The artificial intelligence advantage: Supercharging exploratory data analysis.

Explorative data analysis (EDA) is a critical step in scientific projects, aiming to uncover valuable insights and patterns within data. Traditionally, EDA involves manual inspection, visualization, and various statistical methods. The advent of artificial intelligence (AI) and machine learning (ML) has the potential to improve EDA, offering more sophisticated approaches that enhance its efficacy. This review explores how AI and ML algorithms can improve feature engineering and selection during EDA, leading to more robust predictive models and data-driven decisions. Tree-based models, regularized regression, and clustering algorithms were identified as key techniques. These methods automate feature importance ranking, handle complex interactions, perform feature selection, reveal hidden groupings, and detect anomalies. Real-world applications include risk prediction in total hip arthroplasty and subgroup identification in scoliosis patients. Recent advances in explainable AI and EDA automation show potential for further improvement. The integration of AI and ML into EDA accelerates tasks and uncovers sophisticated insights. However, effective utilization requires a deep understanding of the algorithms, their assumptions, and limitations, along with domain knowledge for proper interpretation. As data continues to grow, AI will play an increasingly pivotal role in EDA when combined with human expertise, driving more informed, data-driven decision-making across various scientific domains. Level of Evidence: Level V - Expert opinion.

Impact of Radiotherapy on Endotracheal Intubation Quality Metrics in Patients with Esophageal Cancer: A Challenge for Advanced Airway Management?

(1) Background: Currently, no data are available in the literature investigating the influence of radiotherapy (RT) on endotracheal intubation success in patients with esophageal cancer. This study aims to evaluate the impact of RT on endotracheal intubation quality metrics in patients with esophageal cancer. (2) Methods: Patients with esophageal cancer who underwent RT followed by surgery between 2012 and 2023 at the University Hospital Heidelberg, Germany, were retrospectively analyzed. (3) Results: Fifty-five patients, predominantly males 65.5% with a mean age of 64 years, were enrolled. Overall, 81.8% of the patients had an ASA class of III, followed by 27.2% ASA II. The mean prescribed cumulative total dose to the primary tumor and lymph node metastasis was 48.2 Gy with a mean single dose of 1.8 Gy. The mean laryngeal total dose was 40.0 Gy. Direct laryngoscopy was performed in 80.0% of cases, followed by 12.1% videolaryngoscopy, and 7.2% required fiberoptic intubation. Overall, 96.4% of patients were successfully intubated on the first attempt. (4) Conclusions: It has been demonstrated that post-RT effects can increase the risk of airway management difficulties and complications. The results of our study did not indicate any evidence of impaired advanced airway management in patients with esophageal cancer who had undergone RT.

Interactions of Fatty Acid and Cholesterol Metabolism with Cellular Stress Response Pathways in Cancer.

Lipids have essential functions as structural components of cellular membranes, as efficient energy storage molecules, and as precursors of signaling mediators. While deregulated glucose and amino acid metabolism in cancer have received substantial attention, the roles of lipids in the metabolic reprogramming of cancer cells are less well understood. However, since the first description of de novo fatty acid biosynthesis in cancer tissues almost 70 years ago, numerous studies have investigated the complex functions of altered lipid metabolism in cancer. Here, we will summarize the mechanisms by which oncogenic signaling pathways regulate fatty acid and cholesterol metabolism to drive rapid proliferation and protect cancer cells from environmental stress. The review also discusses the role of fatty acid metabolism in metabolic plasticity required for the adaptation to changing microenvironments during cancer progression and the connections between fatty acid and cholesterol metabolism and ferroptosis.

Functional Linkers Support Targeting of Multivalent Tweezers to Taspase1.

Taspase 1 is a unique protease not only pivotal for embryonic development but also implicated in leukemias and solid tumors. As such, this enzyme is a promising while still challenging therapeutic target, and with its protein structure featuring a flexible loop preceding the active site a versatile model system for drug development. Supramolecular ligands provide a promising complementary approach to traditional small-molecule inhibitors. Recently, the multivalent arrangement of molecular tweezers allowed the successful targeting of Taspase 1's surface loop. With this study we now want to take the next logic step und utilize functional linker systems that not only allow the implementation of novel properties but also engage in protein surface binding. Consequently, we chose two different linker types differing from the original divalent assembly: a backbone with aggregation-induced emission (AIE) properties to enable monitoring of binding and a calix[4]arene scaffold initially pre-positioning the supramolecular binding units. With a series of four AIE-equipped ligands with stepwise increased valency we demonstrated that the functionalized AIE linkers approach ligand binding affinities in the nanomolar range and allow efficient proteolytic inhibition of Taspase 1. Moreover, implementation of the calix[4]arene backbone further enhanced the ligands' inhibitory potential, pointing to a specific linker contribution.

Merging of a Supramolecular Ligand with a Switchable Luminophore - Light-Responsiveness, Photophysics and Bioimaging.

: In this contribution we report on a novel approach towards luminescent light-responsive ligands. To this end, cyanostilbene- guanidiniocarbonyl-pyrrole hybrids were designed and investigated. Merging of a luminophore with a supramolecular bioactive ligand bears numerous advantages by overcoming the typical drawbacks of drug-labelling, influencing the overall performance of the active species by attachment of a large luminophore. Here we were able to establish a simple and easily accessible synthesis route to different cyanostyryl-guanidininiocarbonyl-pyrrole (CGCP) derivatives. These compounds were investigated regarding their light-responsive double bond isomerisation, their molecular structures in single crystals by means of X-ray diffractometry, their emission properties by state of the art photophysical characterisation as well as bioimaging and assessment of cell toxicity.

An Assessment of 1067 Light Curing Units Measured Twice Between 2015 and 2021.

INTRODUCTION: The physical condition of the tip and the irradiance of LCUs used in dental offices in the United States and Canada was assessed twice. METHODS: The tip irradiance and physical condition of the tip of 1067 LCUs from 544 dental clinics were assessed twice between 2015 and 2021 using the CheckMARC (BlueLight) radiometer. The irradiance values were compared by paired Student's t-test (α = 0.05). RESULTS: There was a wide range of irradiance values (200 to 3,777 mW/cm²). At the first assessment, only 26% of the LCUs had no visible damage or debris on the LCU tip. When retested up to 36 months later, 70% of the LCUs had their tip damage or debris issues entirely or partially resolved. 2.6% of the LCUs delivered an irradiance below 500 mW/cm² on the first and 1.6% on the second assessments. For the 5 brands that had a sufficient sample size, it was concluded that the irradiance increased when the tip damage or presence of tip debris was resolved. CONCLUSIONS: Initially, most LCUs (74%) had at least one problem related to damage or debris on the LCU tip. The irradiance increased when the tip damage or debris was resolved.

Role of imaging in third aortic valve implantation: TAV-in-TAV-in-SAV.

Coronary obstruction remains a primary concern for redo transcatheter aortic valve implantation (TAVI) due to supra-annular leaflets. Hereby, we present two valve-in-valve-in-valve cases, initially incorporating a surgical valve implanted to clarify our concept that the surgical valve serves to safeguard against the coronary ostium obstruction.

No Significant Differences between Bisphosphonates and Placebo for the Treatment of Bone Marrow Lesions of the Knee: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Objectives: The purpose of the present systematic review and meta-analysis is to summarize the current evidence on the role of bisphosphonates in the treatment of knee bone marrow lesions (BMLs), to understand whether they are truly effective in improving symptoms and restoring the subchondral bone status at imaging evaluation. Methods: A literature search was carried out on PubMed, Cochrane, and Google Scholar databases in accordance with the PRISMA guidelines. Potential risk of bias was evaluated using the Cochrane Risk of Bias 2 tool for randomized controlled trials (RCTs) and the ROBINS-I tool for non-randomized studies. Results: A total of 15 studies were included in the present systematic review and meta-analysis. Seven studies were RCTs, two were prospective cohort studies, three were retrospective, and three were case series. Our meta-analysis revealed that bisphosphonates did not significantly improve clinical scores or reduce BML size compared to placebo. Accordingly, the rate of adverse events was also non-significantly higher among bisphosphonate users versus placebo users. Conclusions: The main finding of the present meta-analysis and systematic review is that bisphosphonates show neither significant benefits nor significant adverse events when compared to placebo in the treatment of BMLs of the knee. Level of Evidence: Level IV systematic review of level II-III-IV studies. Level I meta-analysis of level I studies.

Interobserver Agreement and Performance of Concurrent AI Assistance for Radiographic Evaluation of Knee Osteoarthritis.

Background Due to conflicting findings in the literature, there are concerns about a lack of objectivity in grading knee osteoarthritis (KOA) on radiographs. Purpose To examine how artificial intelligence (AI) assistance affects the performance and interobserver agreement of radiologists and orthopedists of various experience levels when evaluating KOA on radiographs according to the established Kellgren-Lawrence (KL) grading system. Materials and Methods In this retrospective observer performance study, consecutive standing knee radiographs from patients with suspected KOA were collected from three participating European centers between April 2019 and May 2022. Each center recruited four readers across radiology and orthopedic surgery at in-training and board-certified experience levels. KL grading (KL-0 = no KOA, KL-4 = severe KOA) on the frontal view was assessed by readers with and without assistance from a commercial AI tool. The majority vote of three musculoskeletal radiology consultants established the reference standard. The ordinal receiver operating characteristic method was used to estimate grading performance. Light kappa was used to estimate interrater agreement, and bootstrapped t statistics were used to compare groups. Results Seventy-five studies were included from each center, totaling 225 studies (mean patient age, 55 years ± 15 [SD]; 113 female patients). The KL grades were KL-0, 24.0% (n = 54); KL-1, 28.0% (n = 63); KL-2, 21.8% (n = 49); KL-3, 18.7% (n = 42); and KL-4, 7.6% (n = 17). Eleven readers completed their readings. Three of the six junior readers showed higher KL grading performance with versus without AI assistance (area under the receiver operating characteristic curve, 0.81 ± 0.017 [SEM] vs 0.88 ± 0.011 [P < .001]; 0.76 ± 0.018 vs 0.86 ± 0.013 [P < .001]; and 0.89 ± 0.011 vs 0.91 ± 0.009 [P = .008]). Interobserver agreement for KL grading among all readers was higher with versus without AI assistance (κ = 0.77 ± 0.018 [SEM] vs 0.85 ± 0.013; P < .001). Board-certified radiologists achieved almost perfect agreement for KL grading when assisted by AI (κ = 0.90 ± 0.01), which was higher than that achieved by the reference readers independently (κ = 0.84 ± 0.017; P = .01). Conclusion AI assistance increased junior readers' radiographic KOA grading performance and increased interobserver agreement for osteoarthritis grading across all readers and experience levels. Published under a CC BY 4.0 license. Supplemental material is available for this article.

Robustness of mitochondrial biogenesis and respiration explain aerobic glycolysis.

A long-standing observation is that in fast-growing cells, respiration rate declines with increasing growth rate and is compensated by an increase in fermentation, despite respiration being more efficient than fermentation. This apparent preference for fermentation even in the presence of oxygen is known as aerobic glycolysis, and occurs in bacteria, yeast, and cancer cells. Considerable work has focused on understanding the potential benefits that might justify this seemingly wasteful metabolic strategy, but its mechanistic basis remains unclear. Here we show that aerobic glycolysis results from the saturation of mitochondrial respiration and the decoupling of mitochondrial biogenesis from the production of other cellular components. Respiration rate is insensitive to acute perturbations of cellular energetic demands or nutrient supplies, and is explained simply by the amount of mitochondria per cell. Mitochondria accumulate at a nearly constant rate across different growth conditions, resulting in mitochondrial amount being largely determined by cell division time. In contrast, glucose uptake rate is not saturated, and is accurately predicted by the abundances and affinities of glucose transporters. Combining these models of glucose uptake and respiration provides a quantitative, mechanistic explanation for aerobic glycolysis. The robustness of specific respiration rate and mitochondrial biogenesis, paired with the flexibility of other bioenergetic and biosynthetic fluxes, may play a broad role in shaping eukaryotic cell metabolism.

Biomarker-guided detection of acute kidney injury in abdominal aortic surgery: the new and the old.

Introduction: Acute kidney injury (AKI) is a common complication in patients undergoing major vascular surgery. Despite significant research efforts in this area, the incidence of AKI remains high, posing a significant challenge to healthcare systems, especially in situations where resources are limited. Early prediction of AKI severity and individualized postoperative care is therefore essential. Methods: The primary objective of this exploratory study was to assess the diagnostic value of urine cell-cycle arrest biomarkers [(TIMP-2) × (IGFBP7)] and soluble urokinase plasminogen activator receptor (suPAR) for predicting moderate or severe AKI within 24 h after open aortic surgery, and compared to routine kidney biomarkers. Seventy-five patients undergoing elective aortic surgery were included. Clinical parameters, urine and blood samples were collected preoperatively, immediately postoperatively, and 24 h later. AKI was defined using KDIGO criteria. Individual and combined diagnostic performance of biomarkers were evaluated. Results: Of the 75 patients, 61% developed AKI, of which 28% developed moderate or severe AKI within 24 h of surgery. Baseline demographics, comorbidities and kidney parameters did not differ between patients with moderate or severe AKI (AKI II/III) and none or mild AKI (AKI 0/I), except for higher preoperative suPAR levels in later AKI II/III patients. Urine osmolality, Cystatin C and serum creatinine had the highest predictive power for AKI II/III with AUCs of 0.75-0.72. (TIMP-2) × (IGFBP7), and neither (TIMP-2) × (IGFBP7) nor suPAR individually showed superior diagnostic value. Combining CysC or SCr with urine osmolality and 6 h urine output gave the best performance with AUCs of 0.86 (95% CI, 0.74-0.96) and 0.85 (95% CI, 0.75-0.95) respectively. Conclusion: Our study suggests that routine parameters like urine osmolality, CysC, SCr and 6 h urine output perform best in predicting postoperative AKI after aortic surgery compared to the new biomarkers (TIMP-2) × (IGFBP7) and suPAR. Combining biomarkers, particularly CysC or SCr with urine output, urine osmolality, may enhance diagnostic accuracy. Further validation in larger cohorts and clinical settings is warranted to establish their clinical utility.

Template-assisted covalent modification underlies activity of covalent molecular glues.

Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans-labeling covalent molecular glue mechanism, termed 'template-assisted covalent modification'. We identified a new series of BRD4 molecular glue degraders that recruit CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). Through comprehensive biochemical, structural and mutagenesis analyses, we elucidated how pre-existing structural complementarity between DCAF16 and BRD4BD2 serves as a template to optimally orient the degrader for covalent modification of DCAF16Cys58. This process stabilizes the formation of BRD4-degrader-DCAF16 ternary complex and facilitates BRD4 degradation. Supporting generalizability, we found that a subset of degraders also induces GAK-BRD4BD2 interaction through trans-labeling of GAK. Together, our work establishes 'template-assisted covalent modification' as a mechanism for covalent molecular glues, which opens a new path to proximity-driven pharmacology.

Fueling the success of transplantation through nutrition: recent insights into nutritional interventions, their interplay with gut microbiota and cellular mechanisms.

PURPOSE OF REVIEW: The role of nutrition in organ health including solid organ transplantation is broadly accepted, but robust data on nutritional regimens remains scarce calling for further investigation of specific dietary approaches at the different stages of organ transplantation. This review gives an update on the latest insights into nutritional interventions highlighting the potential of specific dietary regimens prior to transplantation aiming for organ protection and the interplay between dietary intake and gut microbiota. RECENT FINDINGS: Nutrition holds the potential to optimize patients' health prior to and after surgery, it may enhance patients' ability to cope with the procedure-associated stress and it may accelerate their recovery from surgery. Nutrition helps to reduce morbidity and mortality in addition to preserve graft function. In the case of living organ donation, dietary preconditioning strategies promise novel approaches to limit ischemic organ damage during transplantation and to identify the underlying molecular mechanisms of diet-induced organ protection. Functioning gut microbiota are required to limit systemic inflammation and to generate protective metabolites such as short-chain fatty acids or hydrogen sulfide. SUMMARY: Nutritional intervention is a promising therapeutic concept including the pre- and rehabilitation stage in order to improve the recipients' outcome after solid organ transplantation.

Primary Ciliary Dyskinesia in Adult Bronchiectasis: Data from the German Bronchiectasis Registry PROGNOSIS.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by the malfunction of motile cilia and a specific etiology of adult bronchiectasis of unknown prevalence. A better understanding of the clinical phenotype of adults with PCD is needed to identify individuals for referral to diagnostic testing. RESEARCH QUESTION: What is the frequency of PCD among adults with bronchiectasis; how do people with PCD differ from those with other etiologies; and which clinical characteristics are independently associated with PCD? STUDY DESIGN AND METHODS: We investigated the proportion of PCD among the participants of the German Bronchiectasis Registry PROGNOSIS, applied multiple imputation to account for missing data in 64 (FEV1), 58 (breathlessness), 26 (pulmonary exacerbations), and two patients (BMI), respectively, and identified predictive variables from baseline data using multivariate logistic regression analysis. RESULTS: We consecutively recruited 1,000 patients from 38 centers across all levels of the German health care system. Overall, PCD was the fifth most common etiology of bronchiectasis in 87 patients (9%) after idiopathic, postinfective, COPD, and asthma. People with PCD showed a distinct clinical phenotype. In multivariate regression analysis, the chance of PCD being the etiology of bronchiectasis increased with the presence of upper airway disease (chronic rhinosinusitis and/or nasal polyps; adjusted OR [aOR], 6.3; 95% CI, 3.3-11.9; P < .001), age < 53 years (aOR, 5.3; 95% CI, 2.7-10.4; P < .001), radiologic involvement of any middle and lower lobe (aOR, 3.7; 95% CI, 1.3-10.8; P = .016), duration of bronchiectasis > 15 years (aOR, 3.6; 95% CI, 1.9-6.9; P < .001), and a history of Pseudomonas aeruginosa isolation from respiratory specimen (aOR, 2.4; 95% CI, 1.3-4.5; P = .007). INTERPRETATION: Within our nationally representative cohort, PCD was a common etiology of bronchiectasis. We identified few easy-to-assess phenotypic features, which may promote awareness for PCD among adults with bronchiectasis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02574143; URL: www. CLINICALTRIALS: gov.

A Comparison of Two Transport Monitor Systems With Regard to Efficiency and Staff Satisfaction in the Perioperative Setting.

BACKGROUND: Medical research aims to improve patient safety and efficiency in the perioperative setting. One critical aspect of patient safety is the intrahospital transfer of patients. Also, reliable monitoring of vital signs is crucial to support the medical staff. This study was conducted to assess two monitoring systems in terms of the handover time and staff satisfaction. METHODS: To assess several aspects, two monitoring systems were compared: an organizational unit-related monitoring system that needs to be changed and brought back to the initial organizational unit after the patient transfer and a patient-specific monitoring system that accompanies the patient during the whole perioperative process. RESULTS: In total, 243 patients were included, and 375 transfers were examined to analyze economic factors, including differences in handover times and user-friendliness. To this end, 30 employees of the Heidelberg University Hospital were asked about their satisfaction with the two monitoring systems based on a systematic questionnaire. It could be shown that, especially during transfers from the operating theater to the intensive care unit or the recovery room, the time from arrival to fully centralized monitoring and the total handover time were significantly shorter with the patient-specific monitoring system (p < 0.001). Furthermore, the staff was more satisfied with the patient-specific monitor system in terms of flexibility, cleanability and usability. CONCLUSION: The increased employee satisfaction and significant time benefits during intrahospital transports may increase patient safety and efficiency of patient care, reduce employee workload, and reduce costs in the overall context of patient care.

External Validation of a Model for Persistent Perfusion Deficit in Patients With Incomplete Reperfusion After Thrombectomy: EXTEND-PROCEED.

BACKGROUND AND OBJECTIVES: We recently developed a model (PROCEED) that predicts the occurrence of persistent perfusion deficit (PPD) at 24 hours in patients with incomplete angiographic reperfusion after thrombectomy. This study aims to externally validate the PROCEED model using prospectively acquired multicenter data. METHODS: Individual patient data for external validation were obtained from the Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection, Tenecteplase versus Alteplase Before Endovascular Therapy for Ischemic Stroke part 1 and 2 trials, and a prospective cohort of the Medical University of Graz. The model's primary outcome was the occurrence of PPD, defined as a focal, wedge-shaped perfusion delay on 24-hour follow-up perfusion imaging that corresponds to the capillary phase deficit on last angiographic series in patients with

Analyses of 1,236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype-phenotype correlations.

BACKGROUND: Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterized by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes. METHODS: Genetic variants and clinical findings (age, sex, body mass index, laterality defects, FEV1) were collected from 19 countries using the ERN LUNG International PCD Registry. Genetic data were evaluated according to ACMG guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV1. RESULTS: 1236 individuals carried 908 distinct pathogenic DNA variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%; 47-100%) and laterality defects (mean 42%; 28-69%) varied widely among the countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV1 z-score (-1.66). In the group of individuals with CCNO (-3.26), CCDC39 (-2.49), and CCDC40 (-2.96) variants, FEV1 z-scores were significantly lower, while the group of DNAH11 (-0.83) and ODAD1 (-0.85) variant individuals had significantly milder FEV1 z-score reductions compared to the whole PCD cohort. CONCLUSION: This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of genetic epidemiology of PCD and provides prediction of diagnostic and phenotypic features such as the course of lung function.

Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial.

BACKGROUND: Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. METHODS: This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. FINDINGS: Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed pnon-inferiority=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed pnon-inferiority=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05]). INTERPRETATION: The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. FUNDING: Australian National Health Medical Research Council; Boehringer Ingelheim.