A predictive model of response to metoprolol in children and adolescents with postural tachycardia syndrome.

BACKGROUND: The present work was designed to explore whether electrocardiogram (ECG) index-based models could predict the effectiveness of metoprolol therapy in pediatric patients with postural tachycardia syndrome (POTS). METHODS: This study consisted of a training set and an external validation set. Children and adolescents with POTS who were given metoprolol treatment were enrolled, and after follow-up, they were grouped into non-responders and responders depending on the efficacy of metoprolol. The difference in pre-treatment baseline ECG indicators was analyzed between the two groups in the training set. Binary logistic regression analysis was further conducted on the association between significantly different baseline variables and therapeutic efficacy. Nomogram models were established to predict therapeutic response to metoprolol. The receiver-operating characteristic curve (ROC), calibration, and internal validation were used to evaluate the prediction model. The predictive ability of the model was validated in the external validation set. RESULTS: Of the 95 enrolled patients, 65 responded to metoprolol treatment, and 30 failed to respond. In the responders, the maximum value of the P wave after correction (Pcmax), P wave dispersion (Pd), Pd after correction (Pcd), QT interval dispersion (QTd), QTd after correction (QTcd), maximum T-peak-to-T-end interval (Tpemax), and T-peak-to-T-end interval dispersion (Tped) were prolonged (all P < 0.01), and the P wave amplitude was increased (P < 0.05) compared with those of the non-responders. In contrast, the minimum value of the P wave duration after correction (Pcmin), the minimum value of the QT interval after correction (QTcmin), and the minimum T-peak-to-T-end interval (Tpemin) in the responders were shorter (P < 0.01, < 0.01 and < 0.01, respectively) than those in the non-responders. The above indicators were screened based on the clinical significance and multicollinearity analysis to construct a binary logistic regression. As a result, pre-treatment Pcmax, QTcmin, and Tped were identified as significantly associated factors that could be combined to provide an accurate prediction of the therapeutic response to metoprolol among the study subjects, yielding good discrimination [area under curve (AUC) = 0.970, 95% confidence interval (CI) 0.942-0.998] with a predictive sensitivity of 93.8%, specificity of 90.0%, good calibration, and corrected C-index of 0.961. In addition, the calibration curve and standard curve had a good fit. The accuracy of internal validation with bootstrap repeated sampling was 0.902. In contrast, the kappa value was 0.769, indicating satisfactory agreement between the predictive model and the results from the actual observations. In the external validation set, the AUC for the prediction model was 0.895, and the sensitivity and specificity were 90.9% and 95.0%, respectively. CONCLUSIONS: A high-precision predictive model was successfully developed and externally validated. It had an excellent predictive value of the therapeutic effect of metoprolol on POTS among children and adolescents.

Similarities and differences between multiple inflammatory syndrome in children associated with COVID-19 and Kawasaki disease: clinical presentations, diagnosis, and treatment.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been spreading rapidly around the world, while "multisystem inflammatory syndrome in children" (MIS-C) is a new type of syndrome that has now been reported in many countries. Similar and different characteristics between KD and MIS-C have been reported in a variety of literature. We aimed to focus on reviewing clinical presentations, diagnosis, and treatment of KD and MIS-C. METHODS: We searched articles in the electronic databases, including the Cochrane Library database, EMBASE, and MEDLINE with the keywords "multiple inflammatory syndrome" and/or "COVID-19" and/or "Kawasaki disease" and "children". RESULTS: Main presentations of MIS-C and KD include fever, rashes, mucous membrane involvement, conjunctivitis, hands and feet erythema/edema, and cervical lymphadenopathy. However, compared with the highest incidence of KD among some Asian countries, MIS-C is common among Black and Hispanic children. MIS-C is common in older children and teenagers, whereas classic KD is common in children under five years of age. Gastrointestinal symptoms, shock, and coagulopathy are common in MIS-C patients but are not common in classic KD. Cardiac manifestations are more common than KD, including myocarditis with cardiac dysfunction and coronary artery dilation or aneurysms. Severe cases in MIS-C present with vasodilated or cardiogenic shock that requires fluid resuscitation, muscular support, and even mechanical ventilation and extracorporeal membrane oxygenation (ECMO), whereas KD rarely presents with these manifestations and requires these treatments. Increased serum ferritin, leukopenia, lymphopenia and thrombocytopenia are common in MIS-C. However, thrombocytosis is a characteristic feature of KD. Intravenous immunoglobulin (IVIG) and moderate-high dose aspirin are still a standard recommended treatment for KD. In addition to the above-mentioned medications, steroids and biological drugs are frequently used in patients with MIS-C. Most of the children with KD have a good prognosis; however, the long-term clinical outcomes of MIS-C are not clear. CONCLUSIONS: The overall presentation and treatment of MIS-C appear to overlap with KD. However, there are still great differences between the syndromes, and it is controversial to say whether MIS-C is a new entity or is a "severe type" of KD.

Prediction of intravenous immunoglobulin resistance in Kawasaki disease in children.

BACKGROUND: We aimed to explore predictive measures for intravenous immunoglobulin (IVIG) resistance in children with Kawasaki disease (KD). METHODS: Patients diagnosed with KD were enrolled in this study. Univariate analysis and multiple logistic regression were utilized to analyze the clinical features and laboratory results prior to IVIG-treatment of the two groups. Independent predictors of IVIG resistance were analyzed, and a predictive model for KD children with IVIG resistance was constructed. RESULTS: A total of 277 children with KD, 180 boys and 97 girls, aged 2-128 (median 23) months, were enrolled in the study. Compared with the IVIG-responsive group, the IVIG-resistant group had higher levels of the peripheral neutrophil count, mean platelet volume, mean platelet volume-to-lymphocyte ratio and C-reactive protein, and total serum bilirubin, but lower levels of peripheral lymphocyte count, serum albumin and serum prealbumin. Age (in months), peripheral neutrophil count, lymphocyte count and mean platelet volume and serum albumin were independent indicators for IVIG resistance by multivariate logistic regression analysis. A logistic regression model and a scoring system were set up, where cut-off values of - 0.46 and 6.5 points yielded sensitivities of 83.9% and 77.4%, and specificities of 74.8% and 61.0%, respectively. The areas under the curve (AUC) were 0.808 in the logistic regression model, and 0.750 in the scoring system. CONCLUSION: Our model for predicting IVIG-resistant children with KD, involving age (months), peripheral neutrophil count, lymphocyte count and mean platelet volume and serum albumin prior to IVIG-treatment, is helpful for clinical prediction of children with IVIG-resistant KD.

Hydrogen Sulfide Regulating Myocardial Structure and Function by Targeting Cardiomyocyte Autophagy.

OBJECTIVE: Hydrogen sulfide (H2S), a gaseous signal molecule, plays a crucial role in many pathophysiologic processes in the cardiovascular system. Autophagy has been shown to participate in the occurrence of many cardiac diseases. Increasing evidences indicated that H2S regulates myocardial structure and function in association with the altered autophagy and plays a "switcher" role in the autophagy of myocardial diseases. The aim of this review was to summarize these insights and provide the experimental evidence that H2S targets cardiomyocyte autophagy to regulate cardiovascular function. DATA SOURCES: This review was based on data in articles published in the PubMed databases up to October 30, 2017, with the following keywords: "hydrogen sulfide," "autophagy," and "cardiovascular diseases." STUDY SELECTION: Original articles and critical reviews on H2S and autophagy were selected for this review. RESULTS: When autophagy plays an adaptive role in the pathogenesis of diseases, H2S restores autophagy; otherwise, when autophagy plays a detrimental role, H2S downregulates autophagy to exert a cardioprotective function. For example, H2S has beneficial effects by regulating autophagy in myocardial ischemia/reperfusion and plays a protective role by inhibiting autophagy during the operation of cardioplegia and cardiopulmonary bypass. H2S postpones cardiac aging associated with the upregulation of autophagy but improves the left ventricular function of smoking rats by lowering autophagy. CONCLUSIONS: H2S exerts cardiovascular protection by regulating autophagy. Cardiovascular autophagy would likely become a potential target of H2S therapy for cardiovascular diseases.

[Significance of serum iron in the differential diagnosis between vasovagal syncope and postural orthostatic tachycardia syndrome in children].

OBJECTIVE: To explore the predictive value of serum iron in differentiating between vasovagal syncope (VVS) and postural orthostatic tachycardia syndrome (POTS) in children. METHODS: Totally 57 children (aged 4-17 years, POTS 40 cases, and VVS 17 cases) who were at the syncope clinic or admitted to the Department of Pediatrics, Peking University First Hospital from August 2009 to September 2012 were included in the study. The diagnoses were analyzed by the value of serum iron and receiver operating characteristic (ROC) curves used to explore the predictive value of different serum iron in differential diagnosis between VVS and POTS. RESULTS: There were significant differences in the median value of POTS [17.4 (interquartile range 13.5 -21.8) µmol/L] and VVS [8.9 (interquartile range 7.5-17.6) µmol/L] (P<0.01). When the value of serum iron was 11.8 µmol/L, the sensitivity and specificity of the differential diagnosis between VVS and POTS were 92.5% and 64.7%, respectively. CONCLUSION: The serum iron might be used as an initial diagnostic method in differential diagnosis between VVS and POTS, based on the history of the patients.

The derivation of a chiral substituent code for secondary alcohols and its application to the prediction of enantioselectivity.

A chiral substituent code was proposed based on the features of secondary alcohols, in which a chiral center is attached to two substituents in addition to OH and H substituents. The new chirality code, which was generated by predefining positional information of four substituents attached to stereocenter, was applied to two datasets composed of secondary alcohols as the enantioselective products of asymmetric reactions. In the first dataset, the chemical reaction was catalyzed by a biocatalyst, lipase from Candida rugosa. The catalyst for the second dataset was (-)-diisopinocampheylchloroborane. The structure-enantioselectivity relationship models were constructed using random forests with the chiral substituent code as the input. The resulting models were assessed both in terms of single enantiomers and pairs of enantiomers. Satisfactory results were obtained for both datasets. Although the chiral substituent code was specifically developed for secondary alcohols, it can easily be extended to represent chiral compounds possessing a specific chiral center bonded to two variable substituents.

[A modified Calgary syncope syndrome score in the differential diagnosis between cardiac syncope and vasovagal syncope].

OBJECTIVE: This study aimed at analyzing the usefulness of a modified Calgary Syncope Syndrome Score in the differential diagnosis between cardiac syncope (CS) and vasovagal syncope (VVS) in children through a large sample clinical study. METHOD: Totally 189 children [112 males, 77 females, aged 2 - 18 yrs, mean age (12.4 ± 3.1) yrs] with CS and VVS who were at the syncope clinic or admitted to the Department of Pediatrics, Peking University First Hospital from August 2002 to April 2011 were included in the study. The diagnosis was analyzed by a modified Calgary Syncope Syndrome Score and receiver operating characteristic (ROC) curve was used to explore the predictive value of different Calgary Syncope Syndrome Scores in differential diagnosis between CS and VVS. RESULT: There were significant differences in the score between CS [-5.00(-7, 1)] and VVS [1(-4, 6)] (P < 0.01). When the score was ≤ -2.5, the sensitivity and specificity of the differential diagnosis between CS and VVS were 95.4% and 67.7%, respectively. Since the modified Calgary Syncope Syndrome Score was integer number, CS should be considered when the score was less than -3. CONCLUSION: The modified Calgary Syncope Syndrome Score might be used as an initial diagnostic method in differential diagnosis between CS and VVS, based on the history of the patients.

Online chemical modeling environment (OCHEM): web platform for data storage, model development and publishing of chemical information.

The Online Chemical Modeling Environment is a web-based platform that aims to automate and simplify the typical steps required for QSAR modeling. The platform consists of two major subsystems: the database of experimental measurements and the modeling framework. A user-contributed database contains a set of tools for easy input, search and modification of thousands of records. The OCHEM database is based on the wiki principle and focuses primarily on the quality and verifiability of the data. The database is tightly integrated with the modeling framework, which supports all the steps required to create a predictive model: data search, calculation and selection of a vast variety of molecular descriptors, application of machine learning methods, validation, analysis of the model and assessment of the applicability domain. As compared to other similar systems, OCHEM is not intended to re-implement the existing tools or models but rather to invite the original authors to contribute their results, make them publicly available, share them with other users and to become members of the growing research community. Our intention is to make OCHEM a widely used platform to perform the QSPR/QSAR studies online and share it with other users on the Web. The ultimate goal of OCHEM is collecting all possible chemoinformatics tools within one simple, reliable and user-friendly resource. The OCHEM is free for web users and it is available online at http://www.ochem.eu.

[Clinical characteristics and follow-up study of tachycardia-induced cardiomyopathy in 12 children].

OBJECTIVE: Tachycardia induced cardiomyopathy (TIC), secondary to various tachyarrhythmias, is a reversible condition which can lead to cardiac enlargement and heart failure. The impairment of both structure and function of heart can be reverted completely or partially if tachyarrhythmias are ceased without delay. This study aimed to explore the clinical characteristics, therapeutic regimen and outcome of TIC in children. METHODS: Clinical data of 12 children with TIC, who came from Peking University First Hospital from Feb. 2003 to Jun. 2009, were retrospectively analyzed and followed up. The echocardiogram data on admission were compared with those from 12 homochronous cases with idiopathic dilated cardiomyopathy matched with 12 TIC cases in age and gender. RESULTS: Atrial tachycardia is the commonest arrhythmia in 12 TIC cases (75%). Four cases underwent catheterization for radiofrequency ablation and all succeeded. The cardiac rhythm of 6 out of 8 cases treated with drugs became sinus rhythm after 3 days to 2 weeks antiarrhythmic drugs treatment. The remaining 2 cases still retained atrial rhythm, but the ventricular heart rates declined to normal. The left ventricular end-diastolic dimensions of the 12 cases were decreased compared with those of pretherapy [(37.5 ± 5.3) mm vs. (43.0 ± 5.7) mm, P < 0.01], and the left ventricular ejection fractions were increased [(60.5% ± 5.6%) vs. (33.7% ± 10.3%), P < 0.01], after (3.4 ± 2.3) months. In our (4.3 ± 2.4) year-follow-up, all cases were fine, except in one case the tachyarrhythmia relapsed because of discontinuation of the drug treatment by her parents. The left ventricular end-diastolic dimensions in 12 TIC cases were smaller than those of the 12 age- and gender-matched idiopathic dilated cardiomyopathy [(43.0 ± 5.7) mm vs. (54.8 ± 7.5) mm, t = 7.9, P < 0.01], and the ejection fractions were higher [(33.7% ± 10.3%) vs. (21.8% ± 7.5%), t = 3.7, P < 0.01]. CONCLUSION: The diagnosis of TIC should be considered for the children with tachycardia, cardiac enlargement and cardiac insufficiency. The degree of cardiac enlargement and cardiac insufficiency might be of value for the differential diagnosis between TIC and idiopathic dilated cardiomyopathy. The rhythm control and ventricular rates control could all result in a favorite therapeutic efficacy.

[The value of the New York University Pediatric Heart Failure Index in chronic heart failure in children].

OBJECTIVE: The study was designed to explore the value of the New York University Pediatric Heart Failure Index (NYU PHFI) for diagnosing and grading chronic heart failure in children. METHODS: Totally 105 children with chronic heart failure or structural heart disease but without signs and symptoms of heart failure were enrolled. They were diagnosed using modified Ross score, NYU PHFI and NT-proBNP, respectively. According to modified Ross score as the referent criteria, the diagnostic value of NYU PHFI in quantifying chronic heart failure severity in children was studied. Furthermore, according to the grading of heart failure using modified Ross score, the area under the ROC curves of NYU PHFI was examined, respectively, in order to find out the optimal cut-off point. RESULTS: NYU PHFI score was positively correlated with the modified Ross score (r = 0.909, P = 0.000). According to modified Ross score, NYU PHFI scores in different severity of heart failure in children differed significantly (F = 80.034, P = 0.000). A significantly positive correlation was found between plasma NT-proBNP and modified Ross score, and between NT-proBNP and NYU PHFI score. Correlation coefficients between plasma NT-proBNP and modified Ross score, and between plasma NT-proBNP and NYU PHFI score were 0.752 and 0.918, respectively. The correlation between NYU PHFI and plasma NT-proBNP was superior to that between modified Ross score and plasma NT-proBNP. According to modified Ross scores of 0 - 2 as being without heart failure, 3 - 6 as mild degree of heart failure, 7 - 9 as moderate degree of heart failure and 10 - 12 as severe degree of heart failure, the areas under the ROC curve of the NYU PHFI diagnosing if heart failure was present, differentiating moderate from mild and severe from moderate heart failure were 0.982, 0.942 and 0.918, respectively, and the sum of sensitivity and specificity was favorite when 6, 10 and 13 scores were set as cut-off value diagnosing the presence of heart failure, differentiating moderate from mild, and severe from moderate heart failure, respectively. According to above classification of heart failure based on NYU PHFI score, plasma NT-proBNP concentration was significantly different in different degree of heart failure (F = 53.31, P < 0.001). Plasma NT-proBNP concentration in those without heart failure was significantly lower than that of mild heart failure, and it was also significantly lower in mild heart failure than that of severe heart failure. CONCLUSION: NYU PHFI was highly valuable for diagnosing chronic heart failure in children and 0 - 6 scores as being without heart failure, 7 - 10 scores as mild degree, 11 - 13 scores as moderate degree and 14 - 30 scores as severe degree of heart failure could be used as the reference criteria of different severities of heart failure.

[Diagnosis of unexplained syncope in children: a multi-center study].

OBJECTIVE: To examine the diagnostic value of head-up tilt test in children with unexplained syncope (UPS). METHODS: A total of 379 children (171 males, 208 females) aged 3-18 years, mean age (12 +/- 3) years with unexplained syncope from Beijing, Hunan, Hubei and Shanghai and undergoing baseline head-up tilt tests (BHUTT) or head-up tilt tests potentiated with nitroglycerine (SNHUTT) under a quiet circumstance were selected as the syncope group. Ten healthy children (5 males, 5 females) aged 9-15 years with a mean age of (11.4 +/- 2.1) years, were recruited as the control group. SPSS 10.0 software was used for data analysis. RESULTS: In 379 children with unexplained syncope, 67 (17.7%) were of postural orthostatic tachycardia syndrome (POTS), 157 (41.4%) of vasovagal syncope vasoinhibitory pattern, 14 (3.7%) of vasovagal syncope cardioinhibitory pattern, 47 (12.4%) of vasovagal syncope mixed pattern, 1 (0.3%) of orthostatic hypotension (OH) and 93 children (24.5%) of UPS. In syncope group and control group, the positive rate of BHUTT was 55.9% and 0 respectively and it was 75.5% and 20.0% respectively for SNHUTT. During BHUTT, the mean time of positive response occurrence was (16 +/- 12) minutes, and the posture when positive response appeared was at a tilt angle of 60 degrees. For SNHUTT, the mean time of positive response occurrence was (6 +/- 4) minutes and the posture was at a tilt angle of 60 degrees when potentiated with nitroglycerine. CONCLUSION: HUTT is an objective diagnostic tool of UPS. With a high diagnostic positive rate, SNHUTT can improve the diagnostic positive rate of BHUTT. Meanwhile the time of positive response occurrence during SNHUTT is markedly shorter than BHUTT.

[Clinical characteristics of cardiac syncope in children].

OBJECTIVES: To explore the clinical characteristics of cardiac syncope (CS) in children, and understand their significance in predicting the cardiac syncope. METHODS: Twenty-three patients were referred to our department for evaluation of syncope. The diagnosis of the above cases was cardiac syncope. Each patient was interviewed using a standard questionnaire. The clinical histories and standard baseline electrocardiogram were analyzed to identify the variables contributing to the diagnosis of CS in children. RESULTS: A cardiac cause was identified in 23 syncopal patients presenting to the Department of Pediatrics, Peking University First Hospital: sick sinus syndrome in 7, congenital long QT syndrome in 4, third degree atrioventricular block in 2, supraventricular tachycardia in 2, ventricular tachycardia in 1, atrial fibrillation in 1, pacemaker dysfunction in 1, idiopathic pulmonary hypertension in 3, hypertrophic cardiomyopathy in 1, and dilated cardiomyopathy in 1. The average age of CS patients was 9 years. In totally 23 patients, exertion related syncope spells were found in 14 cases (60.9%), syncope spells at various position 7/23 (30.4%), absence of prodromes in 12/23 (52.2%), syncope spells with incontinence in 4/23 (17.4%), history of heart disease in 4/23 (17.4%). Abnormal standard baseline electrocardiogram was found in 21 cases (91.7%). CONCLUSIONS: The children with cardiac syncope have overt clinical features, especially abnormal findings in electrocardiogram and exertion related syncope spells are the most common clinical features.

[Effect of selective alpha1 receptor agonist in the treatment of children with postural orthostatic tachycardia syndrome].

OBJECTIVE: The study was designed to examine the effect of selective alpha1 receptor agonist midodrine hydrochloride in the treatment of children with postural orthostatic tachycardia syndrome. METHODS: Fifty-five children (23 male, 32 female, age 5 - 19 yrs, mean age 12.3 +/- 3.1 yrs) who came from Peking University First Hospital were included in the study and clinical investigations as well as standing test, basic head-up tilt test and sublingual nitroglycerin-provocated head-up tilt test under quiet circumstance were conducted. They were randomly divided into treatment group (with midodrine hydrochloride and oral rehydration salt treatment) and control group (with oral rehydration salt treatment only). At last, the disease-free rate, improvement rate and effective rate of symptoms, and the rate of HUT from positive to negative response were compared between control group and treatment group. SPSS 10.0 software was used for the statistical analysis of these data. RESULTS: The symptom improvement rate in treatment group was significantly higher than that of control group after three and six weeks of treatment (100.0% vs. 42.4%, P < 0.001; 100.0% vs. 42.4%, chi2 = 19.352, P < 0.001). The disease-free rate at follow-up end-point in treatment group was significantly higher than that of control group (77.3% vs. 27.3%, chi2 = 13.239, P < 0.001). The effective rate at follow-up end-point in treatment group was also significantly higher than that of control group (100.0% vs. 36.4%, chi2 = 22.647, P < 0.001). The rate of HUT changing from positive to negative response between two groups after three weeks of treatment was not significantly different (31.8% vs. 12.1%, P > 0.05), but it was significantly different (81.0% vs. 48.5%, P < 0.05) after six weeks of treatment. CONCLUSION: Selective alpha1 receptor agonist midodrine hydrochloride is effective in the treatment of children with postural orthostatic tachycardia syndrome.

Genome-scale classification of metabolic reactions and assignment of EC numbers with self-organizing maps.

MOTIVATION: The automatic perception of chemical similarities between metabolic reactions is required for a variety of applications ranging from the computer-aided validation of classification systems, to genome-scale reconstruction (or comparison) of metabolic pathways, to the classification of enzymatic mechanisms. Comparison of metabolic reactions has been mostly based on Enzyme Commission (EC) numbers, which are extremely useful and widespread, but not always straightforward to apply, and often problematic when an enzyme catalyzes several reactions, when the same reaction is catalyzed by different enzymes, when official full EC numbers are unavailable or when reactions are not catalyzed by enzymes. Different methods should be available to compare metabolic reactions. Simultaneously, methods are required for the automatic assignment of EC numbers to reactions still not officially classified. RESULTS: We have proposed the MOLMAP reaction descriptors to numerically encode the structural transformations resulting from a chemical reaction. Here, such descriptors are applied to the mapping of a genome-scale database of almost 4000 metabolic reactions by Kohonen self-organizing maps (SOMs), and its screening for inconsistencies in EC numbers. This approach allowed for the SOMs to assign EC numbers at the class, subclass and sub-subclass levels for reactions of independent test sets with accuracies up to 92, 80 and 70%, respectively. Different levels of similarity between training and test sets were explored. The approach also led to the identification of a number of similar reactions bearing differences at the EC class level. AVAILABILITY: The programs to generate MOLMAP descriptors from atomic properties included in SDF files are available upon request for evaluation.