Publications by Year: 2026

BACKGROUND: The efficacy and safety of intravenous thrombolysis with tenecteplase within 24 h after stroke onset due to basilar artery occlusion are not well studied. We aimed to assess whether intravenous tenecteplase administered within 24 h after symptom onset improved functional outcome compared with standard medical treatment in patients with basilar artery occlusion.

METHODS: TRACE-5 was a prospective, randomised, open-label, blinded-endpoint, superiority, phase 3 trial conducted at 66 stroke centres in China. We included patients aged 18 years or older with stroke due to basilar artery occlusion who were eligible for intravenous thrombolytics within 24 h of stroke onset or the time they were last known to be well and had a pre-stroke modified Rankin scale (mRS) score of 3 or less (scores range from 0 to 6, with higher scores indicating greater disability). Patients were randomly assigned to receive a single intravenous bolus of tenecteplase (0·25 mg/kg; maximum 25 mg) within 24 h after symptom onset or standard medical treatment (which could include intravenous alteplase at 0·9 mg/kg, maximum 90 mg, within 4·5 h of symptom onset; anticoagulation; or antiplatelets), with or without endovascular thrombectomy. The primary outcome was a score of 0-1 on the mRS or return to the baseline mRS score (if the baseline pre-stroke mRS score was 2-3) at 90 days. Safety outcomes were symptomatic intracranial haemorrhage and death. The primary outcome and safety outcomes were assessed in all randomly assigned participants included in their originally assigned groups. This trial is registered with ClinicalTrials.gov, NCT06196320.

FINDINGS: Between Jan 24, 2024, and June 20, 2025, 452 patients were enrolled (mean age 66·4 years [SD 11·2], 321 [71%] males, and 131 [29%] females), of whom 222 (49%) subsequently underwent thrombectomy; 221 were randomly assigned to receive tenecteplase and 231 to receive standard medical treatment. Alteplase was used in 80 (35%) of the patients in the standard medical treatment group. An mRS score of 0-1 or return to the baseline mRS score occurred in 83 (38%) patients in the tenecteplase group and 66 (29%) patients in the standard medical treatment group (adjusted relative rate 1·50 [95% CI 1·09-2·08], p=0·014). Symptomatic intracranial haemorrhage within 36 h occurred in four (2%) patients in the tenecteplase group and seven (3%) patients in the standard medical treatment group (adjusted relative rate 0·58 [95% CI 0·17-1·99]). All-cause mortality at 90 days was similar between groups (65 [29%] patients in the tenecteplase group and 71 [31%] patients in the standard medical treatment group; adjusted relative rate 0·87 [95% CI 0·62-1·22]), as was the proportion of patients with an mRS score of 5-6 at 90 days (82 [37%] vs 89 [39%]; 0·87 [0·65-1·18]).

INTERPRETATION: In this trial involving Chinese patients with ischaemic stroke due to basilar artery occlusion, tenecteplase within 24 h after stroke onset improved functional outcome compared with standard medical treatment. The incidence of symptomatic intracranial haemorrhage and death was similar.

FUNDING: Noncommunicable Chronic Diseases-National Science and Technology Major Project, Beijing Municipal Science Fund for Distinguished Young Scholars, National Natural Science Foundation of China, and China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou).

BACKGROUND: Despite overwhelming evidence of clinical benefit for patients with heart failure (HF), the uptake of guideline-directed medical therapies (GDMT) has been slow. Collaborative approaches are critically needed to improve alignment between evidence and clinical practice. Many strategies proposed to improve GDMT implementation have been either ineffective or too resource-intensive to implement at scale across different practice contexts. Furthermore, most existing approaches focus primarily on patients with HF and reduced EF, despite growing evidence for effective pharmacologic therapy in those with HF and mildly reduced or preserved ejection fraction (HFpEF).

HYPOTHESIS: Based on this experience, we designed the Cooperative Program for ImpLementation of Optimal Therapy in Heart Failure (COPILOT-HF) study (NCT05734690).

METHODS: This is a pragmatic, randomized, open-label intervention trial to compare a comprehensive, remote, navigator-led, algorithm-driven strategy for optimization of GDMT prescribing in patients with HF across the full spectrum of ejection fraction with a control intervention focused on patient and provider education regarding the importance of GDMT optimization.

RESULTS: The primary efficacy endpoint of the study is the proportion of patients receiving optimal HF treatment at 3 months. Additional outcomes of interest include the proportion of patients with optimal HF therapy at 6 months and 12 months as well as health resource utilization, including hospitalizations and deaths.

CONCLUSIONS: COPILOT-HF will evaluate the effectiveness of an early implementation of a remote pharmacist-led medication titration strategy across the HF spectrum.

AIM: To map and critically appraise the current literature on Artificial Intelligence (AI) applications in emergency general surgery, with a focus on clinical decision-support tools for preoperative risk stratification and intraoperative assistance, and to identify ethical, structural, and regulatory barriers to implementation.

METHODS: A scoping review was conducted within the ARIES project, following established methodological frameworks. Relevant studies evaluating AI-based tools in emergency surgical settings were systematically identified and analyzed.

RESULTS: The literature describes AI applications mainly in two domains: preoperative decision support, including risk prediction and diagnostic or triage models for acute abdominal and traumatic conditions, and intraoperative assistance, largely focused on computer vision-based systems for anatomical recognition, safety guidance, and navigation in minimally invasive emergency procedures. Additional contributions address training and telementoring platforms, as well as cross-cutting ethical, legal, and regulatory considerations relevant to AI adoption in emergency surgical care.

CONCLUSIONS: AI has the potential to complement emergency surgeons' clinical judgment, but its routine adoption in emergency surgical practice remains limited. Addressing methodological, ethical, and regulatory challenges, together with the development of robust data infrastructures and targeted training pathways, is essential to support safe, effective, and equitable implementation in acute care settings. In addition, the lack of dedicated investment and sustainable funding models for large-scale clinical implementation and prospective evaluation represents a critical barrier to the translation of AI from research into routine emergency surgical practice.

BACKGROUND: Gene therapy (GT) using retroviral vectors (RVs) is efficacious in treating monogenic diseases. However, there is an inherent risk for severe adverse effects due to insertional mutagenesis. Preclinical safety assessment and patient monitoring are inevitable in GT. To assess the genotoxic risk of novel RV vectors, mainly murine hematopoietic stem and progenitor cells (HPSCs) are routinely used, because human HSPCs cannot be immortalized in vitro using mutagenic vectors. In this study, we aim to identify early signs of clonal outgrowth by performing integration site analyses (ISA).

METHODS: The small molecules A83-01, pomalidomide, and UM171 (APU) were used for the ex vivo expansion, lentiviral transduction, and long-term cultivation of umbilical cord blood-derived HSPCs. We determined the influence of APU on the stemness of HSPCs and their differentiation capacity via single-cell RNA sequencing (scRNA seq) and in xenotransplantation studies. To track vector insertion site dynamics, we transduced 7-day expanded HSPCs with a mutagenic or a safer RV. ISA was conducted in human HSPCs over a 5-week cultivation in vitro and compared to the bone marrow of xenotransplanted mice to assess clonal skewings.

RESULTS: APU supported the expansion of CD34+CD38-CD45RA-CD90+EPCR+ HSPCs. scRNA seq confirmed the enrichment of HSC signature genes in APU-expanded HSPCs compared to the clinically used medium SFT3 (SCF, FLT3-L, TPO, IL-3). After RV transduction, APU still maintained around 30% of CD34+ cells for 5 more weeks. Without the compounds, already 2 weeks post-transduction, less than 10% of cells were CD34+. The long-term culture allowed the detection of high-risk integrations of the mutagenic SIN-LV.SF in MEIS1 or SUSD6 due to their increasing abundance over time. Bone marrow of xenotransplanted mice was less clonal but did not support the outgrowth of insertional mutants. Overall, APU increased clonal diversity.

CONCLUSIONS: Our findings propose that long-term cultivation of transduced HSPC in APU allows for outgrowth of clonal integration sites. The decrease of clonality has been observed in gene therapy patient's years after treatment. Thus, the in vitro model could be used to develop novel human HSPC-based genotoxicity assays that predict insertional mutagenesis, in addition to existing preclinical biosafety assays.

BACKGROUND: Tears are an easily accessible biofluid that reflects both emotional states and disease conditions. They are particularly enriched in extracellular vesicles (EVs), which carry proteins and nucleic acids relevant to neurological health. This makes tear EVs a promising source for biomarker discovery. However, limited sample volume and variability pose challenges for identifying reliable biomarkers for clinical diagnosis.

RESULTS: We present AI-driven Biomarker Learning for the Early Diagnosis of Neurodegenerative Diseases (ABLEDx), which applies a conditional variational autoencoder (cVAE) to enhance proteomic analysis of tear EVs. This approach effectively addresses sample limitations and improves the identification of disease-associated biomarkers. Our results reveal that tear EVs capture molecular signals along the eye-brain axis, reflecting contributions from both ocular and central nervous system cells. ABLEDx identified clinically relevant protein modules, which were consistently elevated in patients with neurodegenerative diseases. Moreover, we recognize that KRAS is highly expressed in patients with Alzheimer's disease, Parkinson's disease, and ocular myasthenia gravis, and tear-EV-associated LRG1 and HSPG2 exhibit differentiation between Alzheimer's disease and Parkinson's disease.

CONCLUSIONS: ABLEDx demonstrates the utility of combining AI with tear-EV proteomics for non-invasive biomarker discovery. This strategy enables early and real-time detection of neurodegenerative and ocular diseases, offering new opportunities for clinical diagnostics and translational medicine.

Cerebral ischemia/reperfusion injury (CIRI) commonly occurs during the treatment of ischemic stroke and leads to severe consequences, including neuronal death and permanent loss of motor function. Accurate differentiation between the ischemic penumbra (IP) and the ischemic core area is crucial for timely intervention. Multimodal MRI plays a crucial role in the early diagnosis and treatment evaluation of acute ischemic stroke. PANoptosis is a recently discovered form of programmed cell death including apoptosis, necroptosis, and pyroptosis. It has been implicated in neuronal loss during CIRI, especially through absent in melanoma 2 (AIM2). Melatonin (Mel) exerts neuroprotective effects; however, whether PANoptosis is the main cause of neuronal death in CIRI and whether Mel exerts anti-PANoptotic effects to rescue CIRI remain unclear. This study aimed to examine the effects of Mel on PANoptosis in the IP of rats with CIRI and to systematically investigate the underlying mechanisms using multimodal MRI combined with histopathologic techniques. A rat CIRI model comprising 42 healthy male Sprague-Dawley rats, weighing 240-270 g, was established using the modified Zea-Longa wire bolus method. Multimodal MRI, including T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI)-MRI, and chemical exchange saturation transfer (CEST), was performed to evaluate the ischemic lesions and identify IP. T2WI, DWI-MRI, and tissue staining demonstrated that Mel significantly reduced infarct volume, improved neuron morphology, and decreased the proportion of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. The IP was identified as the mismatch region between CEST and DWI-MRI, which was expanded by Mel treatment. In addition, Mel inhibited the expression of PANoptotic key proteins, as well as AIM2 expression, in IP neurons. In summary, multimodal MRI enables dynamic monitoring of IP after CIRI in vivo and effectively evaluates the neuroprotective effects of Mel on IP. Mel broadens the time window for CIRI rescue and exerts a neuroprotective effect by downregulating AIM2 expression in neurons, thereby suppressing PANoptotic neuronal death in the IP areas and alleviating brain injury in rats with CIRI.

The early developmental profile of Kleefstra syndrome remains undercharacterized. To address this gap, this study investigated a large clinical cohort of patients with Kleefstra syndrome, characterizing age of achievement of infant/toddler developmental milestones and quantifying language and visual motor developmental quotients (DQs) using the Capute Scales developmental screening tool. We conducted a retrospective chart review on individuals with molecularly confirmed Kleefstra syndrome. We reported age of achievement of motor and language milestones. In a subset of this cohort, we evaluated DQs for language and visual motor skills based on the Capute Scales. Among 100 individuals (43 males, 57 females; median age 9 years), rolling occurred at a median of 6 months, sitting at 10 months, independent walking at 1.96 years, and first words at 24 months. Capute Scales testing (n = 24) showed median DQs as follows: visual motor skills (53, IQR = 42-71), overall language (56, IQR = 42-67), expressive language (52, IQR = 35-60), and receptive language (50, IQR = 42-61). This work quantifies the early developmental profile of Kleefstra syndrome and suggests that developmental delay can be significant from an early age, making early initiation of services such as physical therapy, occupational therapy, and speech therapy crucial to ensuring optimal skills development. This cross-sectional analysis highlights the need for incorporating longitudinal developmental assessments into the clinical care of patients with Kleefstra syndrome-particularly during infancy and early childhood-to ensure that appropriate educational supports are in place.

BACKGROUND: The benefits and harms of using macrolides for asthma remain unclear.

OBJECTIVE: As part of upcoming Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters guidelines addressing severe asthma, we systematically reviewed the efficacy and safety of macrolides for asthma.

METHODS: We systematically searched MEDLINE, Embase, and CENTRAL to April 12, 2025, for randomized trials comparing macrolides with placebo or standard care for asthma. Paired reviewers independently screened records and extracted data. Individual patient-level data in random effects analysis of covariance models addressed asthma control and asthma-related quality of life. Random effects meta-analyses addressed severe exacerbations and harms. We used the Grading of Recommendations Assessment, Development and Evaluation approach to evaluate certainty of evidence. Our study protocol is registered in PROSPERO (CRD42023408677).

RESULTS: Our meta-analysis comprised 19 trials enrolling 1825 participants. Compared with placebo, macrolides improve asthma control (6-item Asthma Control Questionnaire; score range 0-6, lower better; between-group mean difference: -0.23 [95% CI -0.32 to -0.13]; 40.6% vs 21.6% improving by minimally important difference of 0.5 point; high certainty), likely reduce severe exacerbations (incidence rate ratio: 0.75 [95% CI 0.57 to 0.98]; rate difference: 0.26 fewer events per patient-year [95% CI 0.45 to 0.02 fewer events]; moderate certainty), and likely modestly improve quality of life (Asthma Quality of Life Questionnaire; score range 1-7, higher better; mean difference: 0.11 [95% CI -0.06 to 0.29]; 47.6% vs 42.4% improving by minimally important difference of 0.5 points; moderate certainty) with little to no effect on serious adverse events and mortality (high certainty). Relative effects were similar among patients with type 2 high inflammation versus type 2 low inflammation asthma.

CONCLUSIONS: Macrolides likely reduce severe exacerbations and improve asthma control and quality of life with little to no difference in serious harms among patients with type 2 high inflammation or type 2 low inflammation asthma.

BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is characterized by chronic progressive stenosis of intracranial vessels and subsequent formation of abnormal collateral vessel networks. Indirect revascularization techniques, such as encephalo-duro-arterio-synangiosis (EDAS), promote angiogenesis to restore perfusion but have variable success rates. This study aimed to identify clinical and radiographic predictors of successful collateral vessel ingrowth after EDAS, emphasizing the role of contralateral interhemispheric collaterals.

MATERIALS AND METHODS: We conducted a single-center retrospective analysis of cerebral hemispheres from adult MMD patients who underwent EDAS. We assessed demographic characteristics, clinical presentation, procedural details, clinical and radiographic outcomes. Angiographic outcomes were assessed using the Orbital Grading System. Univariate analysis was performed to identify factors associated with favorable postoperative collateral development. Consequently, preoperative contralateral interhemispheric collateralization was quantitatively evaluated through pixel density analysis on digital subtraction angiography (DSA), comparing the moyamoya-affected hemisphere to the contralateral hemisphere.

RESULTS: 61 MMD hemispheres of 43 adult patients were included in the study. Median times to last clinical and angiographic follow up were 29.9 months and 13.6 months, respectively. Higher Suzuki-stages (V and VI; p=<0.01), occlusions of the anterior cerebral artery (ACA; p=0.03) and internal carotid artery (ICA; p=0.048) were associated with superior postoperative collateralization. The presence of robust contralateral collaterals on preoperative angiography significantly predicted poor postoperative neovascularization (p=0.01). Pixel density analysis showed that increased pixel density ratios of moyamoya-affected hemisphere to contralateral hemisphere significantly correlated with reduced postoperative collateral vessel formation (Orbital Grading System, OR=130.94, p=0.008; Matsushima grading system, OR=52.09, p=0.018).

CONCLUSION: Higher Suzuki-stages, ACA and ICA occlusion predict successful neovascularization after EDAS. The presence of robust preoperative contralateral interhemispheric collaterals is an important predictor of poor collateral vessel ingrowth following EDAS. This finding suggests that such collateralization might reduce the local ischemic stimulus required for effective indirect revascularization. These findings could refine surgical decision-making by identifying patients who may be less likely to benefit from EDAS.