification in NICM patients. Our results unveil that Gremlin-1 is associated with inflammation and cardiac remodelling in patients with NICM, and patients with Gremlin-1+ EMB and high plasmatic Gremlin-1 concentrations are at elevated risk to develop adverse cardiovascular events. Thus, the histological evaluation of Gremlin-1 may help to improve risk discrimination and management of NICM and HF patients. Non-ischemic cardiomyopathy (NICM) refers to diseases in which the heart muscle becomes abnormal and unable to pump effectively, without being caused by blocked coronary arteries. Predicting which patients will develop serious complications remains difficult using current clinical tests. We examined whether information from small heart tissue samples could improve long-term risk prediction. We analysed 703 NICM patients who underwent comprehensive clinical assessment and endomyocardial biopsy. Heart tissue was assessed for markers of inflammation and scarring, including the protein Gremlin-1, and patients were followed for up to fifteen years for major cardiovascular outcomes. Higher Gremlin-1 expression and circulating Gremlin-1 were associated with scarring, reduced heart function, and increased risk of adverse outcomes. These findings suggest that tissue-based biomarkers including Gremlin-1 may support more accurate risk stratification and personalized management in NICM.
Recent studies have highlighted the crucial role of mechanical properties in the ovarian microenvironment for ovarian function. However, the mechanisms that cause ovarian matrix stiffening during aging remain incompletely understood. Here we utilized atomic force microscopy (AFM) to demonstrate that human ovarian matrix stiffness increases with aging and in pathophysiological conditions, such as chemotherapy-induced premature ovarian insufficiency (POI), polycystic ovary syndrome (PCOS) and ovarian endometriosis. By integrating proteomic analysis of human ovarian tissue with transcriptomic profiling of human ovarian fibroblasts, we identified that IL-11, which is elevated in aging ovaries of mice, rats and humans, activates fibroblasts to secrete extracellular matrix (ECM), thereby increasing ovarian matrix stiffness. Genetic deletion of Il11ra1 in mice mitigated the increase in ovarian matrix stiffness and the decline in ovarian function associated with aging, chemotherapy-induced POI and PCOS. Single-nuclei RNA sequencing (snRNA-seq) revealed that blocking Il11ra1 reduces the proportion of activated fibroblasts. Furthermore, administration of siIl11 nanoparticles to aged mice and rats enhanced fertility and reduced ovarian matrix stiffness. Together, these findings highlight the pro-inflammatory factor IL-11 in regulating ovarian matrix stiffness. We propose that anti-IL-11 therapy represents a promising translational strategy for delaying ovarian aging.
Rapid and accurate assessment of bacterial concentration is essential, yet conventional methods remain constrained by low detection sensitivity at low concentrations with long processing times. Optical density (OD₆₂₅) measurements report a detection sensitivity value of approximately of 93% for high concentrations of [Formula: see text] CFU/mL. Plate count assays under similar bacteria parameters exhibit 62% and require > 24 h for incubation and colony enumeration. In this study, we introduce the dielectrophoretic (DEP)-based crossover frequency (fx0 ) method as a quantitative, frequency-based metric for rapid bacterial concentration assessment, varying concentrations of initial, 1:10, 1:100, and 1:1000 representing bacteria parameter of [Formula: see text]. The initial concentration, 1.5 × 10⁸ CFU mL, yielded an OD₆₂₅ of 0.12, an average plate count of 320 CFU, and an fx0 of 4.5 MHz, corresponding to the densest bacterial population. At a 1:10 concentration, these values decreased to OD₆₂₅ = 0.08, 220 CFU, andfx0 = 3.23 MHz. Further dilution to 1:100 concentration yielded OD₆₂₅ = 0.05, 186 CFU, and fx0 = 2.50 MHz, while the most dilute sample at 1:1000 concentration showed OD₆₂₅ = 0.011, 80 CFU, and fx0 = 0.71 MHz, reflecting reduced cell density and conductivity. Detection sensitivity analysis from the response normalization equation for OD₆₂₅, plate count, and fx0 experimental achieved values of 53.6%, 59.15%, and 60.69%, respectively. Based on the increasing trend of OD₆₂₅, plate count, and DEP-based fx0 values with respect to each method, we plotted a linear fit , OD₆₂₅ (R2 = 0.963), plate count (R2 = 0.949) and DEP-based fx0 (R2 = 0.981). The plotted line serves as a reference for the expected values of OD₆₂₅, plate count, and DEP-based fx0 at the selected medium conductivity (σₘ) for the following evaluation tests. We introduced high σₘ values of 0.8 S/m, 0.6 S/m, 0.4 S/m, and 0.2 S/m, and low σₘ values of 0.08 S/m, 0.06 S/m, 0.04 S/m, and 0.02 S/m in the evaluation test to observe the deviation between the plotted line of the expected trend and the actual measured values. We calculated the deviations between expected and measured values and produced a mean deviation of 116% for OD₆₂₅, 49% for plate count, and 60% for DEP-based fx0 with p < 0.05, indicating a strong linear relationship between expected values and actual values measured of every method, thus demonstrating trend agreement within the tested conductivity range, while also revealing nonlinear deviations at elevated conductivity. This paper aims to study the correlation between DEP-based fx0 OD₆₂₅ and plate count by assessing the detection sensitivity value of each method, reliability, and evaluation based on linear regression of expected and measured values under the same experimental conditions for Staphylococcus aureus concentration assessment. The results showed that DEP-based fx0 was potentially superior in detection sensitivity, with a conductivity-associated correlation based on linear regression analysis.
Neurometabolic analysis is routinely performed using 13C NMR/MRS in conjunction with the administration of 13C-labeled tracers. Despite its widespread use, the low sensitivity of 13C NMR necessitates long acquisition times. To address this limitation, the present study introduces an indirect approach that uses a single 1H NMR acquisition to measure deuterium labeling by exploiting labeling at specific sites, thereby providing a novel and more efficient strategy for assessing neurometabolism. In this study, male SD rats were infused with [6,6'-2H2]glucose for 10-90 min, and the 2H labeling of cortical metabolites was measured ex vivo using 2H NMR spectroscopy. After 90 min of [6,6'-2H2]glucose infusion, resonances corresponding to [3-2H2]lactate, [4-2Hx]glutamate, [4-2Hx]glutamine, and [3-2H]aspartate (∼2.60 ppm) were detected. In contrast, signals corresponding to [2-2H]aspartate (∼3.90 ppm), [2-2H]glutamate (∼3.76 ppm), and [3-2H]glutamate (∼2.09 ppm) were not detected, even after prolonged infusion, suggesting complete loss of the 2H label during the second turn of the tricarboxylic acid cycle. The cerebral metabolic rate of glucose oxidation, estimated by fitting an exponentially saturating curve to the pooled labeling of [4-2Hx]glutamate, [4-2Hx]glutamine, and [3-2H]aspartate, was 0.389 ± 0.031 μmol/g/min. The [4-2Hx]glutamate levels were also derived by subtracting the [4-1H2]glutamate resonance intensity from total [4-1H2]glutamate intensity estimated using the [3-1H2]glutamate intensity in unedited 1H NMR spectra. The concentrations of [4-2Hx]glutamate determined from 1H NMR spectra were comparable to those determined from 2H NMR. Moreover, when applied to 5xFAD mice (2.53 ± 0.43 μmol/g, n = 7), a model of Alzheimer's disease, this indirect approach revealed significantly reduced (p = 0.028) [4-2Hx]glutamate levels compared with controls (2.99 ± 0.15 μmol/g, n = 7). This decrease was comparable to that observed with the direct 2H NMR measurements and was consistent with findings from 13C tracer-based studies.
Immune aging may contribute to Alzheimer's disease. Bacillus Calmette-Guérin (BCG), a vaccine known to induce trained immunity, has been linked to reduced Alzheimer's risk in prior studies. However, whether trained immunity can be observed in the human central nervous system remains unclear. We assessed whether BCG induces trained immunity-like responses in adults with and without Alzheimer's-related changes. We conducted two related one-year, open-label clinical trials in adults aged 55 years or older (n = 12 without Alzheimer's-related pathology; n = 11 with Alzheimer's-related pathology) recruited at a single center. Participants received two intradermal BCG vaccinations one month apart. Protocol-defined objectives included safety, neurocognitive outcomes, and longitudinal immune and Alzheimer's biomarker changes in blood and cerebrospinal fluid. Immune responses were assessed using cytokine assays and single-cell profiling. All enrolled participants were included where data were available; longitudinal changes were analyzed using mixed-effects models. Here we show that BCG induces persistent, trained immunity-like changes in immune cells in cerebrospinal fluid, including enhanced innate responsiveness and associated transcriptional programs. These responses differ from blood, suggesting compartment-specific immune imprinting. In participants without Alzheimer's-related changes, these immune shifts are accompanied by decreased amyloid-β levels in cerebrospinal fluid and increased levels in blood. BCG was well tolerated, with no unexpected safety signals observed. These findings suggest trained immunity-like responses in the central nervous system that may influence Alzheimer's-relevant pathways. This approach may represent an early neurodegenerative intervention strategy, although larger controlled studies are needed to confirm these observations. ClinicalTrials.gov NCT04507126 (June 23, 2020) and NCT05004688 (August 6, 2021). As people age, the immune system becomes less effective and may contribute to diseases like Alzheimer’s disease, a condition that affects memory and thinking. The BCG vaccine, commonly used against tuberculosis, can “train” the immune system to respond better to challenges. In this study, we tested whether BCG could change immune activity in both the blood and the fluid surrounding the brain and spinal cord in older adults with and without Alzheimer’s-related changes. Participants received BCG and were followed for one year with blood and spinal fluid tests. We found that BCG changed how immune cells behaved, including in the fluid surrounding the brain and spinal cord, and altered markers linked to Alzheimer’s disease. These findings suggest that boosting the immune system in specific ways may help maintain brain health during aging, but larger studies are needed to understand whether this could prevent or treat disease.
While multimodal large language models (LLMs) demonstrate significant potential in healthcare applications, their clinical utility is difficult to appraise. Current evaluations of medical-assisting LLMs are often limited by sparse human expertise, narrow specialty scope, and reliance on multiple-choice benchmarks or synthetic vignettes, which can inflate performance and obscure clinical utility. We conducted a multicenter, multidisciplinary study in which more than 400 physicians-spanning seven specialties, varied experience levels, and multiple geographic settings-evaluated LLM-generated free-text responses to real, de-identified clinical cases. In a matched-control design, we also deployed an equivalent number of AI agents configured to mirror physician characteristics to examine whether automated evaluators can supplement or replace human assessment. Our results demonstrated that physician assessments exhibited substantial heterogeneity by clinical seniority and practice environment, leading to notable shifts in relative model rankings across cohorts. While AI agents delivered highly efficient, directionally aligned assessments, they did not fully capture the nuances of human clinical judgment and could not substitute for physician-centered evaluation. Instead, they promise assistive tools that can triage or pre-screen outputs to reduce human burden.
Recovering critical strategic metals from superalloy scraps is indispensable to sustaining the materials supply chain. However, the excellent physicochemical properties of superalloy make them difficult to dissolve and separate, thereby hindering their recycling and reutilization. Here, we design a molten salt metal-air electrolyzer (MMAE) that synergistically oxidizes and pulverizes scraps, which generates oxide powders that can be easily dissolved and separated for all element recovery. The corrosivity of molten chloride and electrochemical polarization can convert scraps at the anode into soluble metal chlorides, while oxygen is reduced to O2- in the form of soluble CaO. Subsequently, the soluble metal cations encounter O2- in molten CaCl2-NaCl to precipitate as insoluble oxides. The MMAE constructs two dynamic metal/metal chloride and oxygen/CaO interfaces, achieving a high dissolution rate of 0.290 g/(cm2∙h). Subsequent roasting process preferentially extracts rhenium (Re) with a recovery efficiency of 90.46%, followed by selective separation and recovery of other metals with a recovery efficiency of >93% under low acid consumption. Life cycle assessment analysis shows its low energy consumption and environmental impact. Overall, the MMAE is a general method to recover a range of superalloy scraps, opening up an effective pathway for advancing sustainable metal recycling.
Hypomimia is a hallmark of Parkinson's disease (PD), but whether emotional expressions show lateralized abnormalities remains unclear. While asymmetry has been described for posed smiles, no study has examined true spontaneous smile asymmetry in PD. The whistle-smile reflex (WSR), an involuntary smile elicited after voluntary whistling, offers an opportunity to investigate a form of smiling that closely resembles typical spontaneous expressions of joy. In the present study, we aimed to assess the frequency, intensity, and asymmetry of smiling elicited by the WSR in PD compared with healthy controls (HCs) and to explore links between facial and motor asymmetry. Fifty PD patients and 22 age-matched HCs underwent standardized video recording of the WSR. Only participants judged as smiling by ≥ 3/4 raters were included in the chimeric-face analysis. Left-left (LL) and right-right (RR) chimeric images were generated, and seven blinded raters evaluated smile presence and hemiface expressivity. Facial Laterality Index (FLI) and Body Laterality Index (BLI) quantified asymmetries. WSR was less frequent in PD than HCs (video: 44% vs. 72%; mouth-only chimeras: 50% vs. 81%, p < 0.01). PD smiles were more often symmetrical (59% vs. 25%, p = 0.03), with no consistent left-right dominance. Facial and motor asymmetry were unrelated (p > 0.05). Symmetric smilers had higher UPDRS-III scores (p = 0.04). In PD, WSR is reduced and bilaterally flattened, with no lateralized asymmetry, possibly reflecting limbic-subcortical dysfunction. Smile symmetry increases with motor severity, supporting its potential as a simple marker of hypomimia. The WSR and chimeric-smile analysis provide practical tools to assess emotional expressivity in PD.