Utility of Artificial Intelligence Plaque Quantification: Results of the DECODE Study.

Background: Artificial Intelligence Plaque Analysis (AI-QCPA, HeartFlow) provides, from a CCTA, quantitative plaque burden information including total plaque and plaque subtype volumes. We sought to evaluate the clinical utility of AI-QCPA in clinical decision making. Methods: One hundred cases were reviewed by 3 highly experienced practicing cardiologists who are SCCT level 3 CCTA readers. Patients had varying levels of calcium (median CACS: 99.5) and CAD-RADS scores. Initial management plan for each case was a majority decision based upon patient demographics, clinical history, and CCTA report. AI-QCPA was then provided for each patient, and the plan was reconsidered. The primary endpoint was the reclassification rate (RR). In a secondary analysis of 40 cases, the above process was repeated but the initial plan was based upon review of the actual CCTA images. Results: RR following AI-QCPA review was 66% (66/100) of cases (95% CI, 56.72%-75.28%). RR ranged from 47% in cases with CACS 0 to 96% in cases with CACS >400, and from 40% in CAD-RADS 1 cases to 94% in CAD-RADS 4 cases. RR was higher in cases with coronary stenoses ≥50% (89.5%) vs cases with stenoses <50% (51.6%). RR was 39% in cases with LDL <70 mg/dL vs 70% in LDL ≥70 mg/dL. Following review of the CCTA images rather than the CCTA report, the RR was 50% (95% CI of 34.51% - 65.49%). The primary reclassification effect was to intensify preventative medical therapy. Conclusions: Adding AI-QCPA to CCTA alone leads to a change in clinical care in two-thirds of patients.

Novel Small-Molecule ROCK2 Inhibitor GNS-3595 Attenuates Pulmonary Fibrosis in Preclinical Studies.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that leads to respiratory decline caused by scarring and thickening of lung tissues. Multiple pathways contribute to the fibrotic process in this disease, such as inflammation, epithelial-to-mesenchymal transition, and oxidative stress. The Rho-associated coiled-coil forming protein kinase (ROCK) signaling pathway is a key regulator of profibrotic signaling, as it affects the organization of actin-myosin and the remodeling of the extracellular matrix. ROCK1/2, a downstream effector of RhoA, is overexpressed in patients with IPF and is a promising target for IPF therapy. However, because of the hypotensive side effects of ROCK1/2 inhibitors, selective ROCK2 compounds are being explored. In this study, we report the discovery of GNS-3595, a potent and selective ROCK2 inhibitor that has ∼80-fold selectivity over ROCK1 at physiological concentrations of ATP. GNS-3595 effectively inhibited ROCK2-mediated phosphorylation of myosin light chain and reduced the expression of fibrosis-related proteins (e.g., collagen, fibronectin, and α-smooth muscle actin) in various in vitro cellular models. GNS-3595 also prevented transforming growth factor ß-induced fibroblast-to-myofibroblast transition. In addition, in a bleomycin-induced mouse model of pulmonary fibrosis, therapeutic exposure to GNS-3595, suppressed lung fibrosis, stabilized body weight loss, and prevented fibrosis-induced lung weight gain. Transcriptome and protein expression analysis from lung tissues showed that GNS-3595 can revert the fibrosis-related gene expression induced by bleomycin. These results indicate that GNS-3595 is a highly potent, selective, and orally active ROCK2 inhibitor with promising therapeutic efficacy against pulmonary fibrosis.

Quasi-2D-Ising-type magnetic critical behavior in trigonal Cr1.27Te2.

Single crystal Cr1.27Te2 samples were synthesized by using the chemical vapor transport method. Single crystal x-ray diffraction studies show a trigonal crystal structure with a P3̄m1 symmetry space group. We then systematically investigate magnetic properties and critical behaviors of single crystal Cr1.27Te2 around its paramagnetic-to-ferromagnetic phase transition. The Arrott plot indicates a second-order magnetic phase transition. We estimate critical exponents ß = 0.2631 ± 0.002, γ = 1.2314 ± 0.007, and TC = 168.48 ± 0.031 K by using the Kouvel-Fisher method. We also estimate other critical exponents δ = 5.31 ± 0.004 by analyzing the critical isotherm at TC = 168.5 K. We further verify the accuracy of our estimated critical exponents by the scaling analysis. Further analysis suggests that Cr1.27Te2 can be best described as a quasi-2D Ising magnetic system.

Prospective deep learning-based quantitative assessment of coronary plaque by computed tomography angiography compared with intravascular ultrasound: the REVEALPLAQUE study.

AIMS: Coronary computed tomography angiography provides non-invasive assessment of coronary stenosis severity and flow impairment. Automated artificial intelligence (AI) analysis may assist in precise quantification and characterization of coronary atherosclerosis, enabling patient-specific risk determination and management strategies. This multicentre international study compared an automated deep learning-based method for segmenting coronary atherosclerosis in coronary computed tomography angiography (CCTA) against the reference standard of intravascular ultrasound (IVUS). METHODS AND RESULTS: The study included clinically stable patients with known coronary artery disease from 15 centres in the USA and Japan. An AI-enabled plaque analysis was utilized to quantify and characterize total plaque (TPV), vessel, lumen, calcified plaque (CP), non-calcified plaque (NCP), and low-attenuation plaque (LAP) volumes derived from CCTA and compared with IVUS measurements in a blinded, core laboratory-adjudicated fashion. In 237 patients, 432 lesions were assessed; mean lesion length was 24.5 mm, and mean IVUS-TPV was 186.0 mm3. AI-enabled plaque analysis on CCTA showed strong correlation and high accuracy when compared with IVUS; correlation coefficient, slope, and Y intercept for TPV were 0.91, 0.99, and 1.87, respectively; for CP volume 0.91, 1.05, and 5.32, respectively; and for NCP volume 0.87, 0.98, and 15.24, respectively. Bland-Altman analysis demonstrated strong agreement with little bias for these measurements. CONCLUSION: AI-enabled CCTA quantification and characterization of atherosclerosis demonstrated strong agreement with IVUS reference standard measurements. This tool may prove effective for accurate evaluation of coronary atherosclerotic burden and cardiovascular risk assessment.

Synthesis and Physical Properties of the Misfit Layered Compound (EuS)1.13(NbSe2)2.

A new misfit layered compound with the stoichiometry (EuS)1+δ(NbSe2)2 (δ ≈ 0.13) has been successfully synthesized. High-resolution transmission electron microscopy and powder X-ray diffraction confirm the misfit structure with (EuS)-(EuS) spacing of 18.30(1) Å. Magnetization, electrical resistivity, heat capacity, and thermal transport measurements show that the material is a heavily doped semiconductor or poor metal with a low thermal conductivity of ∼1 W/m K and an antiferromagnetic ordering transition at TN = 4.7 K. In contrast to the parent materials, the misfit is neither ferromagnetic nor superconducting down to T = 0.4 K. We find evidence of a field-driven transition to a ferromagnetic state due to reorientation of ferromagnetic EuS layers at µoH = 0.5 T at T = 2 K.

An international multidisciplinary consensus on pediatric metabolic dysfunction-associated fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in children and adolescents, particularly those with obesity. NAFLD is considered a hepatic manifestation of the metabolic syndrome due to its close associations with abdominal obesity, insulin resistance, and atherogenic dyslipidemia. Experts have proposed an alternative terminology, metabolic dysfunction-associated fatty liver disease (MAFLD), to better reflect its pathophysiology. This study aimed to develop consensus statements and recommendations for pediatric MAFLD through collaboration among international experts. METHODS: A group of 65 experts from 35 countries and six continents, including pediatricians, hepatologists, and endocrinologists, participated in a consensus development process. The process encompassed various aspects of pediatric MAFLD, including epidemiology, mechanisms, screening, and management. FINDINGS: In round 1, we received 65 surveys from 35 countries and analyzed these results, which informed us that 73.3% of respondents agreed with 20 draft statements while 23.8% agreed somewhat. The mean percentage of agreement or somewhat agreement increased to 80.85% and 15.75%, respectively, in round 2. The final statements covered a wide range of topics related to epidemiology, pathophysiology, and strategies for screening and managing pediatric MAFLD. CONCLUSIONS: The consensus statements and recommendations developed by an international expert panel serve to optimize clinical outcomes and improve the quality of life for children and adolescents with MAFLD. These findings emphasize the need for standardized approaches in diagnosing and treating pediatric MAFLD. FUNDING: This work was funded by the National Natural Science Foundation of China (82070588, 82370577), the National Key R&D Program of China (2023YFA1800801), National High Level Hospital Clinical Research Funding (2022-PUMCH-C-014), the Wuxi Taihu Talent Plan (DJTD202106), and the Medical Key Discipline Program of Wuxi Health Commission (ZDXK2021007).

The Application of Knowledge Engineering via the Use of a Biomimetic Digital Twin Ecosystem, Phenotype-Driven Variant Analysis, and Exome Sequencing to Understand the Molecular Mechanisms of Disease.

Applied artificial intelligence, particularly large language models, in biomedical research is accelerating, but effective discovery and validation requires a toolset without limitations or bias. On January 30, 2023, the National Academies of Sciences, Engineering, and Medicine (NAS) appointed an ad hoc committee to identify the needs and opportunities to advance the mathematical, statistical, and computational foundations of digital twins in applications across science, medicine, engineering, and society. On December 15, 2023, the NAS released a 164-page report, "Foundational Research Gaps and Future Directions for Digital Twins." This report described the importance of using digital twins in biomedical research. The current study was designed to develop an innovative method that incorporated phenotype-ranking algorithms with knowledge engineering via a biomimetic digital twin ecosystem. This ecosystem applied real-world reasoning principles to nonnormalized, raw data to identify hidden or "dark" data. Clinical exome sequencing study on patients with endometriosis indicated four variants of unknown clinical significance potentially associated with endometriosis-related disorders in nearly all patients analyzed. One variant of unknown clinical significance was identified in all patient samples and could be a biomarker for diagnostics. To the best of our knowledge, this is the first study to incorporate the recommendations of the NAS to biomedical research. This method can be used to understand the mechanisms of any disease, for virtual clinical trials, and to identify effective new therapies.

Interaction of AI-Enabled Quantitative Coronary Plaque Volumes on Coronary CT Angiography, FFRCT, and Clinical Outcomes: A Retrospective Analysis of the ADVANCE Registry.

BACKGROUND: Luminal stenosis, computed tomography-derived fractional-flow reserve (FFRCT), and high-risk plaque features on coronary computed tomography angiography are all known to be associated with adverse clinical outcomes. The interactions between these variables, patient outcomes, and quantitative plaque volumes have not been previously described. METHODS: Patients with coronary computed tomography angiography (n=4430) and one-year outcome data from the international ADVANCE (Assessing Diagnostic Value of Noninvasive FFRCT in Coronary Care) registry underwent artificial intelligence-enabled quantitative coronary plaque analysis. Optimal cutoffs for coronary total plaque volume and each plaque subtype were derived using receiver-operator characteristic curve analysis. The resulting plaque volumes were adjusted for age, sex, hypertension, smoking status, type 2 diabetes, hyperlipidemia, luminal stenosis, distal FFRCT, and translesional delta-FFRCT. Median plaque volumes and optimal cutoffs for these adjusted variables were compared with major adverse cardiac events, late revascularization, a composite of the two, and cardiovascular death and myocardial infarction. RESULTS: At one year, 55 patients (1.2%) had experienced major adverse cardiac events, and 123 (2.8%) had undergone late revascularization (>90 days). Following adjustment for age, sex, risk factors, stenosis, and FFRCT, total plaque volume above the receiver-operator characteristic curve-derived optimal cutoff (total plaque volume >564 mm3) was associated with the major adverse cardiac event/late revascularization composite (adjusted hazard ratio, 1.515 [95% CI, 1.093-2.099]; P=0.0126), and both components. Total percent atheroma volume greater than the optimal cutoff was associated with both major adverse cardiac event/late revascularization (total percent atheroma volume >24.4%; hazard ratio, 2.046 [95% CI, 1.474-2.839]; P<0.0001) and cardiovascular death/myocardial infarction (total percent atheroma volume >37.17%, hazard ratio, 4.53 [95% CI, 1.943-10.576]; P=0.0005). Calcified, noncalcified, and low-attenuation percentage atheroma volumes above the optimal cutoff were associated with all adverse outcomes, although this relationship was not maintained for cardiovascular death/myocardial infarction in analyses stratified by median plaque volumes. CONCLUSIONS: Analysis of the ADVANCE registry using artificial intelligence-enabled quantitative plaque analysis shows that total plaque volume is associated with one-year adverse clinical events, with incremental predictive value over luminal stenosis or abnormal physiology by FFRCT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02499679.

Screening for obstructive sleep apnea (OSA) in children and adolescents with obesity: A scoping review of national and international pediatric obesity and pediatric OSA management guidelines.

Obstructive sleep apnea (OSA) is a prevalent complication that affects up to 60% of children and adolescents with obesity. It is associated with poorer cardiometabolic outcomes and neurocognitive deficits. Appropriate screening and intervention for OSA are crucial in the management of children with obesity. We performed a scoping review of international and national pediatric obesity (n = 30) and pediatric OSA (n = 10) management guidelines to evaluate the recommendations on OSA screening in pediatric obesity. Sixteen (53%) of the pediatric obesity guidelines had incorporated OSA screening to varying extents, with no consistent recommendations on when and how to screen for OSA, and subsequent management of OSA in children with obesity. We provide our recommendations that are based on the strength and certainty of evidence presented. These include a clinical-based screening for OSA in all children with body mass index (BMI) ≥ 85th percentile or those with rapid BMI gain (upward crossing of 2 BMI percentiles) and the use of overnight polysomnography to confirm the diagnosis of OSA in those with high clinical suspicion. We discuss further management of OSA unique to children with obesity. An appropriate screening strategy for OSA would facilitate timely intervention that has been shown to improve cardiometabolic and neurocognitive outcomes.

The role of glucagon-like peptide 1 receptor agonists for weight control in individuals with acquired hypothalamic obesity-A systematic review.

Hypothalamic obesity does not respond well to conventional interventions for obesity. GLP-1 receptor agonists have mechanisms independent of the hypothalamus which may be potentially beneficial for managing hypothalamic obesity. This systematic review summarizes the efficacy and safety of GLP-1 receptor agonists use in hypothalamic obesity. A PRISMA-compliant systematic review was performed. Data was extracted from included studies and analysed based on change in weight, body mass index, glycaemic control, satiety, and safety profile with GLP-1 receptor agonist use. Ten studies comprising 5 case reports, 4 case series and 1 randomized-controlled trial included 54 patients (24 males, 30 females) with mean age of 25.2 (range 13-71) years with hypothalamic obesity who had received GLP-1 receptor agonists (exenatide = 48, liraglutide = 5 and dulaglutide = 1) over a mean duration of treatment of 12 (range 3-51) months. Mean weight reduction of 7.4 (SD 7.92) kg was observed in patients in whom weight was reported, with 85.7% of patients experiencing weight loss. All patients on liraglutide had weight reduction post-therapy. The sole trial had reported a non-significant reduction in BMI post-exenatide. Glycaemic control had either improved/maintained in all patients in whom this was measured. The main side effects of GLP-1 receptor agonist in individuals with hypothalamic obesity were nausea and vomiting; there were no major safety concerns. Based on limited published experience, GLP-1RA may be effective and safe for weight control in hypothalamic obesity, with the added benefit of improved glycaemic control in those with concurrent diabetes mellitus.

Derivation and validation of a novel functional FFRCT score incorporating the burden of coronary stenosis severity and flow impairment to predict clinical events.

BACKGROUND: A score combining the burden of stenosis severity on coronary computed tomography angiography (CCTA) and flow impairment by fractional flow reserve derived from computed tomography (FFRCT) may be a better predictor of clinical events than either parameter alone. METHODS: The Functional FFRCT Score (FFS) combines CCTA and FFRCT parameters in an allocated point-based system. The feasibility of the FFS was assessed in cohort of 72 stable chest pain patients with matched CCTA and FFRCT datasets. Validation was performed using 2 cohorts: (a) 4468 patients from the ADVANCE Registry to define its association with revascularization and major adverse cardiovascular events (MACE); (b) 212 patients from the FORECAST trial to determine predictors of MACE. RESULTS: The median calculation time for the FFS was 10 (interquartile range 6-17) seconds, with strong intra-operator and inter-operator agreement (Cohen's Kappa 0.89 (±0.37, p â€‹< â€‹0.001) and 0.83 (±0.04, p â€‹< â€‹0.001, respectively). The FFS correlated strongly with both the CT-SYNTAX and the Functional CT-SYNTAX scores (rS â€‹= â€‹0.808 for both, p â€‹< â€‹0.001). In the ADVANCE cohort the FFS had good discriminatory abilities for revascularization with an area under the curve of 0.82, 95 â€‹% confidence interval (CI) 0.81-0.84, p â€‹< â€‹0.001. Patients in the highest FFS tertile had significantly higher rates of revascularization (61 â€‹% vs 5 â€‹%, p â€‹< â€‹0.001) and MACE (1.9 â€‹% vs 0.5 â€‹%, p â€‹= â€‹0.001) compared with the lowest FFS tertile. In the FORECAST cohort the FFS was an independent predictor of MACE at 9-month follow-up (hazard ratio 1.04, 95 â€‹% CI 1.01-1.08, p â€‹< â€‹0.01). CONCLUSION: The FFS is a quick-to-calculate and reproducible score, associated with revascularization and MACE in two distinct populations of stable symptomatic patients.

Age- and Sex-Specific Nomographic CT Quantitative Plaque Data From a Large International Cohort.

BACKGROUND: With growing adoption of coronary computed tomographic angiography (CTA), there is increasing evidence for and interest in the prognostic importance of atherosclerotic plaque volume. Manual tools for plaque segmentation are cumbersome, and their routine implementation in clinical practice is limited. OBJECTIVES: The aim of this study was to develop nomographic quantitative plaque values from a large consecutive multicenter cohort using coronary CTA. METHODS: Quantitative assessment of total atherosclerotic plaque and plaque subtype volumes was performed in patients undergoing clinically indicated coronary CTA, using an Artificial Intelligence-Enabled Quantitative Coronary Plaque Analysis tool. RESULTS: A total of 11,808 patients were included in the analysis; their mean age was 62.7 ± 12.2 years, and 5,423 (45.9%) were women. The median total plaque volume was 223 mm3 (IQR: 29-614 mm3) and was significantly higher in male participants (360 mm3; IQR: 78-805 mm3) compared with female participants (108 mm3; IQR: 10-388 mm3) (P < 0.0001). Total plaque increased with age in both male and female patients. Younger patients exhibited a higher prevalence of noncalcified plaque. The distribution of total plaque volume and its components was reported in every decile by age group and sex. CONCLUSIONS: The authors developed pragmatic age- and sex-stratified percentile nomograms for atherosclerotic plaque measures using findings from coronary CTA. The impact of age and sex on total plaque and its components should be considered in the risk-benefit analysis when treating patients. Artificial Intelligence-Enabled Quantitative Coronary Plaque Analysis work flows could provide context to better interpret coronary computed tomographic angiographic measures and could be integrated into clinical decision making.

Fe Site Order and Magnetic Properties of Fe1/4NbS2.

Transition-metal dichalcogenides (TMDs) have long been attractive to researchers for their diverse properties and high degree of tunability. Most recently, interest in magnetically intercalated TMDs has resurged due to their potential applications in spintronic devices. While certain compositions featuring the absence of inversion symmetry such as Fe1/3NbS2 and Cr1/3NbS2 have garnered the most attention, the diverse compositional space afforded through the host matrix composition as well as intercalant identity and concentration is large and remains relatively underexplored. Here, we report the magnetic ground state of Fe1/4NbS2 that was determined from low-temperature neutron powder diffraction as an A-type antiferromagnet. Despite the presence of overall inversion symmetry, the pristine compound manifests spin polarization induced by the antiferromagnetic order at generic k points, based on density functional theory band-structure calculations. Furthermore, by combining synchrotron diffraction, pair distribution function, and magnetic susceptibility measurements, we find that the magnetic properties of Fe1/4NbS2 are sensitive to the Fe site order, which can be tuned via electrochemical lithiation and thermal history.

Fertility restoration in mice with chemotherapy induced ovarian failure using differentiated iPSCs.

BACKGROUND: Treatment options for premature ovarian insufficiency (POI) are limited to hormone replacement and donor oocytes. A novel induced pluripotent stem cell (iPSC) transplant paradigm in a mouse model has potential translational applications for management of POI. METHODS: Mouse ovarian granulosa cell derived-iPSCS were labelled with green fluorescent protein (GFP) reporter and differentiated in vitro into oocytes. Differentiated cells were assayed for estradiol and progesterone secretion by enzyme-linked immunosorbent assays. After Fluorescence-Activated Cell Sorting (FACS) for the cell surface marker anti-Mullerian hormone receptor (AMHR2), enriched populations of differentiated cells were surgically transplanted into ovaries of mice that had POI secondary to gonadotoxic pre-treatment with alkylating agents. A total of 100 mice were used in these studies in five separate experiments with 56 animals receiving orthotopic ovarian injections of either FACS sorted or unsorted differentiated iPSCSs and the remaining animals receiving sham injections of PBS diluent. Following transplantation surgery, mice were stimulated with gonadotropins inducing oocyte development and underwent oocyte retrieval. Nine transplanted mice were cross bred with wild-type mice to assess fertility. Lineage tracing of resultant oocytes, F1 (30 pups), and F2 (42 pups) litters was interrogated by GFP expression and validation by short tandem repeat (STR) lineage tracing. FINDINGS: [1] iPSCs differentiate into functional oocytes and steroidogenic ovarian cells which [2] express an ovarian (GJA1) and germ cell (ZP1) markers. [3] Endocrine function and fertility were restored in mice pretreated with gonadotoxic alkylating agents via orthotopic transplantation of differentiated iPSCS, thus generating viable, fertile mouse pups. INTERPRETATION: iPSC-derived ovarian tissue can reverse endocrine and reproductive sequelae of POI. FUNDING: Center for Infertility and Reproductive Surgery Research Award, Siezen Foundation award (RMA). Reproductive Scientist Development Program, Marriott Foundation, Saltonstall Foundation, Brigham Ovarian Cancer Research Fund (K.E).

Influence of Obesity on Coronary Artery Disease and Clinical Outcomes in the ADVANCE Registry.

BACKGROUND: The relationship between body size and cardiovascular events is complex. This study utilized the ADVANCE (Assessing Diagnostic Value of Noninvasive FFRCT in Coronary Care) Registry to investigate the association between body mass index (BMI), coronary artery disease (CAD), and clinical outcomes. METHODS: The ADVANCE registry enrolled patients undergoing evaluation for clinically suspected CAD who had >30% stenosis on cardiac computed tomography angiography. Patients were stratified by BMI: normal <25 kg/m2, overweight 25-29.9 kg/m2, and obese ≥30 kg/m2. Baseline characteristics, cardiac computed tomography angiography and computed tomography fractional flow reserve (FFRCT), were compared across BMI groups. Adjusted Cox proportional hazards models assessed the association between BMI and outcomes. RESULTS: Among 5014 patients, 2166 (43.2%) had a normal BMI, 1883 (37.6%) were overweight, and 965 (19.2%) were obese. Patients with obesity were younger and more likely to have comorbidities, including diabetes and hypertension (all P<0.001), but were less likely to have obstructive coronary stenosis (65.2% obese, 72.2% overweight, and 73.2% normal BMI; P<0.001). However, the rate of hemodynamic significance, as indicated by a positive FFRCT, was similar across BMI categories (63.4% obese, 66.1% overweight, and 67.8% normal BMI; P=0.07). Additionally, patients with obesity had a lower coronary volume-to-myocardial mass ratio compared with patients who were overweight or had normal BMI (obese BMI, 23.7; overweight BMI, 24.8; and normal BMI, 26.3; P<0.001). After adjustment, the risk of major adverse cardiovascular events was similar regardless of BMI (all P>0.05). CONCLUSIONS: Patients with obesity in the ADVANCE registry were less likely to have anatomically obstructive CAD by cardiac computed tomography angiography but had a similar degree of physiologically significant CAD by FFRCT and similar rates of adverse events. An exclusively anatomic assessment of CAD in patients with obesity may underestimate the burden of physiologically significant disease that is potentially due to a significantly lower volume-to-myocardial mass ratio.