Base editing rescues acid α-glucosidase function in infantile-onset Pompe disease patient-derived cells.

Infantile-onset Pompe disease (IOPD) results from pathogenic variants in the GAA gene, which encodes acid α-glucosidase. The correction of pathogenic variants through genome editing may be a valuable one-time therapy for PD and improve upon the current standard of care. We performed adenine base editing in human dermal fibroblasts harboring three transition nonsense variants, c.2227C>T (p.Q743∗; IOPD-1), c.2560C>T (p.R854∗; IOPD-2), and c.2608C>T (p.R870∗; IOPD-3). Up to 96% adenine deamination of target variants was observed, with minimal editing across >50 off-target sites. Post-base editing, expressed GAA protein was up to 0.66-fold normal (unaffected fibroblasts), an improvement over affected fibroblasts wherein GAA was undetectable. GAA enzyme activity was between 81.91 ± 13.51 and 129.98 ± 9.33 units/mg protein at 28 days post-transfection, which falls within the normal range (50-200 units/mg protein). LAMP2 protein was significantly decreased in the most robustly edited cell line, IOPD-3, indicating reduced lysosomal burden. Taken together, the findings reported herein demonstrate that base editing results in efficacious adenine deamination, restoration of GAA expression and activity, and reduction in lysosomal burden in the most robustly edited cells. Future work will assess base editing outcomes and the impact on Pompe pathology in two mouse models, Gaa c.2227C>T and Gaa c.2560C>T.

The role of artificial intelligence in cardiovascular magnetic resonance imaging.

Cardiovascular magnetic resonance (CMR) imaging is the gold standard test for myocardial tissue characterization and chamber volumetric and functional evaluation. However, manual CMR analysis can be time-consuming and is subject to intra- and inter-observer variability. Artificial intelligence (AI) is a field that permits automated task performance through the identification of high-level and complex data relationships. In this review, we review the rapidly growing role of AI in CMR, including image acquisition, sequence prescription, artifact detection, reconstruction, segmentation, and data reporting and analysis including quantification of volumes, function, myocardial infarction (MI) and scar detection, and prediction of outcomes. We conclude with a discussion of the emerging challenges to widespread adoption and solutions that will allow for successful, broader uptake of this powerful technology.

Joint EANM/EANO/RANO/SNMMI practice guideline/procedure standards for diagnostics and therapy (theranostics) of meningiomas using radiolabeled somatostatin receptor ligands: version 1.0.

PURPOSE: To provide practice guideline/procedure standards for diagnostics and therapy (theranostics) of meningiomas using radiolabeled somatostatin receptor (SSTR) ligands. METHODS: This joint practice guideline/procedure standard was collaboratively developed by the European Association of Nuclear Medicine (EANM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the European Association of Neurooncology (EANO), and the PET task force of the Response Assessment in Neurooncology Working Group (PET/RANO). RESULTS: Positron emission tomography (PET) using somatostatin receptor (SSTR) ligands can detect meningioma tissue with high sensitivity and specificity and may provide clinically relevant information beyond that obtained from structural magnetic resonance imaging (MRI) or computed tomography (CT) imaging alone. SSTR-directed PET imaging can be particularly useful for differential diagnosis, delineation of meningioma extent, detection of osseous involvement, and the differentiation between posttherapeutic scar tissue and tumour recurrence. Moreover, SSTR-peptide receptor radionuclide therapy (PRRT) is an emerging investigational treatment approach for meningioma. CONCLUSION: These practice guidelines will define procedure standards for the application of PET imaging in patients with meningiomas and related SSTR-targeted PRRTs in routine practice and clinical trials and will help to harmonize data acquisition and interpretation across centers, facilitate comparability of studies, and to collect larger databases. The current document provides additional information to the evidence-based recommendations from the PET/RANO Working Group regarding the utilization of PET imaging in meningiomas Galldiks (Neuro Oncol. 2017;19(12):1576-87). The information provided should be considered in the context of local conditions and regulations.

The biological significance of tumor grade, age, enhancement and extent of resection in IDH mutant gliomas: how should they inform treatment decision in the era of IDH inhibitors? Invited review.

The 2016 and 2021 World Health Organization (WHO) 2021 Classification of Central Nervous System (CNS) tumors have resulted in a major improvement of the classification of IDH-mutant gliomas. With more effective treatments many patients experience prolonged survival . However, treatment guidelines are often still based on information from historical series comprising both patients with IDHwt and IDH mutant tumors. They provide recommendations for radiotherapy and chemotherapy for so-called high-risk patients, usually based on residual tumor after surgery and age over 40. More up-to-date studies give a better insight into clinical, radiological and molecular factors associated with outcome of patients with IDH-mutant glioma. These insights should be used today for risk stratification and for treatment decisions. In many patients with an IDH-mutant grade 2 and grade 3 glioma, if carefully monitored postponing radiotherapy and chemotherapy is safe, and will not jeopardize overall outcome of patients. With the INDIGO trial showing patient benefit from the IDH inhibitor vorasidenib, there is a sizable population in which it seems reasonable to try this class of agents before recommending radio-chemotherapy with its delayed adverse event profile affecting quality of survival. Ongoing trials should help to further identify the patients that are benefiting from this treatment.

Cognitive enhancing effect of rTMS combined with tDCS in patients with major depressive disorder: a double-blind, randomized, sham-controlled study.

BACKGROUND: Cognitive dysfunction is one of the common symptoms in patients with major depressive disorder (MDD). Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been studied separately in the treatment of cognitive dysfunction in MDD patients. We aimed to investigate the effectiveness and safety of rTMS combined with tDCS as a new therapy to improve neurocognitive impairment in MDD patients. METHODS: In this brief 2-week, double-blind, randomized, and sham-controlled trial, a total of 550 patients were screened, and 240 MDD inpatients were randomized into four groups (active rTMS + active tDCS, active rTMS + sham tDCS, sham rTMS + active tDCS, sham rTMS + sham tDCS). Finally, 203 patients completed the study and received 10 treatment sessions over a 2-week period. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was performed to assess patients' cognitive function at baseline and week 2. Also, we applied the 24-item Hamilton Depression Rating Scale (HDRS-24) to assess patients' depressive symptoms at baseline and week 2. RESULTS: After 10 sessions of treatment, the rTMS combined with the tDCS group showed more significant improvements in the RBANS total score, immediate memory, and visuospatial/constructional index score (all p < 0.05). Moreover, post hoc tests revealed a significant increase in the RBANS total score and Visuospatial/Constructional in the combined treatment group compared to the other three groups but in the immediate memory, the combined treatment group only showed a better improvement than the sham group. The results also showed the RBANS total score increased significantly higher in the active rTMS group compared with the sham group. However, rTMS or tDCS alone was not superior to the sham group in terms of other cognitive performance. In addition, the rTMS combined with the tDCS group showed a greater reduction in HDRS-24 total score and a better depression response rate than the other three groups. CONCLUSIONS: rTMS combined with tDCS treatment is more effective than any single intervention in treating cognitive dysfunction and depressive symptoms in MDD patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2100052122).

Mechanisms of left ventricular systolic dysfunction in light chain amyloidosis: a multiparametric cardiac MRI study.

Background: Cardiac systolic dysfunction is a poor prognostic marker in light-chain (AL) cardiomyopathy, a primary interstitial disorder; however, its pathogenesis is poorly understood. Purpose: This study aims to analyze the effects of extracellular volume (ECV) expansion, a surrogate marker of amyloid burden on myocardial blood flow (MBF), myocardial work efficiency (MWE), and left ventricular (LV) systolic dysfunction in AL amyloidosis. Methods: Subjects with biopsy-proven AL amyloidosis were prospectively enrolled (April 2016-June 2021; Clinicaltrials.gov ID NCT02641145) and underwent cardiac magnetic resonance imaging (MRI) to quantify rest MBF by perfusion imaging, LV ejection fraction (LVEF) by cine MRI, and ECV by pre- and post-contrast T1 mapping. The MWE was estimated as external cardiac work from the stroke volume and mean arterial pressure normalized to the LV myocardial mass. Results: Rest MBF in 92 subjects (62 ± 8 years, 52 men) with AL amyloidosis averaged 0.87 ± 0.21 ml/min/g and correlated with MWE (r = 0.42; p < 0.001). Rest MBF was similarly low in subjects with sustained hematologic remission after successful AL amyloidosis therapy (n = 21), as in those with recently diagnosed AL amyloidosis. Both MBF and MWE decreased by ECV tertile (p < 0.01 for linear trends). The association of ECV with MWE comprised a direct effect (84% of the total effect; p < 0.001) on MWE from adverse interstitial remodeling assessed by ECV and an indirect effect (16% of the total effect; p < 0.001) mediated by MBF. There was a significant base-to-apex gradient of rest MBF in subjects with higher amyloid burden. Conclusions: In AL amyloidosis, both MBF and MWE decrease as cardiac amyloid burden and ECV expansion increase. Both structural and vascular changes from ECV expansion and myocardial amyloid burden appear to contribute to lower MWE.

A Neuroradiologist's Guide to Operationalizing the Response Assessment in Neuro-Oncology (RANO) Criteria Version 2.0 for Gliomas in Adults.

Radiographic assessment plays a crucial role in the management of patients with central nervous system (CNS) tumors, aiding in treatment planning and evaluation of therapeutic efficacy by quantifying response. Recently, an updated version of the Response Assessment in Neuro-Oncology (RANO) criteria (RANO 2.0) was developed to improve upon prior criteria and provide an updated, standardized framework for assessing treatment response in clinical trials for gliomas in adults. This article provides an overview of significant updates to the criteria including (1) the use of a unified set of criteria for high and low grade gliomas in adults; (2) the use of the post-radiotherapy MRI scan as the baseline for evaluation in newly diagnosed high-grade gliomas; (3) the option for the trial to mandate a confirmation scan to more reliably distinguish pseudoprogression from tumor progression; (4) the option of using volumetric tumor measurements; and (5) the removal of subjective non-enhancing tumor evaluations in predominantly enhancing gliomas (except for specific therapeutic modalities). Step-by-step pragmatic guidance is hereby provided for the neuroradiologist and imaging core lab involved in operationalization and technical execution of RANO 2.0 in clinical trials, including the display of representative cases and in-depth discussion of challenging scenarios.ABBREVIATIONS: BTIP = Brain Tumor Imaging Protocol; CE = Contrast-Enhancing; CNS = Central Nervous System; CR = Complete Response; ECOG = Eastern Cooperative Oncology Group; HGG = High-Grade Glioma; IDH = Isocitrate Dehydrogenase; IRF = Independent Radiologic Facility; LGG = Low-Grade Glioma; KPS = Karnofsky Performance Status; MR = Minor Response; mRANO = Modified RANO; NANO = Neurological Assessment in Neuro-Oncology; ORR = Objective Response Rate; OS = Overall Survival; PD = Progressive Disease; PFS = Progression-Free Survival; PR = Partial Response; PsP = Pseudoprogression; RANO = Response Assessment in Neuro-Oncology; RECIST = Response Evaluation Criteria In Solid Tumors; RT = Radiation Therapy; SD = Stable Disease; Tx = Treatment.

Cardiac Magnetic Resonance Evaluation of LV Remodeling Post-Myocardial Infarction: Prognosis, Monitoring and Trial Endpoints.

Adverse left ventricular remodeling (ALVR) and subsequent heart failure after myocardial infarction (MI) remain a major cause of patient morbidity and mortality worldwide. Overt inflammation has been identified as the common pathway underlying myocardial fibrosis and development of ALVR post-MI. With its ability to simultaneously provide information about cardiac structure, function, perfusion, and tissue characteristics, cardiac magnetic resonance (CMR) is well poised to inform prognosis and guide early surveillance and therapeutics in high-risk cohorts. Further, established and evolving CMR-derived biomarkers may serve as clinical endpoints in prospective trials evaluating the efficacy of novel anti-inflammatory and antifibrotic therapies. This review provides an overview of post-MI ALVR and illustrates how CMR may help clinical adoption of novel therapies via mechanistic or prognostic imaging markers.

Towards Consistency in Pediatric Brain Tumor Measurements: Challenges, Solutions, and the Role of AI-Based Segmentation.

MR imaging is central to the assessment of tumor burden and changes over time in neuro-oncology. Several response assessment guidelines have been set forth by the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working groups in different tumor histologies; however, the visual delineation of tumor components using MRIs is not always straightforward, and complexities not currently addressed by these criteria can introduce inter- and intra-observer variability in manual assessments. Differentiation of non-enhancing tumor from peritumoral edema, mild enhancement from absence of enhancement, and various cystic components can be challenging; particularly given a lack of sufficient and uniform imaging protocols in clinical practice. Automated tumor segmentation with artificial intelligence (AI) may be able to provide more objective delineations, but rely on accurate and consistent training data created manually (ground truth). Herein, this paper reviews existing challenges and potential solutions to identifying and defining subregions of pediatric brain tumors (PBTs) that are not explicitly addressed by current guidelines. The goal is to assert the importance of defining and adopting criteria for addressing these challenges, as it will be critical to achieving standardized tumor measurements and reproducible response assessment in PBTs, ultimately leading to more precise outcome metrics and accurate comparisons among clinical studies.

Generation and applications of synthetic computed tomography images for neurosurgical planning.

OBJECTIVE: CT and MRI are synergistic in the information provided for neurosurgical planning. While obtaining both types of images lends unique data from each, doing so adds to cost and exposes patients to additional ionizing radiation after MRI has been performed. Cross-modal synthesis of high-resolution CT images from MRI sequences offers an appealing solution. The authors therefore sought to develop a deep learning conditional generative adversarial network (cGAN) which performs this synthesis. METHODS: Preoperative paired CT and contrast-enhanced MR images were collected for patients with meningioma, pituitary tumor, vestibular schwannoma, and cerebrovascular disease. CT and MR images were denoised, field corrected, and coregistered. MR images were fed to a cGAN that exported a "synthetic" CT scan. The accuracy of synthetic CT images was assessed objectively using the quantitative similarity metrics as well as by clinical features such as sella and internal auditory canal (IAC) dimensions and mastoid/clinoid/sphenoid aeration. RESULTS: A total of 92,981 paired CT/MR images obtained in 80 patients were used for training/testing, and 10,068 paired images from 10 patients were used for external validation. Synthetic CT images reconstructed the bony skull base and convexity with relatively high accuracy. Measurements of the sella and IAC showed a median relative error between synthetic CT scans and ground truth images of 6%, with greater variability in IAC reconstruction compared with the sella. Aerations in the mastoid, clinoid, and sphenoid regions were generally captured, although there was heterogeneity in finer air cell septations. Performance varied based on pathology studied, with the highest limitation observed in evaluating meningiomas with intratumoral calcifications or calvarial invasion. CONCLUSIONS: The generation of high-resolution CT scans from MR images through cGAN offers promise for a wide range of applications in cranial and spinal neurosurgery, especially as an adjunct for preoperative evaluation. Optimizing cGAN performance on specific anatomical regions may increase its clinical viability.

Improved optic nerve visualization and treatment planning through a dedicated optic nerve MRI protocol.

OBJECTIVE: This study describes an innovative optic nerve MRI protocol for better delineating optic nerve anatomy from neighboring pathology. METHODS: Twenty-two patients undergoing MRI examination of the optic nerve with the dedicated protocol were identified and included for analysis of imaging, surgical strategy, and outcomes. T2-weighted and fat-suppressed T1-weighted gadolinium-enhanced images were acquired perpendicular and parallel to the long axis of the optic nerve to achieve en face and in-line views along the course of the nerve. RESULTS: Dedicated optic nerve MRI sequences provided enhanced visualization of the nerve, CSF within the nerve sheath, and local pathology. Optic nerve sequences leveraged the "CSF ring" within the optic nerve sheath to create contrast between pathology and normal tissue, highlighting areas of compression. Tumor was readily tracked along the longitudinal axis of the nerve by images obtained parallel to the nerve. The findings augmented treatment planning. CONCLUSIONS: The authors present a dedicated optic nerve MRI protocol that is simple to use and affords improved cross-sectional and longitudinal visualization of the nerve, surrounding CSF, and pathology. This improved visualization enhances radiological evaluation and treatment planning for optic nerve lesions.

Bulk osteochondral allograft for massive Hill-Sachs defect combined with Latarjet procedure for bipolar bone loss in anterior instability.

A proportion of patients with anterior glenohumeral instability present with bipolar bone loss comprising large Hill-Sachs lesions and substantial glenoid defect. These are surgically difficult cases to treat. We describe a novel surgical procedure of bulk size-matched osteochondral allograft reconstruction for massive Hill-Sachs lesions combined with the Latarjet procedure for these challenging cases.

Prognostic value of visual and quantitative CMR regional myocardial function in patients with suspected myocarditis.

According to updated Lake-Louise Criteria, impaired regional myocardial function serves as a supportive criterion in diagnosing myocarditis. This study aimed to assess visual regional wall motional abnormalities (RWMA) and novel quantitative regional longitudinal peak strain (RLS) for risk stratification in the clinical setting of myocarditis. In patients undergoing CMR and meeting clinical criteria for suspected myocarditis global longitudinal strain (GLS), late gadolinium enhancement (LGE), RWMA and RLS were assessed in the anterior, septal, inferior, and lateral regions and correlated to the occurrence of major adverse cardiac events (MACE), including heart failure hospitalization, sustained ventricular tachycardia, recurrent myocarditis, and all-cause death. In 690 consecutive patients (age: 48.0 ± 16.0 years; 37.7% female) with suspected myocarditis impaired RLS was correlated with RWMA and LV-GLS but not with the presence of LGE. At median follow up of 3.8 years, MACE occurred in 116 (16.8%) patients. Both, RWMA and RLS in anterior-, septal-, inferior-, and lateral- locations were univariately associated with outcomes (all p < 0.001), but not after adjusting for clinical characteristics and LV-GLS. In the subgroup of patients with normal LV function, RWMA were not predictive of outcomes, whereas septal RLS had incremental and independent prognostic value over clinical characteristics (HRadjusted = 1.132, 95% CI 1.020-1.256; p = 0.020). RWMA and RLS can be used to assess regional impairment of myocardial function in myocarditis but are of limited prognostic value in the overall population. However, in the subgroup of patients with normal LV function, septal RLS represents a distinctive marker of regional LV dysfunction, offering potential for risk-stratification.

An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation.

Introduction: High sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT. Methods: Here, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment. Results: In total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week. Discussion: These case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted.

Diversity, Equity, and Inclusion in Orthopaedic Surgery: Local and National Efforts.

Orthopaedic surgery has not experienced the same increase in diversity as other surgical subspecialties over time. Professional orthopaedic societies across the nation, including the American Academy of Orthopaedic Surgeons, are now making sincere efforts to improve diversity, equity, and inclusion (DEI) within the field. Several national groups provide funding to support DEI -related research as well as scholarships to national meetings. Others are more focused on mentorship and mitigation of residency attrition amongst underrepresented minorities (URMs). Individual residency programs, including the Department of Orthopaedics at Brown University, are engaging in community outreach to attract more diverse candidates to orthopaedics and providing away rotation scholarship support for medical students that identify as female or URMs. These local and national efforts will hopefully lead to a more inclusive environment for all trainees and practitioners within orthopaedics and ultimately improved orthopaedic care for all patients.

Auto-segmentation of Adult-Type Diffuse Gliomas: Comparison of Transfer Learning-Based Convolutional Neural Network Model vs. Radiologists.

Segmentation of glioma is crucial for quantitative brain tumor assessment, to guide therapeutic research and clinical management, but very time-consuming. Fully automated tools for the segmentation of multi-sequence MRI are needed. We developed and pretrained a deep learning (DL) model using publicly available datasets A (n = 210) and B (n = 369) containing FLAIR, T2WI, and contrast-enhanced (CE)-T1WI. This was then fine-tuned with our institutional dataset (n = 197) containing ADC, T2WI, and CE-T1WI, manually annotated by radiologists, and split into training (n = 100) and testing (n = 97) sets. The Dice similarity coefficient (DSC) was used to compare model outputs and manual labels. A third independent radiologist assessed segmentation quality on a semi-quantitative 5-scale score. Differences in DSC between new and recurrent gliomas, and between uni or multifocal gliomas were analyzed using the Mann-Whitney test. Semi-quantitative analyses were compared using the chi-square test. We found that there was good agreement between segmentations from the fine-tuned DL model and ground truth manual segmentations (median DSC: 0.729, std-dev: 0.134). DSC was higher for newly diagnosed (0.807) than recurrent (0.698) (p < 0.001), and higher for unifocal (0.747) than multi-focal (0.613) cases (p = 0.001). Semi-quantitative scores of DL and manual segmentation were not significantly different (mean: 3.567 vs. 3.639; 93.8% vs. 97.9% scoring ≥ 3, p = 0.107). In conclusion, the proposed transfer learning DL performed similarly to human radiologists in glioma segmentation on both structural and ADC sequences. Further improvement in segmenting challenging postoperative and multifocal glioma cases is needed.

Sex Differences in Revascularization, Treatment Goals, and Outcomes of Patients With Chronic Coronary Disease: Insights From the ISCHEMIA Trial.

BACKGROUND: Women with chronic coronary disease are generally older than men and have more comorbidities but less atherosclerosis. We explored sex differences in revascularization, guideline-directed medical therapy, and outcomes among patients with chronic coronary disease with ischemia on stress testing, with and without invasive management. METHODS AND RESULTS: The ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial randomized patients with moderate or severe ischemia to invasive management with angiography, revascularization, and guideline-directed medical therapy, or initial conservative management with guideline-directed medical therapy alone. We evaluated the primary outcome (cardiovascular death, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest) and other end points, by sex, in 1168 (22.6%) women and 4011 (77.4%) men. Invasive group catheterization rates were similar, with less revascularization among women (73.4% of invasive-assigned women revascularized versus 81.2% of invasive-assigned men; P<0.001). Women had less coronary artery disease: multivessel in 60.0% of invasive-assigned women and 74.8% of invasive-assigned men, and no ≥50% stenosis in 12.3% versus 4.5% (P<0.001). In the conservative group, 4-year catheterization rates were 26.3% of women versus 25.6% of men (P=0.72). Guideline-directed medical therapy use was lower among women with fewer risk factor goals attained. There were no sex differences in the primary outcome (adjusted hazard ratio [HR] for women versus men, 0.93 [95% CI, 0.77-1.13]; P=0.47) or the major secondary outcome of cardiovascular death/myocardial infarction (adjusted HR, 0.93 [95% CI, 0.76-1.14]; P=0.49), with no significant sex-by-treatment-group interactions. CONCLUSIONS: Women had less extensive coronary artery disease and, therefore, lower revascularization rates in the invasive group. Despite lower risk factor goal attainment, women with chronic coronary disease experienced similar risk-adjusted outcomes to men in the ISCHEMIA trial. REGISTRATION: URL: http://wwwclinicaltrials.gov. Unique identifier: NCT01471522.

Effect of six month's treatment with omega-3 acid ethyl esters on long-term outcomes after acute myocardial infarction: The OMEGA-REMODEL randomized clinical trial.

BACKGROUND: Omega-3 polyunsaturated fatty acids (O3-FA) have been shown to reduce inflammation and adverse cardiac remodeling after acute myocardial infarction (AMI). However, the impact of O3-FA on long-term clinical outcomes remains uncertain. AIMS: To investigate the impact of O3-FA on adverse cardiac events in long-term follow up post AMI in a pilot-study. METHODS: Consecutive patients with AMI were randomized 1:1 to receive 6 months of O3-FA (4 g/daily) or placebo in the prospective, multicenter OMEGA-REMODEL trial. Primary endpoint was a composite of major adverse cardiovascular events (MACE) encompassing all-cause death, heart failure hospitalizations, recurrent acute coronary syndrome, and late coronary artery bypass graft (CABG). RESULTS: A total of 358 patients (62.8% male; 48.1 ± 16.1 years) were followed for a median of 6.6 (IQR: 5.0-9.1) years. Among those receiving O3-FA (n = 180), MACE occurred in 65 (36.1%) compared to 62 (34.8%) of 178 assigned to placebo. By intention-to-treat analysis, O3-FA treatment assignment did not reduce MACE (HR = 1.014; 95%CI = 0.716-1.436; p = 0.938), or its individual components. However, patients with a positive response to O3-FA treatment (n = 43), defined as an increase in the red blood cell omega-3 index (O3I) ≥5% after 6 months of treatment, had lower annualized MACE rates compared to those without (2.9% (95%CI = 1.2-5.1) vs 7.1% (95%CI = 5.7-8.9); p = 0.001). This treatment benefit persisted after adjustment for baseline characteristics (HRadjusted = 0.460; 95%CI = 0.218-0.970; p = 0.041). CONCLUSION: In long-term follow-up of the OMEGA-REMODEL randomized trial, O3-FA did not reduce MACE after AMI by intention to treat principle, however, patients who achieved a ≥ 5% increase of O3I subsequent to treatment had favorable outcomes.

Expert-centered Evaluation of Deep Learning Algorithms for Brain Tumor Segmentation.

Purpose To present results from a literature survey on practices in deep learning segmentation algorithm evaluation and perform a study on expert quality perception of brain tumor segmentation. Materials and Methods A total of 180 articles reporting on brain tumor segmentation algorithms were surveyed for the reported quality evaluation. Additionally, ratings of segmentation quality on a four-point scale were collected from medical professionals for 60 brain tumor segmentation cases. Results Of the surveyed articles, Dice score, sensitivity, and Hausdorff distance were the most popular metrics to report segmentation performance. Notably, only 2.8% of the articles included clinical experts' evaluation of segmentation quality. The experimental results revealed a low interrater agreement (Krippendorff α, 0.34) in experts' segmentation quality perception. Furthermore, the correlations between the ratings and commonly used quantitative quality metrics were low (Kendall tau between Dice score and mean rating, 0.23; Kendall tau between Hausdorff distance and mean rating, 0.51), with large variability among the experts. Conclusion The results demonstrate that quality ratings are prone to variability due to the ambiguity of tumor boundaries and individual perceptual differences, and existing metrics do not capture the clinical perception of segmentation quality. Keywords: Brain Tumor Segmentation, Deep Learning Algorithms, Glioblastoma, Cancer, Machine Learning Clinical trial registration nos. NCT00756106 and NCT00662506 Supplemental material is available for this article. © RSNA, 2023.