NG-SEM: an effective non-Gaussian structural equation modeling framework for gene regulatory network inference from single-cell RNA-seq data.

Inference of gene regulatory network (GRN) from gene expression profiles has been a central problem in systems biology and bioinformatics in the past decades. The tremendous emergency of single-cell RNA sequencing (scRNA-seq) data brings new opportunities and challenges for GRN inference: the extensive dropouts and complicated noise structure may also degrade the performance of contemporary gene regulatory models. Thus, there is an urgent need to develop more accurate methods for gene regulatory network inference in single-cell data while considering the noise structure at the same time. In this paper, we extend the traditional structural equation modeling (SEM) framework by considering a flexible noise modeling strategy, namely we use the Gaussian mixtures to approximate the complex stochastic nature of a biological system, since the Gaussian mixture framework can be arguably served as a universal approximation for any continuous distributions. The proposed non-Gaussian SEM framework is called NG-SEM, which can be optimized by iteratively performing Expectation-Maximization algorithm and weighted least-squares method. Moreover, the Akaike Information Criteria is adopted to select the number of components of the Gaussian mixture. To probe the accuracy and stability of our proposed method, we design a comprehensive variate of control experiments to systematically investigate the performance of NG-SEM under various conditions, including simulations and real biological data sets. Results on synthetic data demonstrate that this strategy can improve the performance of traditional Gaussian SEM model and results on real biological data sets verify that NG-SEM outperforms other five state-of-the-art methods.

LogBTF: gene regulatory network inference using Boolean threshold network model from single-cell gene expression data.

MOTIVATION: From a systematic perspective, it is crucial to infer and analyze gene regulatory network (GRN) from high-throughput single-cell RNA sequencing data. However, most existing GRN inference methods mainly focus on the network topology, only few of them consider how to explicitly describe the updated logic rules of regulation in GRNs to obtain their dynamics. Moreover, some inference methods also fail to deal with the over-fitting problem caused by the noise in time series data. RESULTS: In this article, we propose a novel embedded Boolean threshold network method called LogBTF, which effectively infers GRN by integrating regularized logistic regression and Boolean threshold function. First, the continuous gene expression values are converted into Boolean values and the elastic net regression model is adopted to fit the binarized time series data. Then, the estimated regression coefficients are applied to represent the unknown Boolean threshold function of the candidate Boolean threshold network as the dynamical equations. To overcome the multi-collinearity and over-fitting problems, a new and effective approach is designed to optimize the network topology by adding a perturbation design matrix to the input data and thereafter setting sufficiently small elements of the output coefficient vector to zeros. In addition, the cross-validation procedure is implemented into the Boolean threshold network model framework to strengthen the inference capability. Finally, extensive experiments on one simulated Boolean value dataset, dozens of simulation datasets, and three real single-cell RNA sequencing datasets demonstrate that the LogBTF method can infer GRNs from time series data more accurately than some other alternative methods for GRN inference. AVAILABILITY AND IMPLEMENTATION: The source data and code are available at https://github.com/zpliulab/LogBTF.

A simplified reverse wire technique using an angulated supercross microcatheter.

Bifurcation lesion with an extreme angulated side branch remains a challenge in coronary intervention. Reverse wire technique was originally described by Dr. Kawasaki and nowadays this can be done by double-lumen catheter. We report a novel "simplified reverse wire technique with a specialized angle tip microcatheter," Supercross microcatheter™ (Teleflex). This can facilitate wiring of extreme angulated side branch by this simple and feasible method without using double lumen catheter.

A rare variant of transthyretin-related amyloidosis associated with exclusive cardiomyopathy in a Hong Kong Chinese patient.

Hereditary transthyretin-related amyloidosis (ATTR, MIM #105210), also previously known as familial amyloidotic polyneuropathy, is one of the most life-threatening types of amyloidosis. ATTR is inherited in autosomal dominant mode with variable penetrance. If untreated, it is a relentless and lethal disease. Patients typically present with polyneuropathy, carpal tunnel syndrome, autonomic insufficiency, cardiomyopathy, and gastrointestinal features, occasionally accompanied by vitreous opacities and renal insufficiency. Frequency of transthyretin (TTR)-related cardiac amyloidosis amongst Chinese populations is unknown. We report here a 63-year-old Chinese man suffering from TTR-related cardiac amyloidosis presented with exclusive cardiomyopathy. He had no other systemic involvement and no significant family history. Echocardiography revealed severe global myocardial impairment and left ventricular ejection fraction of 35%. Serum kappa-to-lambda ratio was normal. Genetic test detected a heterozygous TTR variant, NM_000371.3:c.425T > C p.(Val142Ala). To our knowledge, this is the first case of TTR-related cardiac amyloidosis caused by p.Val142Ala mutation reported in Asian patient. .

Usefulness of ECG to differentiate Takotsubo cardiomyopathy from acute coronary syndrome.

OBJECTIVE: We aimed to describe the evolution of ECG changes in TC compared with MI, and evaluate ECG features which might help to distinguish between these conditions. BACKGROUND: Takotsubo cardiomyopathy (TC) can mimic both ST-elevation (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) but management is different. Several electrocardiographic (ECG) abnormalities have been identified which might help to differentiate TC with and without ST-elevation, from STEMI and NSTEMI, respectively. METHODS: We prospectively identified 100 consecutive patients with TC and 100 MI patients. They were divided into 2 groups according to the presence of ST-segment elevation (STE). Serial ECGs from admission to Day 2 were compared. RESULTS: Thirty-five TC patients had STE on admission. Compared with STEMI patients they had less prominent STE (median peak elevation 2mm vs. 3mm, P<0.05), less reciprocal ST-segment depression and no abnormal Q-waves. By Day 2 all STEMI patients had pathological Q-waves but none of the TC patients. Compared with NSTE-TC patients, NSTEMI patients had more ST-segment depression (28.2% vs. 0%, P<0.05), but less T-wave inversion (33.8% vs. 11.3%, P<0.05) on admission. By Day 2 the ECG criterion which best distinguished NSTE-TC from NSTEMI was the presence of T-wave inversion in ≥6 leads (sensitivity 74%, specificity 92%). CONCLUSION: ECG changes seen in TC within two days of presentation are distinctive and important clues for clinicians to suspect the diagnosis.

Clinical characteristics and outcome of apical ballooning syndrome in Auckland, New Zealand.

BACKGROUND: Apical ballooning syndrome (ABS) mimics myocardial infarction but is characterised by transient left ventricular (LV) dysfunction without significant coronary artery obstruction. METHODS: We prospectively identified 100 consecutive patients presenting in the Auckland region between March 2004 and July 2010 and obtained clinical, laboratory, electrocardiography, echocardiography, coronary angiography and long-term follow-up data. RESULTS: Chest pain or dyspnoea were the most common presenting symptom, 95% were women (mean age 65 ± 11 years). An associated stressor was identified in two-thirds of patients, troponin was elevated in all patients, and one-third had ECG ST-elevation. There was a similar range of initial LV ejection fraction (EF), myocardial damage, LV recovery and prognosis in those with and without ST-elevation, and with and without identifiable stressors. One-quarter had a complicated in-hospital course. Lower admission LVEF, but not peak troponin level or ECG ST-elevation, was associated with a complicated in-hospital course. The mean follow-up was 3.0 ± 1.7 years. One patient died in hospital. Four died late after discharge, all from non-cardiac causes. Seven had recurrent ABS. CONCLUSION: In this large, prospective, New Zealand ABS cohort a quarter of patients had a complicated in-hospital course, but almost all recovered, recurrence was infrequent and long-term prognosis dependent on associated non-cardiac disease.

Primary cardiac angiosarcoma: morphologically deceptive benign appearance and potential pitfalls in diagnosis.

Cardiac angiosarcoma is the most common malignant primary cardiac tumour. We report a case of cardiac angiosarcoma with recurrent complex pericardial effusion. Histological diagnosis was elusive underscoring the potential difficulty in differentiating this tumour from normal vascular endothelium.

Transseptal fine needle aspiration of a large left atrial tumour.

The diagnosis of cardiac tumours is often based on images without tissue diagnosis or tissue obtained at surgery. Percutaneous myocardial biopsy via a transvenous approach has been described in literatures but this technique is not feasible with left atrial tumours. We report a patient presenting with heart failure and left atrial tumour. The diagnosis of spindle cell neoplasm was established pre-operatively via successful transseptal fine needle aspiration of cells from a left atrial tumour. We believe this technique worth consideration to aid pre-surgery diagnosis.

Outcome and prognostic factors on 57 cases of infective endocarditis in a single centre.

AIM: We aim to evaluate the clinical characteristics and outcome of infective endocarditis in our hospital, and the prognostic significance of recurrent endocarditis. METHODS: A single centre retrospective review of all cases of infective endocarditis (IE) was undertaken for a 5-year period from June 2002. RESULTS: There were 57 episodes of IE in 47 patients. Seventy percent were definite IE using the modified Duke Criteria (2000). The most commonly isolated organisms were Streptococci (37%) and Staphylococcus aureus (35%). Forty-nine percent of patients remained event-free from death, recurrence, or operation at the end of follow-up period. Five cases (8.5%) had early recurrence of endocarditis within 60 days. Eleven patients (23%) died during follow-up (mean 14 months). There was no significant increase in mortality of patients with history of recurrent endocarditis (38% vs 28%; p=0.39). Staphylococcus aureus was associated with increased mortality or need for valve surgery (OR 4.5; 95%CI 1.38-14.8), risk of neurological events (OR 8.9; 1.5-52), renal failure (OR 7.2; 1.7-30) and thrombocytopenia (OR 5.6; 1.4-22). CONCLUSIONS: The mortality of IE remains high. Less than half of this cohort remained event-free. The micro-organism involved is more predictive of mortality or need for surgery than recurrent endocarditis.

Eosinophilia and coronary artery vasospasm.

OBJECTIVE: To describe the clinical features, natural history and response to treatment of coronary vasospasm associated with eosinophilia. METHODS: Two patients with eosinophilia who had recurrent acute coronary events due to multi-vessel coronary artery spasm are described. The clinical presentation and outcomes of these 2 patients and 17 additional cases of eosinophilia and coronary artery vasospasm identified on a systematic literature review are presented. RESULTS: Patients were usually admitted because of repeated episodes of angina at rest and raised plasma markers of myocyte necrosis. Dynamic ST elevation was observed in 15 (83%) patients. Coronary angiography was performed in all patients. Spontaneous (n=7) or provoked (n=8) coronary artery spasm, which was usually multi-focal, was observed in 15 (83%) patients. Symptoms often continued despite high dose vasodilators but responded well to prednisone. Recurrent coronary events were frequent, and included sudden death (n=4), resuscitated cardiac arrest (n=2), myocardial infarction (n=10) and unstable angina (n=11). Recurrent events were more frequent when not taking compared to when taking prednisone (4.2 versus 0.4 events/year, p=0.002, hazard ratio 11, 95% confidence interval 2.4-50). CONCLUSION: Published case reports suggest that coronary vasospasm associated with eosinophilia responds poorly to conventional vasodilator treatment and the risk of recurrent coronary events is high. Most patients respond to treatment which suppresses the eosinophilia.