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Natalie R Stokes,1 Brett W Dietz,1 Jackson J Liang2 1Perelman School of Medicine, University of Pennsylvania, 2Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, PA, USAAbstract: Dyspnea is a common chief complaint in the emergency department, with over 4 million visits annually in the US. Establishing the correct diagnosis can be challenging, because the subjective sensation of dyspnea can result from a wide array of underlying pathology, including pulmonary, cardiac, neurologic, psychiatric, toxic, and metabolic disorders. Further, the presence of dyspnea is linked with increased mortality in a variety of conditions, and misdiagnosis of the cause of dyspnea leads to poor patient-level outcomes. In combination with the history and physical, efficient, and focused use of laboratory studies, the various cardiopulmonary biomarkers can be useful in establishing the correct diagnosis and guiding treatment decisions in a timely manner. Use and interpretation of such tests must be guided by the clinical context, as well as an understanding of the current evidence supporting their use. This review discusses current standards and research regarding the use of established and emerging cardiopulmonary laboratory markers in the evaluation of acute dyspnea, focusing on recent evidence assessing the diagnostic and prognostic utility of various tests. These markers include brain natriuretic peptide (BNP) and N-terminal prohormone (NT-proBNP), mid-regional peptides proatrial NP and proadrenomedullin, cardiac troponins, D-dimer, soluble ST2, and galectin 3, and included is a discussion on the use of arterial and venous blood gases.Keywords: cardiopulmonary, emergency, heart failure, troponin, BNP, galectin 3, MR-proANP, MR-proADM

Competing Interests: Declarations Conflict of interest Erica Cohen has received income for consulting and participating in advisory boards for Abbvie, BMS, Pfizer and Johnson and Johnson. She is on the speaker bureau for Abbvie, Johnson and Johnson, and Takeda. Raymond K. Cross has received income for consulting and participation in advisory boards for Abbvie, Adiso, BMS, Fresenius Kabi, Fzata, Janssen, Magellan Health, Option Care, Pfizer, Pharmacosmos, Samsung Bioepis, Sandoz, and Sebela, has a research grant with Janssen, is a member of the Executive Committee for the IBD Education Group, and is a Scientific Co-Advisor for the CorEvitas Registry. Kiran Motwani and John J. Liang declare no relevant funding.

Background: Tangshenning (TSN) is a safe and effective formula to treat diabetic nephropathy (DN), and clinical studies have demonstrated that its therapeutic effects are related to oxidative stress improvements in patients. Herein, this study aims to explore the potential mechanism of how TSN alleviates diabetic renal tubular injury., Methods: The ultrahigh pressure liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-QTOF/MS) was used to identify the chemical composition and serum components of TSN. KK-Ay mice served to investigate the protective effects and regulatory mechanisms of TSN on tubular damage in DN. Furthermore, inhibitors and inducers of ferroptosis were employed in high glucose-cultured tubular epithelial cells (TECs) to verify the potential mechanisms of TSN. The expressions of proteins related to renal tubular injury, ferroptosis and solute carrier family 7, member 11 (SLC7A11)/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis were analyzed by western blot and immunofluorescence. Mitochondrial ultrastructure was observed in kidney tissues and TECs by a transmission electron microscope. Pathological changes in the renal tissues were observed by HE, PAS, and Prussian blue staining. Ferroptosis-related reactive oxygen species (ROS), malondialdehyde (MDA), ferrous ion, the intake of cystine, GSH, and oxidized glutathione (GSSG) were evaluated and contrasted in vivo or in vitro., Results: 51 compounds of TSN powder and 11 components in TSN-containing serum were identified by UPLC-QTOF/MS method. Administration of TSN ameliorated the elevated levels of proteinuria, serum creatinine, blood urea nitrogen, abnormal expression of renal tubular injury markers, and pathological damage to the renal tubules in DN mice model. Intriguingly, a strong inhibition of ferroptosis after TSN treatment occurred in both DN mice model and high glucose-cultured TECs. Notably, induction of ferroptosis by erastin attenuated the protective effect of TSN in high glucose-cultured TECs, while the ferroptosis inhibition by ferrostatin-1 treatment protected renal tubular, which was similar to TSN, suggesting the contribution of TSN-mediated by the inhibition of ferroptosis in DN progression. Mechanistically, TSN upregulated the SLC7A11/GSH/GPX4 axis to inhibit ferroptosis., Conclusion: TSN may delay the DN progression and attenuate the renal tubular injury by inhibiting the ferroptosis regulated by the SLC7A11/GSH/GPX4 axis., (© 2024. The Author(s).)

Background: Dofetilide is a class III antiarrhythmic agent approved for the treatment of atrial fibrillation and atrial flutter. Given the efficacy of other class III agents, it has been used off-label for the treatment of premature ventricular complexes (PVCs) and ventricular tachycardias (VTs)., Objective: The purpose of this study was to determine the efficacy and safety of dofetilide for ventricular arrythmias (VAs)., Methods: In this retrospective cohort study, 81 patients (59 men; age = 60 ± 14 years; LVEF = 0.34 ± 0.16) were admitted for dofetilide initiation to treat PVCs (29), VTs (42) or both (10). A ≥ 80% decrease in PVC burden was defined as a satisfactory response. An ICD was present in 72 patients (89%). Another antiarrhythmic was previously used in 50 patients (62%). Prior catheter ablation had been performed in 33 patients (41%)., Results: During intitiation, dofetilide was discontinued in 12 patients (15%) due to QT prolongation (8) and inefficacy to suppress VAs (4). Among the 32 patients with PVCs who successfully started dofetilide, the mean PVC burden decreased from 20 ± 10% to 8 ± 8% at a median follow-up of 2.6 months (p < .001). PVC burden was reduced by ≥80% in only 11/32 patients (34%). During 7 ± 1 years of follow-up, 41/69 patients (59%) continued to have VAs and received appropriate ICD therapies for monomorphic VTs (35) and polymorphic VT/VF (6) at a median of 8.0 (IQR 2.6-33.2) months. Dofetilide had to be discontinued in 50/69 patients (72%) due to inefficacy or intolerance. The composite outcome of VT/VF recurrence, heart transplantation, or death occurred in 6/12 patients (50%) without dofetilide and 49/69 patients (71%) with dofetilide. The event free survival was similar between patients treated with and without dofetilide (log-rank p = .55)., Conclusions: Treatment with dofetilide was associated with a decrease in PVCs, however clinically significant suppression occurred in a minority of patients. Dofetilide failed to suppress the occurrence of VTs in a majority of patients., (© 2024 The Author(s). Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.)

USP25 encodes ubiquitin-specific protease 25, a key member of the deubiquitinating enzyme family that is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown aetiology. Five heterozygous USP25 variants, including two de novo and three co-segregated variants, were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared with the East Asian population and all populations in the gnomAD database. The mean age at onset of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom, except that one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was expressed ubiquitously in mouse brain with two peaks, on embryonic Days 14-16 and postnatal Day 21, respectively. In human brain, likewise, USP25 is expressed in the fetus/early childhood stage and with a second peak at ∼12-20 years old, consistent with the seizure onset age in patients during infancy and in juveniles. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knockout mice, which showed increased seizure susceptibility compared with wild-type mice in a pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we used multiple functional detections. In HEK293 T cells, the variant associated with a severe phenotype (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed stable truncated dimers with an increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del variants increased neuronal excitability in mouse brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating that USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play an epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have a profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Ablation of premature ventricular complexes (PVCs) originating from the parahisian area is challenging. Late gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) scar may influence procedural outcomes; the impact of cardiac scar on parahisian PVCs has not been described., Objective: The objective of this study was to examine the incidence and significance of LGE-CMR scarring in patients undergoing ablation for parahisian PVCs., Methods: Consecutive patients who underwent preprocedure LGE-CMR imaging and ablation of parahisian PVCs were included. Acute and long-term outcomes were examined., Results: Forty-eight patients were included (male, n = 37; age, 66 ± 10 years; ejection fraction, 50% ± 12%; preprocedure PVC burden, 21% ± 12%). Intramural LGE-CMR scar was present in 33 of 48 (69%) patients. Cryoablation was used in 9 patients; ablation in multiple chambers was required in 28 (58%) patients. The PVC site of origin (SOO) was intramural (n = 25 patients), left ventricular (n = 5), and right ventricular (n = 18). Patients with LGE-CMR scar were more likely to have intramural PVCs (64% vs 27%; P < .04) and to require ablation in multiple cardiac chambers (58% vs 13%; P < .02). Patients with intramural scar required longer duration of ablation delivery (31 ± 20 minutes vs 17 ± 8 minutes; P < .02). Acute procedural success was 69%; PVC burden on follow-up was 6% ± 9% and similar for those with and without scar., Conclusion: Ablation of parahisian PVCs often requires mapping and ablation of multiple cardiac chambers, with an intramural SOO identified in most patients. An intramural scar was associated with an intramural SOO of the PVCs requiring more extensive ablation procedures, with similar long-term outcomes compared with those without scar., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

An investigation into an outbreak of Salmonella Newport infections in Canada was initiated in July 2020. Cases were identified across several provinces through whole-genome sequencing (WGS). Exposure data were gathered through case interviews. Traceback investigations were conducted using receipts, invoices, import documentation, and menus. A total of 515 cases were identified in seven provinces, related by 0-6 whole-genome multi-locus sequence typing (wgMLST) allele differences. The median age of cases was 40 (range 1-100), 54% were female, 19% were hospitalized, and three deaths were reported. Forty-eight location-specific case sub-clusters were identified in restaurants, grocery stores, and congregate living facilities. Of the 414 cases with exposure information available, 71% (295) had reported eating onions the week prior to becoming ill, and 80% of those cases who reported eating onions, reported red onion specifically. The traceback investigation identified red onions from Grower A in California, USA, as the likely source of the outbreak, and the first of many food recall warnings was issued on 30 July 2020. Salmonella was not detected in any tested food or environmental samples. This paper summarizes the collaborative efforts undertaken to investigate and control the largest Salmonella outbreak in Canada in over 20 years.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome encodes 29 proteins including four structural, 16 nonstructural (nsps), and nine accessory proteins (https://epimedlab.org/sars-cov-2-proteome/). Many of these proteins contain potential targetable sites for the development of antivirals. Despite the widespread use of vaccinations, the emergence of variants necessitates the investigation of new therapeutics and antivirals. Here, the EpiMed Coronabank Chemical Collection (https://epimedlab.org/crl/) was utilized to investigate potential antivirals against the nsp14 exoribonuclease (ExoN) domain. Molecular docking was performed to evaluate the binding characteristics of our chemical library against the nsp14 ExoN site. Based on the initial screen, trisjuglone, ararobinol, corilagin, and naphthofluorescein were identified as potential lead compounds. Molecular dynamics (MD) simulations were subsequently performed, with the results highlighting the stability of the lead compounds in the nsp14 ExoN site. Protein-RNA docking revealed the potential for the lead compounds to disrupt the interaction with RNA when bound to the ExoN site. Moreover, hypericin, cyanidin-3-O-glucoside, and rutin were previously identified as lead compounds targeting the papain-like protease (PL pro ) naphthalene binding site. Through performing MD simulations, the stability and interactions of lead compounds with PL pro were further examined. Overall, given the critical role of the exonuclease activity of nsp14 in ensuring viral fidelity and the multifunctional role of PL pro in viral pathobiology and replication, these nsps represent important targets for antiviral drug development. Our databases can be utilized for in silico studies, such as the ones performed here, and this approach can be applied to other potentially druggable SARS-CoV-2 protein targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Sustained ventricular tachycardia (VT) in cardiac amyloidosis is uncommon, and the substrate and outcomes of catheter ablation are not defined., Methods: We included 22 consecutive patients (mean age, 68±10 years; male sex, 91%) with cardiac amyloidosis (ATTR [transthyretin], n=16; light chain, n=6) undergoing catheter ablation for VT/ventricular fibrillation (VF) between 2013 and 2023 in a retrospective, observational, international study. The primary efficacy outcome was recurrent VT/VF during follow-up, while the primary safety end point included major procedure-related adverse events., Results: The indication for ablation was drug-refractory VT in 17 patients (77%), and premature ventricular complex-initiated polymorphic VT/VF in 5 patients (23%). Catheter ablation was performed using endocardial (n=17.77%) or endo-epicardial approaches (n=5.23%). Complete endocardial electroanatomical voltage maps of the left and right ventricles were obtained in 17 (77%) and 10 (45%) patients, respectively. Each patient had evidence of low-voltage areas, most commonly involving the interventricular septum (n=16); late potentials were recorded in 16 patients (73%). A median of 1 (1-2) VT was inducible per patient; 12 of the 26 mappable VTs (46%) originated from the interventricular septum. Complete procedural success was achieved in 16 patients (73%), with 4 (18%) major procedure-related adverse events. After a median follow-up of 32 (14-42) months, sustained VT/VF recurrence was observed in 9 patients (41%); survival free from VT/VF recurrence was 56% (95% CI, 36%-86%) at 36-month follow-up, and most patients remained on antiarrhythmic drugs. A significant reduction in per patient implantable cardioverter defibrillator therapies was noted in the 6-month period after ablation (before: 6 [4-9] versus after: 0 [0-0]; P <0.001). In multivariable analysis, complete procedural success was associated with reduced risk of recurrent VT/VF (hazard ratio, 0.002; P =0.034)., Conclusions: Catheter ablation can achieve control of recurrent VT/VF in more than half of patients with cardiac amyloidosis, and the reduction in VT/VF burden post-ablation may be relevant for quality of life. Septal substrate and risk of procedure-related complications challenge successful management of patients with cardiac amyloidosis and VT/VF., Competing Interests: Dr Dello Russo is a consultant for Abbott Medical. Dr Stevenson has received speaking honoria from Boston Scientific, Abbott, Medtronic, Johnson and Johnson, and Biotronik. Dr Tondo receives educational, tutoring, and lecture fees from Abbott Medical, Boston Scientific, and Biosense & Webster. Dr Natale is a consultant for Biosense Webster, Abbott, Boston Scientific, Biotronik, and iRhythm. Dr Casella has received speaker honoraria from Biosense Webster. The other authors report no conflicts.

Background: Chinese medaka (Oryzias sinensis) is widely distributed in freshwater rivers in China. Similar to the medaka (Oryzias latipes), Chinese medaka has the characteristics of small size, rapid reproductive cycle, and strong adaptability, which makes it suitable as a model organism for studies in basic biology and environmental toxicology. Chinese medaka exhibits distinct sexual dimorphism. However, due to the lack of complete genomic information, the regulation of sex determination and differentiation-related genes in Chinese medaka remains unclear., Methods: Chinese medaka dmrt1 (Osdmrt1) was cloned by PCR, and transgenic individuals of medaka [Tg(CMV:Osdmrt1)] overexpressing Osdmrt1 were generated to investigate the role of Osdmrt1 in sex determination. Western blot was used to validate the integration of the Osdmrt1 into the medaka genome. Tissue sectioning and HE staining were used to identify Tg(CMV:Osdmrt1) physiological gender and phenotype. qRT-PCR was used to analyze the expression of gonad-specific genes., Results: Osdmrt1 was cloned and identified, and it shared similar evolutionary relationships with medaka dmrt1. Tg(CMV:Osdmrt1) exhibited partial sex reversal from female to male in the F2 generation, with genetically female individuals developing testes and producing functional sperm. Additionally, the secondary sexual characteristics of the transgenic females also changed to males., Conclusion: The Chinese medaka dmrt1 gene could convert females to males in medaka., General Significance: These results not only elucidate the function of Chinese medaka dmrt1, but also accumulate knowledge for studying the function of economically important fish genes in model fish by transgenic technology., Competing Interests: Declaration of competing interest, (Copyright © 2023. Published by Elsevier B.V.)

Background: China exited strict Zero-COVID policy with a surge in Omicron variant infections in December 2022. Given China's pandemic policy and population immunity, employing Baidu Index (BDI) to analyze the evolving disease landscape and estimate the nationwide pneumonia hospitalizations in the post Zero COVID period, validated by hospital data, holds informative potential for future outbreaks., Methods: Retrospective observational analyses were conducted at the conclusion of the Zero-COVID policy, integrating internet search data alongside offline records. Methodologies employed were multidimensional, encompassing lagged Spearman correlation analysis, growth rate assessments, independent sample T-tests, Granger causality examinations, and Bayesian structural time series (BSTS) models for comprehensive data scrutiny., Results: Various diseases exhibited a notable upsurge in the BDI after the policy change, consistent with the broader trajectory of the COVID-19 pandemic. Robust connections emerged between COVID-19 and diverse health conditions, predominantly impacting the respiratory, circulatory, ophthalmological, and neurological domains. Notably, 34 diseases displayed a relatively high correlation (r > 0.5) with COVID-19. Among these, 12 exhibited a growth rate exceeding 50% post-policy transition, with myocarditis escalating by 1,708% and pneumonia by 1,332%. In these 34 diseases, causal relationships have been confirmed for 23 of them, while 28 garnered validation from hospital-based evidence. Notably, 19 diseases obtained concurrent validation from both Granger causality and hospital-based data. Finally, the BSTS models approximated approximately 4,332,655 inpatients diagnosed with pneumonia nationwide during the 2 months subsequent to the policy relaxation., Conclusion: This investigation elucidated substantial associations between COVID-19 and respiratory, circulatory, ophthalmological, and neurological disorders. The outcomes from comprehensive multi-dimensional cross-over studies notably augmented the robustness of our comprehension of COVID-19's disease spectrum, advocating for the prospective utility of internet-derived data. Our research highlights the potential of Internet behavior in predicting pandemic-related syndromes, emphasizing its importance for public health strategies, resource allocation, and preparedness for future outbreaks., Competing Interests: LX, ML, and YH were employed by Hybribio Medical Laboratory Group Ltd. 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 Yu, Tan, Tang, Zhao, Ji, Lin, He, Gu, Liang, Wang, Chen, Yang, Xie, Wang, Liu, He, Chen, Wang, Wu, Zhao, Liu, Wang, Hao, Cen, Yao, Zhang, Liu, Lye, Hao, Wong and Cen.)

Background: Patients may develop atrial tachycardia (AT) after left atrial (LA) ablation of persistent atrial fibrillation (AF)., Methods: The population consisted of 101 consecutive patients (age = 64.3 ± 8.7 years, 70 males (69%), LA = 4.6 ± 0.8 cm, ejection fraction = 48.5 ± 16%) undergoing their initial procedure for persistent AF. After pulmonary vein isolation, patients either underwent posterior LA isolation (n = 50; study group) or linear ablation at the LA roof with verification of conduction block (n = 51; control group)., Results: A repeat procedure was performed in 17 (34%) and 28 (55%) patients in the study and control groups, respectively (p = 0.02). Patients in the study group were less likely to develop AT (9/50 [18%] vs. 18/51 [35%]; p = 0.02), roof-dependent (1/50 [2%] vs. 8/51 [16%]; p = 0.008), and multi-loop AT (6/50 [12%] vs. 14/51 [27%]; p = 0.03) as compared to controls. Among various factors, only posterior LA isolation was associated with a lower likelihood of AT recurrence and roof tachycardia at redo procedure (OR, 0.37; 95% CI, 0.1 to 1.00, p = 0.05, and OR, 0.1, 95% CI, 0.01 to 0.96; p < 0.05, respectively)., Conclusions: In patients with persistent AF, posterior LA isolation is associated with a lower risk of a redo procedure, roof-dependent macro-reentry, and post-ablation AT in general as compared to controls who only received roof ablation. Posterior LA isolation also obviates the need for pacing maneuvers, and may be a more definitive endpoint than linear ablation at the LA roof., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Disclosures The authors have no conflicts of interest to disclose.

Modern studies have revealed gender and race-related disparities in the management and outcomes of cardiac arrhythmias, but few studies have focused on outcomes for ventricular arrhythmias (VAs) such as ventricular tachycardia (VT) or ventricular fibrillation (VF). The aim of this article is to review relevant studies and identify outcome differences in the management of VA among Black and female patients. We found that female patients typically present younger for VA, are more likely to have recurrent VA after catheter ablation, are less likely to be prescribed antiarrhythmic medication, and are less likely to receive primary prevention ICD placement as compared to male patients. Additionally, female patients appear to derive similar overall mortality benefit from primary prevention ICD placement as compared to male patients, but they may have an increased risk of acute post-procedural complications. We also found that Black patients presenting with VA are less likely to undergo catheter ablation, receive appropriate primary prevention ICD placement, and have significantly higher risk-adjusted 1-year mortality rates after hospital discharge as compared to White patients. Black female patients appear to have the worst outcomes out of any demographic subgroup., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Quinidine, the first antiarrhythmic drug, was widely used during the 20th century. Multiple studies have been conducted to provide insights into the pharmacokinetics and pleiotropic effects of Class Ia antiarrhythmic drugs. However, safety concerns and the emergence of new drugs led to a decline in their use during the 1990s. Despite this, recent studies have reignited the interest in quinidine, particularly for ventricular arrhythmias, where other antiarrhythmics have failed. In conditions such as Brugada syndrome, idiopathic ventricular fibrillation, early repolarization syndrome, short QT syndrome, and electrical storms, quinidine remains a valuable asset. Starting from the European and American recommendations, this comprehensive review aimed to explore the various indications for quinidine and the studies that support its use. We also discuss the potential future of quinidine, including the necessary research to optimize its use and patient selection. Additionally, it addresses the imperative task of mitigating the iatrogenic burden associated with quinidine usage and confronts the challenge of ensuring drug accessibility., Competing Interests: Declaration of competing interest RPM has received lecture fees from Biosense Webster., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In a landmark study, oleocanthal (OLC), a major phenolic in extra virgin olive oil (EVOO), was found to possess anti-inflammatory activity similar to ibuprofen, involving inhibition of cyclooxygenase (COX) enzymes. EVOO is a rich source of bioactive compounds including fatty acids and phenolics; however, the biological activities of only a small subset of compounds associated with Olea europaea have been explored. Here, the OliveNet TM library (consisting of over 600 compounds) was utilized to investigate olive-derived compounds as potential modulators of the arachidonic acid pathway. Our first aim was to perform enzymatic assays to evaluate the inhibitory activity of a selection of phenolic compounds and fatty acids against COX isoforms (COX-1 and COX-2) and 15-lipoxygenase (15-LOX). Olive compounds were found to inhibit COX isoforms, with minimal activity against 15-LOX. Subsequent molecular docking indicated that the olive compounds possess strong binding affinities for the active site of COX isoforms, and molecular dynamics (MD) simulations confirmed the stability of binding. Moreover, olive compounds were predicted to have favorable pharmacokinetic properties, including a readiness to cross biological membranes as highlighted by steered MD simulations and umbrella sampling. Importantly, olive compounds including OLC were identified as non-inhibitors of the human ether-à-go-go-related gene (hERG) channel based on patch clamp assays. Overall, this study extends our understanding of the bioactivity of Olea-europaea -derived compounds, many of which are now known to be, at least in part, accountable for the beneficial health effects of the Mediterranean diet.

A novel methodology for the synthesis of nitrones via palladium-catalyzed redox cross-coupling of nitro compounds and alcohols is established. The protocol is a mild, convenient, ligand-free, and scalable synthesis method that can be compatible with various nitro compounds and alcohols. Nitrone is a significant multifunctional platform synthon which can be synthesized directly and efficiently via this tactic from commercially available and cheap raw materials.

For peritoneal metastases from a primary appendiceal mucinous neoplasm to exist, the thin wall of the appendix must perforate to allow mucus or mucus plus tumor cells to gain access to the peritoneal spaces. The proportion of specimens containing tumor cells within mucus as compared to mucus only outside the appendix may have prognostic significance. The histopathology of tumor masses was determined from the specimens resected at the cytoreductive surgery (CRS). The presence versus absence of tumor cells in mucus and the proportion of specimens with tumor cells was determined and correlated with the overall survival of these patients. In 418 patients with a complete cytoreduction for a low-grade appendiceal mucinous neoplasm (LAMN), the cellularity of all resected specimens was determined. The hazard ratio of overall survival of patients whose specimens had no cells as compared to specimens with cells in mucus by histology was 4.41 (1.61, 12.1) (p = 0.0039). If overall survival of patients with all specimens without tumor cells was compared to patients with specimens with 1-99 % tumor and compared to patients with 100 % of specimens with tumor cells, the hazard ratios were 4.3 (1.34, 13.8) (p = 0.0143) and 9.62 (2.93, 31.6) (p = 0.0002), respectively. The cellularity of mucus within the specimens removed by a complete CRS has strong prognostic implications in LAMN patients. LAMN with acellular specimens (LAMNa) as compared to LAMN with tumor cells in specimens (LAMNb) should be staged as different histologic subtypes of mucinous appendiceal neoplasms., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (© 2024 Elsevier Ltd, BASO ∼ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Left atrial appendage exclusion (LAAE) is an effective alternative to long-term anticoagulation in patients with atrial fibrillation. Not all patients considered for LAAE undergo the procedure because of ineligibility, anatomic or medical constraints, and preference of the patient., Objective: The objective of this study was to report on the management strategies and long-term clinical outcomes of patients referred to a dedicated multidisciplinary LAAE clinic, including all who subsequently did and did not undergo LAAE., Methods: This was a retrospective analysis of prospectively acquired data from all patients referred to the comprehensive multidisciplinary LAAE clinic at the University of Michigan between 2016 and 2022. A consecutive 301 patients (age, 75 ± 8 years; 106 women) with atrial fibrillation were evaluated. LAAE was performed in 168 patients (56%) with use of the Watchman device in 146 (49%) and surgically in 22 (7%). LAAE was not performed in 133 patients (44%, no-LAAE group) because of ineligibility in 62 (21%), anatomic constraints in 23 (7%), and preference of the patient in 48 (36%). The CHA 2 DS 2 -VASc score (4.7 ± 1.5 vs 4.1 ± 1.6; P = .002) and HAS-BLED score (3.4 ± 1.0 vs 2.8 ± 1.1; P < .001) were higher in the LAAE groups., Results: Anticoagulant therapy was discontinued in 137 of 146 (94%) and 61 of 133 (61%) in the Watchman and no-LAAE groups, respectively (P < .001). During a median follow-up of 2.2 years (interquartile range, 1.2-4.0 years), in the LAAE (n = 168) and no-LAAE (n = 133) groups, respectively, 39 (23%) vs 29 (22%) deaths, 13 (8%) vs 5 (4%) thromboembolic events, and 24 (14%) vs 23 (17%) bleeding complications occurred. Continued long-term anticoagulation was not a predictor of clinical outcomes., Conclusion: After a comprehensive evaluation in a multidisciplinary clinic, ∼50% of the patients referred for LAAE did not proceed with LAAE and resumed anticoagulation., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Lumbar intervertebral disc herniation (LDH) is a common and frequently-occurring disease, which usually causes lumbar and leg pain. Studies have shown that acupuncture can improve the symptoms of LDH patients. In the present paper, we summarize the progress of researches on the mechanisms of acupuncture underlying improvement of symptoms of LDH in recent 10 years from 1) delaying the intervertibral disc degeneration (by down-regulating the expressions of matrix metalloproteinase ［MMP］-3 and MMP-4, up-regulating the expressions of diosaccharides and polyglycoprotein, inhibiting apoptosis and promoting mitochondrial autophagy of nucleus pulposus cells, etc.), 2) maintaining spinal column stability (by relieving rachiasmus and improving lumbar flexor and extensor muscle strength, lowering the degree of polyfidus edema and fat infiltration, and restoring the biomechanics of the spine), 3) regulating inflammation (by inhibiting the production of proinflammatory factors and increasing the production of anti-inflammatory factors, etc.), 4) regulating immune response (by promoting the activity of T cells and other immune cells, lowering serum levels of MMP-3, transforming growth factor-β1 and prostaglandin E2, raising serum levels of IgA, IgG and IgM to improve immune function ), 5) modulating neural structure and function (by promoting myelin regeneration of sciatic nerve fibers, and reducing the edema of Schwann cells' cytoplasm and mitochondria, and improving neural ultrastructure, and sensory and motor functions of peripheral nerves, etc.), 6) relieving lumbar pain (by down-regulating expression of Ca 2+ /calmodulin-dependent protein kinase and activation of lumbar spinal cord glial cells, blocking nociceptive signal conduction, regulating the levels of pain-related factors, etc.), and 7) improving local microcirculation. These results may provide scientific evidence for acupuncture treatment of LDH.

The Mediterranean diet well known for its beneficial health effects, including mood enhancement, is characterised by the relatively high consumption of extra virgin olive oil (EVOO), which is rich in bioactive phenolic compounds. Over 200 phenolic compounds have been associated with Olea europaea , and of these, only a relatively small fraction have been characterised. Utilising the OliveNet TM library, phenolic compounds were investigated as potential inhibitors of the epigenetic modifier lysine-specific demethylase 1 (LSD1). Furthermore, the compounds were screened for inhibition of the structurally similar monoamine oxidases (MAOs) which are directly implicated in the pathophysiology of depression. Molecular docking highlighted that olive phenolics interact with the active site of LSD1 and MAOs. Protein-peptide docking was also performed to evaluate the interaction of the histone H3 peptide with LSD1, in the presence of ligands bound to the substrate-binding cavity. To validate the in silico studies, the inhibitory activity of phenolic compounds was compared to the clinically approved inhibitor tranylcypromine. Our findings indicate that olive phenolics inhibit LSD1 and the MAOs in vitro. Using a cell culture model system with corticosteroid-stimulated human BJ fibroblast cells, the results demonstrate the attenuation of dexamethasone- and hydrocortisone-induced MAO activity by phenolic compounds. The findings were further corroborated using human embryonic stem cell (hESC)-derived neurons stimulated with all-trans retinoic acid. Overall, the results indicate the inhibition of flavin adenine dinucleotide (FAD)-dependent amine oxidases by olive phenolics. More generally, our findings further support at least a partial mechanism accounting for the antidepressant effects associated with EVOO and the Mediterranean diet.

Since its emergence, SARS-CoV-2 has been continuously evolving, hampering the effectiveness of current vaccines against COVID-19. mAbs can be used to treat patients at risk of severe COVID-19. Thus, the development of broadly protective mAbs and an understanding of the underlying protective mechanisms are of great importance. Here, we isolated mAbs from donors with breakthrough infection with Omicron subvariants using a single-B cell screening platform. We identified a mAb, O5C2, which possesses broad-spectrum neutralization and antibody-dependent cell-mediated cytotoxic activities against SARS-CoV-2 variants, including EG.5.1. Single-particle analysis by cryo-electron microscopy revealed that O5C2 targeted an unusually large epitope within the receptor-binding domain of spike protein that overlapped with the angiotensin-converting enzyme 2 binding interface. Furthermore, O5C2 effectively protected against BA.5 Omicron infection in vivo by mediating changes in transcriptomes enriched in genes involved in apoptosis and interferon responses. Our findings provide insights into the development of pan-protective mAbs against SARS-CoV-2.

Hepatic encephalopathy (HE) is a clinically severe and devastating complication of decompensated liver disease affecting mortality, quality of life for patients and families, hospital admission rates, and overall health-care costs globally. Depending on the cause of HE, several medical treatment options have been developed and become available. In some refractory HE, such as spontaneous portosystemic shunt-related HE (SPSS-HE) or posttransjugular intrahepatic portosystemic shunt HE (post-TIPS HE), advanced interventional radiology (IR) procedures have been used, and shown to be effective in these conditions. This review presents 2 effective IR procedures for managing SPSS-HE and post-TIPS HE., Competing Interests: Disclosure None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Intraocular pressure elevation can induce retinal ganglion cell death and is a clinically reversible risk factor for glaucoma, the leading cause of irreversible blindness. We previously demonstrated that casein kinase-2 inhibition can promote retinal ganglion cell survival and axonal regeneration in rats after optic nerve injury. To investigate the underlying mechanism, in the current study we increased the intraocular pressure of adult rats to 75 mmHg for 2 hours and then administered a casein kinase-2 inhibitor (4,5,6,7-tetrabromo-2-azabenzimidazole or 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole) by intravitreal injection. We found that intravitreal injection of 4,5,6,7-tetrabromo-2-azabenzimidazole or 2-dimethylamino-4,5,6,7-tetrabromo- 1 H-benzimidazole promoted retinal ganglion cell survival and reduced the number of infiltrating macrophages. Transcriptomic analysis showed that the mitogen activated protein kinase signaling pathway was involved in the response to intraocular pressure elevation but was not modulated by the casein kinase-2 inhibitors. Furthermore, casein kinase-2 inhibition downregulated the expression of genes (Cck, Htrsa, Nef1, Htrlb, Prph, Chat, Slc18a3, Slc5a7, Scn1b, Crybb2, Tsga10ip, and Vstm21) involved in intraocular pressure elevation. Our data indicate that inhibition of casein kinase-2 can enhance retinal ganglion cell survival in rats after acute intraocular pressure elevation via macrophage inactivation., Competing Interests: None

To investigate the plasma lipoprotein subclasses in patients with primary open-angle glaucoma (POAG), a total of 20 Chinese POAG patients on intraocular pressure (IOP)-lowering treatment and 20 age-matched control subjects were recruited. Based on the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), the study subjects were divided into elevated- and normal-level subgroups. The plasma lipoprotein, lipoprotein subclasses, and oxidized LDL (oxLDL) levels were quantitatively measured. The discrimination potential of the lipoproteins was evaluated using the area under the receiver operating characteristic curve (AUC), and their correlation with clinical parameters was also evaluated. Compared to the control subjects with elevated TC and/or LDL-C levels, the levels of TC, LDL-C, non-high-density lipoprotein cholesterol (non-HDL), LDL subclass LDL3 and small dense LDL (sdLDL), and oxLDL were significantly higher in POAG patients with elevated TC and/or LDL-C levels. No differences in any lipoproteins or the subclasses were found between the POAG patients and control subjects with normal TC and LDL-C levels. Moderate-to-good performance of TC, LDL-C, non-HDL, LDL3, sdLDL, and oxLDL was found in discriminating between the POAG patients and control subjects with elevated TC and/or LDL-C levels (AUC: 0.710-0.950). Significant negative correlations between LDL3 and sdLDL with retinal nerve fiber layer (RNFL) thickness in the superior quadrant and between LDL3 and average RNFL thickness were observed in POAG patients with elevated TC and/or LDL-C levels. This study revealed a significant elevation of plasma lipoproteins, especially the LDL subclasses, in POAG patients with elevated TC and/or LDL-C levels, providing insights on monitoring specific lipoproteins in POAG patients with elevated TC and/or LDL-C.

The conjunctiva of primary open angle glaucoma patients showed high level of oxidized low-density lipoprotein (ox-LDL), which is associated with the inflammatory response. Microglia and macrophages are the immune cells involved in retinal ganglion cell survival regulation; yet, their roles of the ox-LDL-induced inflammation in glaucoma remain elusive. Here we aimed to investigate the lipid uptake, inflammatory cytokine expression, and metabolomics profiles of human and murine-derived microglial and macrophage cell lines treated with ox-LDL. Under the same ox-LDL concentration, macrophages exhibited higher lipid uptake and expression of pro-inflammatory cytokines as compared to microglia. The ox-LDL increased the levels of fatty acid metabolites in macrophages and sphingomyelin metabolites in microglia. In summary, this study revealed the heterogeneity in the inflammatory capacity and metabolic profiles of macrophages and microglia under the stimulation of ox-LDL., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

We have identified the biosynthetic gene cluster ( hvm ) for the sterol O -acyltransferase inhibitor helvamide ( 1 ) from the genome of Aspergillus rugulosus MST-FP2007. Heterologous expression of hvm in A. nidulans produced a previously unreported analog helvamide B ( 5 ). An α-ketoglutarate-dependent oxygenase Hvm1 was shown to catalyze intramolecular cyclization of 1 to yield 5 . The biosynthetic branch to the related hancockiamides and helvamides was found to be controlled by the substrate selectivity of monomodular nonribosomal peptide synthetases.

Background and Purpose: The objective of this investigation was to assess the therapeutic efficacy of distinct glucocorticoid therapy dosages in the management of acute nonarteritic anterior ischemic optic neuropathy (NAION)., Materials and Methods: This retrospective, unmasked, and non-randomized study included a total of 85 patients. The patients were categorized into four groups: Group 1 (control) consisted of 15 patients who did not receive glucocorticoids, Group 2 included 16 patients administered with oral prednisone at a dosage of 1 mg/kg/d for 14 days, Group 3 comprised 30 patients who received 250 units of methylprednisolone once daily for 3 days, followed by oral prednisone at a dosage of 1 mg/kg/d for 11 days, and Group 4 encompassed 24 patients who received 500 units of methylprednisolone once daily for 3 days, followed by oral prednisone at a dosage of 1 mg/kg/d for 11 days. The best-corrected visual acuity (BCVA) was assessed at baseline and the final follow-up (> 7 days post-treatment). The changes in visual acuity between baseline and the 7-14 day follow-up, as well as between baseline and the concluding appraisal, were employed as metrics for assessing the extent of visual enhancement., Results: No significant differences were noted in the final visual outcomes or in the changes between final visual acuity and baseline across the four groups. In Group 1 (control), the best-corrected visual acuity (BCVA) remained unchanged during final follow-ups compared to baseline. Conversely, the intervention groups exhibited statistically significant enhancements in BCVA during final follow-up (p = 0.012, p = 0.03, and p = 0.009 for Group 2, Group 3, and Group 4, respectively) when compared to baseline. During the 7-14 day follow-up, there was a significant difference in the changes between baseline BCVA and follow-up BCVA across the groups (p = 0.035). Go a step further by Bonferroni correction for multiple comparisons, group 4 showed a greater change in vision compared with group1 (p = 0.045)., Conclusion: Our study on acute nonarteritic anterior ischemic optic neuropathy (NAION) showed no significant final visual outcome differences. Nevertheless, Groups 2, 3, and 4 demonstrated improved best-corrected visual acuity (BCVA) during the final follow-up. Notably, a 500-unit dose of methylprednisolone resulted in short-term BCVA enhancement. This suggests potential consideration of 500 units of methylprednisolone for short-term NAION vision improvement, despite its limited long-term impact., (© 2024. The Author(s).)

Background: Desmoplakin (DSP) pathogenic variants are rare causes of arrhythmogenic cardiomyopathy and often involve the right and left ventricles. Ventricular tachycardia (VT) ablations may be required in these patients, but procedural characteristics have not been reported., Objectives: In this study, the authors sought to report a multicenter experience of VT ablation in patients with DSP pathogenic variants., Methods: VT ablations performed in patients with known DSP pathogenic variants were analyzed across 6 centers in 3 countries. Patient characteristics and acute and long-term procedural outcomes were reported., Results: A total of 20 patients (13 men, median age 43 years [Q1-Q3: 41.5-53.0 years], left ventricular ejection fraction 43.0% [Q1-Q3: 41.5%-53.0%], 11 previous failed ablations) were referred for VT ablation procedures. All patients had symptomatic VTs, with ICD therapy in 19 patients. Epicardial procedures were performed in 16 of the 20 patients. VT target sites were located in the right ventricular (RV) endocardium (n = 11), the RV epicardium (n = 4), the left ventricular (LV) endocardium (n = 2) and the LV epicardium (n = 7). In 3 patients, the VT target sites were in close proximity to coronary arteries, limiting ablation. During follow-up, VTs recurred in 11 patients, and repeated ablations were performed in 9 patients. Allowing for multiple procedures, 19 of the 20 patients remained free of VT recurrence after a median follow-up of 18 months [Q1-Q3: 5-60 months]., Conclusions: Patients with DSP cardiomyopathy often have biventricular involvement, and ablation procedures often require ablation in both ventricles and the epicardium. Recurrences are not uncommon, and the pathologic substrate can be located in close proximity to epicardial coronary arteries, limiting the success rate of ablations., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Neonicotinoid insecticides, which target insect nicotinic acetylcholine receptors (nAChRs), have been widely and intensively used to control the whitefly, Bemisia tabaci, a highly damaging, globally distributed, crop pest. This has inevitably led to the emergence of populations with resistance to neonicotinoids. However, to date, there have been no reports of target-site resistance involving mutation of B. tabaci nAChR genes. Here we characterize the nAChR subunit gene family of B. tabaci and identify dual mutations (A58T&R79E) in one of these genes (BTβ1) that confer resistance to multiple neonicotinoids. Transgenic D. melanogaster, where the native nAChR Dβ1 was replaced with BTβ1A58T&R79E, were significantly more resistant to neonicotinoids than flies where Dβ1 were replaced with the wildtype BTβ1 sequence, demonstrating the causal role of the mutations in resistance. The two mutations identified in this study replace two amino acids that are highly conserved in >200 insect species. Three-dimensional modelling suggests a molecular mechanism for this resistance, whereby A58T forms a hydrogen bond with the R79E side chain, which positions its negatively-charged carboxylate group to electrostatically repulse a neonicotinoid at the orthosteric site. Together these findings describe the first case of target-site resistance to neonicotinoids in B. tabaci and provide insight into the molecular determinants of neonicotinoid binding and selectivity., Competing Interests: The authors have declared that no conflict of interest exists., (Copyright: © 2024 Yin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Electrochemical performances can be effectively improved by introducing metal-organic units (MOUs) into polyoxometalates (POMs). However, regulating the bonding strength between POMs and MOUs at the molecular level to improve the electrochemical performance is a challenging task. Three new POM-based metal-organic complexes (MOCs), namely H{Zn 2 (Hpytty) 2 (H 2 O) 8 [CrMo 6 (OH) 6 O 18 ]}·2H 2 O (1), H{Zn 2 (Hpyttz) 2 (H 2 O) 6 [CrMo 6 (OH) 6 O 18 ]}·8H 2 O (2), and {(μ 2 -OH) 2 Zn 6 (pyttz) 2 (H 2 O) 10 [TeMo 6 O 24 ]}·2H 2 O (3) (H 2 pytty = 3-(pyrazin-2-yl)-5-(1 H -1,2,4-triazol-3-yl)-1,2,4-triazolyl, H 2 pyttz = 3-(pyrid-2-yl)-5-(1 H -1,2,4-triazol-3-yl)-1,2,4-triazolyl), were obtained. Single-crystal X-ray diffraction shows that the bonding strength (from the hydrogen bond to the coordination bond) between Zn-bistriazole-pyrazine/pyridine units and diverse Anderson-type POMs gradually increases from complexes 1 to 3. Glassy carbon electrodes modified with complex 3 (3-GCE) has the highest specific capacitance, which is 930 F g -1 at 1 A g -1 . Moreover, carbon paste electrodes (1-3-CPEs) modified with complexes 1-3 are used as electrochemical sensors for detecting Cr(VI) ions, with limits of detection well below the World Health Organization (WHO) maximum level in drinking water.

A chemical investigation of leaves of Viburnum chingii afforded eleven compounds, including one undescribed lignan ( 1 ), a pair of known phenylpropanoid enantiomers ( 2a / 2b ), and eight known lignans ( 3 - 10 ). Their structures were elucidated by detailed spectroscopic and comparative literature data analysis. The absolute configurations of compounds 1 was determined by comparing the experimental ECD data with the calculated values. The compounds 2a / 2b were separated successfully by a chiral chromatographic column. In addition, the acetylcholinesterase (AChE) inhibitory activities of described compounds were evaluated.

Knowledge of social determinants of health (SDOH), which refer to nonmedical factors influencing health outcomes, can help providers improve patient care. However, SDOH are often documented in unstructured notes, making them more inaccessible. Although previous works have attempted SDOH extraction from clinical notes, most efforts defined SDOH more narrowly and focused on the note's social history (SH) section, where social factors are traditionally documented. Here, we introduce a new SDOH dataset covering a broad range of SDOH content that is annotated over entire notes. We characterize what, where, and how SDOH information is documented in clinical text, present baseline systems using a token classification and generative approach, and investigate whether training only on the SH section can effectively extract SDOH from the entire note. The final dataset, consisting of 2,007 annotations covering 7 open-ended SDOH domains over 500 notes, will be publicly released to encourage further research in this area., (©2023 AMIA - All rights reserved.)