Meta-lasso: new insight on infection prediction after minimally invasive surgery.

Surgical site infection (SSI) after minimally invasive lung cancer surgery constitutes an important factor influencing the direct and indirect economic implications, patient prognosis, and the 5-year survival rate for early-stage lung cancer patients. In the realm of predictive healthcare, machine learning algorithms have been instrumental in anticipating various surgical outcomes, including SSI. However, accurately predicting infection after minimally invasive surgery remains a clinical challenge due to the multitude of physiological and surgical factors associated with it. Furthermore, clinical patient data, in addition to being high-dimensional, often exists the long-tail problem, posing difficulties for traditional machine learning algorithms in effectively processing such data. Based on this insight, we propose a novel approach called meta-lasso for infection prediction following minimally invasive surgery. Our approach leverages the sparse learning algorithm lasso regression to select informative features and introduces a meta-learning framework to mitigate bias towards the dominant class. We conducted a retrospective cohort study on patients who had undergone minimally invasive surgery for lung cancer at Shanghai Chest Hospital between 2018 and 2020. The evaluation encompassed key performance metrics, including sensitivity, specificity, precision (PPV), negative predictive value (NPV), and accuracy. Our approach has surpassed the performance of logistic regression, random forest, Naive Bayes classifier, gradient boosting decision tree, ANN, and lasso regression, with sensitivity at 0.798, specificity at 0.779, precision at 0.789, NPV at 0.798, and accuracy at 0.788 and has greatly improved the classification performance of the inferior class.

Comparing the influence of big data resources on medical knowledge recall for staff with and without medical collaboration platform.

BACKGROUND: This study aims to examine how big data resources affect the recall of prior medical knowledge by healthcare professionals, and how this differs in environments with and without remote consultation platforms. METHOD: This study investigated two distinct categories of medical institutions, namely 132 medical institutions with platforms, and 176 medical institutions without the platforms. Big data resources are categorized into two levels-medical institutional level and public level-and three types, namely data, technology, and services. The data are analyzed using SmartPLS2. RESULTS: (1) In both scenarios, shared big data resources at the public level have a significant direct impact on the recall of prior medical knowledge. However, there is a significant difference in the direct impact of big data resources at the institutional level in both scenarios. (2) In institutions with platforms, for the three big data resources (the medical big data assets and big data deployment technical capacity at the medical institutional level, and policies of medical big data at the public level) without direct impacts, there exist three indirect pathways. (3) In institutions without platforms, for the two big data resources (the service capability and big data technical capacity at the medical institutional level) without direct impacts, there exist three indirect pathways. CONCLUSIONS: The different interactions between big data, technology, and services, as well as between different levels of big data resources, affect the way clinical doctors recall relevant medical knowledge. These interaction patterns vary between institutions with and without platforms. This study provides a reference for governments and institutions to design big data environments for improving clinical capabilities.

Particle filter-based parameter estimation algorithm for prognostic risk assessment of progression in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a malignant tumor that threatens human life and health. The development of a new NSCLC risk assessment model based on electronic medical records has great potential for reducing the risk of cancer recurrence. In this process, machine learning is a powerful method for automatically extracting risk factors and indicating impact weights for NSCLC deaths. However, when the number of samples reaches a certain value, it is difficult for machine learning to improve the prediction accuracy, and it is also challenging to use the characteristic data of subsequent patients effectively. Therefore, this study aimed to build a postoperative survival risk assessment model for patients with NSCLC that updates the model parameters and improves model accuracy based on new patient data. The model perspective was a combination of particle filtering and parameter estimation. To demonstrate the feasibility and further evaluate the performance of our approach, we performed an empirical analysis experiment. The study showed that our method achieved an overall accuracy of 92% and a recall of 71% for deceased patients. Compared with traditional machine learning models, the accuracy of the model estimated by particle filter parameters has been improved by 2%, and the recall rate for dead patients has been improved by 11%. Additionally, this study outcome shows that this method can better utilize subsequent patients' characteristic data, be more relevant to different patients, and help achieve precision medicine.

Resynchronization effects and clinical outcomes during left bundle branch area pacing with and without conduction system capture.

BACKGROUND: Left bundle branch area pacing (LBBAP) includes left bundle branch pacing (LBBP) and left ventricular (LV) septal myocardial pacing (LVSP). HYPOTHESIS: The study aimed to assess resynchronization effects and clinical outcomes by LBBAP in heart failure (HF) patients with cardiac resynchronization therapy (CRT) indications. METHODS: LBBAP was successfully performed in 29 consecutive patients and further classified as the LBBP-group (N = 15) and LVSP-group (N = 14) based on the LBBP criteria and novel LV conduction time measurement (LV CT, between LBBAP site and LV pacing (LVP) site). AV-interval optimized LBBP or LVSP, or LVSP combined with LVP (LVSP-LVP) was applied. LV electrical and mechanical synchrony and clinical outcomes were assessed. RESULTS: All 15 patients in the LBBP-group received optimized LBBP while 14 patients in the LVSP-group received either optimized LVSP (5) or LVSP-LVP (9). The LV CT during LBBP was significantly faster than that during LVP (p < .001), while LV CT during LVSP were similar to LVP (p = .226). The stimulus to peak LV activation time (Stim-LVAT, 71.2 ± 8.3 ms) and LV mechanical synchrony (TSI-SD, 35.3 ± 9.5 ms) during LBBP were significantly shorter than those during LVSP (Stim-LVAT 89.1 ± 19.5 ms, TSI-SD 49.8 ± 14.4 ms, both p < .05). Following 17(IQR 8) months of follow-up, the improvement of LVEF (26.0%(IQR 16.0)) in the LBBP-group was significantly greater than that in the LVSP-group (6.0%(IQR 20.8), p = .001). CONCLUSIONS: LV activation in LBBP propagated significantly faster than that of LVSP. LBBP generated superior electrical and mechanical resynchronization and better LVEF improvement over LVSP in HF patients with CRT indications.

T-Cell Mineralocorticoid Receptor Deficiency Attenuates Pathologic Ventricular Remodelling After Myocardial Infarction.

BACKGROUND: Mineralocorticoid receptor (MR) antagonists have been widely used to treat heart failure (HF). Studies have shown that MR in T cells plays important roles in hypertension and myocardial hypertrophy. However, the function of T-cell MR in myocardial infarction (MI) has not been elucidated. METHODS: In this study, we used T-cell MR knockout (TMRKO) mouse to investigate the effects of T-cell MR deficiency on MI and to explore the underlying mechanisms. Echocardiography and tissue staining were used to assess cardiac function, fibrosis, and myocardial apoptosis after MI. Flow cytometry and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect immune cell infiltration and inflammation. RESULTS: T-cell MR deficiency significantly improved cardiac function, promoted myocardial repair, and inhibited myocardial apoptosis, fibrosis, and inflammation after MI. Luminex assays revealed that TMRKO mice had significantly lower levels of interferon-gamma (IFN-γ) and interleukin-6 (IL-6) in serum and infarcted myocardium than littermate control mice. In cultured splenic T cells, MR deficiency suppressed IL-6 expression, whereas MR overexpression enhanced IL-6 expression. Chromatin immunoprecipitation (ChIP) assay demonstrated that MR bound to the MR response element on the promoter of IL-6 gene. Finally, T-cell MR deficiency significantly suppressed accumulation of macrophages in infarcted myocardium and differentiation of proinflammatory macrophages, thereby alleviating the consequences of MI. CONCLUSIONS: T-cell MR deficiency improved pathologic ventricular remodelling after MI, likely through inhibition of accumulation and differentiation of proinflammatory macrophages. At the molecular level, MR may work through IFN-γ and IL-6 in T cells to exert functions in MI.

Noninvasive evaluation of pulmonary hypertension using the second heart sound parameters collected by a mobile cardiac acoustic monitoring system.

Background: Pulmonary hypertension (PH) is linked to higher rates of morbidity and mortality worldwide. Early diagnosis of PH is important for clinical treatment. The estimated pulmonary artery systolic pressure (ePASP ≥ 35 mmHg) measured by echocardiography helps screen PH patients. In this paper, we report a novel PH screening method through a mobile cardiac acoustic monitoring system. Methods: In the retrospective study, patients admitted to our hospital between January 2022 and April 2023 were classified into PH and control groups using ePASP and compared with acoustic cardiographic parameters. According to ePASP, PH severity was classified as mild, moderate, and severe. We analyzed the first and second heart sound (S1, S2) characteristics, including amplitude (S1A, S2A), energy (S1E, S2E), and frequency (S1F, S2F). Results: The study included 209 subjects, divided into PH (n = 121) and control (n = 88) groups. Pearson correlation analysis confirmed the positive correlation between S2F and ePASP. The diagnostic performance of S2F as assessed by the area under the ROC curve was 0.775 for PH. The sensitivity and specificity of diagnosing ePASP ≥ 35 mmHg when S2F ≥ 36 Hz were found to be 79.34% and 67.05%, respectively, according to ROC analysis. Severity classification was performed using S2F, the area under the ROC curve was 0.712-0.838 for mild PH, 0.774-0.888 for moderate PH, and 0.826-0.940 for severe PH. Conclusions: S2F collected by the mobile cardiac acoustic monitoring system offers a convenient method for remote PH screening, potentially improving PH management and outcomes.

Thrombus-specific/responsive biomimetic nanomedicine for spatiotemporal thrombolysis and alleviation of myocardial ischemia/reperfusion injury.

Acute myocardial infarction (AMI) is usually caused by coronary thrombosis. However, the short half-life, lack of targetability and inevitable ischemia/reperfusion injury secondary to revascularization, which characterizes tissue plasminogen activator (tPA) limit its thrombolytic efficacy for AMI. To address the targeted and site-specific delivery of tPA, the current study reports the construction of a thrombus-targeting and responsive biomimetic nanoparticle (PTPN) for spatiotemporal treatment of AMI. PTPN was constituted by the thrombus microenvironment- responsive phenylboronic acid (PBA) nanocarrier, antioxidant molecular protocatechualdehyde (PC) and tPA with thrombolytic effect, which were enclosed by the platelet membrane. The thrombus-targeting capability of the platelet membrane enabled the adhesion of PTPN to damaged endothelial cells. The nanoparticle disintegrated under slightly acid condition and re-opened the infarct-related artery during the period of ischemia. Sequentially, ROS induced by blood reperfusion was eliminated by PC released from particle disintegration, and the cardiomyocyte mitochondrial function was protected from reperfusion injury. Therefore, this thrombus-specific/responsive biomimetic nanomedicine provides a spatiotemporal paradigm for AMI treatment with promising clinical translation prospects.

Reporter Molecules Embedded Au@Ag Core-Shell Nanospheres as SERS Nanotags for Cardiac Troponin I Detection.

Rapid and accurate detection of acute myocardial infarction can improve patients' chances of survival. Cardiac troponin I (cTn I) is an important diagnostic biomarker for acute myocardial infarction. However, current immunoassays are insufficient to accurately measure cTn I, as they have limited detection sensitivity and are time-consuming. Surface-enhanced Raman scattering (SERS) is a brilliant fingerprints diagnostic technique characterised by ultrasensitivity, fast response, and qualitative and quantitative analysis capabilities. In this study, reporter molecules (4-Mercaptobenzoic acid, 4-MBA) embedded Au@Ag core-shell nanospheres as SERS nanotags were prepared for the detection of cTn I. As the Raman reporters were embedded between the core and the shell, they could be protected from the external environment and nanoparticle aggregation. Excellent SERS performances were obtained due to the enhanced local electromagnetic field in the gap of core and shell metals. In a standard phosphate buffered saline (PBS) environment, the limit of detection for cTn I was 0.0086 ng mL-1 (8.6 ppt) with a good linear relationship. The excellent Raman detection performance was attributed to the localized surface plasmon resonance effect and strong electromagnetic field enhancement effect produced by the gap between the Au core and the Ag shell. The SERS nanotags we prepared were facile to synthesize, and the analysis procedure could be completed quickly (15 min), which made the detection of cTn I faster. Therefore, the proposed SERS nanotags have significant potential to be a faster and more accurate tool for acute myocardial infarction diagnostics.

Development of a Nomogram for Predicting Surgical Site Infection in Patients with Resected Lung Neoplasm Undergoing Minimally Invasive Surgery.

Background: Predictive models are necessary to target high-risk populations and provide precision interventions for patients with lung neoplasm who suffer from surgical site infections (SSI). Patients and Methods: This case control study included patients with lung neoplasm who underwent minimally invasive surgeries (MIS). Logistic regression was used to generate the prediction model of SSI, and a nomogram was created. A receiver operator characteristic (ROC) curve was used to examine the predictive value of the model. Results: A total of 151 patients with SSI were included, and 604 patients were randomly selected among the patients without SSI (ratio 4:1). Male gender (odds ratio [OR], 2.55; 95% confidence interval [CI], 1.57-4.15; p < 0.001), age >60 years (OR, 2.10; 95% CI, 1.29-3.44, p = 0.003), operation time >60 minutes (all categories, p < 0.05), treatments for diabetes mellitus (OR, 2.96; 95% CI, 1.75-4.98l; p < 0.001), and best forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC; OR, 0.96; 95% CI, 0.94-0.99; p = 0.008) were independently associated with SSI. The model based on these variables showed an area under the curve (AUC) of 0.813 for predicting SSI. Conclusions: A nomogram predictive model was successfully established for predicting SSI in patients receiving MIS, with good predictive value.

Polydopamine stabilizes silver nanoparticles as a SERS substrate for efficient detection of myocardial infarction.

Rapid and accurate detection of myocardial infarction (MI) can boost the patient's chance of survival. Surface enhanced Raman scattering (SERS) is an outstanding diagnostic technique because of its strong light stability, high resolution, and qualitative and quantitative analysis based on the characteristic fingerprint. However, its reliability, stability and specificity remain to be improved, especially in the quantitative analysis of serum samples. In this study, we developed in situ silver nanoparticles (Ag NPs) on the surface of polydopamine (PDA) as a SERS substrate and found that PDA could act as a reducing agent to support the nucleation and growth of Ag NPs and control the distance and aggregation of Ag NPs to stabilize the Raman signal. In a standard phosphate buffered saline (PBS) environment, PDA@Ag could reach a low detection limit of 0.01 ng mL-1 cardiac troponin I (cTn I) with a good linear relationship. At the same time, the PDA@Ag substrate also possessed excellent stability, specificity and biocompatibility for cTn I detection. In addition, we verified the application potentiality of PDA@Ag in real serum samples and found that the performance of SERS was almost the same as that in PBS. This excellent detection performance of PDA@Ag could be attributed to both the enhanced electromagnetic field and the increased Raman cross-section, dominated by the gap distance between Ag NPs, reaction force between the antigen and the antibody and excellent biocompatibility and reducibility of PDA. In conclusion, this work may provide a new perspective for the in situ synthesis and growth of a uniform SERS substrate on the carrier to achieve the stability and specificity of SERS-based biological detection of MI.

Circular RNA hsa_circ_0008896 accelerates atherosclerosis by promoting the proliferation, migration and invasion of vascular smooth muscle cells via hsa-miR-633/CDC20B (cell division cycle 20B) axis.

Circular RNAs, a class of circularly closed non-coding RNAs, play essential roles in the formation of atherosclerosis, which is a frequent cause of cardiovascular and cerebrovascular diseases. Although many circular RNAs are found to be involved in the progression of atherosclerosis, more circular RNA regulators still need to be identified, to improve the understanding of the regulatory networks of atherosclerosis. Here, we found that hsa_circ_0008896 was significantly up-regulated in both in vitro and in vivo atherosclerosis models, indicating hsa_circ_0008896 was involved in the progression of atherosclerosis. Further functional analyses confirmed that knockdown of hsa_circ_0008896 decreased proliferation, migration, and invasion of VSMCs. In addition, we conducted bioinformatics analysis and found that hsa-miR-633 could directly bind to hsa_circ_0008896, which was confirmed by RNA immune-precipitation (RIP) assays. Results of proliferation, migration, and invasion assays showed that hsa-miR-633 inhibitor reversed the si-circ_0008896 phenotypes, indicating that hsa_circ_0008896 functionally bound to hsa-miR-633. At last, combining bioinformatics and experimental analyses, we found the protein target of hsa_circ_0008896/hsa-miR-633, CDC20B (cell division cycle 20B). The expression level of CDC20B was regulated by hsa-miR-633, and knockdown of CDC20B decreased proliferation, migration, and invasion of VSMCs. Taken together, hsa_circ_0008896 regulated the expression of CDC20B by sponging hsa-miR-633, and then enhanced proliferation, migration, and invasion of VSMCs to promote the progression of atherosclerosis.

Engineered Biomimetic Nanoplatform Protects the Myocardium Against Ischemia/Reperfusion Injury by Inhibiting Pyroptosis.

Protection of cardiomyocytes against oxidative stress is vital to alleviate myocardial ischemia/reperfusion injury (MI/RI). However, antioxidative treatment is hampered by the lack of safe and effective therapeutics. Polydopamine (PDA), as a biodegradable class of nanomaterial with excellent antioxidant properties, has shown great potential in treating MI/RI. To achieve site-specific antioxidative efficacy, we established a PDA-based biomimetic nanoplatform (PDA@M), which consisted of a polydopamine core and a macrophage membrane shell to form a shell-core structure. By inheriting the inherent migration capability of macrophages, PDA@M was able to target the infarcted myocardium and exert an antioxidative effect to protect the myocardium. The results demonstrated that the accumulation of the membrane-wrapped nanoparticles (NPs) in the infarcted myocardium was greatly increased as compared with PDA alone, which effectively relieved the MI/RI-induced oxidative stress. PDA@M largely decreased the infarct size and improved the cardiac function post-MI/RI. Our study revealed that PDA@M could inhibit cell pyroptosis by suppressing the NLRP3/caspase-1 pathway, which is known to play a significant role in the antioxidant signaling pathway. In summary, PDA@M can target the infarcted myocardium and exert antioxidative and antipyroptosis functions to protect the myocardium against MI/RI-induced oxidative stress, suggesting that it may prove to be a potential therapeutic agent for MI/RI.

CYP2C19 and ABCB1 genetic polymorphisms correlate with the recurrence of ischemic cardiovascular adverse events after clopidogrel treatment.

BACKGROUND: This study was aimed to investigate the correlation between CYP2C19 and ABCB1 polymorphisms and the recurrence of ischemic cardiovascular adverse events in patients with coronary artery disease treated with clopidogrel. METHODS: A total of 168 patients with coronary heart disease who underwent PCI operation and received clopidogrel treatment were enrolled. Dual antiplatelet therapy was applied to the treatment of patients for 2 years. Thromboelastography was used to test the efficiency of blood coagulation. Polymerase chain reaction (PCR) was used to detect CYP2C19 and ABCB1 3435CT polymorphisms. One-year follow-up visit was carried out to record the incidence of cardiovascular adverse events after drug-eluting stent implantation was inset. RESULTS: Follow-up visit results suggested that the patients with high on-treatment platelet reactivity (HPR) had a higher recurrence rate of cardiovascular adverse events after PCI operation and clopidogrel treatment. Gene polymorphism testing results indicated that patients with CYP2C19*3 had a significantly higher incidence of HPR, whereas CYP2C19*2 and ABCB1 3435CT were not significantly correlated with HPR. Multivariable logistic regression analysis showed that CYP2C19*3 might be an independent predictive factor of post-PCI HPR. In addition, CYP2C19*3 as well as post-PCI HPR could function as independent predictive factors of cardiovascular adverse events. CONCLUSION: CYP2C19*3 polymorphism could be an important predictive factor of HPR and ischemic cardiovascular adverse events after clopidogrel treatment.

AMPK/NF-κB signaling pathway regulated by ghrelin participates in the regulation of HUVEC and THP1 Inflammation.

Endothelial inflammation and monocyte plays an essential role in the initiation and progression of atherosclerosis. Ghrelin is beneficial for atherosclerosis progression. However, the detailed and precise molecular mechanisms of how ghrelin regulates endothelial inflammation are not clear. In this study, we investigated the regulation mechanism of ghrelin on TNF-α-activated endothelial inflammation and monocyte adhesion. It was found that TNF-α-induced monocyte adhesion on HUVEC was significantly attenuated by ghrelin. Furthermore, we found that ghrelin effectively suppressed TNF-α-induced inflammatory factors' (including ICAM-1, VCAM-1, MCP-1, and IL-1ß) expression through inhibiting AMPK phosphorylation and p65 expression both in HUVEC and THP-1. This phenomenon was further demonstrated by using AMPK agonist AICAR and inhibitor compound C, respectively. Our findings suggest that ghrelin may mediate TNF-α-induced endothelial inflammation and monocyte adhesion, in part via AMPK/NF-κB signaling pathway. These novel anti-inflammatory and immunoregulatory actions of ghrelin may play a certain role in understanding the formation and development of atherosclerosis.

Prevalence and spectrum of NKX2.5 mutations in patients with congenital atrial septal defect and atrioventricular block.

Congenital atrial septal defect (ASD) and progressive atriventricular block (AVB) are the two most common phenotypes linked to NK2 homeobox 5 (NKX2.5) mutations in animals and humans. However, the prevalence and spectrum of NKX2.5 mutation in patients with ASD and AVB remain to be elucidated. In the present study, the coding exons and flanking introns of the NKX2.5 gene, which encodes a homeobox­containing transcription factor essential for development of the heart, were sequenced in a cohort of 62 unrelated patients with ASD and AVB, and subsequently in a mutation carrier's available family members. As controls, 300 unrelated, ethnically­matched healthy individuals were recruited, who were also genotyped for NKX2.5. The functional consequence of the mutant NKX2.5 was evaluated in contrast to its wild­type counterpart using a dual­luciferase reporter assay system. As a result, a novel heterozygous NKX2.5 mutation, p.Q181X, was identified in an index patient with ASD and AVB, with a prevalence of ~1.61%. Genetic analysis of the proband's pedigree revealed that the mutation co­segregated with ASD and AVB with complete penetrance. The nonsense mutation, which eliminated partial homeobox and the carboxyl terminus, was absent in the 600 control chromosomes. Functional evaluation showed that the NKX2.5 mutant had no transcriptional activity. Furthermore, the mutation disrupted the synergistic activation between NKX2.5 and GATA binding protein 4, another cardiac core transcription factor associated with ASD. The results of the present study expand the spectrum of NKX2.5 mutations linked to ASD and AVB, and indicated that NKX2.5 loss­of­function mutations are an uncommon cause of ASD and AVB in humans.

Relationship between thromboelastography and long-term ischemic events as gauged by the response to clopidogrel in patients undergoing elective percutaneous coronary intervention.

Ischemic events after percutaneous coronary intervention (PCI) remain a major concern for patients with coronary heart disease (CHD). The aim of the current study was to investigate whether thromboelastography (TEG) was a satisfactory technique to measure platelet function in vitro in order to improve risk stratification and the individual response to antiplatelet therapy. The diagnostic and prognostic utility of the maximum amplitude of adenosine diphosphate induced platelet-fibrin clots (MAADP) was measured with TEG in 759 patients undergoing elective PCI. A 600-mg dose of clopidogrel was taken more than 12 h before surgery in addition to a maintenance dose of aspirin 100 mg/day and clopidogrel 75 mg/day for 2 y. Platelet-fibrin clot strength was also measured in this study. An MAADP > 34 mm significantly predicted ischemic events after PCI, as indicated by an area under the curve (AUC) of 0.79 (95% CI: 0.72-0.87, P < 0.05) according to receiver operating characteristic (ROC) curve analysis. The multivariate Cox proportional hazards model identified MAADP > 34 mm and an FBG level > 7.0 mmol/L as significant independent predictors of first ischemic events at the 2-year time point (P < 0.05). With adequate clopidogrel pretreatment, patients who underwent elective PCI and who experienced ischemic events could be diagnosed with a certain MAADP according to TEG. TEG could be a good tool to measure platelet function.

CASZ1 loss-of-function mutation contributes to familial dilated cardiomyopathy.

BACKGROUND: The zinc finger transcription factor CASZ1 plays a key role in cardiac development and postnatal adaptation, and in mice, deletion of the CASZ1 gene leads to dilated cardiomyopathy (DCM). However, in humans whether genetically defective CASZ1 contributes to DCM remains unclear. METHODS: The coding exons and splicing junction sites of the CASZ1 gene were sequenced in 138 unrelated patients with idiopathic DCM. The available family members of the index patient harboring an identified CASZ1 mutation and 200 unrelated, ethnically matched healthy individuals used as controls were genotyped for CASZ1. The functional characteristics of the mutant CASZ1 were analyzed in contrast to its wild-type counterpart using a luciferase reporter assay system. RESULTS: A novel heterozygous CASZ1 mutation, p.K351X, was identified in an index patient with DCM. Genetic analysis of the mutation carrier's family showed that the mutation co-segregated with DCM, which was transmitted in an autosomal dominant pattern with complete penetrance. The nonsense mutation, which was absent in 400 referential chromosomes, altered the amino acid that was highly conserved evolutionarily. Biological investigations revealed that the mutant CASZ1 had no transcriptional activity. CONCLUSIONS: The current study reveals CASZ1 as a new gene responsible for human DCM, which provides novel mechanistic insight and potential therapeutic target for CASZ1-associated DCM, implying potential implications in improved prophylactic and therapeutic strategies for DCM, the most common type of primary myocardial disease.

TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome.

Previous genome-wide association studies have demonstrated that single nucleotide polymorphisms in T­box (TBX)5 are associated with increased susceptibility to atrial fibrillation (AF), and a recent study has causally linked a TBX5 mutation to atypical Holt-Oram syndrome and paroxysmal AF. However, the prevalence and spectrum of TBX5 mutations in patients with AF remain to be elucidated. In the present study, a cohort of 190 unrelated patients with idiopathic AF were prospectively recruited, with 400 unrelated healthy individuals recruited as controls. The coding exons and flanking introns of the TBX5 gene were sequenced in the participants. The functional characteristics of the mutant TBX5 were delineated in contrast with its wild­type counterpart using a dual­luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.P132S, was identified in an index patient with AF, with a mutational prevalence of ~0.53%. Genetic analysis of the proband's family showed that the mutation co­segregated with AF, and was transmitted in an autosomal dominant pattern. The missense mutation was absent in the 800 control chromosomes, and the altered amino acid was completely evolutionarily conserved across species. Functional analyses revealed that the mutant TBX5 had significantly reduced transcriptional activity. Furthermore, the mutation markedly decreased the synergistic activation between TBX5 and NK2 homeobox 5, another transcription factor which has been causatively linked to AF. The present study was the first, to the best of our knowledge, to report on the association between a TBX5 loss­of­function mutation and increased susceptibility to AF. These results provide novel insight into the molecular mechanism underpinning AF, and have potential implications in the development of novel prophylactic and therapeutic strategies for AF, the most common form of sustained cardiac arrhythmia.