The circular RNA Edis regulates neurodevelopment and innate immunity.

Circular RNAs (circRNAs) are widely expressed in eukaryotes. However, only a subset has been functionally characterized. We identify and validate a collection of circRNAs in Drosophila, and show that depletion of the brain-enriched circRNA Edis (circ_Ect4) causes hyperactivation of antibacterial innate immunity both in cultured cells and in vivo. Notably, Edis depleted flies display heightened resistance to bacterial infection and enhanced pathogen clearance. Conversely, ectopic Edis expression blocks innate immunity signaling. In addition, inactivation of Edis in vivo leads to impaired locomotor activity and shortened lifespan. Remarkably, these phenotypes can be recapitulated with neuron-specific depletion of Edis, accompanied by defective neurodevelopment. Furthermore, inactivation of Relish suppresses the innate immunity hyperactivation phenotype in the fly brain. Moreover, we provide evidence that Edis encodes a functional protein that associates with and compromises the processing and activation of the immune transcription factor Relish. Importantly, restoring Edis expression or ectopic expression of Edis-encoded protein suppresses both innate immunity and neurodevelopment phenotypes elicited by Edis depletion. Thus, our study establishes Edis as a key regulator of neurodevelopment and innate immunity.

STEMI and NSTEMI ACS in a 30-Year-Old Patient: An Extremely Rare Complication of a Left Atrial Myxoma.

Primary cardiac tumors are a rare entity whose incidence in the general population ranges from 0.0017% to 0.28%. Myxomas represent nearly half of all primary benign cardiac tumors and they prevalently affect female patients. Embolic manifestation is rare with a reported incidence of 0.06%.We present the case of a 30-year-old male patient with acute anterolateral infarction caused by total occlusion of the left anterior descending artery as a consequence of a left atrial myxoma embolization. Urgent surgical resection of the mass didn't avoid early recurrence of atrial myxoma, whose second presentation was again myocardial infarction.This case alerts physicians to "unusual" myocardial infarction patients, when atherosclerotic pathogenesis appears unlikely. In these cases early echocardiographic evaluation should be mandatory and atrial myxoma should be considered among the possible causes. Complete surgical resection is the only effective therapeutic option to improve prognosis; the chance of tumor recurrence should dictate careful research for additional myxomas during surgery and stricter follow-up planning.

Bayesian Networks in the Management of Hospital Admissions: A Comparison between Explainable AI and Black Box AI during the Pandemic.

Artificial Intelligence (AI) and Machine Learning (ML) approaches that could learn from large data sources have been identified as useful tools to support clinicians in their decisional process; AI and ML implementations have had a rapid acceleration during the recent COVID-19 pandemic. However, many ML classifiers are "black box" to the final user, since their underlying reasoning process is often obscure. Additionally, the performance of such models suffers from poor generalization ability in the presence of dataset shifts. Here, we present a comparison between an explainable-by-design ("white box") model (Bayesian Network (BN)) versus a black box model (Random Forest), both studied with the aim of supporting clinicians of Policlinico San Matteo University Hospital in Pavia (Italy) during the triage of COVID-19 patients. Our aim is to evaluate whether the BN predictive performances are comparable with those of a widely used but less explainable ML model such as Random Forest and to test the generalization ability of the ML models across different waves of the pandemic.

The Role of Native T1 and T2 Mapping Times in Identifying PD-L1 Expression and the Histological Subtype of NSCLCs.

We investigated the association of T1/T2 mapping values with programmed death-ligand 1 protein (PD-L1) expression in lung cancer and their potential in distinguishing between different histological subtypes of non-small cell lung cancers (NSCLCs). Thirty-five patients diagnosed with stage III NSCLC from April 2021 to December 2022 were included. Conventional MRI sequences were acquired with a 1.5 T system. Mean T1 and T2 mapping values were computed for six manually traced ROIs on different areas of the tumor. Data were analyzed through RStudio. Correlation between T1/T2 mapping values and PD-L1 expression was studied with a Wilcoxon-Mann-Whitney test. A Kruskal-Wallis test with a post-hoc Dunn test was used to study the correlation between T1/T2 mapping values and the histological subtypes: squamocellular carcinoma (SCC), adenocarcinoma (ADK), and poorly differentiated NSCLC (PD). There was no statistically significant correlation between T1/T2 mapping values and PD-L1 expression in NSCLC. We found statistically significant differences in T1 mapping values between ADK and SCC for the periphery ROI (p-value 0.004), the core ROI (p-value 0.01), and the whole tumor ROI (p-value 0.02). No differences were found concerning the PD NSCLCs.

Performance of an AI algorithm during the different phases of the COVID pandemics: what can we learn from the AI and vice versa.

Background: Artificial intelligence (AI) has proved to be of great value in diagnosing and managing Sars-Cov-2 infection. ALFABETO (ALL-FAster-BEtter-TOgether) is a tool created to support healthcare professionals in the triage, mainly in optimizing hospital admissions. Methods: The AI was trained during the pandemic's "first wave" (February-April 2020). Our aim was to assess the performance during the "third wave" of the pandemics (February-April 2021) and evaluate its evolution. The neural network proposed behavior (hospitalization vs home care) was compared with what was actually done. If there were discrepancies between ALFABETO's predictions and clinicians' decisions, the disease's progression was monitored. Clinical course was defined as "favorable/mild" if patients could be managed at home or in spoke centers and "unfavorable/severe" if patients need to be managed in a hub center. Results: ALFABETO showed accuracy of 76%, AUROC of 83%; specificity was 78% and recall 74%. ALFABETO also showed high precision (88%). 81 hospitalized patients were incorrectly predicted to be in "home care" class. Among those "home-cared" by the AI and "hospitalized" by the clinicians, 3 out of 4 misclassified patients (76.5%) showed a favorable/mild clinical course. ALFABETO's performance matched the reports in literature. Conclusions: The discrepancies mostly occurred when the AI predicted patients could stay at home but clinicians hospitalized them; these cases could be handled in spoke centers rather than hubs, and the discrepancies may aid clinicians in patient selection. The interaction between AI and human experience has the potential to improve both AI performance and our comprehension of pandemic management.

Emergent Conversion to Open Heart Surgery during Transcatheter Aortic Valve Implantation: The Presence of a Rescue Team Improves Outcomes.

OBJECTIVE: Transcatheter aortic valve implant (TAVI) is the gold standard for the high-surgical-risk group of patients with aortic valve disease and it is an alternative to surgery in patients at intermediate risk. Lethal complications can occur, and many of these are manageable only with emergent conversion to open heart surgery. We retrospectively evaluate the outcome of all patients undergoing TAVI in our departments and the impact of a complete cardiac rescue team to reduce 30-day mortality. METHODS: Data from all patients undergoing TAVI between January 2020 and August 2023 in our center were analyzed. An expert complete rescue was present in catheter laboratory. Primary outcomes were in-hospital and at 30-day mortality and evaluation of all cases needed for emergent conversion to open heart surgery. RESULTS: 825 patients were enrolled. The total mortality was 19/825 (2.3%). Eleven of the total patients (1.3%) required emergent conversion to open heart surgery. Among them, eight were alive (73%), with a theoretical decrease of 0.98% in overall mortality. CONCLUSIONS: surgical treatment is rare during TAVI. The presence of an expert complete rescue team as support means an increase in survival. Surgery must be used only to restore circulatory and to treat complication while percutaneous approaches should complete the procedure.

Transcatheter Valve-in-Valve Implantation in an Aortic Bioprosthesis With Severe Regurgitation and a Challenging Aortic Anatomy.

Valve-in-valve transcatheter aortic valve replacement for failing surgical bioprosthetic valves becomes troublesome if a stiff vascular prosthesis replaces the ascending aorta. We report the off-label use of a new transcatheter aortic valve for treatment of a patient with a bioprosthetic valve with central regurgitation, a horizontal aorta, and kinking of the aortic prosthesis. (Level of Difficulty: Intermediate.).

Correlation between PD-L1 Expression of Non-Small Cell Lung Cancer and Data from IVIM-DWI Acquired during Magnetic Resonance of the Thorax: Preliminary Results.

This study aims to investigate the correlation between intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) parameters in magnetic resonance imaging (MRI) and programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer (NSCLC). Twenty-one patients diagnosed with stage III NSCLC from April 2021 to April 2022 were included. The tumors were distinguished into two groups: no PD-L1 expression (<1%), and positive PD-L1 expression (≥1%). Conventional MRI and IVIM-DWI sequences were acquired with a 1.5-T system. Both fixed-size ROIs and freehand segmentations of the tumors were evaluated, and the data were analyzed through a software using four different algorithms. The diffusion (D), pseudodiffusion (D*), and perfusion fraction (pf) were obtained. The correlation between IVIM parameters and PD-L1 expression was studied with Pearson correlation coefficient. The Wilcoxon−Mann−Whitney test was used to study IVIM parameter distributions in the two groups. Twelve patients (57%) had PD-L1 ≥1%, and 9 (43%) <1%. There was a statistically significant correlation between D* values and PD-L1 expression in images analyzed with algorithm 0, for fixed-size ROIs (189.2 ± 65.709 µm²/s × 104 in no PD-L1 expression vs. 122.0 ± 31.306 µm²/s × 104 in positive PD-L1 expression, p = 0.008). The values obtained with algorithms 1, 2, and 3 were not significantly different between the groups. The IVIM-DWI MRI parameter D* can reflect PD-L1 expression in NSCLC.

Transcatheter Therapies in Challenging Aortic Ailments: TAVR in Extreme Horizontal Aortic Root With CoA Stenting.

Transcatheter aortic valve replacement (TAVR) for severe aortic stenosis in older adults may be challenging because of additional aortic comorbidities such as aortic coarctation (CoA). We report successful snared-assisted transfemoral TAVR in a patient with an extremely horizontal ventriculoaortic axis that was worsened by a previous endovascular repair of complex CoA. (Level of Difficulty: Advanced.).

Mechanical circulatory support and intravascular lithotripsy in high-risk patients undergoing percutaneous coronary intervention and transcatheter aortic valve replacement: a case series.

BACKGROUND: Patients undergoing transcatheter aortic valve replacement (TAVR) usually have multiple comorbidities, such as severely impaired left ventricular function (LVF) and heavily calcified coronary lesions. When they undergo pre-TAVR high-risk percutaneous coronary interventions (HR-PCIs) for severely calcified left main (LM) lesions, potential life-threatening intra-procedural complications associated with the different techniques available to treat calcified lesions can arise. In this setting, mechanical circulatory support proves its usefulness. However, the choice of device can be troublesome. CASE SUMMARY: We report two clinical scenarios of intravascular lithotripsy (IVL) for the treatment of heavily calcified LM coronary lesions, wherein peripheral veno-arterial extracorporeal membrane oxygenation (VA-ECMO), alone or combined with an intra-aortic balloon pump (IABP), were used as an upfront strategy to support the procedure. The use of these techniques was particularly effective during multi-vessel HR-PCIs and TAVR, and no complications occurred, which suggested their safety. DISCUSSION: These cases provide multiple insights into the strategy of using IVL + VA-ECMO, alone or with IABP, to treat heavily calcified LM coronary lesions in patients with severely compromised LVF undergoing TAVR. IVL safely and effectively overcame shortcomings related to other plaque ablation techniques, and VA-ECMO proved to be effective when facing the combination of high-risk coronary and valve interventions.

Safe and Effective Management of Antiplatelet Therapy in a Clopidogrel-Naive Patient Undergoing "Ad Hoc" Complex Coronary Intervention: A Case Report.

BACKGROUND: "Ad hoc" percutaneous coronary intervention (PCI) is a frequent practice as reported in large real-life registries, but most of the patients undergo PCI without being on full and effective dual antiplatelet therapy or clopidogrel is administered orally only a few minutes before the beginning of the procedure. This practice, especially in complex PCI, could be affected by a higher rate of peri-procedural adverse events. CASE SUMMARY: We present the case of a 72-year old male diabetic, hypertensive and hyperlipidemic, clopidogrel-naïve, with stable angina who underwent coronary angiography showing several tight stenoses on the left descending artery (LAD) and followed by a chronic total occlusion (CTO) of the vessel. The two main diagonal branches were severely stenosed at the origin as well. Due to patient's decision an ad hoc complex PCI (CTO and multiple Bifurcations) was successfully performed using cangrelor, instead of cath-lab clopidogrel pretreatment, in order to reduce the incidence of peri-procedural myocardial infarction risk, as suggested by recent evidence. Finally, the patient was started on dual antiplatelet therapy with ticagrelor, as guidelines recommend to consider in complex procedures, and discharged 48 h later without complications or significant increases of myocardial enzymes. DISCUSSION: Current Guidelines recommend loading dose (I/A) or pre-treatment with clopidogrel, nevertheless trials have not demonstrated its benefit, unlike cangrelor. This case highlights the role of aggressive antiplatelet therapy administered in the cath lab to reduce periprocedural ischemic events during elective treatment of complex lesions requiring multiple stenting in clopidogrel-naïve patients.

Transcatheter aortic valve-in-valve post-dilatation as an overlooked risk factor of delayed coronary obstruction: a case report.

BACKGROUND: The risk of coronary obstruction during transcatheter aortic valve-in-valve replacement (VIV-TAVR) in patients deemed at high risk for surgical re-intervention is still a concerning issue. CASE SUMMARY: A 78-year-old woman with a past medical history of hypertension, chronic kidney disease, and rheumatoid arthritis was referred for a symptomatic and severely stenotic surgical Mitroflow n.21 bio-prosthesis and was subsequently recommended for a VIV procedure. Multiple anatomical risk factors for coronary occlusion required a pre-emptive coronary chimney stenting protection. The implantation of an Evolut-R 23 mm valve resulted in a gradient of 21 mmHg thus, a post-dilatation with an 18 mm balloon was performed. Both electrocardiographic and haemodynamic parameters remained excellent, however, a hazardous leaflet dislodgment became evident. Regardless, a prophylactic chimney stenting was performed because of the operator's perceived high risk of late coronary occlusion. DISCUSSION: The implantation of transcatheter valves inside failed surgically implanted aortic bio-prosthesis is broadly recognized as a safe and less-invasive alternative to repeated high-risk surgery. Although procedural success is achieved in the great majority of patients, this therapy may be jeopardized by rare but serious complications such as impending or established acute coronary occlusion. Several specific anatomical and procedural risk factors have been identified and primary coronary prevention strategies are often mandatory when they arise. Valve-in-valve post-dilation has been overlooked in its role as an additional risk factor of late coronary obstruction. Therefore, chimney stenting, performed after balloon post-dilation to prevent delayed coronary obstruction, even if the acute coronary event does not occur intra-procedurally, is strongly advisable.

A cascade of multiple complications hampering a complex high-risk percutaneous coronary intervention (CHIP-PCI): When ingenuity overcomes troubles!

Even skilled CHIP operators can run into multiple complications. Some are unexpected and not related to the operator, and others are fully preventable by careful procedural choices. If those occur, the knowledge of devices and cognitive skills become lifesaving elements and sudden issues need to be dealt with calmly and efficiently.

Intracoronary Lithoplasty in Percutaneous Treatment of Challenging Calcified Coronary Lesions.

Unexpanded stents in calcified coronary stenosis is a problem where intravascular lithotripsy could be effectively employed. In these 2 cases, we report possible issues associated with the use of this technology. (Level of Difficulty: Intermediate.).

A study of the intermolecular interactions of tolmetin/N-acetyl-L-tyrosine ethyl ester complex.

The formation of tolmetin/N-acetyl-l-tyrosine ethyl ester (ATEE) complex has been reported by means of both theoretical and experimental studies, including quantum mechanical calculations as well as UV-vis absorption, fluorescence and time-resolved spectroscopy measurements. It has been found that the fluorescence of ATEE is quenched due to the formation of a non-fluorescent complex between ATEE and tolmetin in the ground state. The geometrical parameters of ATEE/tolmetin complex have been determined with the use of the DFT method applying the B3LYP correlation-exchange functional and 6-31G(d) basis set. The results of experiments indicated the static ATEE quenching by tolmetin. Additionally, the experimental and theoretically predicted Gibbs free energy of complexation has been calculated.

A Simple One-step Dissection Protocol for Whole-mount Preparation of Adult Drosophila Brains.

There is an increasing interest in using Drosophila to model human brain degenerative diseases, map neuronal circuitries in adult brains, and study the molecular and cellular basis of higher brain functions. A whole-mount preparation of adult brains with well-preserved morphology is critical for such whole brain-based studies, but can be technically challenging and time-consuming. This protocol describes an easy-to-learn, one-step dissection approach of an adult fly head in less than 10 s, while keeping the intact brain attached to the rest of the body to facilitate subsequent processing steps. The procedure helps remove most of the eye and tracheal tissues normally associated with the brain that can interfere with the later imaging step, and also places less demand on the quality of the dissecting forceps. Additionally, we describe a simple method that allows convenient flipping of the mounted brain samples on a coverslip, which is important for imaging both sides of the brains with similar signal intensity and quality. As an example of the protocol, we present an analysis of dopaminergic (DA) neurons in adult brains of WT (w1118) flies. The high efficacy of the dissection method makes it particularly useful for large-scale adult brain-based studies in Drosophila.

Studying polyglutamine diseases in Drosophila.

Polyglutamine (polyQ) diseases are a family of dominantly transmitted neurodegenerative disorders caused by an abnormal expansion of CAG trinucleotide repeats in the protein-coding regions of the respective disease-causing genes. Despite their simple genetic basis, the etiology of these diseases is far from clear. Over the past two decades, Drosophila has proven to be successful in modeling this family of neurodegenerative disorders, including the faithful recapitulation of pathological features such as polyQ length-dependent formation of protein aggregates and progressive neuronal degeneration. Additionally, it has been valuable in probing the pathogenic mechanisms, in identifying and evaluating disease modifiers, and in helping elucidate the normal functions of disease-causing genes. Knowledge learned from this simple invertebrate organism has had a large impact on our understanding of these devastating brain diseases.

Huntingtin functions as a scaffold for selective macroautophagy.

Selective macroautophagy is an important protective mechanism against diverse cellular stresses. In contrast to the well-characterized starvation-induced autophagy, the regulation of selective autophagy is largely unknown. Here, we demonstrate that Huntingtin, the Huntington disease gene product, functions as a scaffold protein for selective macroautophagy but it is dispensable for non-selective macroautophagy. In Drosophila, Huntingtin genetically interacts with autophagy pathway components. In mammalian cells, Huntingtin physically interacts with the autophagy cargo receptor p62 to facilitate its association with the integral autophagosome component LC3 and with Lys-63-linked ubiquitin-modified substrates. Maximal activation of selective autophagy during stress is attained by the ability of Huntingtin to bind ULK1, a kinase that initiates autophagy, which releases ULK1 from negative regulation by mTOR. Our data uncover an important physiological function of Huntingtin and provide a missing link in the activation of selective macroautophagy in metazoans.