Meta-Analysis of Interobserver Agreement in Assessment of Interstitial Lung Disease Using High-Resolution CT.

Background High-resolution CT (HRCT) is central to the assessment of interstitial lung disease (ILD), and accurate classification of disease has important implications for patients. Evaluation of imaging features can be challenging, even for experienced thoracic radiologists. Previous work has provided equivocal evidence on the interpretation of HRCT features at ILD-related imaging. Purpose To perform a meta-analysis to assess the level of agreement among expert thoracic radiologists in interpreting ILD-related imaging. Materials and Methods A systematic literature search from January 2000 to October 2023 of the Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases was performed for articles reporting assessments of interobserver agreement between thoracic radiologists for evaluation of ILD findings, such as severity and progression of disease, presence of features such as honeycombing and ground-glass opacification, and classification based on the 2011 and 2018 American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Asociación Latinoamericana del Tórax (ATS/ERS/JRS/ALAT) guidelines for idiopathic pulmonary fibrosis (IPF). Meta-analysis was performed using a random-effects model to obtain pooled κ or intraclass correlation coefficient (ICC) values as measures of interobserver agreement. Results The final analysis included 13 studies consisting of 6943 images and 146 radiologists. In 10 studies assessing agreement of specific radiologic findings in ILD, the pooled κ value was 0.56 (95% CI: 0.43, 0.70). In eight studies, the assessed interobserver agreement of the ATS/ERS/JRS/ALAT diagnostic guidelines for IPF based on usual interstitial pneumonia (UIP) patterns, the pooled κ value was 0.61 (95% CI: 0.48, 0.74). One study reported a κ value of 0.87 for ILD progression. Seven studies assessing ILD severity could not be pooled; the individual κ values for ILD severity ranged from 0.64 to 0.90, and ICC values ranged from 0.63 to 0.96. Conclusion There was moderate agreement between thoracic radiologists when assessing ILD features and UIP pattern diagnosis but little evidence on agreement of disease severity, extent, or progression. Meta-analysis registry no. PROSPERO CRD42022361803 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Humbert in this issue.

Establishing minimally important differences for cardiac MRI end-points in pulmonary arterial hypertension.

BACKGROUND: Cardiac magnetic resonance (CMR) is the gold standard technique to assess biventricular volumes and function, and is increasingly being considered as an end-point in clinical studies. Currently, with the exception of right ventricular (RV) stroke volume and RV end-diastolic volume, there is only limited data on minimally important differences (MIDs) reported for CMR metrics. Our study aimed to identify MIDs for CMR metrics based on US Food and Drug Administration recommendations for a clinical outcome measure that should reflect how a patient "feels, functions or survives". METHODS: Consecutive treatment-naïve patients with pulmonary arterial hypertension (PAH) between 2010 and 2022 who had two CMR scans (at baseline prior to treatment and 12 months following treatment) were identified from the ASPIRE registry. All patients were followed up for 1 additional year after the second scan. For both scans, cardiac measurements were obtained from a validated fully automated segmentation tool. The MID in CMR metrics was determined using two distribution-based (0.5sd and minimal detectable change) and two anchor-based (change difference and generalised linear model regression) methods benchmarked to how a patient "feels" (emPHasis-10 quality of life questionnaire), "functions" (incremental shuttle walk test) or "survives" for 1-year mortality to changes in CMR measurements. RESULTS: 254 patients with PAH were included (mean±sd age 53±16 years, 79% female and 66% categorised as intermediate risk based on the 2022 European Society of Cardiology/European Respiratory Society risk score). We identified a 5% absolute increase in RV ejection fraction and a 17 mL decrease in RV end-diastolic or end-systolic volumes as the MIDs for improvement. Conversely, a 5% decrease in RV ejection fraction and a 10 mL increase in RV volumes were associated with worsening. CONCLUSIONS: This study establishes clinically relevant CMR MIDs for how a patient "feels, functions or survives" in response to PAH treatment. These findings provide further support for the use of CMR as a clinically relevant clinical outcome measure and will aid trial size calculations for studies using CMR.

Plain language summaryPulmonary arterial hypertension (PAH) is a disease of the vessels of the lung that causes their narrowing and stiffening. As a result, the heart pumping blood into these diseased lung vessels has to work harder and eventually gets worn out. PAH can affect patients' ability to function in daily activities and impact their quality of life. It also reduces their life expectancy dramatically. Patients are, therefore, often monitored and undergo several investigations to adapt treatment according to their situation. These investigations include a survey of how a patient feels (the emPHasis-10 questionnaire), functions (walking test) and how well the heart is coping with the disease (MRI of the heart). Until now, it is unclear how changes on MRI of the heart reflect changes in how a patient feels and functions. Our study identified patients that had the emPHasis-10 questionnaire, walking test and MRI of the heart at both the time of PAH diagnosis and one year later. This allowed us to compare how the changes in the different tests relate to each other. And because previous research identified thresholds for important changes in the emPHasis-10 questionnaire and the walking tests, we were able to use these tests as a benchmark for changes in the MRI of the heart. Our study identified thresholds for change on heart MRI that might indicate whether a patient has improved or worsened. This finding might have implications for how patients are monitored in clinical practice and future research on PAH treatments.

Automated 4D flow cardiac MRI pipeline to derive peak mitral inflow diastolic velocities using short-axis cine stack: two centre validation study against echocardiographic pulse-wave doppler.

BACKGROUND: Measurement of peak velocities is important in the evaluation of heart failure. This study compared the performance of automated 4D flow cardiac MRI (CMR) with traditional transthoracic Doppler echocardiography (TTE) for the measurement of mitral inflow peak diastolic velocities. METHODS: Patients with Doppler echocardiography and 4D flow cardiac magnetic resonance data were included retrospectively. An established automated technique was used to segment the left ventricular transvalvular flow using short-axis cine stack of images. Peak mitral E-wave and peak mitral A-wave velocities were automatically derived using in-plane velocity maps of transvalvular flow. Additionally, we checked the agreement between peak mitral E-wave velocity derived by 4D flow CMR and Doppler echocardiography in patients with sinus rhythm and atrial fibrillation (AF) separately. RESULTS: Forty-eight patients were included (median age 69 years, IQR 63 to 76; 46% female). Data were split into three groups according to heart rhythm. The median peak E-wave mitral inflow velocity by automated 4D flow CMR was comparable with Doppler echocardiography in all patients (0.90 ± 0.43 m/s vs 0.94 ± 0.48 m/s, P = 0.132), sinus rhythm-only group (0.88 ± 0.35 m/s vs 0.86 ± 0.38 m/s, P = 0.54) and in AF-only group (1.33 ± 0.56 m/s vs 1.18 ± 0.47 m/s, P = 0.06). Peak A-wave mitral inflow velocity results had no significant difference between Doppler TTE and automated 4D flow CMR (0.81 ± 0.44 m/s vs 0.81 ± 0.53 m/s, P = 0.09) in all patients and sinus rhythm-only groups. Automated 4D flow CMR showed a significant correlation with TTE for measurement of peak E-wave in all patients group (r = 0.73, P < 0.001) and peak A-wave velocities (r = 0.88, P < 0.001). Moreover, there was a significant correlation between automated 4D flow CMR and TTE for peak-E wave velocity in sinus rhythm-only patients (r = 0.68, P < 0.001) and AF-only patients (r = 0.81, P = 0.014). Excellent intra-and inter-observer variability was demonstrated for both parameters. CONCLUSION: Automated dynamic peak mitral inflow diastolic velocity tracing using 4D flow CMR is comparable to Doppler echocardiography and has excellent repeatability for clinical use. However, 4D flow CMR can potentially underestimate peak velocity in patients with AF.

The Role of Artificial Intelligence in Predicting Outcomes by Cardiovascular Magnetic Resonance: A Comprehensive Systematic Review.

Background and Objectives: Interest in artificial intelligence (AI) for outcome prediction has grown substantially in recent years. However, the prognostic role of AI using advanced cardiac magnetic resonance imaging (CMR) remains unclear. This systematic review assesses the existing literature on AI in CMR to predict outcomes in patients with cardiovascular disease. Materials and Methods: Medline and Embase were searched for studies published up to November 2021. Any study assessing outcome prediction using AI in CMR in patients with cardiovascular disease was eligible for inclusion. All studies were assessed for compliance with the Checklist for Artificial Intelligence in Medical Imaging (CLAIM). Results: A total of 5 studies were included, with a total of 3679 patients, with 225 deaths and 265 major adverse cardiovascular events. Three methods demonstrated high prognostic accuracy: (1) three-dimensional motion assessment model in pulmonary hypertension (hazard ratio (HR) 2.74, 95%CI 1.73−4.34, p < 0.001), (2) automated perfusion quantification in patients with coronary artery disease (HR 2.14, 95%CI 1.58−2.90, p < 0.001), and (3) automated volumetric, functional, and area assessment in patients with myocardial infarction (HR 0.94, 95%CI 0.92−0.96, p < 0.001). Conclusion: There is emerging evidence of the prognostic role of AI in predicting outcomes for three-dimensional motion assessment in pulmonary hypertension, ischaemia assessment by automated perfusion quantification, and automated functional assessment in myocardial infarction.

Advancements in cardiac structures segmentation: a comprehensive systematic review of deep learning in CT imaging.

Background: Segmentation of cardiac structures is an important step in evaluation of the heart on imaging. There has been growing interest in how artificial intelligence (AI) methods-particularly deep learning (DL)-can be used to automate this process. Existing AI approaches to cardiac segmentation have mostly focused on cardiac MRI. This systematic review aimed to appraise the performance and quality of supervised DL tools for the segmentation of cardiac structures on CT. Methods: Embase and Medline databases were searched to identify related studies from January 1, 2013 to December 4, 2023. Original research studies published in peer-reviewed journals after January 1, 2013 were eligible for inclusion if they presented supervised DL-based tools for the segmentation of cardiac structures and non-coronary great vessels on CT. The data extracted from eligible studies included information about cardiac structure(s) being segmented, study location, DL architectures and reported performance metrics such as the Dice similarity coefficient (DSC). The quality of the included studies was assessed using the Checklist for Artificial Intelligence in Medical Imaging (CLAIM). Results: 18 studies published after 2020 were included. The DSC scores median achieved for the most commonly segmented structures were left atrium (0.88, IQR 0.83-0.91), left ventricle (0.91, IQR 0.89-0.94), left ventricle myocardium (0.83, IQR 0.82-0.92), right atrium (0.88, IQR 0.83-0.90), right ventricle (0.91, IQR 0.85-0.92), and pulmonary artery (0.92, IQR 0.87-0.93). Compliance of studies with CLAIM was variable. In particular, only 58% of studies showed compliance with dataset description criteria and most of the studies did not test or validate their models on external data (81%). Conclusion: Supervised DL has been applied to the segmentation of various cardiac structures on CT. Most showed similar performance as measured by DSC values. Existing studies have been limited by the size and nature of the training datasets, inconsistent descriptions of ground truth annotations and lack of testing in external data or clinical settings. Systematic Review Registration: [www.crd.york.ac.uk/prospero/], PROSPERO [CRD42023431113].

A systematic review of artificial intelligence tools for chronic pulmonary embolism on CT pulmonary angiography.

Background: Chronic pulmonary embolism (PE) may result in pulmonary hypertension (CTEPH). Automated CT pulmonary angiography (CTPA) interpretation using artificial intelligence (AI) tools has the potential for improving diagnostic accuracy, reducing delays to diagnosis and yielding novel information of clinical value in CTEPH. This systematic review aimed to identify and appraise existing studies presenting AI tools for CTPA in the context of chronic PE and CTEPH. Methods: MEDLINE and EMBASE databases were searched on 11 September 2023. Journal publications presenting AI tools for CTPA in patients with chronic PE or CTEPH were eligible for inclusion. Information about model design, training and testing was extracted. Study quality was assessed using compliance with the Checklist for Artificial Intelligence in Medical Imaging (CLAIM). Results: Five studies were eligible for inclusion, all of which presented deep learning AI models to evaluate PE. First study evaluated the lung parenchymal changes in chronic PE and two studies used an AI model to classify PE, with none directly assessing the pulmonary arteries. In addition, a separate study developed a CNN tool to distinguish chronic PE using 2D maximum intensity projection reconstructions. While another study assessed a novel automated approach to quantify hypoperfusion to help in the severity assessment of CTEPH. While descriptions of model design and training were reliable, descriptions of the datasets used in training and testing were more inconsistent. Conclusion: In contrast to AI tools for evaluation of acute PE, there has been limited investigation of AI-based approaches to characterising chronic PE and CTEPH on CTPA. Existing studies are limited by inconsistent reporting of the data used to train and test their models. This systematic review highlights an area of potential expansion for the field of AI in medical image interpretation.There is limited knowledge of A systematic review of artificial intelligence tools for chronic pulmonary embolism in CT. This systematic review provides an assessment on research that examined deep learning algorithms in detecting CTEPH on CTPA images, the number of studies assessing the utility of deep learning on CTPA in CTEPH was unclear and should be highlighted.

Clinical assessment of an AI tool for measuring biventricular parameters on cardiac MR.

Introduction: Cardiac magnetic resonance (CMR) is of diagnostic and prognostic value in a range of cardiopulmonary conditions. Current methods for evaluating CMR studies are laborious and time-consuming, contributing to delays for patients. As the demand for CMR increases, there is a growing need to automate this process. The application of artificial intelligence (AI) to CMR is promising, but the evaluation of these tools in clinical practice has been limited. This study assessed the clinical viability of an automatic tool for measuring cardiac volumes on CMR. Methods: Consecutive patients who underwent CMR for any indication between January 2022 and October 2022 at a single tertiary centre were included prospectively. For each case, short-axis CMR images were segmented by the AI tool and manually to yield volume, mass and ejection fraction measurements for both ventricles. Automated and manual measurements were compared for agreement and the quality of the automated contours was assessed visually by cardiac radiologists. Results: 462 CMR studies were included. No statistically significant difference was demonstrated between any automated and manual measurements (p > 0.05; independent T-test). Intraclass correlation coefficient and Bland-Altman analysis showed excellent agreement across all metrics (ICC > 0.85). The automated contours were evaluated visually in 251 cases, with agreement or minor disagreement in 229 cases (91.2%) and failed segmentation in only a single case (0.4%). The AI tool was able to provide automated contours in under 90 s. Conclusions: Automated segmentation of both ventricles on CMR by an automatic tool shows excellent agreement with manual segmentation performed by CMR experts in a retrospective real-world clinical cohort. Implementation of the tool could improve the efficiency of CMR reporting and reduce delays between imaging and diagnosis.

How should studies using AI be reported? lessons from a systematic review in cardiac MRI.

Recent years have seen a dramatic increase in studies presenting artificial intelligence (AI) tools for cardiac imaging. Amongst these are AI tools that undertake segmentation of structures on cardiac MRI (CMR), an essential step in obtaining clinically relevant functional information. The quality of reporting of these studies carries significant implications for advancement of the field and the translation of AI tools to clinical practice. We recently undertook a systematic review to evaluate the quality of reporting of studies presenting automated approaches to segmentation in cardiac MRI (Alabed et al. 2022 Quality of reporting in AI cardiac MRI segmentation studies-a systematic review and recommendations for future studies. Frontiers in Cardiovascular Medicine 9:956811). 209 studies were assessed for compliance with the Checklist for AI in Medical Imaging (CLAIM), a framework for reporting. We found variable-and sometimes poor-quality of reporting and identified significant and frequently missing information in publications. Compliance with CLAIM was high for descriptions of models (100%, IQR 80%-100%), but lower than expected for descriptions of study design (71%, IQR 63-86%), datasets used in training and testing (63%, IQR 50%-67%) and model performance (60%, IQR 50%-70%). Here, we present a summary of our key findings, aimed at general readers who may not be experts in AI, and use them as a framework to discuss the factors determining quality of reporting, making recommendations for improving the reporting of research in this field. We aim to assist researchers in presenting their work and readers in their appraisal of evidence. Finally, we emphasise the need for close scrutiny of studies presenting AI tools, even in the face of the excitement surrounding AI in cardiac imaging.

Evaluating the performance of artificial intelligence software for lung nodule detection on chest radiographs in a retrospective real-world UK population.

OBJECTIVES: Early identification of lung cancer on chest radiographs improves patient outcomes. Artificial intelligence (AI) tools may increase diagnostic accuracy and streamline this pathway. This study evaluated the performance of commercially available AI-based software trained to identify cancerous lung nodules on chest radiographs. DESIGN: This retrospective study included primary care chest radiographs acquired in a UK centre. The software evaluated each radiograph independently and outputs were compared with two reference standards: (1) the radiologist report and (2) the diagnosis of cancer by multidisciplinary team decision. Failure analysis was performed by interrogating the software marker locations on radiographs. PARTICIPANTS: 5722 consecutive chest radiographs were included from 5592 patients (median age 59 years, 53.8% women, 1.6% prevalence of cancer). RESULTS: Compared with radiologist reports for nodule detection, the software demonstrated sensitivity 54.5% (95% CI 44.2% to 64.4%), specificity 83.2% (82.2% to 84.1%), positive predictive value (PPV) 5.5% (4.6% to 6.6%) and negative predictive value (NPV) 99.0% (98.8% to 99.2%). Compared with cancer diagnosis, the software demonstrated sensitivity 60.9% (50.1% to 70.9%), specificity 83.3% (82.3% to 84.2%), PPV 5.6% (4.8% to 6.6%) and NPV 99.2% (99.0% to 99.4%). Normal or variant anatomy was misidentified as an abnormality in 69.9% of the 943 false positive cases. CONCLUSIONS: The software demonstrated considerable underperformance in this real-world patient cohort. Failure analysis suggested a lack of generalisability in the training and testing datasets as a potential factor. The low PPV carries the risk of over-investigation and limits the translation of the software to clinical practice. Our findings highlight the importance of training and testing software in representative datasets, with broader implications for the implementation of AI tools in imaging.

The reproducibility of manual RV/LV ratio measurement on CT pulmonary angiography.

Objectives: Right ventricular (RV) dysfunction carries elevated risk in acute pulmonary embolism (PE). An increased ratio between the size of the right and left ventricles (RV/LV ratio) is a biomarker of RV dysfunction. This study evaluated the reproducibility of RV/LV ratio measurement on CT pulmonary angiography (CTPA). Methods: 20 inpatient CTPA scans performed to assess for acute PE were retrospectively identified from a tertiary UK centre. Each scan was evaluated by 14 radiologists who provided a qualitative overall opinion on the presence of RV dysfunction and measured the RV/LV ratio. Using a threshold of 1.0, the RV/LV ratio measurements were classified as positive (≥1.0) or negative (<1.0) for RV dysfunction. Interobserver agreement was quantified using the Fleiss κ and intraclass correlation coefficient (ICC). Results: Qualitative opinion of RV dysfunction showed weak agreement (κ = 0.42, 95% CI 0.37-0.46). The mean RV/LV ratio measurement for all cases was 1.28 ± 0.68 with significant variation between reporters (p < 0.001). Although agreement for RV/LV measurement was good (ICC = 0.83, 95% CI 0.73-0.91), categorisation of RV dysfunction according to RV/LV ratio measurements showed weak agreement (κ = 0.46, 95% CI 0.41-0.50). Conclusion: Both qualitative opinion and quantitative manual RV/LV ratio measurement show poor agreement for identifying RV dysfunction on CTPA. Advances in knowledge: Caution should be exerted if using manual RV/LV ratio measurements to inform clinical risk stratification and management decisions.

Semi-automatic thresholding of RV trabeculation improves repeatability and diagnostic value in suspected pulmonary hypertension.

Objectives: Right ventricle (RV) mass is an imaging biomarker of mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance (PVR). Some methods of RV mass measurement on cardiac MRI (CMR) exclude RV trabeculation. This study assessed the reproducibility of measurement methods and evaluated whether the inclusion of trabeculation in RV mass affects diagnostic accuracy in suspected pulmonary hypertension (PH). Materials and methods: Two populations were enrolled prospectively. (i) A total of 144 patients with suspected PH who underwent CMR followed by right heart catheterization (RHC). Total RV mass (including trabeculation) and compacted RV mass (excluding trabeculation) were measured on the end-diastolic CMR images using both semi-automated pixel-intensity-based thresholding and manual contouring techniques. (ii) A total of 15 healthy volunteers and 15 patients with known PH. Interobserver agreement and scan-scan reproducibility were evaluated for RV mass measurements using the semi-automated thresholding and manual contouring techniques. Results: Total RV mass correlated more strongly with MPAP and PVR (r = 0.59 and 0.63) than compacted RV mass (r = 0.25 and 0.38). Using a diagnostic threshold of MPAP ≥ 25 mmHg, ROC analysis showed better performance for total RV mass (AUC 0.77 and 0.81) compared to compacted RV mass (AUC 0.61 and 0.66) when both parameters were indexed for LV mass. Semi-automated thresholding was twice as fast as manual contouring (p < 0.001). Conclusion: Using a semi-automated thresholding technique, inclusion of trabecular mass and indexing RV mass for LV mass (ventricular mass index), improves the diagnostic accuracy of CMR measurements in suspected PH.

Quality of reporting in AI cardiac MRI segmentation studies - A systematic review and recommendations for future studies.

Background: There has been a rapid increase in the number of Artificial Intelligence (AI) studies of cardiac MRI (CMR) segmentation aiming to automate image analysis. However, advancement and clinical translation in this field depend on researchers presenting their work in a transparent and reproducible manner. This systematic review aimed to evaluate the quality of reporting in AI studies involving CMR segmentation. Methods: MEDLINE and EMBASE were searched for AI CMR segmentation studies in April 2022. Any fully automated AI method for segmentation of cardiac chambers, myocardium or scar on CMR was considered for inclusion. For each study, compliance with the Checklist for Artificial Intelligence in Medical Imaging (CLAIM) was assessed. The CLAIM criteria were grouped into study, dataset, model and performance description domains. Results: 209 studies published between 2012 and 2022 were included in the analysis. Studies were mainly published in technical journals (58%), with the majority (57%) published since 2019. Studies were from 37 different countries, with most from China (26%), the United States (18%) and the United Kingdom (11%). Short axis CMR images were most frequently used (70%), with the left ventricle the most commonly segmented cardiac structure (49%). Median compliance of studies with CLAIM was 67% (IQR 59-73%). Median compliance was highest for the model description domain (100%, IQR 80-100%) and lower for the study (71%, IQR 63-86%), dataset (63%, IQR 50-67%) and performance (60%, IQR 50-70%) description domains. Conclusion: This systematic review highlights important gaps in the literature of CMR studies using AI. We identified key items missing-most strikingly poor description of patients included in the training and validation of AI models and inadequate model failure analysis-that limit the transparency, reproducibility and hence validity of published AI studies. This review may support closer adherence to established frameworks for reporting standards and presents recommendations for improving the quality of reporting in this field. Systematic Review Registration: [www.crd.york.ac.uk/prospero/], identifier [CRD42022279214].

Investigating the relationship between diffusion kurtosis tensor imaging (DKTI) and histology within the normal human brain.

Measurements of water diffusion with MRI have been used as a biomarker of tissue microstructure and heterogeneity. In this study, diffusion kurtosis tensor imaging (DKTI) of the brain was undertaken in 10 healthy volunteers at a clinical field strength of 3 T. Diffusion and kurtosis metrics were measured in regions-of-interest on the resulting maps and compared with quantitative analysis of normal post-mortem tissue histology from separate age-matched donors. White matter regions showed low diffusion (0.60 ± 0.04 × 10-3 mm2/s) and high kurtosis (1.17 ± 0.06), consistent with a structured heterogeneous environment comprising parallel neuronal fibres. Grey matter showed intermediate diffusion (0.80 ± 0.02 × 10-3 mm2/s) and kurtosis (0.82 ± 0.05) values. An important finding is that the subcortical regions investigated (thalamus, caudate and putamen) showed similar diffusion and kurtosis properties to white matter. Histological staining of the subcortical nuclei demonstrated that the predominant grey matter was permeated by small white matter bundles, which could account for the similar kurtosis to white matter. Quantitative histological analysis demonstrated higher mean tissue kurtosis and vector standard deviation values for white matter (1.08 and 0.81) compared to the subcortical regions (0.34 and 0.59). Mean diffusion on DKTI was positively correlated with tissue kurtosis (r = 0.82, p < 0.05) and negatively correlated with vector standard deviation (r = -0.69, p < 0.05). This study demonstrates how DKTI can be used to study regional structural variations in the cerebral tissue microenvironment and could be used to probe microstructural changes within diseased tissue in the future.

Evaluation of stroke thrombectomy including patients where IV thrombolysis is contraindicated or has failed: a randomized trial of two novel thrombectomy devices.

BACKGROUND: Study was a PROBE design phase II randomized controlled trial (RCT). We assessed trial feasibility and technical efficacy and safety of two novel thrombectomy devices - ERIC (a retriever device) and SOFIA (a distal access catheter) - used alone or in combination depending on operator preference. METHODS: Four UK neuroscience centers enrolled adults with proximal large artery occlusion (LAO) stroke on imaging where arterial puncture was achievable within 5.5 hours (8.5 hours for posterior circulation) of symptom onset; National Institutes of Health Stroke Scale (NIHSS) ≥6 with limited ischemic change on CT imaging. Randomization was 2:1 into intervention arm (ERIC and/or SOFIA). Patients and core lab were blinded to allocation. Primary outcome was independent core lab adjudication of reperfusion (modified Thrombolysis in Cerebral Infarction (mTICI) scale). Secondary outcomes were modified Rankin score (mRS) at 90 and 365 days (independence and shift analysis), 30-day mortality, symptomatic intracranial hemorrhage (sICH), procedural complications and NIHSS change. RESULTS: Sixty-six patients were enrolled. TICI 2B/3 reperfusion was achieved in 72% in intervention compared with 90% in control arm on intention to treat (ITT) analysis (P=0.2) and 78% compared with 86% on per protocol analysis (P=0.7). Functional independence at 90 days was 40% (intervention) compared with 43% (control) on ITT analysis (P=1.0). sICH rates were low at 0% and 5%, respectively (P=0.3). The 30-day mortality was 9% intervention compared with 14% control (P=0.7). CONCLUSIONS: Study indicated feasibility of a phase II RCT trial approach for assessing new thrombectomy devices. In a broad LAO stroke population ERIC and SOFIA were not statistically different from control devices. Larger trials are needed.

Local epigenetic reprogramming induced by G-quadruplex ligands.

DNA and histone modifications regulate transcriptional activity and thus represent valuable targets to reprogram the activity of genes. Current epigenetic therapies target the machinery that regulates these modifications, leading to global transcriptional reprogramming with the potential for extensive undesired effects. Epigenetic information can also be modified as a consequence of disrupting processive DNA replication. Here, we demonstrate that impeding replication by small-molecule-mediated stabilization of G-quadruplex nucleic acid secondary structures triggers local epigenetic plasticity. We report the use of the BU-1 locus of chicken DT40 cells to screen for small molecules able to induce G-quadruplex-dependent transcriptional reprogramming. Further characterization of the top hit compound revealed its ability to induce a dose-dependent inactivation of BU-1 expression in two steps: the loss of H3K4me3 and then subsequent DNA cytosine methylation, changes that were heritable across cell divisions even after the compound was removed. Targeting DNA secondary structures thus represents a potentially new approach for locus-specific epigenetic reprogramming.

Contributions of the specialised DNA polymerases to replication of structured DNA.

It is becoming increasingly clear that processive DNA replication is threatened not only by DNA damage but also by secondary structures that can form in the DNA template. Failure to resolve these structures promptly leads to both genetic instability, for instance DNA breaks and rearrangements, and to epigenetic instability, in which inaccurate propagation of the parental chromatin state leads to unscheduled changes in gene expression. Multiple overlapping mechanisms are needed to deal with the wide range of potential DNA structural challenges to replication. This review focuses on the emerging mechanisms by which specialised DNA polymerases, best known for their role in the replication of damaged DNA, contribute to the replication of undamaged but structured DNA, particularly G quadruplexes.