To characterize relapse patterns, identify relapse-related risk factors, and evaluate prognostic determinants of post-relapse outcomes in pediatric acute lymphoblastic leukemia (ALL) patients treated with the Chinese Children's Cancer Group (CCCG)-ALL-2015 protocol. This retrospective study included 380 children diagnosed with ALL between 2016 and 2019. We analyzed relapse timing (very early, early, late), relapse sites (bone marrow (BM) vs. extramedullary), early treatment response (morphology and minimal residual disease (MRD)), and post-relapse outcomes. Survival was estimated using Kaplan-Meier methods. Relapse rate was 11.1% (42/380), predominantly isolated BM (69.0%) and very early timing (47.6%). Relapse varied significantly by risk group (low-risk: 5.9%; intermediate-risk: 10.4%; high-risk: 22.4%; P < 0.001), immunophenotype (B-ALL: 9.8% vs. T-ALL: 23.5%; P = 0.015), Day 19 morphology (M1:9.9% vs. M3:20.0%; P < 0.001), Day 46 morphology (M1:10.5% vs. M3:21.4%; P = 0.025), and Day 46 MRD status (positive:21.4% vs. negative:8.7%; P = 0.002). Fusion gene positivity was significantly associated with earlier relapse timing (P < 0.05). Post-relapse survival differed by relapse timing (very early: 7.2 months; early: 23.2 months; late: 37.8 months; P < 0.001) and initial risk group (low-risk: 38.2 months; high-risk: 18.1 months; P = 0.006). Non-remission on Days 19/46, Day 46 MRD positivity, and high-risk status predict ALL relapse. High-risk patients experience earlier relapses and poorer survival. Fusion gene positivity is associated with earlier relapse timing.
Interface engineering using multifunctional materials is central to advancing both efficiency and operational stability in perovskite solar cells (PSCs). Here, we report a family of enol-centered small-molecule hole-transporting materials (HTMs) DKcH, DKPh, and DKTPA rationally designed to couple efficient hole extraction with intrinsic interfacial defect passivation. The cooperative C═O and ‒OH moieties act as bidentate coordination sites, enabling strong chemical interactions with undercoordinated species at the perovskite surface. Systematic modulation of the secondary side arm from cyclohexyl to phenyl and triphenylamine progressively increases molecular conjugation, strengthens π-π stacking, and improves film cohesion and thermal robustness, establishing clear structure-property-function relationships. Benefiting from optimized electronic structure and interfacial functionality, DKTPA delivers superior device performance, enabling inverted MAPb(I0.9C0.1)3-based PSCs to achieve a high-power conversion efficiency of 22.74%. Notably, DKTPA-based devices retain 90.35% of their initial efficiency after 500 h of continuous one-sun illumination. This work introduces enol-centered HTMs as a versatile functional-materials platform and provides general molecular design principles for stable, dopant-free interfacial layers in high-performance perovskite photovoltaics.
The sluggish kinetics of the oxygen reduction reaction (ORR) and the high cost of Pt-based catalysts remain major barriers for alkaline fuel cell (AFC) technologies. Here we report a Cu-decorated CoO@Pd catalyst in which atomic-to-subnanometer CuOx species reconstruct the Pd-Co-Cu heterointerface and enable a cooperative multi-site ORR pathway. Structural and spectroscopic analyses reveal that low Cu loading produces atomically dispersed CuOx motifs that enrich oxygen vacancies (OV)s, preserve metallic Pd, and stabilize oxygen-deficient Co3 + centers. Operando PFY-XANES/EXAFS further uncovers a synergistic mechanism in which OVs around Cu serve as rapid O2 activation sites, Pd mediates lateral *Oads spillover, and OVs around Co act as the primary *Oads reduction centers. This division of labor maximizes four-electron ORR kinetics, yielding a on-set potential of 0.935 V and a mass activity (MA) of ∼1.6 × 104 mA mgCu - 1 without decay for 50k potential cycles, surpassing commercial Pt/C by over two orders of magnitude. When integrated into AFCs, the optimized catalyst (CPCu-1) delivers a peak power density of ∼430 mW cm- 2, approximately 60% higher than Pt/C, and exhibits a characteristic three-stage durability governed by dynamic CuOx-CoOx interface reconstruction. These findings establish atomic CuOx interface engineering strategy for designing high-performance, noble-metal-efficient ORR catalysts.
Epidermal necrolysis (EN), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), is a rare but severe cutaneous reaction with a high risk of long-term sequelae. However, data on their frequency, severity and socio-professional impact remain limited. To describe the prevalence and severity of EN sequelae, and their associations with acute-phase disease characteristics and long-term functional outcomes. This single-centre retrospective study from 2015 to 2022 included all adult EN survivors with ≥ 3 months of follow-up. Sequelae were classified according to anatomical systems and were graded by severity. Associations between sequelae and clinical variables were analysed with multivariable analyses and unsupervised clustering. We included 129 patients. One or more sequelae were observed in 93.8% of patients. Cutaneous (76%) and ocular (71.3%) sequelae were the most frequent. Severe ocular sequelae were associated with TEN diagnosis (OR: 2.07, 95% CI: 1.19-3.71), number of mucous membranes involved (OR: 1.56, 95% CI: 1.05-2.44) and length of stay (OR: 1.01 per day, 95% CI: 1.00-1.01), cutaneous sequelae were associated with TEN diagnosis (OR: 1.84, 95% CI: 1.15-2.97), while severe psychological sequelae (29.4%) only correlated with prior psychiatric history (OR: 2.33, 95% CI: 1.35-3.97). Clustering analysis identified three patient profiles: mild or no sequelae, severe cutaneous and pulmonary sequelae, and severe ocular, oral and genital sequelae. Almost half of active patients (43/88, 48.9%) did not return to work, mainly due to psychological sequelae (p = 0.01). EN survivors frequently experience multiple and severe sequelae, resulting in significant burden. Long-term, multidisciplinary and personalized follow-up is essential to improve patients' quality of life. What is the disease? Epidermal necrolysis (EN) is a rare but serious skin condition that includes Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). It usually occurs after certain medications and causes widespread skin and mucosal damage. Survivors often face long‐term complications affecting the skin, eyes, mental health and other organs. Location of the study: The study was conducted in France at Henri Mondor Hospital and the national Reference Center for Toxic Bullous Diseases (TOXIBUL) in Créteil. The study aimed to describe how frequent and severe long‐term complications are in EN survivors, identify risk factors and assess their social and professional impact. This retrospective study included 129 patients who survived EN and were followed for at least 3 months after their acute illness between 2015 and 2022. Clinical data were collected from medical records, sequelae were graded for severity, and statistical and clustering analyses were performed to identify patterns. Almost all patients (94%) had at least one long‐term complication. Skin issues affected 76%, eye problems 71% and severe psychological problems 29%. Severe eye complications were associated with TEN and more extensive initial disease, while psychological complications were more frequent in patients with a prior psychiatric history. Nearly half of previously working patients did not return to their former jobs and one‐quarter required social support. Long‐term complications after EN are frequent, often severe, and can substantially affect daily life. Multidisciplinary, personalized follow‐up—including dermatology, ophthalmology and mental health care—is essential to support recovery and improve quality of life for survivors.
Immune checkpoint inhibitor (ICI)-myopathy-myocarditis is an immune-related adverse event, with high mortality despite first-line immunosuppression. Emerging data suggest upregulation of the interleukin-6 (IL-6) pathway in ICI-myopathy, raising interest in IL-6 receptor blockade as escalation therapy. We aimed to characterize acute and long-term functional and oncologic outcomes for severe ICI-myopathy-myocarditis, with focus on those treated with tocilizumab after failure of first-line therapy. We performed a retrospective cohort study of patients admitted with severe (Common Terminology Criteria for Adverse Events [CTCAE] grade 3 or 4) ICI-myopathy-myocarditis managed at a Canadian tertiary referral center. Clinical characteristics, investigations, treatment, and functional and long-term cancer outcomes were summarized. Patients were stratified by treatment with tocilizumab after first-line therapy. Primary outcomes were in-hospital mortality and acute-phase survival. Secondary outcomes included functional status at last follow-up, final CTCAE grade, and oncologic response. Eleven patients were identified. Eight patients received second-line tocilizumab at a median of 13 days after admission; weakness improved in all, but only 4 survived hospitalization. Among acute-phase survivors, median follow-up was 8.1 months, with final median CTCAE grade of 1. Limb strength normalized before oculobulbar weakness. Most survivors demonstrated partial oncologic response, followed by later disease progression at a median 8 months. No patients were rechallenged with ICI therapy. In severe ICI-myopathy-myocarditis refractory to first-line therapy, escalation with IL-6 receptor blockade was temporally associated with limb muscle strength improvement and favorable long-term functional outcomes among survivors. These findings support further evaluation of tocilizumab as second-line therapy in this high-risk population.
Noneconomic damage caps, a form of medical malpractice law, remain controversial, as several states have enacted such laws since 2010, whereas others have repealed them. The clinical consequences of repealing these caps are poorly understood, and understanding these associations can inform the ongoing debate about medical malpractice reform. To examine whether repealing noneconomic damage caps is associated with changes in maternal care and infant health outcomes. This cross-sectional study adopted a difference-in-differences design, comparing between 2 treated states (Georgia and Illinois) that repealed their noneconomic damage caps in 2008 to 2009 and 16 control states that retained their caps during the entire study period between 2005 and 2019. The Centers for Disease Control and Prevention All-County Natality Files were used to estimate multivariate linear models, controlling for maternal and infant characteristics and county-level and state-level covariates. Estimates were stratified by county rurality and birth risk conditions. Data were analyzed from April 1, 2024, to April 9, 2026. The primary outcomes were 4 measures of maternal care and procedures (physician-attended births, inductions, cesarean delivery births, and prenatal visits) and 3 birth outcomes (low Apgar score, low birth weight, and preterm births). Difference-in-differences models with 2-way fixed effects were estimated, and linear models for the study outcomes were specified. The sample included 20 426 267 live births (mean [SD] gestational age, 38.55 [1.35] weeks). Compared with their counterparts in the control states, rural counties in the treated states experienced a statistically significant increase of 2.92 percentage points (pp) (95% CI, 1.40-4.50 pp; Bonferroni-adjusted P = .01) in physician-attended births. The increase held for both low-risk (3.10 pp; 95% CI, 1.33-4.90 pp; P = .004) and high-risk (2.56 pp; 95% CI, 0.77-4.34 pp; P = .01) births in rural counties. There was no difference between treated and control states for physician-attended births overall or in urban counties. No statistically significant associations were observed for cesarean deliveries, inductions, prenatal visits, or infant health outcomes after adjusting for multiple comparisons. In this cross-sectional study of 20 426 267 live births across 18 states, repealing noneconomic damage caps was associated with increased physician-attended births in rural counties but was not associated with statistically significant changes in other maternal care measures or infant health outcomes. These findings suggest that increased liability risk after repealing the caps may shift the composition of birth attendants in resource-constrained settings without demonstrable changes in infant health.
Current guidelines recommend early surveillance following piecemeal polypectomy due to recurrence risk; however, this contributes substantially to colonoscopy burden. We aimed to identify subgroups in which surveillance can be safely deferred beyond current guideline intervals. We performed a two-center retrospective study of consecutive patients undergoing first (SC1) and second (SC2) surveillance colonoscopy following piecemeal resection. Primary outcome was histological recurrence; secondary outcome was detection of additional high-risk polyps. A total of 221 lesions, 130 conventional adenomas (CA) and 91 serrated lesions (SL), were resected piecemeal in 202 patients, with 76% removed using cold snare technique. Recurrence following cold resection occurred in 11% of CA ≥ 20 mm and 15% of CA < 20 mm, while recurrence in SL was low (5% for < 20 mm; 0% for ≥ 20 mm). Hot snare resection was predominantly used for larger CA (79% ≥ 20 mm) and was associated with a recurrence rate of 14%. At SC1, additional high-risk polyps were detected in 27% of patients, particularly following resection of larger index lesions. No advanced neoplasia was detected at SC2 in patients with serrated lesions without recurrence at SC1. In this real-world study, most piecemeal polypectomy was performed using cold snare technique. There was a clinically significant risk of recurrence in CA including those < 20 mm supporting current recommendations of surveillance at 6 months unless technical advances can be shown to reduce recurrence. Our findings suggest a lower risk of recurrence in SL of all sizes and if confirmed on further studies, surveillance intervals may be able to safely lengthen in these cases.
Investigating the environmental ramifications of Polyethylene terephthalate microplastics degradation, this study centered on the deployment of a multi-species microbial consortium-comprising Azotobacter chroococcum, Rhizobium leguminosarum, Azospirillum brasilense, and Trichoderma viride-to initiate biotransformation pathways under laboratory conditions. Metabolites were rigorously characterized using FTIR and GC-MS, then assessed their influence on a range of aquatic systems, including reservoir, reverse osmosis-purified, and distillery-derived waters. Quantitative analyses of ionic composition, acid-base buffering, and oxygenation metrics revealed that the introduction of microbial metabolites did not disrupt the established physicochemical profiles. Concurrent microbiological evaluations demonstrated unchanged growth kinetics and biofilm formation in pathogenic species such as Salmonella enterica, Klebsiella pneumoniae, and Citrobacter freundii. Bioassays with Oreochromis niloticus further affirmed normative survival and developmental indices. Computational modelling of molecular interactions with Micromonas commoda proteins substantiated non-toxicity at the metabolic level. These findings collectively indicate that microbial PET microplastic remediation produces environmentally compatible outcomes, preserving aquatic system stability, and safeguarding biota.
Sentinel lymph node biopsy (SLNB) is the standard for axillary staging in early breast cancer, yet its relevance is increasingly questioned in patients with favorable tumor biology when nodal status does not influence systemic treatment decisions. We conducted a retrospective, single-center observational study including 162 women with clinically and sonographically node-negative (cN0) pT1 invasive breast cancer treated between 2019 and 2024 at a French university hospital. All patients underwent axillary staging and had complete molecular profiling. Among the 25 patients with pathologically positive nodes (pN+), two multidisciplinary team (MDT) discussions were simulated: one blinded to nodal status (limited-information MDT) and one with complete clinicopathologic data (full-information MDT). Recommendations for adjuvant chemotherapy and genomic testing (Oncotype DX) were compared. Most tumors were hormone receptor-positive (90%) and HER2-negative (87%); 9% were triple-negative. Despite negative preoperative axillary ultrasound, nodal involvement was identified in 25 patients (15%). In the limited-information MDT, chemotherapy was recommended in 8 patients and genomic testing in 11 patients. In contrast, the full-information MDT recommended chemotherapy in 16 patients and genomic testing in 9 patients, with 2 additional patients ultimately receiving chemotherapy. Omission of nodal status during MDT deliberation was associated with a significant reduction in chemotherapy recommendations (p < 0.01). Genomic testing contributed to treatment de-escalation in both scenarios. In selected patients with pT1 breast cancer, omission of axillary nodal status during MDT decision-making may safely reduce adjuvant chemotherapy use without compromising treatment planning, supporting current axillary de-escalation strategies.
Ocular surface malignancies pose risks to vision and survival yet are frequently misdiagnosed as benign lesions because of their subtle presentation and the lack of widely accessible screening tools, potentially resulting in treatment delays and the need for extensive surgical intervention. To develop and validate a smartphone-based, media-facilitated artificial intelligence (AI) system for proactive self-screening of ocular surface malignancies in the general population. A nonrandomized clinical trial was conducted across China from December 2022 to June 2023. A deep learning model was initially trained and validated using 12 years of multicenter slitlamp images. The system was then optimized for smartphone-based photography and deployed through a widely disseminated mobile application. Data analysis was performed from July 2023 to June 2024. Participants used the CaptureTumor standardized smartphone application, incorporating real-time AI-guided photography instructions, to capture images of suspected lesions. The application provided immediate binary (benign vs malignant) and multiclass risk stratification and triaged high-risk cases for expedited clinical referral. The primary outcome was area under the receiver operating characteristic curve (AUC) for differentiating malignant from benign lesions. Secondary outcomes included sensitivity, specificity, and the number of histopathologically confirmed malignancies detected. Multimedia outreach via television, social media, and internet hospitals reached 256 053 individuals, with 614 completing at-home self-screening through the app. Of these participants, the median (IQR) age was 46 (11) years (range, 4-87 years); 301 (49%) were female and 313 (51%) male. After optimizing the image quality, the smartphone-based CaptureTumor achieved an AUC of 0.905 (95% CI, 0.837-0.973), comparable with the performance of the slitlamp-based model (AUC = 0.945; 95% CI, 0.918-0.972). During real-world screening, 20 malignancies were pathologically confirmed among the 614 participants, with 19 of 20 participants (95%) newly diagnosed, and no cases requiring enucleation. At the population level, CaptureTumor demonstrated an AUC of 0.977 (95% CI, 0.964-0.990), a sensitivity of 89.3% (95% CI, 86.7%-91.9%), and a specificity of 95.9% (95% CI, 94.2%-97.6%). This trial found that the integration of smartphone-enabled imaging, AI-driven diagnostics, and targeted media outreach established a scalable, accessible, and potentially clinically effective strategy for population-level screening of rare ocular malignancies. This closed-loop mobile health model potentially addresses gaps in early detection and equitable care delivery for vision- and life-threatening rare diseases. ClinicalTrials.gov Identifier: NCT05645341.
If noninvasive optical coherence tomography (OCT) retinal imaging could predict 2-year neurodevelopment of very preterm (VPT; <32 weeks' gestational age) infants in neonatal intensive care, it might help to guide management. To evaluate whether retinal microanatomy findings on OCT in VPT infants at 36 weeks' postmenstrual age (PMA) are associated with 2-year neurodevelopmental outcomes. The prospective, longitudinal cohort study BabySTEPS (Study of Eye Imaging in Preterm Infants), which enrolled infants from August 12, 2016, through November 12, 2019, evaluated VPT infants at risk for retinopathy of prematurity at a single-center neonatal intensive care unit through their outpatient neurodevelopmental visit at age 2 years. Data analysis was conducted from January 5, 2023, to December 1, 2025. OCT imaging of both eyes concurrent with eye examinations for retinopathy of prematurity. Multivariate linear regression analysis of associations between OCT measures of retinal layers at 36 ± 2 weeks' PMA and neurodevelopmental outcomes at 2 years, assessed by the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), Child Behavior Checklist, and Modified Checklist for Autism in Toddlers-Revised (M-CHAT-R), adjusted for the following infant factors: gestational age (GA), small for GA at birth, mother's highest education level, and PMA at imaging. In 72 infants (33 [45.8%] female; mean [SD] GA, 27.6 [2.6] weeks; birth weight, 945.5 [287.8] g) with retinal OCT imaging and neurodevelopmental follow-up at 2 years, greater retinal nerve fiber layer (RNFL) thickness was associated with higher BSID-III motor scores (mean score change per 10-µm increase in RNFL thickness, 7.50 [95% CI, 4.38-10.62]; P < .001) and cognitive scores (mean score change per 10-µm increase in RNFL thickness, 3.71 [95% CI, 0.73-6.69]; P = .02) and lower M-CHAT-R autism risk scores (mean score change per 10-µm increase in RNFL thickness, -0.64 [95% CI, -1.19 to -0.09]; P = .03) and Child Behavior Checklist internalizing problems scores (mean score change per 10-µm increase in RNFL thickness, -2.25 [95% CI, -4.41 to -0.09]; P = .04). Greater choroidal thickness was associated with higher motor scores (mean score change per 100-µm increase in choroidal thickness, 4.84 [95% CI, 0.45-9.23]; P = .03). When considered in addition to infant factors, RNFL thickness improved prediction of the BSID-III motor score (R2 increased from 0.36 to 0.53; difference, 0.17 [95% CI, 0.04-0.26]) and cognitive score (R2 increased from 0.29 to 0.35; difference, 0.06 [95% CI, 0.00-0.16]); choroidal thickness improved predictions less than RNFL thickness and did not add to the improved predictions with RNFL thickness. In this cohort study, RNFL thickness in VPT infants at 36 weeks' PMA predicted motor and cognitive neurodevelopmental outcomes at age 2 years. These findings, if confirmed independently, could help guide management of VPT infants through age 2 years.
Intravenous lidocaine therapy (IVLT) is often used in perioperative multimodal analgesia due to its analgesic, anti-hyperalgesic, and anti-inflammatory effects. In adults, IVLT doses of 1-2 mg/kg/h produce plasma concentrations of 1-2 μg/mL, within the presumed therapeutic range of 1-5 μg/mL. The dose range, expected plasma concentrations, and presumed therapeutic range are not well defined in children. We aimed to review available pharmacokinetic data in pediatric patients receiving IVLT. We searched MEDLINE, EMBASE, and CINAHL databases for studies reporting pharmacokinetic data for IVLT in healthy 1-18-year-olds, with plasma lidocaine or metabolite levels collected post-infusion, excluding studies involving non-therapeutic infusions or children with comorbidities affecting lidocaine metabolism. Bias was assessed using validated tools. We conducted narrative data synthesis due to reporting variability and summarized plasma lidocaine and/or metabolite levels and the incidence of reported adverse events. Four studies comprising 174 children were included. A study (n = 22) using a 1.5 mg/kg bolus over 30 min followed by a 1 mg/kg/h infusion for 6 h post-surgery achieved highest mean drug concentrations of 2.82 ± 0.65 μg/mL immediately following surgery. Another study (n = 46) utilized a 1.5 mg/kg bolus over 5 min followed by a 2 mg/kg/h infusion and achieved peak concentrations of 4 to < 5 μg/mL. Two studies (n = 106) utilized a 1.5 mg/kg bolus and 1.5 mg/kg/h infusion until transfer to the post-operative anesthesia care unit or six hours post-operatively achieved concentrations that were detectable and < 5 μg/mL. The only adverse event reported was a single participant who experienced transient sensory disturbances. Existing pharmacokinetic data for pediatric IVLT is extremely limited. Reported plasma concentrations were detectable and lower than presumed toxic levels with one reported adverse event. Large-scale, multicenter research is needed to determine optimal pediatric dosing, elucidate dose response curves, and ensure safe and effective use of IVLT in the pediatric population. Prospective Register of Systematic Reviews (PROSPERO): CRD42025636554.
This essay explores how cancer is depicted in the work of Georgia O’Keeffe and Hannah Wilke.
To evaluate femtosecond-laser-assisted cataract surgery combined with the implantation of a PanOptix multifocal intraocular lens (IOL) in a patient with a history of keratopigmentation. A 62-year-old female patient sought a permanent change in her eye color. She had no previous history of ocular or systemic diseases and had not undergone any ocular surgery. After the necessary evaluations, a corneal color change was performed using the femtosecond laser aesthetic annular keratopigmentation method. Six months after the keratopigmentation procedure, the patient underwent femtosecond-laser-assisted cataract surgery on both eyes and received the Acrysof PanOptix multifocal IOL. A 3-month follow-up was conducted to assess her vision and refraction. The outcome of the keratopigmentation was completely satisfactory in cosmetic appearance and visual function. In the following months, the patient expressed a desire to stop using glasses for both distance and near vision. At that time, her uncorrected distance visual acuity measured 20/200 in the right eye and 20/70 in the left eye, whereas her best-corrected visual acuity in both eyes was 20/20. Three weeks and 3 months after cataract surgery, her uncorrected distance visual acuity and best-corrected visual acuity in both eyes were recorded at 20/20, and her near visual acuity was assessed at J2. The patient reported no visual disturbances such as glare or halos and expressed complete satisfaction with the surgical outcomes. No complications were observed during or after the surgical procedure. The results of the present study suggest that integrating keratopigmentation with multifocal IOL implantation could enhance patient satisfaction.
Neuroinflammation, oxidative stress, and ferroptosis are implicated in Parkinson' s disease (PD) pathogenesis. Epidemiological studies suggest that elevated uric acid (UA) levels may reduce PD risk, but the precise molecular mechanisms involved remain unclear. In this study, we investigated the effects of UA in lipopolysaccharide (LPS) or MPP+-stimulated BV2 microglia and MPTP-induced PD mouse models. BV2 cells are recognized as a standardized and reproducible neural inflammatory cell model for mechanism exploration. The anti-ferroptosis and anti-inflammatory effects of UA were assessed in LPS or MPP+ stimulated BV2 microglia and in an MPTP-induced PD mouse model. Western blot, qPCR, ELISA, and immunofluorescence were used to analyse the expression of inflammasome-related markers. ROS, MDA, GSH, and Fe²⁺ levels were measured using testing kits, while mitochondrial ultrastructure was evaluated through transmission electron microscopy. PD-related markers were assessed by ethology and immunohistochemistry. The Nrf2 inhibitor ML385 was employed to validate pathway specificity. We found that UA treatment reduced the expression of proinflammatory cytokines (TNF-α, IL-6, and IL-1β), ROS production, lipid peroxidation, and intracellular Fe²⁺ in BV2 microglia while increasing the antioxidant capacity and preserving the mitochondrial ultrastructure. In MPTP-treated mice, UA improved motor performance, preserved dopaminergic neuron density in the substantia nigra, and reduced neuroinflammation. UA activated Nrf2 signalling and upregulated GPX4 expression, which were attenuated by ML385, confirming the Nrf2 dependence of these effects. UA alleviates ferroptosis and neuroinflammation in LPS or MPP+ stimulated BV2 microglia and MPTP-induced PD mouse models through the activation of the Nrf2 signalling pathway.
The pathophysiological changes of lung perfusion and ventilation in fibrosing interstitial lung diseases (F-ILD) remain inadequately characterized. This study aimed to analyze lung perfusion and ventilation characteristics in F-ILD patients using phase-resolved functional lung magnetic resonance imaging (PREFUL MRI) as well as their correlation with the severity of F-ILD. This cross-sectional study prospectively included 30 patients diagnosed with F-ILD (19 males, 64.6 ± 9.5 years) and 30 age- and sex-matched normal controls. All participants underwent PREFUL MRI as well as pulmonary function tests. High-resolution CT (HRCT) was performed for the patient cohort. Ventilation and perfusion-related parameters obtained from PREFUL MRI were analyzed and correlated with PFTs and fibrotic lesions identified on HRCT. Compared with normal controls, F-ILD patients showed significant differences in mean perfusion (7.55% vs 4.60%), Mean Ventilation (13.95% vs 18.65%), Perfusion Defect (QDPexclusive) (3.65% vs 15.50%), ventilation-perfusion matched non-defect percentage (VQMnon-defect) (87.55% vs 70.10%), and ventilation-perfusion matched defect percentage (VQMdefect) (0.15% vs 1.35%) (all p < 0.05). Mean perfusion correlated positively with DLCO SB (single breath) %pred (ρ = 0.682, p < 0.001) and DLCO/VA (alveolar volume) %pred (ρ = 0.634, p < 0.001), while QDPexclusive correlated negatively with these parameters. Mean perfusion showed negative correlations with honeycombing, fibrotic lesions, and total interstitial lesion burden on HRCT, whereas QDPexclusive correlated positively with these abnormalities (all p < 0.05). PREFUL MRI provides a quantitative functional evaluation of ventilation and perfusion in F-ILD patients, demonstrating strong correlations with pulmonary function parameters and fibrotic lesions. It shows potential as a valuable monitoring tool enabling severity assessment of F-ILD. PREFUL MRI provides a non-invasive, free-radiation method in the assessment of ventilation and perfusion in F-ILD, enabling severity evaluation. In patients with F-ILD, lung perfusion decreased, and ventilation increased. Lung ventilation and perfusion correlated with lung function parameters in F-ILD; however, they are similar between idiopathic pulmonary fibrosis (IPF) and other types of F-ILD. After controlling demographics, PREFUL MRI perfusion parameters (mean perfusion and QDPexclusive) remain significant, independent predictors of gas-exchange capacity and fibrotic burden.
This cohort study compared the incidence of age-related macular degeneration in users and nonusers of metformin among multiethnic Asian patients with diabetes.
For patients with advanced non-small cell lung cancer (NSCLC) and programmed cell death 1 ligand 1 (PD-L1) expression of 50% or higher, programmed cell death 1 protein or PD-L1 (PD-[L]1) inhibitor monotherapy is commonly used as first-line therapy; however, whether adding chemotherapy improves outcomes in this population remains unknown. To compare overall survival (OS) and progression-free survival (PFS) associated with PD-(L)1 inhibitor monotherapy vs chemoimmunotherapy in treatment-naive patients with advanced NSCLC and high PD-L1 expression. PubMed, Embase, and major oncology conference proceedings were searched for phase 3 randomized clinical trials (RCTs) published before August 3, 2025. Eligible studies were phase 3 RCTs that enrolled patients with untreated advanced NSCLC, evaluated PD-(L)1 inhibitor monotherapy or chemoimmunotherapy vs chemotherapy alone, and reported outcomes in patients with high PD-L1 expression. Hazard ratios (HRs) for OS and PFS were extracted from published studies and synthesized using inverse variance methods. Additional analyses included meta-regression, network meta-analysis, and reconstructed individual patient data from published Kaplan-Meier curves. Primary outcome was OS; secondary outcome was PFS. Among 24 trials including 5546 patients with PD-L1-high NSCLC, 16 evaluated chemoimmunotherapy and 8 PD-(L)1 inhibitor monotherapy. Compared with chemotherapy, survival was improved by both chemoimmunotherapy (OS: HR, 0.63 [95% CI, 0.56-0.72]; P < .001; PFS: HR, 0.44 [95% CI, 0.39-0.49]; P < .001) and PD-(L)1 inhibitor monotherapy (OS: HR, 0.74 [95% CI, 0.69-0.80]; P < .001; PFS: HR, 0.70 [95% CI, 0.65-0.76]; P < .001). Tests for subgroup differences suggested improved benefit with chemoimmunotherapy compared to PD-(L)1 inhibitor monotherapy (OS: χ21 = 4.1; P = .04; I2 = 75.8%; PFS: χ21 = 48.1; P < .001; I2 = 97.9%), consistent with meta-regression analyses (OS: HR, 0.85 [95% CI, 0.72-1.00]; P = .048; PFS: HR, 0.61 [95% CI, 0.50-0.75]; P < .001) and network meta-analyses (OS: HR, 0.85 [95% CI, 0.73-0.99]; PFS: HR, 0.61 [95% CI, 0.50-0.75]). In the reconstructed individual patient data analysis, median OS was longer with chemoimmunotherapy (n = 704 patients) compared to PD-(L)1 inhibitor monotherapy (n = 1706 patients) (29.2 months [95% CI, 25.2-35.4] vs 19.8 months [95% CI, 18.3-21.7]; HR, 0.74 [95% CI, 0.66-0.82]; P < .001). Similarly, median PFS was significantly longer with chemoimmunotherapy (n = 701 patients) compared to PD-(L)1 inhibitor monotherapy (n = 1706 patients) (11.3 months [95% CI, 10.3-13.5] vs 6.8 months [95% CI, 6.2-7.1]; HR, 0.67 [95% CI, 0.60-0.75]; P < .001). In this meta-analysis of phase 3 RCTs, chemoimmunotherapy was associated with significantly improved OS and PFS compared with PD-(L)1 inhibitor monotherapy in patients with advanced NSCLC and high PD-L1 expression. Prospective trials are needed to confirm these findings.
Psoriasis is a chronic, systemic inflammatory disease associated with cardiovascular and metabolic comorbidities. It is driven by a sustained immune response in the skin, orchestrated by keratinocytes and both innate and adaptive immune cells. The initial phase of the pathology remains largely unclear. It likely involves the activation of dendritic cells by stress signals from keratinocytes with the NLRP3 inflammasome potentially acting as a key innate sensor. Here we investigate the effects of the topical administration of the selective NLRP3 inhibitor MCC950, in the imiquimod-induced psoriasis-like inflammation model with the aim to achieve the inhibition of both cutaneous and systemic manifestations. Topical MCC950 effectively suppressed NLRP3 inflammasome activation by preventing pro-caspase-1 cleavage and generation of the active p20 subunit in the skin. Gene expression analysis showed that inhibition of NLRP3 suppressed the expression of psoriasis hallmark genes, including Il17, Tnf, S100a8/a9 and Il1b. Furthermore, network analysis identified NLRP3 as a central hub in the psoriasis-associated inflammatory module, supporting the concept that inflammasome inhibition dampens multiple downstream inflammatory pathways. In psoriasis-like condition, MCC950 reduced the skin infiltration of CD3+ T cells, CD11b+ myeloid and CD11c+ dendritic cells. Notably, MCC950 also prevented the systemic effects of psoriasis-like inflammation. Analysis in the spleen shows that it effectively prevented the phenotypic changes induced by psoriasis-like inflammation including the increased frequency of IL-17 A+ T cells. Finally, MCC950 prevented the systemic increase of serum IL-6. These findings highlight that upstream targeting of the NLRP3 inflammasome by MCC950 represents a promising strategy to inhibit both initiation and the systemic spread of psoriasis-like inflammation.
Multiple myeloma (MM) remains an aggressive and largely incurable plasma cell malignancy, with relapse common despite therapeutic advances. Although CAR-T cells have transformed the field, their clinical use is constrained by toxicity, complex manufacturing, and limited accessibility. These limitations have accelerated interest in CAR-engineered natural killer (CAR-NK) cells as a safer, more scalable, and potentially off-the-shelf immunotherapeutic platform. This review goes beyond a descriptive summary of CAR-NK research in MM by providing an integrated framework that connects antigen targeting, synthetic engineering, tumor microenvironment adaptation, biomarker-guided response monitoring, and translational manufacturing barriers. In doing so, it highlights not only what has been achieved, but also what currently limits clinical implementation and where the field is most likely to advance next. We performed a comprehensive literature analysis of preclinical and clinical studies on CAR-NK cell therapy in MM, focusing on target selection, persistence-enhancing strategies, immune evasion, biomarker development, combination approaches, and GMP-compatible manufacturing platforms. CAR-NK cells offer several advantages over CAR-T therapy, including lower risks of cytokine release syndrome, neurotoxicity, and graft-versus-host disease. Beyond summarizing currently explored targets such as BCMA, CD138, SLAMF7, and GPRC5D, this review identifies the main design principles driving next-generation CAR-NK development: cytokine armoring, genome editing, dual-targeting strategies, and nanotechnology-enabled delivery. Importantly, we also synthesize emerging translational priorities, including predictive biomarkers for patient stratification, serial monitoring of treatment response, and scalable closed-system manufacturing approaches that may determine clinical feasibility. CAR-NK therapy is evolving from a promising concept into a realistic therapeutic platform for MM. This review contributes a forward-looking translational roadmap by integrating engineering innovation, biomarker-based precision medicine, and manufacturing scalability, thereby defining the key steps needed to move CAR-NK cells toward durable and clinically meaningful impact in refractory MM.