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Chang-Sheng Ma,1,2,* Ya-Ping Ma,1,3,* Bo Han,1,2,* Wan-Li Duan,1 Shu-Chen Meng,1 Min Bai,1 Hao Dong,1 Li-Ying Zhang,1 Meng-Yuan Duan,1,2 Jing Liu,1 Ai-Jun Deng,2 Mao-Tao He1,2 1Department of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong, People’s Republic of China; 2Department of Ophthalmology, Affiliated Hospital of Shandong Second Medical University, Weifang, People’s Republic of China; 3Department of Pathology, The 942Hospital of the People’s Liberation Army Joint Logistic Support Force, Yinchuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mao-Tao He, Department of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong, People’s Republic of China, Tel +86-18209617186, Fax +86-0536-3081201, Email hemaotao@sdsmu.edu.cn Ai-Jun Deng, Department of Ophthalmology, Affiliated Hospital of Shandong Second Medical University, Weifang, People’s Republic of China, Email dengaijun@hotmail.comPurpose: Ischemic stroke is a refractory disease wherein the reperfusion injury caused by sudden restoration of blood supply is the main cause of increased mortality and disability. However, current therapeutic strategies for the inflammatory response induced by cerebral ischemia-reperfusion (I/R) injury are unsatisfactory. This study aimed to develop a functional nanoparticle (MM/ANPs) comprising apelin-13 (APNs) encapsulated in macrophage membranes (MM) modified with distearoyl phosphatidylethanolamine-polyethylene glycol-RVG29 (DSPE-PEG-RVG29) to achieve targeted therapy against ischemic stroke.Methods: MM were extracted from RAW264.7. PLGA was dissolved in dichloromethane, while Apelin-13 was dissolved in water, and CY5.5 was dissolved in dichloromethane. The precipitate was washed twice with ultrapure water and then resuspended in 10 mL to obtain an aqueous solution of PLGA nanoparticles. Subsequently, the cell membrane was evenly dispersed homogeneously and mixed with PLGA-COOH at a mass ratio of 1:1 for the hybrid ultrasound. DSPE-PEG-RVG29 was added and incubated for 1 h to obtain MM/ANPs.Results: In this study, we developed a functional nanoparticle delivery system (MM/ANPs) that utilizes macrophage membranes coated with DSPE-PEG-RVG29 peptide to efficiently deliver Apelin-13 to inflammatory areas using ischemic stroke therapy. MM/ANPs effectively cross the blood-brain barrier and selectively accumulate in ischemic and inflamed areas. In a mouse I/R injury model, these nanoparticles significantly improved neurological scores and reduced infarct volume. Apelin-13 is gradually released from the MM/ANPs, inhibiting NLRP3 inflammasome assembly by enhancing sirtuin 3 (SIRT3) activity, which suppresses the inflammatory response and pyroptosis. The positive regulation of SIRT3 further inhibits the NLRP3-mediated inflammation, showing the clinical potential of these nanoparticles for ischemic stroke treatment. The biocompatibility and safety of MM/ANPs were confirmed through in vitro cytotoxicity tests, blood-brain barrier permeability tests, biosafety evaluations, and blood compatibility studies.Conclusion: MM/ANPs offer a highly promising approach to achieve ischemic stroke-targeted therapy inhibiting NLRP3 inflammasome-mediated pyroptosis. Keywords: apelin-13, cerebral ischemia-reperfusion injury, macrophage membrane, ischemic stroke therapy, pyroptosis

Jing Wen,1,2 Liu He,1 Xin Du,1 Chang-Sheng Ma1 1Department of Cardiology, Capital Medical University Affiliated Anzhen Hospital; National Clinical Research Center for Cardiovascular Diseases, Beijing, People’s Republic of China; 2Department of Geriatrics, Beijing Fengtai Hospital, Beijing, People’s Republic of ChinaCorrespondence: Chang-Sheng Ma; Xin Du, Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, No. 2 Beijing Anzhen Road, Chaoyang District, Beijing, 100029, People’s Republic of China, Tel +86-10-84005363, Fax +86-10-84005361, Email chshma@vip.sina.com; duxinheart@sina.comBackground: It is uncertain whether the effect of hyperglycemia on mortality among patients with acute coronary syndrome (ACS) could be adjusted by other modifiable risk factors. Greater body mass index (BMI) might enhance the effect of fasting blood glucose (FPG) on cardiovascular mortality in patients with ACS.Methods: We retrospectively enrolled patients admitted for ACS from 2008 to 2017 in Beijing and divided them into three BMI groups (normal weight ≤ 25 kg/m2, overweight 25– 29.9 kg/m2, obese ≥ 30 kg/m2). The relationships between the blood glucose levels and all-cause or cardiovascular mortalities and their heterogeneities across the groups were analyzed using Cox regression models.Results: A total of 8,086 patients were enrolled, with 746 all-cause and 496 cardiovascular mortalities recorded during the follow-up period. Each 1 mmol/L increase in FPG was associated with an increased risk of all-cause mortality across all groups (adjusted hazard ratio [HR] 1.06, 95% confidence interval [CI] 1.02– 1.09 for normal weight patients; adjusted HR: 1.09, 95% CI: 1.05– 1.13 for overweight patients; adjusted HR: 1.12, 95% CI: 1.03– 1.22 for obese patients), and was associated with an increased risk of cardiovascular mortality among overweight (adjusted HR: 1.10, 95% CI: 1.05– 1.14) and obese patients (adjusted HR: 1.15, 95% CI: 1.04– 1.26), which was greater (p for heterogeneity = 0.006) than the association in the normal weight group (adjusted HR: 1.03, 95% CI: 0.99– 1.08). Similar results were found among 2,537 patients with ACS diagnosed with diabetes.Conclusion: Greater BMI enhances the effect of FPG on cardiovascular mortality among patients with ACS.Keywords: acute coronary syndrome, mortality, fasting plasma glucose, body mass index

Carolyn SJ Ma Department of Pharmacy Practice, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Honolulu, HI, USA Abstract: Oncology pharmacists, also known as oncology pharmacy specialists (OPSs) have specialized knowledge of anticancer medications and their role in cancer. As essential member of the interdisciplinary team, OPSs optimize the benefits of drug therapy, help to minimize toxicities and work with patients on supportive care issues. The OPSs expanded role as experts in drug therapy extends to seven major key elements of medication management that include: selection, procurement, storage, preparation/dispensing, prescribing/dosing/transcribing, administration and monitoring/evaluation/education. As front line caregivers in hospital, ambulatory care, long-term care facilities, and community specialty pharmacies, the OPS also helps patients in areas of supportive care including nausea and vomiting, hematologic support, nutrition and infection control. This role helps the patient in the recovery phase between treatment cycles and adherence to chemotherapy treatment schedules essential for optimal treatment and outcome. Keywords: oncology pharmacist, oncology pharmacy specialist, medication management, chemotherapy

Global warming leads to an increase in extreme heat events, posing significant challenges for insects. Sitobion avenae, Metopolophium dirhodum, and Rhopalosiphum padi are important co-existing aphid species known to cause damage to cereal crops worldwide. The three species differ in thermal tolerance, with R. padi being much more heat tolerant than the other two species. However, it remains unclear whether interspecific variation in heat tolerance is due to differences in metabolic responses to heat stress. Here, we compared their metabolic signatures during and after recovery from the same injury level of heat stress (at 34°C for half and full durations to cause 50% mortality in each species), as well as the identical duration of heat stress. Using quantitative GC-MS, we found that after the same injury level of heat exposure, the three species showed similar changes in most metabolites. However, the heat-tolerant species, R. padi, had higher levels of polyols and amino acids, and uniquely accumulated glycerol. In addition, after the same duration of heat exposure, R. padi maintained a relatively stable metabolic profile, while the less tolerant species showed marked alterations with shift from aerobic to anaerobic metabolism. We suggest that polyols and amino acids play a pivotal role in protecting R. padi from heat damage, conferring its superior thermal tolerance. Overall, this comparative metabolomics study provides insight into the relationship between metabolic responses and heat tolerance of co-existing species, which helps to understand the underlying mechanism of heat tolerance., (© 2025. Published by The Company of Biologists.)

Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.

Infants with biallelic IL7R loss-of-function variants have severe combined immune deficiency (SCID) characterized by the absence of autologous T lymphocytes, but normal counts of circulating B and NK cells (T-B+NK+ SCID). We report 6 adults (aged 22 to 59 years) from 4 kindreds and 3 ancestries (Colombian, Israeli Arab, Japanese) carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency (CID). Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and innate lymphoid cells. By contrast, the patients had profound T cell lymphopenia, with low proportions of innate-like adaptive mucosal-associated invariant T and invariant NK T cells. They also had low blood counts of T cell receptor (TCR) excision circles, recent thymic emigrant T cells and naive CD4+ T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output. The proportions of effector memory CD4+ and CD8+ T cells were high, indicating IL-7-independent homeostatic T cell proliferation in the periphery. Intriguingly, the proportions of other T cell subsets, including TCRγδ+ T cells and some TCRαβ+ T cell subsets (including Th1, Tfh, and Treg) were little affected. Peripheral CD4+ T cells displayed poor proliferation, but normal cytokine production upon stimulation with mitogens in vitro. Thus, inherited IL-7 deficiency impairs T cell development less severely and in a more subset-specific manner than IL-7R deficiency. These findings suggest that another IL-7R-binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7-independent pathway of human T cell development.

The recent acceleration of industrialization and urbanization has brought significant attention to N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ), an emerging environmental pollutant from tire wear, due to its long-term effects on the environment and organisms. Recent studies suggest that 6-PPDQ can disrupt neurotransmitter synthesis and release, impact receptor function, and alter signaling pathways, potentially causing oxidative stress, inflammation, and apoptosis. This review investigates the potential neurotoxic effects of prolonged 6-PPDQ exposure, the mechanisms underlying its cytotoxicity, and the associated health risks. We emphasize the need for future research, including precise exposure assessments, identification of individual differences, and development of risk assessments and intervention strategies. This article provides a comprehensive overview of 6-PPDQ's behavior, impact, and neurotoxicity in the environment, highlighting key areas and challenges for future research., 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.)

Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette-Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis 1 . Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells 2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette-Guérin disease and tuberculosis 3 . Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents., (© 2024. The Author(s).)

Background: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM)., Methods and Results: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation., Conclusions: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM., Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

Germline activating mutations in STAT3 cause a multi-systemic autoimmune and autoinflammatory condition. By studying a mouse model, Toth et al. (https://doi.org/10.1084/jem.20232091) propose a role for dysregulated IL-22 production by Th17 cells in causing some aspects of immune-mediated skin inflammation in human STAT3 GOF syndrome., (© 2024 Ma and Tangye.)

Background: Stroke and thromboembolism in nonvalvular atrial fibrillation (NVAF) primarily arise from thrombi or sludge in the left atrial appendage (LAA). Comprehensive insight into the characteristics of these formations is essential for effective risk assessment and management., Methods: We conducted a single-center retrospective observational of 176 consecutive NVAF patients with confirmed atrial/appendage thrombus or sludge determined by a pre-ablation transesophageal echocardiogram (TEE) from December 2017 to April 2019. We obtained clinical and echocardiographic characteristics, including left atrial appendage emptying velocity (LAAeV) and filling velocity (LAAfV). Data analysis focused on identifying the morphology and location of thrombus or sludge. Patients were divided into the solid thrombus and sludge groups, and the correlation between clinical and echocardiographic variables and thrombotic status was analyzed., Results: Morphological classification: In total, thrombi were identified in 78 patients, including 71 (40.3%) mass and 7 (4.0%) lamellar, while sludge was noted in 98 (55.7%). Location classification: 92.3% (72/78) of patients had thrombus confined to the LAA; 3.8% (3/78) had both LA and LAA involvement; 2.7% (2/78) had LA, LAA and RAA extended into the RA, the remained 1.2%(1/78) was isolated to RAA. 98.0% (96/98) of patients had sludge confined to the LAA; the remaining 2.0% (2/98) were present in the atrial septal aneurysm, which protrusion of interatrial septum into the RA. The thrombus and sludge groups showed low LAAeV (19.43 ± 9.59 cm/s) or LAAfV (17.40 ± 10.09 cm/s). Only LA dimension ≥ 40 mm was independently associated with the thrombus state in the multivariable model., Conclusion: This cohort study identified rare thrombus morphology and systematically summarized the classification of thrombus morphology. The distribution of thrombus and sludge outside limited to LAA was updated, including bilateral atrial and appendage involvement and rare atrial septal aneurysm sludge. LAAeV and LAAfV were of limited value in distinguishing solid thrombus from sludge., Clinical Trial Number: ChiCTR-OCH-13,003,729., (© 2024. The Author(s).)

Background: Atrial fibrillation (AF) can lead to a decline in left atrial appendage (LAA) function, potentially increasing the likelihood of LAA thrombus (LAAT) and spontaneous echo contrast (SEC). Measuring LAA flow velocity through transesophageal echocardiography (TEE) is currently the primary method for evaluating LAA function. This study aims to explore the potential correlation between anterior mitral annular plane systolic excursion (aMAPSE) and LAA stasis in patients with non-valvular atrial fibrillation (NVAF)., Methods: A total of 465 patients with NVAF were enrolled between October 2018 and November 2021. Transthoracic echocardiography (TTE) and TEE were performed before scheduled electrical cardioversion. Propensity score matching (PSM) was used to balance confounders between the groups with and without LAAT/dense SEC., Results: Patients in the LAAT/dense SEC group showed increased left atrial (LA) diameter, LAA area, alongside reduced left ventricular ejection fraction (LVEF), LAA velocity, conjunction thickening ratio, aMAPSE, and LAA fraction area change (FAC) compared to those in the non-LAAT/dense SEC group. Multivariate logistic regression analysis identified aMAPSE and LAA FAC as independent predictors for LAAT/dense SEC. Specifically, an aMAPSE of < 6.76 mm and an LAA FAC of < 29.65% predicted LAAT/dense SEC with high diagnostic accuracy, demonstrated by an area under the curve (AUC) of 0.81 (sensitivity 0.81, specificity 0.80) for aMAPSE, and an AUC of 0.80 (sensitivity 0.70, specificity 0.84) for LAA FAC., Conclusions: Both aMAPSE and LAA FAC independently correlated with and accurately predict LAAT/dense SEC. Incorporating aMAPSE into routine TEE evaluations for LAA function alongside LAA flow velocity is recommended., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Aims: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF., Methods and Results: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m 2 , elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials., Conclusions: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRαβ+CD4-CD8- T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4-CD8- αβ T cells exhibit intact responses to HLA class II-restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei., (© 2024 Guérin et al.)

To study the effect of internal particle size on the microstructure properties and thermal decomposition characteristics of site mixed emulsion explosive at different altitudes. Site mixed emulsion explosive was prepared with different shear rate. The particle size, viscosity, sensitized bubbles, detonation velocity and peak pressure of the emulsion explosive were tested after stored at different simulated altitudes. The thermal decomposition characteristics of emulsion matrix prepared at three different rotational speeds were measured by thermogravimetric analyzer and kinetic analysis was performed by non-isothermal model Kissinger-Akah-Sunose (KAS) method. The results show that with the increase in altitude, the internal phase size showed a trend of first increasing and then decreasing, and the number of sensitized bubbles within the emulsion explosive decreases. At an altitude of 0 m, the detonation velocity and peak overpressure of the emulsion explosive prepared by 1600 r min -1 increased 4.78% and 29.09%, respectively compared with 1200 r min -1 , and at an altitude of 4500 m, the detonation velocity increased 11.87%, the peak overpressure increased 43.98%. The thermal decomposition activation energy of the emulsion matrix at 1600 r min -1 increased 13.14% compared to 1200 r min -1 . It shows that in the production of site mixed emulsion explosive at high altitude, reducing the particle size of the internal phase of emulsion explosives in a certain range can effectively improve the performance of emulsion explosives., (© 2024. The Author(s).)

Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases 1,2 . The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder 3 . Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV 4 . Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit 5,6 . In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation 7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8 + T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, significantly impacting patients' quality of life and increasing the risk of death, stroke, heart failure, and dementia. Over the past two decades, there have been significant breakthroughs in AF risk prediction and screening, stroke prevention, rhythm control, catheter ablation, and integrated management. During this period, the scale, quality, and experience of AF management in China have greatly improved, providing a solid foundation for the development of guidelines for the diagnosis and management of AF. To further promote standardized AF management, and apply new technologies and concepts to clinical practice in a timely and comprehensive manner, the Chinese Society of Cardiology of the Chinese Medical Association and the Heart Rhythm Committee of the Chinese Society of Biomedical Engineering have jointly developed the Chinese Guidelines for the Diagnosis and Management of Atrial Fibrillation . The guidelines have comprehensively elaborated on various aspects of AF management and proposed the CHA 2 DS 2 -VASc-60 stroke risk score based on the characteristics of AF in the Asian population. The guidelines have also reevaluated the clinical application of AF screening, emphasized the significance of early rhythm control, and highlighted the central role of catheter ablation in rhythm control., Competing Interests: None., (© 2024 JGC All rights reserved; www.jgc301.com.)

Introduction: Mild cognitive impairment (MCI) is an important intervenable stage for the prevention of dementia. Hypertension is associated with impaired cognition, and when combined with MCI, it may lead to a poor prognosis. Digital computerised cognitive training (CCT) has recently become a potential instrument for improving cognition, but evidence for its efficacy remains limited. This study aims to evaluate the efficacy of a digital adaptive CCT intervention in older patients with hypertension and MCI., Methods and Analysis: The multicentre, double-blinded, randomised, actively -controlled clinical trial will recruit 200 older (≥60 years) patients with hypertension and MCI from 11 hospitals across China. Participants will be randomly assigned in a 1:1 ratio to the intervention group (multidomain adaptative CCT) and active control group (non-adaptive cognitive training) for 12-week cognitive training for 30 min/day and 5 days/week. Those who have completed their 12-week training in the intervention group will be rerandomised into the continuation and discontinuation training groups. All participants will be followed up to 24 weeks. Neuropsychological assessments and structural and functional 7.0 T MRI will be obtained at baseline and at 12-week and 24-week follow-up. The primary outcome is the possible improvement of global cognitive function at 12 weeks, as measured by the Basic Cognitive Aptitude Tests. Secondary and exploratory endpoints include the major cognitive domain function improvement, self-efficacy, mental health, quality of life and MRI measurements of the brain., Ethics and Dissemination: The trial has been approved by the institutional review board of Beijing Anzhen Hospital and thereafter by all other participating centres. Trial findings will be disseminated in peer-reviewed journals and conference presentations., Trial Registration Number: NCT05704270., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The incorporation of mechanically interlocked structures into polymer backbones has been shown to confer remarkable functionalities to materials. In this work, a [c2]daisy chain unit based on dibenzo-24-crown-8 is covalently embedded into the backbone of a polymer network, resulting in a synthetic material possessing remarkable shape-memory properties under thermal control. By decoupling the molecular structure into three control groups, we demonstrate the essential role of the [c2]daisy chain crosslinks in driving the shape memory function. The mechanically interlocked topology is found to be an essential element for the increase of glass transition temperature and consequent gain of shape memory function. The supramolecular host-guest interactions within the [c2]daisy chain topology not only ensure robust mechanical strength and good network stability of the polymer, but also impart the shape memory polymer with remarkable shape recovery properties and fatigue resistance ability. The incorporation of the [c2]daisy chain unit as a building block has the potential to lay the groundwork for the development of a wide range of shape-memory polymer materials., (© 2024. The Author(s).)

Objective: To analyze the clinical characteristics of patients with common cardiovascular diseases (CVD, including hypertension, coronary heart disease, atrial fibrillation, and heart failure) combined with mild cognitive impairment (MCI) and explore the potential risk factors of MCI in patients with CVD. Methods: A total of 2 294 patients with common cardiovascular diseases who met the criteria at Cardiology Medical Center in Beijing Anzhen Hospital, Capital Medical University, from June 1, 2021, to January 5, 2022, were retrospectively included. The patients were divided into the normal cognitive function group (1 107 cases) and the MCI group (1 187 cases). Demographic information and CVD status were collected. The information of cognitive function were collected using the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) scales. The difference between normal cognitive function and MCI were compared and analyzed. The logistic regression analysis was used to explored risk factors of MCI in CVD patients. Results: A total of 2 294 patients aged (60.6±10.4) years were included, among whom there were 29.99% (688 cases) females. Compared with patients in the normal cognitive function group, patients in the MCI group were older [ (57.9±11.4) vs (63.1±8.9) years old, P <0.001], with a higher proportion of women [26.47% (293 cases) vs 33.28% (395 cases), P <0.001]; there was a higher proportion of patients suffering from hypertension in the MCI group [59.62% (660 cases) vs 64.62% (767 cases), P =0.014］, and more components of CVD [(1.68±0.62) vs (1.74±0.65) components, P =0.017]. The risk factors of MCI in patients with common CVD were increased age, increased depression score, combined with hypertension, and ≥3 common components of CVD, with OR (95% CI ) of 1.043 (1.032-1.054), 1.021 (1.004-1.037), 1.151 (1.142-3.439), and 1.137 (1.023-1.797), respectively (all P values <0.05). Increasing education level was observed to be associated with reduced risk of MCI with OR (95% CI ) of 0.319 (0.271-0.378) ( P <0.05). Conclusions: The incidence of MCI was high in CVD patients. The risk factors of MCI in CVD patients included hypertension and≥3 common components of CVD.

Patients with obstructive hypertrophic cardiomyopathy (oHCM) have increased risk of arrhythmia, stroke, heart failure, and sudden death. Contemporary management of oHCM has decreased annual hospitalization and mortality rates, yet patients have worsening health-related quality of life due to impaired exercise capacity and persistent residual symptoms. Here we consider the design of clinical trials evaluating potential oHCM therapies in the context of SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). This large, phase 3 trial is now fully enrolled (N = 282). Baseline characteristics reflect an ethnically diverse population with characteristics typical of patients encountered clinically with substantial functional and symptom burden. The study will assess the effect of aficamten vs placebo, in addition to standard-of-care medications, on functional capacity and symptoms over 24 weeks. Future clinical trials could model the approach in SEQUOIA-HCM to evaluate the effect of potential therapies on the burden of oHCM. (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM [SEQUOIA-HCM]; NCT05186818)., Competing Interests: Funding Support and Author Disclosures The SEQUOIA-HCM trial is funded by Cytokinetics, Incorporated. Representatives of Cytokinetics have been involved in the design and conduct of the study reported in this manuscript. Dr Coats has received speaker fees from Alnylam and Roche, and advisory fees from Cytokinetics. Dr Maron has received consultant/advisor fees from Imbria and Takeda, and Steering Committee fees for SEQUOIA-HCM from Cytokinetics, Incorporated. Dr Olivotto has received Speakers Bureau fees from Boston Scientific, Amicus, and Novartis; consultant/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Tenaya, and Rocket Pharma; and research grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, and Boston Scientific. Dr Lee has received research grants to his institution from AstraZeneca and Boehringer Ingelheim, and Clinical Endpoint Committee fees from Bayer. Dr Arad has received consultant and lecture fees from Bristol Myers Squibb. Dr Cardim is on the advisory boards for Bristol Myers Squibb and Cytokinetics. Dr Düngen has received grants from Novartis, CSL Behring, and Cytokinetics. Dr Garcia-Pavia has received Speakers Bureau fees from Pfizer, AstraZeneca, NovoNordisk, Bristol Myers Squibb, BridgeBio, Ionis, and Alnylam; consultant/advisor fees from Pfizer, Alnylam, MyoKardia/Bristol Myers Squibb, Cytokinetics, Neurimmune, BridgeBio, Attralus, Intellia, Rocket Pharma, Lexeo Therapeutics, and AstraZeneca; and research/educational grants to his institution from Pfizer, BridgeBio, NovoNordisk, AstraZeneca, and Alnylam. Dr Hagège has received consultant/advisor fees from Alnylam, Amicus Therapeutics, Bayer, MyoKardia/Bristol Myers Squibb, Pfizer, and Sanofi Genzyme; and Steering Committee fees for SEQUOIA-HCM from Cytokinetics, Incorporated. Dr Lewis has received research funding from the National Institutes of Health (R01-HL 151841, R01-HL131029, and R01-HL159514), American Heart Association (15GPSGC-24800006), Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, and SoniVie; honoraria for advisory boards from Pfizer, Merck, Boehringer Ingelheim, Novartis, American Regent, Cyclerion, Cytokinetics, and Amgen; and royalties from UpToDate for scientific content authorship related to exercise physiology. Dr Michels’ institution has received a research grant from Bristol Myers Squibb. Dr Michels has received consultant/advisor fees from Cytokinetics and Bristol Myers Squibb/Myokardia; and Speakers Bureau fees from Bristol Myers Squibb and Pfizer. Dr Oreziak has received investigator fees from Bristol Myers Squibb/MyoKardia; consultant/advisor fees from Biotronik Polska, Abbott Polska; and traveling fees from Hammermed. Dr Owens has received consultant/advisor fees from Cytokinetics, Bristol Myers Squibb/MyoKardia, and Pfizer. Dr Tfelt-Hansen is a consultant for Leo Pharma, MicroPort, and Johnson and Johnson. Dr Watkins has received consultant/advisor fees from Cytokinetics, BioMarin, and BridgeBio. Dr Heitner, Dr Jacoby, Dr Kupfer, Dr Malik, Dr Meng, and Ms Wohltman are employees of Cytokinetics, Incorporated and hold stock in Cytokinetics, Incorporated. Dr Masri has received consultant/advisor fees from Tenaya, Attralus, Cytokinetics, Bristol Myers Squibb, Eidos, Pfizer, Lexicon, Alnylam, Haya, Intellia, and Ionis; and research grants from Ionis, Akcea, Pfizer, Cytokinetics, Ultromics, and the Wheeler Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with atrial fibrillation (AF) and prior stroke history have a high risk of cardiovascular events despite anticoagulation therapy. It is unclear whether catheter ablation (CA) has further benefits in these patients., Methods: AF patients with a previous history of stroke or systemic embolism (SE) from the prospective Chinese Atrial Fibrillation Registry study between August 2011 and December 2020 were included in the analysis. Patients were matched in a 1:1 ratio to CA or medical treatment (MT) based on propensity score. The primary outcome was a composite of all-cause death or ischemic stroke (IS)/SE., Results: During a total of 4.1 ± 2.3 years of follow-up, the primary outcome occurred in 111 patients in the CA group (3.3 per 100 person-years) and in 229 patients in the MT group (5.7 per 100 person-years). The CA group had a lower risk of the primary outcome compared to the MT group [hazard ratio (HR) = 0.59, 95% CI: 0.47-0.74, P < 0.001]. There was a significant decreasing risk of all-cause mortality (HR = 0.43, 95% CI: 0.31-0.61, P < 0.001), IS/SE (HR = 0.73, 95% CI: 0.54-0.97, P = 0.033), cardiovascular mortality (HR = 0.32, 95% CI: 0.19-0.54, P < 0.001) and AF recurrence (HR = 0.33, 95% CI: 0.30-0.37, P < 0.001) in the CA group compared to that in the MT group. Sensitivity analysis generated consistent results when adjusting for time-dependent usage of anticoagulants., Conclusions: In AF patients with a prior stroke history, CA was associated with a lower combined risk of all-cause death or IS/SE. Further clinical trials are warranted to confirm the benefits of CA in these patients., (© 2023 JGC All rights reserved; www.jgc301.com.)

Aims: The clinical correlates and outcomes of asymptomatic atrial fibrillation (AF) in hospitalized patients are largely unknown. We aimed to investigate the clinical correlates and in-hospital outcomes of asymptomatic AF in hospitalized Chinese patients., Methods and Results: We conducted a cross-sectional registry study of inpatients with AF enrolled in the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation Project between February 2015 and December 2019. We investigated the clinical characteristics of asymptomatic AF and the association between the clinical correlates and the in-hospital outcomes of asymptomatic AF. Asymptomatic and symptomatic AF were defined according to the European Heart Rhythm Association score. Asymptomatic patients were more commonly males (56.3%) and had more comorbidities such as hypertension (57.4%), diabetes mellitus (18.6%), peripheral artery disease (PAD; 2.3%), coronary artery disease (55.5%), previous history of stroke/transient ischaemic attack (TIA; 17.9%), and myocardial infarction (MI; 5.4%); however, they had less prevalent heart failure (9.6%) or left ventricular ejection fractions ≤40% (7.3%). Asymptomatic patients were more often hospitalized with a non-AF diagnosis as the main diagnosis and were more commonly first diagnosed with AF (23.9%) and long-standing persistent/permanent AF (17.0%). The independent determinants of asymptomatic presentation were male sex, long-standing persistent AF/permanent AF, previous history of stroke/TIA, MI, PAD, and previous treatment with anti-platelet drugs. The incidence of in-hospital clinical events such as all-cause death, ischaemic stroke/TIA, and acute coronary syndrome (ACS) was higher in asymptomatic patients than in symptomatic patients, and asymptomatic clinical status was an independent risk factor for in-hospital all-cause death, ischaemic stroke/TIA, and ACS., Conclusion: Asymptomatic AF is common among hospitalized patients with AF. Asymptomatic clinical status is associated with male sex, comorbidities, and a higher risk of in-hospital outcomes. The adoption of effective management strategies for patients with AF should not be solely based on clinical symptoms., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: This study aims to provide representative information on heart failure (HF) patients in China, especially older adults aged ≥75 years. We aim to clarify the age-related discrepancies in performance measures and the modifying effect of age on the impact of HF patients' characteristics on clinical outcomes., Methods and Results: All HF patients admitted into five tertiary and four secondary hospitals of the Capital Medical University were divided into two groups according to age: 1419 (53.3%) were <75 years, and 1244 (46.7%) were ≥75 years. Older HF patients were more likely to be women, with higher left ventricular ejection fraction, with co-morbidities including chronic obstructive pulmonary disease/asthma, anaemia, chronic kidney disease, stroke/transient ischemic attack (TIA), atrial fibrillation/atrial flutter, hypertension, and coronary artery disease, while obesity, diabetes mellitus, hypercholesterolaemia and valvular heart disease were more prevalent among younger HF patients. Left ventricular ejection fraction assessment was performed in a similar proportion of patients in the younger and older groups (81.7% vs. 80.5%, P = 0.426), while B-type natriuretic peptide/N terminal pro brain natriuretic peptide was tested in a lower proportion in the younger group (84.8% vs. 89%, P = 0.001). At discharge, HF with reduced ejection fraction patients were less likely to receive beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, or combined beta-blockers and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers therapy in the older group (49.74% vs. 63.2%, P = 0.002; 52.9% vs. 64.7%, P = 0.006; and 28.57% vs. 45.5%, P < 0.001, respectively) but were equally likely to receive mineralocorticoid receptor antagonists in the two age groups (80.8% vs. 84.1%, P = 0.322). Older patients with HF had higher risk of in-hospital and 1 year mortality (2.7% vs. 1.3%, P = 0.011; 21.7% vs. 12.5%; P < 0.001, respectively). Higher body mass index was associated with better outcomes in both age groups. New York Heart Association functional class IV and estimated glomerular filtration rate < 60 mL/min/1.73 m 2 were independent predictors of 1 year mortality. The associations between patients' characteristics and risk of mortality were not modified by age., Conclusions: HF patients aged ≥75 years had distinct clinical profiles, received worse in-hospital therapies and experienced higher in-hospital and 1 year mortality., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Data on the performance of risk scores in predicting mortality risk after atrial fibrillation (AF) ablations are limited., Objectives: The purpose of this study was to investigate the associations of mortality with preablation biomarkers and evaluate the performance of age, biomarker, and clinical history (ABC)-death score in patients with AF undergoing catheter ablation., Methods: Patients with AF undergoing catheter ablations between 2013 and 2019 in the Chinese Atrial Fibrillation Registry were enrolled. Biomarkers associated with ABC-death score were quantified from baseline blood samples collected before AF ablation. Clinical outcomes were all-cause mortality and cardiac mortality. Discrimination, reclassification, clinical use, and calibration were further evaluated., Results: We identified 4,218 patients with AF undergoing catheter ablations. During a median follow-up period of 4.0 years, 119 patients died due to all causes, with 49 dying due to cardiac causes. Biomarker levels were all independently associated with an increased risk of all-cause death and cardiac death. The ABC-death score was superior to the CHA 2 DS 2 -VASc score in predicting all-cause death (C index 0.73 vs 0.63; P  = 0.001) and cardiac death (C index 0.83 vs 0.71; P  = 0.007). Reclassification analysis revealed significant reclassification improvements of the ABC-death score compared with the CHA 2 DS 2 -VASc (cardiac failure or dysfunction, hypertension, age ≥75 [doubled], diabetes mellitus, stroke [doubled]-vascular disease, age 65 to 74 years and sex category [female]) score. Decision curve analysis showed the greater net benefit of use of the ABC-death score. Calibration plots presented an overestimation of the observed mortality event rate by ABC-death score., Conclusions: Preablation biomarkers associated with ABC-death score were independently related to increased all-cause and cardiac mortality risk. Despite the overestimation of the event rate, the ABC-death score outperformed the CHA 2 DS 2 -VASc score in discriminating and reclassifying mortality risk, especially for cardiac mortality., Competing Interests: This work was funded by the National Key Research and Development Program of China (2017YFC0908800, 2020YFC2004803), the National Natural Science Foundation of China (82100326, 82103904), the Beijing Municipal Science and Technology Commission (D171100006817001), and the Beijing Municipal Education Commission (KM202210025012). The construction of Chinese Atrial Fibrillation Registry was supported by grants from Bristol Myers Squibb, Pfizer, Johnson & Johnson, Boehringer Ingelheim, and Bayer. Roche Diagnostics (Shanghai) Limited supported this study by providing reagents for sample detection. Dr Dong has received lecture fees from Johnson & Johnson. Dr Lip has served as a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo, Dr Ma has received lecture fees and honoraria from Bristol Myers Squibb, Pfizer, Johnson & Johnson, Boehringer Ingelheim, and Bayer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Carbon supported intermetallic compound nanoparticles with high activity and stability are promising cathodic catalysts for oxygen reduction reaction in proton-exchange-membrane fuel cells. However, the synthesis of intermetallic catalysts suffers from large diffusion barrier for atom ordering, resulting in low ordering degree and limited performance. We demonstrate a low-melting-point metal doping strategy for the synthesis of highly ordered L1 0 -type M-doped PtCo (M = Ga, Pb, Sb, Cu) intermetallic catalysts. We find that the ordering degree of the M-doped PtCo catalysts increases with the decrease of melting point of M. Theoretic studies reveal that the low-melting-point metal doping can decrease the energy barrier for atom diffusion. The prepared highly ordered Ga-doped PtCo catalyst exhibits a large mass activity of 1.07 A mg Pt -1 at 0.9 V in H 2 -O 2 fuel cells and a rated power density of 1.05 W cm -2 in H 2 -air fuel cells, with a Pt loading of 0.075 mg Pt  cm -2 ., (© 2023. Springer Nature Limited.)

Objective: To explore the risk factors of anxiety in patients with atrial fibrillation and their caregivers. Methods: From September 2020 to March 2021, patients with atrial fibrillation and one primary family member as caregiver of each patient from Beijing Anzhen Hospital were enrolled. Basic data of patients and their caregivers were collected, and anxiety of patients and caregivers were evaluated by Generalized Anxiety Disorder-7 scale (GAD-7). A total of 374 patients with atrial fibrillation and their caregivers were included in this study. Multivariate logistic regression analysis was used to analyze the risk factors of anxiety of patients and their caregivers. Results: The mean age of the patients was (58.3±10.6) years, and 124 (33.2%) were female. The caregivers were (53.6±11.6) years old, and 247 (66%) were female. 69 (18.4%) patients and 38 (10.2%) caregivers had mild anxiety (GAD-7:5-9 scores), 13 (3.5%) patients and 9 (2.4%) caregivers had moderate or higher anxiety (GAD-7:10-21 scores). Multivariate analysis showed that the risk factors of anxiety in patients with atrial fibrillation included EHRA score≥3 ( OR =1.73,95% CI :1.03-2.89, P =0.039) and female sex ( OR =1.90,95% CI :1.06-3.40, P =0.032). EHRA score of patients≥3 ( OR =2.11,95% CI :1.05-4.24, P =0.036) or anxiety of patients ( OR =2.76,95% CI :1.36-5.60, P= 0.005) were associated with higher anxiety of caregivers. Moreover, age of≥65 years old ( OR =3.97,95% CI :1.68-9.38, P =0.002), female sex ( OR =3.83,95% CI :1.64-8.93, P =0.002) and number of comorbidities of caregivers≥2 ( OR =2.57,95% CI :1.03-6.41, P =0.043) were also associated with anxiety of caregivers. Conclusions: Patients with severe symptoms have a higher proportion of anxiety, and their caregivers are more likely to experience anxiety. Anxiety rate is higher in caregivers of patients with anxiety.

Background: Spontaneous echo contrast (SEC) observed in transesophageal echocardiography (TEE) is a reliable predictor of the risk of future ischemic stroke in patients with non-valvular atrial fibrillation (NVAF). Left atrial strain globally reflects atrial function, remodeling and distensibility. The left atrial appendage (LAA) is a myogenic remnant of the left atrium, which can actively relax and contract. The left atrial appendage (LAA) is an important part of releasing the pressure of the left atrium. The key role of the left atrium is to regulate the left ventricular filling pressure, act as a reservoir for pulmonary venous return during ventricular contraction, and act as a conduit, transferring blood to the Left ventricle during early ventricular diastole. The purpose of this study was to explore the relationship between left atrial function and left atrial appendage spontaneous echo contrast (LAASEC)., Methods: A retrospective study of 338 patients with non-valvular AF was conducted. Two-dimensional speckle-tracking echocardiography provided the following metrics of LA strain: LA strain during the reservoir phase (LASr), LA strain during the conduit phase (LAScd). LA or LAA has the dense SEC of more than grade 3, which is defined as mud like change or pre thrombosis., Results: Patients with level 3 SEC ( n  = 81) has lower LASr than those with lower grades of SEC ( n  = 257) (7.20 ± 3.70 vs. 17.48 ± 8.67, P  < 0.001). Multivariate logistic regression model showed that the type of atrial fibrillation (persistent∼), increased heart rate, decreased LASr were independently associated with the dense LAASEC (OR (CI 95%), 5.558 (1.618-19.09), 1.016 (1.006-1.026) 0.002, 1.224 (1.085-1.381), both P  < 0.01). Venn Diagram showed that lower CHADVASC2 score groups had dense SEC cases. Receiver operating characteristic (ROC) curve was used for analyzing results and selecting cut off values. The cut off point for LASr < 8.85% and CHADVASC2 score was >2 scores with sensitivity and specificity were 79% and 85%., Conclusion: Lower LASr is independently associated with the dense LAASEC in NVAF and has incremental values superior to clinical scores. The decrease of LASr may be a potential non-invasive parameter for evaluating the higher risk of LAA thrombosis., Competing Interests: The 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., (© 2023 Ma, Sun, Wang, Zhou and Dong.)

B cells develop from hematopoietic stem cells in the bone marrow. Once generated, they serve multiple roles in immune regulation and host defense. However, their most important function is producing antibodies (Ab) that efficiently clear invading pathogens. This is achieved by generating memory B cells that rapidly respond to subsequent Ag exposure, and plasma cells (PCs) that continually secrete Ab. These B cell subsets maintain humoral immunity and host protection against recurrent infections for extended periods of time. Thus, the generation of antigen (Ag)-specific memory cells and PCs underlies long-lived serological immunity, contributing to the success of most vaccines. Our understanding of immunity is often derived from animal models. However, analysis of individuals with monogenic defects that disrupt immune cell function are unprecedented models to link genotypes to clinical phenotypes, establish mechanisms of disease pathogenesis, and elucidate critical pathways for immune cell development and differentiation. Here, we review fundamental breakthroughs in unraveling the complexities of humoral immunity in humans that have come from the discovery of inborn errors disrupting B cell function., (© 2023 Tangye et al.)

Background: Evidence on outcomes of catheter ablation (CA) for atrial fibrillation (AF) in patients with autoimmune disease (AD) is limited., Hypothesis: Patients with AD had worse outcomes after CA procedures for AF., Methods: A retrospective analysis was performed in patients undergoing AF ablation between 2012 and 2021. The risk of recurrence after ablation was investigated in patients with AD and a 1:4 propensity score matched non-AD group., Results: We identified 107 patients with AD (64 ± 10 years, female 48.6%) who were matched with 428 non-AD patients (65 ± 10 years, female 43.9%). Patients with AD exhibited more severe AF-related symptoms. During the index procedure, a higher proportion of AD patients received nonpulmonary vein trigger ablation (18.7% vs. 8.4%, p = 0.002). Over a median follow-up of 36.3 months, patients with AD experienced a similar risk of recurrence with the non-AD group (41.1% vs. 36.2%, p = 0.21, hazard ratio [HR]: 1.23, 95% confidence interval [CI]: 0.86-1.76) despite a higher incidence of early recurrences (36.4% vs. 13.5%, p = 0.001). Compared with non-AD patients, patients with connective tissue disease were at an increased risk of recurrence (46.3% vs. 36.2%, p = 0.049, HR: 1.43, 95% CI: 1.00-2.05). Multivariate Cox regression analysis showed that the duration of AF history and corticosteroid therapy were independent predictors of postablation recurrence in patients with AD., Conclusions: In patients with AD, the risk of recurrence after ablation for AF during the follow-up was comparable with non-AD patients, but a higher risk of early recurrence was observed. Further research into the impact of AD on AF treatment is warranted., (© 2023 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Heterozygous loss-of-function (LOF) mutations in PIK3R1 (encoding phosphatidylinositol 3-kinase [PI3K] regulatory subunits) cause activated PI3Kδ syndrome 2 (APDS2), which has a similar clinical profile to APDS1, caused by heterozygous gain-of-function (GOF) mutations in PIK3CD (encoding the PI3K p110δ catalytic subunit). While several studies have established how PIK3CD GOF leads to immune dysregulation, less is known about how PIK3R1 LOF mutations alter cellular function. By studying a novel CRISPR/Cas9 mouse model and patients' immune cells, we determined how PIK3R1 LOF alters cellular function. We observed some overlap in cellular defects in APDS1 and APDS2, including decreased intrinsic B cell class switching and defective Tfh cell function. However, we also identified unique APDS2 phenotypes including defective expansion and affinity maturation of Pik3r1 LOF B cells following immunization, and decreased survival of Pik3r1 LOF pups. Further, we observed clear differences in the way Pik3r1 LOF and Pik3cd GOF altered signaling. Together these results demonstrate crucial differences between these two genetic etiologies., (© 2023 Nguyen et al.)