Increased regional Hurst exponent reflects response inhibition related neural complexity alterations in pediatric bipolar disorder patients during an emotional Go-Nogo task.

Fractal patterns have been shown to change in resting- and task-state blood oxygen level-dependent signals in bipolar disorder patients. However, fractal characteristics of brain blood oxygen level-dependent signals when responding to external emotional stimuli in pediatric bipolar disorder remain unclear. Blood oxygen level-dependent signals of 20 PBD-I patients and 17 age- and sex-matched healthy controls were extracted while performing an emotional Go-Nogo task. Neural responses relevant to the task and Hurst exponent of the blood oxygen level-dependent signals were assessed. Correlations between clinical indices and Hurst exponent were estimated. Significantly increased activations were found in regions covering the frontal lobe, parietal lobe, temporal lobe, insula, and subcortical nuclei in PBD-I patients compared to healthy controls in contrast of emotional versus neutral distractors. PBD-I patients exhibited higher Hurst exponent in regions that involved in action control, such as superior frontal gyrus, inferior frontal gyrus, inferior temporal gyrus, and insula, with Hurst exponent of frontal orbital gyrus correlated with onset age. The present study exhibited overactivation, increased self-similarity and decreased complexity in cortical regions during emotional Go-Nogo task in patients relative to healthy controls, which provides evidence of an altered emotional modulation of cognitive control in pediatric bipolar disorder patients. Hurst exponent may be a fractal biomarker of neural activity in pediatric bipolar disorder.

Late gadolinium enhanced cardiac MR derived radiomics approach for predicting all-cause mortality in cardiac amyloidosis: a multicenter study.

OBJECTIVES: To evaluate the prognostic value of radiomics features based on late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) images in patients with cardiac amyloidosis (CA). METHODS: This retrospective study included 120 CA patients undergoing CMR at three institutions. Radiomics features were extracted from global and three different segments (base, mid-ventricular, and apex) of left ventricular (LV) on short-axis LGE images. Primary endpoint was all-cause mortality. The predictive performance of the radiomics features and semi-quantitative and quantitative LGE parameters were compared by ROC. The AUC was used to observe whether Rad-score had an incremental value for clinical stage. The Kaplan-Meier curve was used to further stratify the risk of CA patients. RESULTS: During a median follow-up of 12.9 months, 30% (40/120) patients died. There was no significant difference in the predictive performance of the radiomics model in different LV sections in the validation set (AUCs of the global, basal, middle, and apical radiomics model were 0.75, 0.77, 0.76, and 0.77, respectively; all p > 0.05). The predictive performance of the Rad-score of the base-LV was better than that of the LGE total enhancement mass (AUC:0.77 vs. 0.54, p < 0.001) and LGE extent (AUC: 0.77 vs. 0.53, p = 0.004). Rad-score combined with Mayo stage had better predictive performance than Mayo stage alone (AUC: 0.86 vs. 0.81, p = 0.03). Rad-score (≥ 0.66) contributed to the risk stratification of all-cause mortality in CA. CONCLUSIONS: Compared to quantitative LGE parameters, radiomics can better predict all-cause mortality in CA, while the combination of radiomics and Mayo stage could provide higher predictive accuracy. CLINICAL RELEVANCE STATEMENT: Radiomics analysis provides incremental value and improved risk stratification for all-cause mortality in patients with cardiac amyloidosis. KEY POINTS: • Radiomics in LV-base was superior to LGE semi-quantitative and quantitative parameters for predicting all-cause mortality in CA. • Rad-score combined with Mayo stage had better predictive performance than Mayo stage alone or radiomics alone. • Rad-score ≥ 0.66 was associated with a significantly increased risk of all-cause mortality in CA patients.

Structural basis for ligand binding modes of CTP synthase.

Cytidine triphosphate synthase (CTPS), which comprises an ammonia ligase domain and a glutamine amidotransferase domain, catalyzes the final step of de novo CTP biosynthesis. The activity of CTPS is regulated by the binding of four nucleotides and glutamine. While glutamine serves as an ammonia donor for the ATP-dependent conversion of UTP to CTP, the fourth nucleotide GTP acts as an allosteric activator. Models have been proposed to explain the mechanisms of action at the active site of the ammonia ligase domain and the conformational changes derived by GTP binding. However, actual GTP/ATP/UTP binding modes and relevant conformational changes have not been revealed fully. Here, we report the discovery of binding modes of four nucleotides and a glutamine analog 6-diazo-5-oxo-L-norleucine in Drosophila CTPS by cryo-electron microscopy with near-atomic resolution. Interactions between GTP and surrounding residues indicate that GTP acts to coordinate reactions at both domains by directly blocking ammonia leakage and stabilizing the ammonia tunnel. Additionally, we observe the ATP-dependent UTP phosphorylation intermediate and determine interacting residues at the ammonia ligase. A noncanonical CTP binding at the ATP binding site suggests another layer of feedback inhibition. Our findings not only delineate the structure of CTPS in the presence of all substrates but also complete our understanding of the underlying mechanisms of the allosteric regulation and CTP synthesis.

The prognostic value of CT-derived fractional flow reserve in coronary artery bypass graft: a retrospective multicenter study.

OBJECTIVES: To investigate the predictive value of CT-derived fractional flow reserve (FFRCT) in anastomosis occlusion after coronary artery bypass graft (CABG) surgery. METHODS: Patients undergoing CABG with both pre- and post-operative coronary computed tomographic angiography (CCTA) were retrospectively included. Preoperative CCTA studies were used to evaluate anatomical and FFRCT information of target vessels. A diameter stenosis (DS) ≥ 70% or left main > 50% was considered to be anatomically severe, while FFRCT value ≤ 0.80 be functionally significant. The primary endpoint was anastomosis occlusion evaluated on post-operative CCTA during follow-up. Predictors of anastomosis occlusion were assessed by the multivariate binary logistic regression with generalized estimating equations. RESULTS: A total of 270 anastomoses were identified in 88 enrolled patients. Forty-one anastomoses from 30 patients exhibited occlusion during a follow-up of 15.3 months after CABG. The occluded group had significantly increased prevalence of non-severe DS (58.5% vs. 40.2%; p = 0.023) and non-significant FFRCT (48.8% vs. 10.0%; p < 0.001). Multivariable analysis indicated FFRCT ≤ 0.80 (odds ratio [OR]: 0.10, 95% CI: 0.03-0.33; p < 0.001) and older age (OR: 0.92, 95% CI: 0.87-0.97; p = 0.001) were predictors for bypass patency during follow-up, while myocardial infarction history and anastomosis to a local lesion or bifurcation (all p value < 0.05) were predictors of occlusion. Adding FFRCT into the model based on the clinical and anatomical predictors had an improved AUC of 0.848 (p = 0.005). CONCLUSIONS: FFRCT ≤ 0.80 was associated with a significant risk reduction of anastomosis occlusion after CABG. Preoperative judgment of the hemodynamic significance may improve the CABG surgery strategy and reduce graft failure. KEY POINTS: • FFRCT ≤ 0.80 was associated with a significant risk reduction of anastomosis occlusion after CABG. • The addition of FFRCT into the integrated model including clinical (age and history of myocardial infarction) and anatomical CCTA indicators (local lesion and bifurcation) significantly improved the model performance with an AUC of 0.848 (p = 0.005). • Preoperative judgment of the hemodynamic significance may help improve the decision-making and surgery planning in patients indicated for CABG and significantly reduce graft failure, without an extra radiation exposure and risk of invasive procedure.

Evaluation of gray matter reduction in patients with typhoon-related posttraumatic stress disorder using causal network analysis of structural MRI.

BACKGROUND: The structural changes recent-onset posttraumatic stress disorder (PTSD) subjects were rarely investigated. This study was to compare temporal and causal relationships of structural changes in recent-onset PTSD with trauma-exposed control (TEC) subjects and non-TEC subjects. METHODS: T1-weighted magnetic resonance images of 27 PTSD, 33 TEC and 30 age- and sex-matched healthy control (HC) subjects were studied. The causal network of structural covariance was used to evaluate the causal relationships of structural changes in PTSD patients. RESULTS: Volumes of bilateral hippocampal and left lingual gyrus were significantly smaller in PTSD patients and TEC subjects than HC subjects. As symptom scores increase, reduction in gray matter volume began in the hippocampus and progressed to the frontal lobe, then to the temporal and occipital cortices (p < 0.05, false discovery rate corrected). The hippocampus might be the primary hub of the directional network and demonstrated positive causal effects on the frontal, temporal and occipital regions (p < 0.05, false discovery rate corrected). The frontal regions, which were identified to be transitional points, projected causal effects to the occipital lobe and temporal regions and received causal effects from the hippocampus (p < 0.05, false discovery rate corrected). CONCLUSIONS: The results offer evidence of localized abnormalities in the bilateral hippocampus and remote abnormalities in multiple temporal and frontal regions in typhoon-exposed PTSD patients.

Influence of diabetes mellitus on the diagnostic performance of machine learning-based coronary CT angiography-derived fractional flow reserve: a multicenter study.

OBJECTIVES: To examine the diagnostic accuracy of machine learning-based coronary CT angiography-derived fractional flow reserve (FFRCT) in diabetes mellitus (DM) patients. METHODS: In total, 484 patients with suspected or known coronary artery disease from 11 Chinese medical centers were retrospectively analyzed. All patients underwent CCTA, FFRCT, and invasive FFR. The patients were further grouped into mild (25~49 %), moderate (50~69 %), and severe (≥ 70 %) according to CCTA stenosis degree and Agatston score < 400 and Agatston score ≥ 400 groups according to coronary artery calcium severity. Propensity score matching (PSM) was used to match DM (n  = 112) and non-DM (n  = 214) groups. Sensitivity, specificity, accuracy, and area under the curve (AUC) with 95 % confidence interval (CI) were calculated and compared. RESULTS: Sensitivity, specificity, accuracy, and AUC of FFRCT were 0.79, 0.96, 0.87, and 0.91 in DM patients and 0.82, 0.93, 0.89, and 0.89 in non-DM patients without significant difference (all p > 0.05) on a per-patient level. The accuracies of FFRCT had no significant difference among different coronary stenosis subgroups and between two coronary calcium subgroups (all p > 0.05) in the DM and non-DM groups. After PSM grouping, the accuracies of FFRCT were 0.88 in the DM group and 0.87 in the non-DM group without a statistical difference (p > 0.05). CONCLUSIONS: DM has no negative impact on the diagnostic accuracy of machine learning-based FFRCT. KEY POINTS: • ML-based FFRCT has a high discriminative accuracy of hemodynamic ischemia, which is not affected by DM. • FFRCT was superior to the CCTA alone for the detection of ischemia relevance of coronary artery stenosis in both DM and non-DM patients. • Coronary calcification had no significant effect on the diagnostic accuracy of FFRCT to detect ischemia in DM patients.

One-year outcomes of CCTA alone versus machine learning-based FFRCT for coronary artery disease: a single-center, prospective study.

OBJECTIVES: To explore downstream management and outcomes of machine learning (ML)-based CT derived fractional flow reserve (FFRCT) strategy compared with an anatomical coronary computed tomography angiography (CCTA) alone assessment in participants with intermediate coronary artery stenosis. METHODS: In this prospective study conducted from April 2018 to March 2019, participants were assigned to either the CCTA or FFRCT group. The primary endpoint was the rate of invasive coronary angiography (ICA) that demonstrated non-obstructive disease at 90 days. Secondary endpoints included coronary revascularization and major adverse cardiovascular events (MACE) at 1-year follow-up. RESULTS: In total, 567 participants were allocated to the CCTA group and 566 to the FFRCT group. At 90 days, the rate of ICA without obstructive disease was higher in the CCTA group (33.3%, 39/117) than that (19.8%, 19/96) in the FFRCT group (risk difference [RD] = 13.5%, 95% confidence interval [CI]: 8.4%, 18.6%; p = 0.03). The ICA referral rate was higher in the CCTA group (27.5%, 156/567) than in the FFRCT group (20.3%, 115/566) (RD = 7.2%, 95% CI: 2.3%, 12.1%; p = 0.003). The revascularization-to-ICA ratio was lower in the CCTA group than that in the FFRCT group (RD = 19.8%, 95% CI: 14.1%, 25.5%, p = 0.002). MACE was more common in the CCTA group than that in the FFRCT group at 1 year (HR: 1.73; 95% CI: 1.01, 2.95; p = 0.04). CONCLUSION: In patients with intermediate stenosis, the FFRCT strategy appears to be associated with a lower rate of referral for ICA, ICA without obstructive disease, and 1-year MACE when compared to the anatomical CCTA alone strategy. KEY POINTS: • In stable patients with intermediate stenosis, ML-based FFRCT strategy was associated with a lower referral ICA rate, a lower normalcy rate of ICA, and higher revascularization-to-ICA ratio than the CCTA strategy. • Compared with the CCTA strategy, ML-based FFRCTshows superior outcome prediction value which appears to be associated with a lower rate of 1-year MACE. • ML-based FFRCT strategy as a non-invasive "one-stop-shop" modality may be the potential to change diagnostic workflows in patients with suspected coronary artery disease.

Functional CAD-RADS using FFRCT on therapeutic management and prognosis in patients with coronary artery disease.

OBJECTIVES: To propose a novel functional Coronary Artery Disease-Reporting and Data System (CAD-RADS) category system integrated with coronary CT angiography (CCTA)-derived fractional flow reserve (FFRCT) and to validate its effect on therapeutic decision and prognosis in patients with coronary artery disease (CAD). METHODS: Firstly, we proposed a novel functional CAD-RADS and evaluated the performance of functional CAD-RADS for guiding treatment strategies with actual clinical treatment as a reference standard in a retrospective multicenter cohort with CCTA and invasive FFR performed in all patients (n = 466). Net reclassification improvement (NRI) of functional CAD-RADS over anatomical CAD-RADS was calculated. Secondly, the prognostic value of functional CAD-RADS in a prospective two-arm cohort (566 [FFRCT arm] vs. 567 [CCTA arm]) was calculated, after a 1-year follow-up, functional CAD-RADS in FFRCT arm (n = 513) and anatomical CAD-RADS in CCTA arm (n = 511) to determine patients at risk of adverse outcomes were compared with a Cox hazard proportional model. RESULTS: Functional CAD-RADS demonstrated superior value over anatomical CAD-RADS (AUC: 0.828 vs. 0.681, p < 0.001) and comparable performance to FFR (AUC: 0.828 vs. 0.848, p = 0.253) in guiding therapeutic decisions. Functional CAD-RADS resulted in the revision of management plan as determined by anatomical CAD-RADS in 30.0% of patients (n = 140) (NRI = 0.369, p < 0.001). Functional CAD-RADS was an independent predictor for 1-year outcomes with indexes of concordance of 0.795 and the corresponding value was 0.751 in anatomical CAD-RADS. CONCLUSION: The novel functional CAD-RADS gained incremental value in guiding therapeutic decision-making compared with anatomical CAD-RADS and comparable power in 1-year prognosis with anatomical CAD-RADS in a real-world scenario. KEY POINTS: • The novel functional CAD-RADS category system with FFRCT integrated into the anatomical CAD-RADS categories was originally proposed. • The novel functional CAD-RADS category system was validated superior value over anatomical CAD-RADS (AUC: 0.828 vs. 0.681, p < 0.001) in guiding therapeutic decisions and revised management plan in 30.0% of patients as determined by anatomical CAD-RADS (net reclassification improvement index = 0.369, p < 0.001). • Functional CAD-RADS was an independent predictor with an index of concordance of 0.795 and 0.751 in anatomical CAD-RADS for 1-year prognosis of adverse outcomes.

Decreased functional connectivity of hippocampal subregions and methylation of the NR3C1 gene in Han Chinese adults who lost their only child.

BACKGROUND: Losing one's only child is a major traumatic life event that may lead to post-traumatic stress disorder (PTSD); however, the underlying mechanisms of its psychological consequences remain poorly understood. Here, we investigated subregional hippocampal functional connectivity (FC) networks based on resting-state functional magnetic resonance imaging and the deoxyribonucleic acid methylation of the human glucocorticoid receptor gene (NR3C1) in adults who had lost their only child. METHODS: A total of 144 Han Chinese adults who had lost their only child (51 adults with PTSD and 93 non-PTSD adults [trauma-exposed controls]) and 50 controls without trauma exposure were included in this fMRI study (age: 40-67 years). FCs between hippocampal subdivisions (four regions in each hemisphere: cornu ammonis1 [CA1], CA2, CA3, and dentate gyrus [DG]) and methylation levels of the NR3C1 gene were compared among the three groups. RESULTS: Trauma-exposed adults, regardless of PTSD diagnosis, had weaker positive FC between the left hippocampal CA1, left DG, and the posterior cingulate cortex, and weaker negative FC between the right CA1, right DG, and several frontal gyri, relative to healthy controls. Compared to non-PTSD adults, PTSD adults showed decreased negative FC between the right CA1 region and the right middle/inferior frontal gyri (MFG/IFG), and decreased negative FC between the right DG and the right superior frontal gyrus and left MFG. Both trauma-exposed groups showed lower methylation levels of the NR3C1 gene. CONCLUSIONS: Adults who had lost their only child may experience disrupted hippocampal network connectivity and NR3C1 methylation status, regardless of whether they have developed PTSD.

Detection of renal allograft fibrosis with MRI: arterial spin labeling outperforms reduced field-of-view IVIM.

OBJECTIVE: To compare the value of reduced field-of-view (FOV) intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) and arterial spin labeling (ASL) for assessing renal allograft fibrosis and predicting long-term dysfunction. METHODS: This prospective study included 175 renal transplant recipients undergoing reduced FOV IVIM DWI, ASL, and biopsies. Renal allograft fibrosis was categorized into ci0, ci1, ci2, and ci3 fibrosis according to biopsy results. A total of 83 participants followed for a median of 39 (IQR, 21-42) months were dichotomized into stable and impaired allograft function groups based on follow-up estimated glomerular filtration rate. Total apparent diffusion coefficient (ADCT), pure diffusion ADC, pseudo-perfusion ADC, perfusion fraction f from IVIM DWI, and renal blood flow (RBF) from ASL were calculated and compared. The area under the receiver operating characteristic curve (AUC) was calculated to assess the diagnostic and predictive performances. RESULTS: RBF was different in ci0 vs ci1 (147.9 ± 46.3 vs 126.0 ± 49.4 ml/min/100 g, p = .02) and ci2 vs ci3 (92.9 ± 46.9 vs 70.8 ± 37.8 ml/min/100 g, p = .03). RBF in the stable group was higher than that in the impaired group (144.73 ± 49.33 vs 102.19 ± 47.58 ml/min/100 g, p < .001). AUCs in distinguishing renal allograft fibrosis and predicting long-term allograft dysfunction for RBF were higher than cortical ADCT (ci0 vs ci1-3, 0.76 vs 0.59, p < .001; ci0-1 vs ci2-3, 0.79 vs 0.68, p = .01; ci0-2 vs ci3, 0.79 vs 0.68, p = .01; 0.76 vs 0.60, p = .04, respectively). CONCLUSION: Compared to reduced FOV IVIM DWI, ASL was a more promising technique for noninvasively distinguishing renal allograft fibrosis degree and predicting long-term allograft dysfunction. KEY POINTS: • Compared to total ADC from rFOV IVIM DWI, RBF from ASL can distinguish no fibrosis (ci0) vs mild fibrosis (ci1) (p = .02) and moderate fibrosis (ci2) vs severe fibrosis (ci3) (p = .04). • RBF had superior performance than diffusion parameters in discriminating fibrosis (no fibrosis [ci0] vs fibrosis [ci1-3], mild fibrosis [ci0-1] vs moderate to severe fibrosis [ci2-3], non-severe [ci0-2] vs severe [ci3] fibrosis; AUC = 0.76 vs 0.59, p < .001; 0.79 vs 0.68, p = .01; 0.79 vs 0.68, p = .01). • Compared to reduced FOV IVIM DWI, ASL was a more promising technique for noninvasively predicting long-term allograft dysfunction (AUC = 0.76 vs 0.60, p = .04).