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Verity plots: a novel method of visualizing reliability assessments of artificial intelligence methods in quantitative cardiovascular magnetic resonance.
Get PDFBACKGROUND: Artificial intelligence (AI) methods have established themselves in cardiovascular magnetic resonance (CMR) as automated quantification tools for ventricular volumes, function, and myocardial tissue characterization. Quality assurance approaches focus on measuring and controlling AI-expert differences but there is a need for tools that better communicate reliability and agreement. This study introduces the Verity plot, a novel statistical visualization that communicates the reliability of quantitative parameters (QP) with clear agreement criteria and descriptive statistics. METHODS: Tolerance ranges for the acceptability of the bias and variance of AI-expert differences were derived from intra- and interreader evaluations. AI-expert agreement was defined by bias confidence and variance tolerance intervals being within bias and variance tolerance ranges. A reliability plot was designed to communicate this statistical test for agreement. Verity plots merge reliability plots with density and a scatter plot to illustrate AI-expert differences. Their utility was compared against Correlation, Box and Bland-Altman plots. RESULTS: Bias and variance tolerance ranges were established for volume, function, and myocardial tissue characterization QPs. Verity plots provided insights into statstistcal properties, outlier detection, and parametric test assumptions, outperforming Correlation, Box and Bland-Altman plots. Additionally, they offered a framework for determining the acceptability of AI-expert bias and variance. CONCLUSION: Verity plots offer markers for bias, variance, trends and outliers, in addition to deciding AI quantification acceptability. The plots were successfully applied to various AI methods in CMR and decisively communicated AI-expert agreement
BIRC5 dependency defines a targetable vulnerability in TP53 mutant acute myeloid leukemia
No full textTP53 mutations across multiple cancers, including acute myeloid leukemia (AML), are associated with poor outcomes irrespective of treatment modality. However, druggable vulnerabilities beyond canonical p53 targets remain largely unexplored. We identify BIRC5 (encodes survivin), an inhibitor of the apoptosis protein (IAP) family, as a novel vulnerability in TP53 mutant AML using an unbiased, comprehensive multiomics approach; whole-genome CRISPR knockout screen, bulk and single-cell RNA-seq, proteomics, and high-throughput drug screen. Mechanistically, BIRC5 deletion in AML restored caspase-9 and -3/7 activity and downregulated other IAPs, implicating BIRC5 as the central post-mitochondrial regulator for blocking apoptosis. p53 stabilization suppressed BIRC5 selectively in TP53 wild-type AML, explaining BIRC5 upregulation in TP53 mutant lines and AML primary tumors (n > 700). Longitudinal single-cell RNAseq (n = 22 pairs) revealed expansion of BIRC5high stem and progenitor leukemia clones in TP53 mutant AML patients post-VenAza therapy. Survivin and IAP inhibitors emerged as top combination partners with VenAza in TP53 mutant AML cells and showed potent in vivo leukemic blast inhibition in xenograft models and primary tumors. Beyond AML, BIRC5 was upregulated broadly across 17 of 25 TP53 mutant cancers in the TCGA cohort, and combination with survivin inhibitors overcame chemotherapy resistance in TP53 deficient triple negative breast and colorectal cancers. These findings define BIRC5 as a critical, targetable dependency and unveil survivin/IAP inhibition as a promising therapeutic axis to overcome p53-related resistance across both hematologic and solid malignancies
Gut-heart axis: the role of gut microbiota and metabolites in heart failure
No full textHeart failure is a global health issue with significant mortality and morbidity. There is increasing evidence that alterations in the gastrointestinal microbiome, gut epithelial permeability, and gastrointestinal disorders contribute to heart failure progression through various pathways, including systemic inflammation, metabolic dysregulation, and modulation of cardiac function. Moreover, several medications used to treat heart failure directly impact the microbiome. The relationship between the gastrointestinal tract and the heart is bidirectional, termed the gut-heart axis. It is increasingly understood that diet-derived microbial metabolites are key mechanistic drivers of the gut-heart axis. This includes, for example, trimethylamine N-oxide and short-chain fatty acids. This review discusses current insights into the interplay between heart failure, its associated risk factors, and the gut microbiome, focusing on key metabolic pathways, the role of dietary interventions, and the potential for gut-targeted therapies. Understanding these complex interactions could pave the way for novel strategies to mitigate heart failure progression and improve patient outcomes
Brain characteristics in patients with myelin oligodendrocyte glycoprotein antibody-associated disorder by 7.0 Tesla MRI
Get PDFBACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can radiographically mimic multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). The disease hallmarks cortical lesion, central vein sign (CVS) and paramagnetic rim lesions identified in MS have not yet been comprehensively investigated in MOGAD. METHODS: We have characterized 45 patients with MOGAD using 7.0 Tesla (7 T) MRI at two academic research hospitals in China and Germany. 7 T MRI, laboratory, and clinical data were collected. The classification of cortical lesions, proportion of CVS, and the phase shifts of lesions on susceptibility weighted imaging were analyzed. RESULTS: Of the 45 patients enrolled with MOGAD, 282 lesions were identified. We further detected 31 (11%) cortical lesions including leukocortical, intracortical, and subpial types, of which intracortical lesions (16/31, 52%) were frequently involved. CVS was identified in 53 (19%) lesions of 21 (47%) patients, 154 (55%) lesions showed multiple veins sign (MVS) in 30 (67%) patients. The number (4.3 ± 6.0 vs. 1.5 ± 2.1, p = 0.0049) and percentage (52% vs. 18%, p < 0.0001) of MVS lesions for each MOGAD patient were higher than those of CVS. Eight patients (18%) had 39 (14%) lesions of hypointense signal with paramagnetic phase shifts on SWI, showing nodular phase changes and irregular borders in appearance. CONCLUSIONS: In our observational MOGAD cohort, all three types of cortical lesions were recognized, with intracortical lesions being the most common. The number and proportion of lesions with MVS were higher than those with CVS. Lesions with paramagnetic phase changes were rare and non-rim-like in appearance. These findings provide a better understanding of the underlying pathology of MOGAD and will help in the differentiation of MOGAD from other demyelinating disorders
Small intestinal neuroendocrine tumors lack early genomic drivers, acquire DNA repair defects and harbor hallmarks of low REST expression
Get PDFThe tumorigenesis of small intestinal neuroendocrine tumors (siNETs) is not understood and comprehensive genomic and transcriptomic data sets are limited. Therefore, we performed whole genome and transcriptome analysis of 39 well differentiated siNET samples. Our genomic data revealed a lack of recurrent driver mutations and demonstrated that multifocal siNETs from individual patients can arise genetically independently. We detected germline mutations in Fanconi anemia DNA repair pathway (FANC) genes, involved in homologous recombination (HR) DNA repair, in 9% of patients and found mutational signatures of defective HR DNA repair in late-stage tumor evolution. Furthermore, transcriptomic analysis revealed low expression of the transcriptional repressor REST. Summarizing, we identify a novel common transcriptomic signature of siNETs and demonstrate that genomic alterations alone do not explain initial tumor formation, while impaired DNA repair likely contributes to tumor evolution and represents a potential pharmaceutical target in a subset of patients
Environmental reservoir of resistance genes for the last resort antibiotic Cefiderocol
Get PDFAntibiotic resistance poses a global public health threat. Cefiderocol, a recently introduced siderophore cephalosporin, employs a “Trojan Horse” mechanism by exploiting bacterial iron uptake systems for cell entry. Yet, resistant clinical isolates are already observed in clinics and resistance mechanisms are difficult to characterize. Here, we applied functional metagenomics to identify cefiderocol resistance genes. Functional metagenomic DNA libraries from diverse environmental samples collected across several countries were expressed in a cefiderocol-sensitive Escherichia coli host. This yielded four resistant clones with DNA originating from wastewater or freshwater DNA libraries. The identified antibiotic resistance genes (ARGs) causing an increase in cefiderocol minimum inhibitory concentrations encoded for beta-lactamases (VEB-3, OXA-372 homolog and YbxI homolog) and a partial penicillin binding protein homolog. Three of four shared closest homologs in pathogenic bacteria. One ARG was associated with a mobile genetic element and was broadly distributed across all wastewater samples from every country surveyed. This study underscores the critical importance of environmental surveillance for ARGs, particularly for novel agents like cefiderocol with limited understanding of resistance mechanisms
Prognostic factors for multiple sclerosis symptoms in radiologically isolated syndrome
No full textIMPORTANCE: Understanding the risk factors for symptom development will allow clinicians to stratify people with radiologically isolated syndrome (pwRIS) more effectively and tailor their management strategies accordingly. OBJECTIVE: To identify prognostic factors at radiologically isolated syndrome (RIS) diagnosis associated with the development of multiple sclerosis (MS) symptoms. DESIGN, SETTING, AND PARTICIPANTS: This cohort study was performed in samples collected between July 2004 and September 2022 and included 33 MS centers. All pwRIS who meet the 2017 McDonald criteria for dissemination in space with a sample collected near the diagnostic magnetic resonance imaging were included. No patients who met eligibility criteria were excluded. The data were analyzed from July 2024 to November 2024. EXPOSURE: Body fluid biomarkers and environmental factors in pwRIS. MAIN OUTCOMES AND MEASURES: The main outcome was the development of MS symptoms. Analyses involved univariable and multivariable Cox proportional hazards models, including age, sex, and treatment following RIS diagnosis, as additional independent variables. RESULTS: The study included 273 pwRIS (mean age, 38.6 [SD 11.6] years; 207 women [75.8%] and 66 men [24.2%]) with a median follow-up of 5.0 [IQR, 2.5-7.7] years. A total of 101 pwRIS developed MS symptoms (37.0%). The presence of immunoglobulin G oligoclonal bands (OBs) (hazard ratio [HR], 5.09; 95% CI, 2.36-10.97; P < .001), immunoglobulin M OBs (HR, 2.58; 95% CI, 1.61-4.14; P < .001), and a κ free light chain index of 6.1 or more (HR, 2.79; 95% CI, 1.37-5.67; P = .005) were associated with MS symptoms. High cerebrospinal fluid neurofilament light chain (NfL) levels (HR, 1.31; 95% CI, 1.18-1.45; P < .001) and high serum NfL z scores (HR, 1.42; 95% CI, 1.16-1.72; P = .005) were also associated with an increased risk of MS symptoms. In contrast, high anti-cytomegalovirus titers (HR, 0.59; 95% CI, 0.38-0.93; P = .02) and high ultraviolet radiation exposure in the year before (HR, 0.52; 95% CI, 0.37-0.74; P < .001) and the year after (HR, 0.54, 95% CI, 0.38-0.75; P < .001) diagnosis reduced the risk of MS symptoms. For all these prognostic factors, the multivariable analysis yielded similar results. The combination of high serum NfL z scores and positive immunoglobulin G OBs conferred a 5-year risk of clinical symptoms of 58.3% (95% CI, 45.9-67.9). This risk increased to 81.6% (95% CI, 60.9-91.4) in pwRIS who were younger and positive for immunoglobulin M OBs. CONCLUSIONS AND RELEVANCE: The study elucidates the prognostic factors that significantly impact the risk of developing MS symptoms in pwRIS at diagnosis, thereby, enhancing the potential for tailored clinical interventions
Comorbidities are associated with unfavorable outcome in aquaporin-4 antibody positive neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody-associated disease: exploratory study from the CROCTINO cohort
Get PDFBACKGROUND: Comorbidities occur in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and double seronegative NMOSD (DN-NMOSD), potentially contributing to a less favorable disease course. OBJECTIVES: To characterize comorbidities in AQP4-NMOSD, MOGAD, and DN-NMOSD and assess their association with optic neuritis (ON) outcomes by optical coherence tomography (OCT) in AQP4-NMOSD. METHODS: Four hundred and forty-two participants from the CROCTINO cohort were evaluated for comorbidities. RESULTS: In AQP4-NMOSD patients (n = 360), 43.5% (n = 161) had comorbidities, equally divided between single and multiple. In MOGAD (n = 49), 40.8% had comorbidities, with 75% (n = 15) single and 25% (n = 5) multiple. In DN-NMOSD (n = 33), 36.4% (n = 12) had comorbidities equally split. AQP4-NMOSD patients had more multiple comorbidities (50%, n = 81/161) than MOGAD (25%, n = 5/20, p = 0.03) and more autoimmune disorders (AID) (40.4%, n = 65) than MOGAD (20%, n = 4, p = 0.09) and DN-NMOSD (none, p = 0.004). Cardiovascular comorbidities and related risk factors (CVC/RF) occurred in 34.8% (n = 56) of AQP4-NMOSD, 50% (n = 10) of MOGAD, and 33.3% (n = 4) of DN-NMOSD. Expanded Disability Status Scale was higher in MOGAD (3.0 vs. 2.0, p = 0.006) and DN-NMOSD (5.0 vs. 2.0, p = 0.008) with comorbidities. AQP4-NMOSD patients with CVC/RF had higher ON relapse rates than those with AID (1.06 ± 3.33 vs. 0.49 ± 0.98, p < 0.001). OCT revealed reduced inner nuclear layer thickness in AQP4-NMOSD with comorbidities compared to non-comorbidity (B = -1.52, p = 0.047), more pronounced with CVC/RF (B = -2.96, p = 0.009). CONCLUSION: Comorbidities are frequent in AQP4-NMOSD and MOGAD and are associated with ON frequency and disability. These findings highlight the need for proactive comorbidity management to improve patient care
Cell-mechanical parameter estimation from 1D cell trajectories using simulation-based inference
Get PDFTrajectories of motile cells represent a rich source of data that provide insights into the mechanisms of cell migration via mathematical modeling and statistical analysis. However, mechanistic models require cell type dependent parameter estimation, which in case of computational simulation is technically challenging due to the nonlinear and inherently stochastic nature of the models. Here, we employ simulation-based inference (SBI) to estimate cell specific model parameters from cell trajectories based on Bayesian inference. Using automated time-lapse image acquisition and image recognition large sets of 1D single cell trajectories are recorded from cells migrating on microfabricated lanes. A deep neural density estimator is trained via simulated trajectories generated from a previously published mechanical model of cell migration. The trained neural network in turn is used to infer the probability distribution of a limited number of model parameters that correspond to the experimental trajectories. Our results demonstrate the efficacy of SBI in discerning properties specific to non-cancerous breast epithelial cell line MCF-10A and cancerous breast epithelial cell line MDA-MB-231. Moreover, SBI is capable of unveiling the impact of inhibitors Latrunculin A and Y-27632 on the relevant elements in the model without prior knowledge of the effect of inhibitors. The proposed approach of SBI based data analysis combined with a standardized migration platform opens new avenues for the installation of cell motility libraries, including cytoskeleton drug efficacies, and may play a role in the evaluation of refined models
Linking latent trajectories of ageing-related atrophy, white matter hyperintensities, and cognitive ageing over four years: insights into brain maintenance
Get PDFINTRODUCTION: We studied brain maintenance, examining the co-evolution of ageing-related atrophy, white matter hyperintensities (WMH), and cognition, alongside domain-specific and domain-general contributions of lifestyle and personality. METHODS: In 543 cognitively unimpaired DELCODE participants, we modelled four-year interrelations between medial temporal lobe to ventricle ratio (MTLV-ratio), WMH, and PACC5 performance using latent growth curve modelling. We quantified unique contributions of brain changes to cognitive change and derived a domain-general brain maintenance index. Associations with lifestyle and personality were examined post-hoc. RESULTS: Steeper MTLV-ratio decline related to baseline WMH and its progression. Braindomain changes independently contributed to cognitive changes. Neuroticism, depressive symptoms, and low cognitive engagement related to unfavourable domain-specific trajectories and brain maintenance index. DISCUSSION: Dynamics of WMH and ageing-related atrophy on cognitive ageing highlight their relevance for brain maintenance. Our results suggest that maintaining cerebrovascular and mental health alongside cognitive engagement could promote brain maintenance, delay cognitive decline and dementia