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Abstract Background New neurons are generated in the adult brain from stem cells found in the subventricular zone (SVZ). These cells proliferate in the SVZ, generating neuroblasts which then migrate to the main olfactory bulb (MOB), ending their migration in the glomerular layer (GLL) and the granule cell layer (GCL) of the MOB. Neuronal populations in these layers undergo turnover throughout life, but whether all neuronal subtypes found in these areas are replaced and when neurons begin to express subtype-specific markers is not known. Results Here we use BrdU injections and immunohistochemistry against (calretinin, calbindin, N-copein, tyrosine hydroxylase and GABA) and show that adult-generated neurons express markers of all major subtypes of neurons in the GLL and GCL. Moreover, the fractions of new neurons that express subtype-specific markers at 40 and 75 days post BrdU injection are very similar to the fractions of all neurons expressing these markers. We also show that many neurons in the glomerular layer do not express NeuN, but are readily and specifically labeled by the fluorescent nissl stain Neurotrace. Conclusion The expression of neuronal subtype-specific markers by new neurons in the GLL and GCL changes rapidly during the period from 14–40 days after BrdU injection before reaching adult levels. This period may represent a critical window for cell fate specification similar to that observed for neuronal survival.

A hemangioma of the mitral valve and aortomitral curtain was incidentally discovered in an adolescent. The lesion was surgically excised, and the mitral valve was reconstructed with complete preservation of valvular function. Pertinent principles of multimodality imaging-based diagnosis and nuances of operative management of this rare, vascular tumor are discussed., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Coronary computed tomography angiography (CCTA) allows the assessment of the presence and severity of obstructive and nonobstructive atherosclerotic coronary artery disease. With software developments incorporating artificial intelligence-based automated image analysis along with improved spatial resolution of CT scanners, volumetric measurements of atherosclerotic plaque, detection of high-risk plaque features, and delineation of pericoronary adipose tissue density can now be readily and accurately evaluated for a given at-risk patient. Many of these expanded diagnostic measures have been shown to be prognostically useful for prediction of major adverse cardiac events. The incremental value of plaque quantification over diameter stenosis has yet to be thoroughly discovered in current studies. Furthermore, the physiological significance of lesions can also be assessed with CT-derived fractional flow reserve, myocardial CT perfusion, and more recently shear stress, potentially leading to selective invasive coronary angiography and revascularization. Along with these technological advancements, there has been additional high-quality evidence for CCTA including large randomized clinical trials supporting high-level recommendations from many international clinical practice guidelines. Current trials largely compare a CCTA vs functional testing strategy, yet there is minimal evidence on CCTA plaque-guided therapeutic trials to measure regression of atherosclerosis and prevention of major coronary artery disease events. In this review, we summarize current evidence on comprehensive risk assessment with CCTA and future directions., (© 2024 The Author(s).)

Preclinical and clinical studies suggest that lipid-induced hepatic insulin resistance is a primary defect that predisposes to dysfunction in islets, implicating a perturbed liver-pancreas axis underlying the comorbidity of T2DM and MASLD. To investigate this hypothesis, we developed a human biomimetic microphysiological system (MPS) coupling our vascularized liver acinus MPS (vLAMPS) with pancreatic islet MPS (PANIS) enabling MASLD progression and islet dysfunction to be assessed. The modular design of this system (vLAMPS-PANIS) allows intra-organ and inter-organ dysregulation to be deconvoluted. When compared to normal fasting (NF) conditions, under early metabolic syndrome (EMS) conditions, the standalone vLAMPS exhibited characteristics of early stage MASLD, while no significant differences were observed in the standalone PANIS. In contrast, with EMS, the coupled vLAMPS-PANIS exhibited a perturbed islet-specific secretome and a significantly dysregulated glucose stimulated insulin secretion response implicating direct signaling from the dysregulated liver acinus to the islets. Correlations between several pairs of a vLAMPS-derived and a PANIS-derived factors were significantly altered under EMS, as compared to NF conditions, mechanistically connecting MASLD and T2DM associated hepatic-factors with islet-derived GLP-1 synthesis and regulation. Since vLAMPS-PANIS is compatible with patient-specific iPSCs, this platform represents an important step towards addressing patient heterogeneity, identifying disease mechanisms, and advancing precision medicine., (© 2024. The Author(s).)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide health epidemic with a global occurrence of approximately 30%. The pathogenesis of MASLD is a complex, multisystem disorder driven by multiple factors, including genetics, lifestyle, and the environment. Patient heterogeneity presents challenges in developing MASLD therapeutics, creating patient cohorts for clinical trials, and optimizing therapeutic strategies for specific patient cohorts. Implementing pre-clinical experimental models for drug development creates a significant challenge as simple in vitro systems and animal models do not fully recapitulate critical steps in the pathogenesis and the complexity of MASLD progression. To address this, we implemented a precision medicine strategy that couples the use of our liver acinus microphysiology system (LAMPS) constructed with patient-derived primary cells. We investigated the MASLD-associated genetic variant patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 (I148M variant) in primary hepatocytes as it is associated with MASLD progression. We constructed the LAMPS with genotyped wild-type and variant PNPLA3 hepatocytes, together with key non-parenchymal cells, and quantified the reproducibility of the model. We altered media components to mimic blood chemistries, including insulin, glucose, free fatty acids, and immune-activating molecules to reflect normal fasting (NF), early metabolic syndrome (EMS), and late metabolic syndrome (LMS) conditions. Finally, we investigated the response to treatment with resmetirom, an approved drug for metabolic syndrome-associated steatohepatitis (MASH), the progressive form of MASLD. This study, using primary cells, serves as a benchmark for studies using "patient biomimetic twins" constructed with patient induced pluripotent stem cell (iPSC)-derived liver cells using a panel of reproducible metrics. We observed increased steatosis, immune activation, stellate cell activation, and secretion of pro-fibrotic markers in the PNPLA3 GG variant compared to the wild-type CC LAMPS, consistent with the clinical characterization of this variant. We also observed greater resmetirom efficacy in the PNPLA3 wild-type CC LAMPS compared to the GG variant in multiple MASLD metrics, including steatosis, stellate cell activation, and the secretion of pro-fibrotic markers. In conclusion, our study demonstrates the capability of the LAMPS platform for the development of MASLD precision therapeutics, enrichment of patient cohorts for clinical trials, and optimization of therapeutic strategies for patient subgroups with different clinical traits and disease stages., Competing Interests: DT, AG, and MS have equity in Nortis, a company supplying MPS chips/some automation, and Eve AnalyticsTM, analyzing and computationally modeling data on patient-derived microphysiology systems. JB received research grant funding from Gilead, Pfizer, AstraZeneca, and ENDRA Life Sciences. His institution has had research contracts with Intercept, Pfizer, Galectin, Exact Sciences, Inventiva, Enanta, Shire, Gilead, Allergan, Celgene, Galmed, Genentech, Rhythm Pharmaceuticals, and Madrigal. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xia, Varmazyad, Pla-Palacín, Gavlock, DeBiasio, LaRocca, Reese, Florentino, Faccioli, Brown, Vernetti, Schurdak, Stern, Gough, Behari, Soto-Gutierrez, Taylor and Miedel.)

Background: 18 F-Fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET)/magnetic resonance (MR) can identify inflammation and fibrosis, which are high-risk features in cardiac sarcoidosis., Objective: The purpose of this study was to evaluate whether the involvement of certain myocardial segments is associated with higher risk compared to others., Methods: One hundred twenty-four patients with suspected clinical sarcoidosis underwent 18 F-FDG-PET/MR. Late gadolinium enhancement (LGE) and focal 18 F-FDG uptake were evaluated globally and in the 16 myocardial segments. Presence of LGE was defined when the percentage of LGE exceeded 5.7% globally (relative to myocardial volume) and in each myocardial segment. Patients were followed up for 5.5 years. Events were defined as ventricular arrhythmia (VA) (including sustained ventricular tachycardia, ventricular fibrillation, and appropriate implantable cardioverter-defibrillator discharge), heart failure hospitalization, or all-cause death., Results: Mean age was 57.1 ± 8.9 years, and 39.5% were female. Twenty-two patients (17.6%) had an event during follow-up, and 9 (7.2%) presented with VA. LGE and 18 F-FDG uptake were more frequent in patients with than without events (36.4% vs 7.8%, P = .001). Presence of LGE and 18 F-FDG in the basal anterior segment were independent predictors for events after adjustment for left ventricular ejection fraction and relative enhanced volume (LGE: odds ratio [1.2-92.4], P = .034; 18 F-FDG: odds ratio 5.5 [1.1-27.5], P = .038). LGE presence in basal to mid-anterior, mid-anteroseptal, and basal to mid-inferoseptal segments was an independent predictor of VA. Presence of 18 F-FDG in basal to mid-anterior, mid-inferoseptal and mid-inferior segments was an independent predictor of VA., Conclusion: Involvement of specific myocardial segments, particularly basal to mid-anterior and mid-septal segments, is associated with higher rates of events in patients with suspected cardiac sarcoidosis., Competing Interests: Disclosures The authors have no conflicts to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

A 73-year-old man with a history of hypertension, hyperlipidemia, and obesity presented for cardiovascular evaluation. He was experiencing mild fatigue and dyspnea on exertion. Transthoracic echocardiogram (TTE) showed right ventricular dilation, which was otherwise unremarkable.

Competing Interests: Conflict of interest: None declared.

Competing Interests: Conflict of interest: None declared.

Competing Interests: Conflict of interest: None declared.