New pediatric percentiles of liver enzyme serum levels (alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase): Effects of age, sex, body mass index, and pubertal stage.

The present study aims to clarify the effects of sex, age, body mass index (BMI), and puberty on transaminase serum levels in children and adolescents and to provide new age- and sex-related percentiles for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyltransferase (GGT). Venous blood and anthropometric data were collected from 4,126 cases. Excluded were cases of participants with potential hepatotoxic medication, with evidence of potential illness at the time of blood sampling and non-normal BMI (BMI <10th or >90th). The resulting data (N = 3,131 cases) were used for the calculations of ALT, AST, and GGT percentiles. Age- and sex-related reference intervals were established by using an LMS method of Cole-type method. Serum levels of transaminases follow age-specific patterns and relate to the onset of puberty. This observation is more pronounced in girls than in boys. ALT percentiles showed similar-shaped patterns in both sexes. Multivariate regression confirmed significant effects of puberty and BMI-SDS (ß = 2.21) on ALT. Surprisingly, AST serum levels were negatively influenced by age (ß = -1.42) and BMI-SDS (ß = -0.15). GGT percentiles revealed significant sex-specific differences, correlated positively with age (ß = 0.37) and showed significant association with BMI-SDS (ß = 1.16). CONCLUSION: Current reference values of ALT, AST, and GGT serum levels were calculated for children between 11 months and 16.0 years, using modern analytical and statistical methods. This study extends the current knowledge about transaminases by revealing influences of age, sex, BMI, and puberty on serum concentrations of all three parameters and has for these parameters one of the largest sample sizes published so far. (Hepatology 2017).

Evaluation of hair cortisol and cortisone change during pregnancy and the association with self-reported depression, somatization, and stress symptoms.

Hair cortisol levels are used to measure long-term stress, while its inactive metabolite cortisone is often not assessed. We measured hair cortisol concentrations (HCC) and hair cortisone concentrations (HCNC) via liquid chromatography quadrupole linear ion trap mass spectrometry (LC-MS3) in 62 pregnant women who participated in the LIFE CHILD STUDY in their 2nd and 3rd trimester between 12/2011 and 11/2014. Sociodemographic factors, pregnancy-related factors, and hair characteristics were assessed. Degree of severity of depression, somatization, and stress were evaluated in both trimesters with a self-reported Patient Health Questionnaire (PHQ). Multivariate regression analyses were conducted between HCC and potential influencing factors, as well as with subscales of the PHQ, with HCNC and with the ratio of HCNC to HCC. Spearman correlation coefficients were calculated between steroid concentrations and subscale scores of the PHQ, as well as between the log2-fold change in HCC and HCNC and the change in PHQ subscale scores. HCC increased 1.3-fold and HCNC increased 1.5-fold by the 3rd trimester. HCNC was more than three times higher than HCC in both trimesters. We found significant associations of PHQ subscores with HCNC. The PHQ depression score was negatively correlated with HCNC in the 2nd trimester (p < .05). The PHQ stress score change was negatively correlated with the fold change of HCNC (p < .05) and with the change in the ratio of HCNC to HCC (p < .001). Our study suggests an association of cortisol/cortisone metabolism with self-reported stress in the 2nd and 3rd trimester of pregnancy. Since associations with PHQ subscores were only found with cortisone or the ratio of cortisone to cortisol, but not with cortisol alone, both cortisone and cortisol should be used as a marker for stress in pregnant woman.

Prognostic relevance of the interaction between short-term, metronome-paced heart rate variability, and inflammation: results from the population-based CARLA cohort study.

AIMS: To determine the interaction between HRV and inflammation and their association with cardiovascular/all-cause mortality in the general population. METHODS AND RESULTS: Subjects of the CARLA study (n = 1671; 778 women, 893 men, 45-83 years of age) were observed for an average follow-up period of 8.8 years (226 deaths, 70 cardiovascular deaths). Heart rate variability parameters were calculated from 5-min segments of 20-min resting electrocardiograms. High-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and soluble tumour necrosis factor-alpha receptor type 1 (sTNF-R1) were measured as inflammation parameters. The HRV parameters determined included the standard deviation of normal-to-normal intervals (SDNN), the root-mean-square of successive normal-interval differences (RMSSD), the low- and high-frequency (HF) power, the ratio of both, and non-linear parameters [Poincaré plot (SD1, SD2, SD1/SD2), short-term detrended fluctuation analysis]. We estimated hazard ratios by using covariate-adjusted Cox regression for cardiovascular and all-cause mortality incorporating an interaction term of HRV/inflammation parameters. Relative excess risk due to interactions (RERIs) were computed. We found an interaction effect of sTNF-R1 with SDNN (RERI: 0.5; 99% confidence interval (CI): 0.1-1.0), and a weaker effect with RMSSD (RERI: 0.4; 99% CI: 0.0-0.9) and HF (RERI: 0.4; 99% CI: 0.0-0.9) with respect to cardiovascular mortality on an additive scale after covariate adjustment. Neither IL-6 nor hsCRP showed a significant interaction with the HRV parameters. CONCLUSION: A change in TNF-α levels or the autonomic nervous system influences the mortality risk through both entities simultaneously. Thus, TNF-α and HRV need to be considered when predicating mortality.

Longitudinal association of short-term, metronome-paced heart rate variability and echocardiographically assessed cardiac structure at a 4-year follow-up: results from the prospective, population-based CARLA cohort.

AIMS: To assess the value of cardiac structure/function in predicting heart rate variability (HRV) and the possibly predictive value of HRV on cardiac parameters. METHODS AND RESULTS: Baseline and 4-year follow-up data from the population-based CARLA cohort were used (790 men, 646 women, aged 45-83 years at baseline and 50-87 years at follow-up). Echocardiographic and HRV recordings were performed at baseline and at follow-up. Linear regression models with a quadratic term were used. Crude and covariate adjusted estimates were calculated. Missing values were imputed by means of multiple imputation. Heart rate variability measures taken into account consisted of linear time and frequency domain [standard deviation of normal-to-normal intervals (SDNN), high-frequency power (HF), low-frequency power (LF), LF/HF ratio] and non-linear measures [detrended fluctuation analysis (DFA1), SD1, SD2, SD1/SD2 ratio]. Echocardiographic parameters considered were ventricular mass index, diastolic interventricular septum thickness, left ventricular diastolic dimension, left atrial dimension systolic (LADS), and ejection fraction (Teichholz). A negative quadratic relation between baseline LADS and change in SDNN and HF was observed. The maximum HF and SDNN change (an increase of roughly 0.02%) was predicted at LADS of 3.72 and 3.57 cm, respectively, while the majority of subjects experienced a decrease in HRV. There was no association between further echocardiographic parameters and change in HRV, and there was no evidence of a predictive value of HRV in the prediction of changes in cardiac structure. CONCLUSION: In the general population, LADS predicts 4-year alteration in SDNN and HF non-linearly. Because of the novelty of the result, analyses should be replicated in other populations.

The LIFE Child study: a population-based perinatal and pediatric cohort in Germany.

The LIFE Child study is a large population-based longitudinal childhood cohort study conducted in the city of Leipzig, Germany. As a part of LIFE, a research project conducted at the Leipzig Research Center for Civilization Diseases, it aims to monitor healthy child development from birth to adulthood and to understand the development of lifestyle diseases such as obesity. The study consists of three interrelated cohorts; the birth cohort, the health cohort, and the obesity cohort. Depending on age and cohort, the comprehensive study program comprises different medical, psychological, and sociodemographic assessments as well as the collection of biological samples. Optimal data acquisition, process management, and data analysis are guaranteed by a professional team of physicians, certified study assistants, quality managers, scientists and statisticians. Due to the high popularity of the study, more than 3000 children have already participated until the end of 2015, and two-thirds of them participate continuously. The large quantity of acquired data allows LIFE Child to gain profound knowledge on the development of children growing up in the twenty-first century. This article reports the number of available and analyzable data and demonstrates the high relevance and potential of the study.

Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

Intra-aortic balloon pump counterpulsation (IABP) for myocardial infarction complicated by cardiogenic shock.

BACKGROUND: Intra-aortic balloon pump counterpulsation (IABP) is currently the most commonly used mechanical assist device for patients with cardiogenic shock due to acute myocardial infarction. Although there has been only limited evidence from randomised controlled trials, the previous guidelines of the American Heart Association/American College of Cardiology (AHA/ACC) and the European Society of Cardiology (ESC) strongly recommended the use of the IABP in patients with infarction-related cardiogenic shock on the basis of pathophysiological considerations, non-randomised trials and registry data. The recent guidelines downgraded the recommendation based on a meta-analysis which could only include non-randomised trials showing conflicting results. Up to now, there have been no guideline recommendations and no actual meta-analysis including the results of the large randomised multicentre IABP-SHOCK II Trial which showed no survival benefit with IABP support. This systematic review is an update of the review published in 2011. OBJECTIVES: To evaluate, in terms of efficacy and safety, the effect of IABP versus non-IABP or other assist devices guideline compliant standard therapy on mortality and morbidity in patients with acute myocardial infarction complicated by cardiogenic shock. SEARCH METHODS: Searches of CENTRAL, MEDLINE (Ovid) and EMBASE (Ovid), LILACS, IndMed and KoreaMed, registers of ongoing trials and proceedings of conferences were updated in October 2013. Reference lists were scanned and experts in the field contacted to obtain further information. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials on patients with acute myocardial infarction complicated by cardiogenic shock. DATA COLLECTION AND ANALYSIS: Data collection and analysis were performed according to the published protocol. Individual patient data were provided for six trials and merged with aggregate data. Summary statistics for the primary endpoints were hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs). MAIN RESULTS: Seven eligible studies were identified from a total of 2314 references. One new study with 600 patients was added to the original review. Four trials compared IABP to standard treatment and three to other percutaneous left assist devices (LVAD). Data from a total of 790 patients with acute myocardial infarction and cardiogenic shock were included in the updated meta-analysis: 406 patients were treated with IABP and 384 patients served as controls; 339 patients were treated without assisting devices and 45 patients with other LVAD. The HR for all-cause 30-day mortality of 0.95 (95% CI 0.76 to 1.19) provided no evidence for a survival benefit. Different non-fatal cardiovascular events were reported in five trials. During hospitalisation, 11 and 4 out of 364 patients from the intervention groups suffered from reinfarction or stroke, respectively. Altogether 5 out of 363 patients from the control group suffered from reinfarction or stroke. Reocclusion was treated with subsequent re-revascularization in 6 out of 352 patients from the intervention group and 13 out of 353 patients of the control group. The high incidence of complications such as moderate and severe bleeding or infection in the control groups has to be attributed to interventions with other LVAD. Possible reasons for bias were more frequent in small studies with high cross-over rates, early stopping and the inclusion of patients with IABP at randomisation. AUTHORS' CONCLUSIONS: Available evidence suggests that IABP may have a beneficial effect on some haemodynamic parameters. However, this did not result in survival benefits so there is no convincing randomised data to support the use of IABP in infarct-related cardiogenic shock.

The trend-renewal process: a useful model for medical recurrence data.

Time-to-event data analysis has a long tradition in applied statistics. Many models have been developed for data where each subject or observation unit experiences at most one event during its life. In contrast, in some applications, the subjects may experience more than one event. Recurrent events appear in science, medicine, economy, and technology. Often the events are followed by a repair action in reliability or a treatment in life science. A model to deal with recurrent event times for incomplete repair of technical systems is the trend-renewal process. It is composed of a trend and a renewal component. In the present paper, we use a Weibull process for both of these components. The model is extended to include a Cox type covariate term to account for observed heterogeneity. A further extension includes random effects to account for unobserved heterogeneity. We fit the suggested version of the trend-renewal process to a data set of hospital readmission times of colon cancer patients to illustrate the method for application to clinical data.

Speaking Voice in Children and Adolescents: Normative Data and Associations with BMI, Tanner Stage, and Singing Activity.

OBJECTIVES: The aim of this study was to establish normative data concerning the speaking voice of children and adolescents for clinical diagnostics. STUDY DESIGN: Population-based mixed cross-sectional and longitudinal childhood cohort study. METHODS: Normative data measuring the speaking voice profile of 1352 male and 1274 female participants aged 6 to 17 years were collected. To evaluate the voice range, five different intensity levels as the quietest voicing speaking voice (Level I), conversational voice (Level II), classroom voice (Level III), shouting voice (Level IV), and again the quietest speaking voice (Level V) were investigated. Multivariable analyses were performed to describe the effects of body mass index, Tanner stage, and singing activity on the outcome variables. RESULTS: A clear distinction in frequencies and sound pressure levels between the five different voice levels can be found in both genders. In females the mean fundamental frequency of the conversational voice lowers from 223.3 to 205.8 Hz. In male participants it lowers from 223.3 to 102.3 Hz. The most substantial decrease in the fundamental frequency of the speaking voice in boys occurs at 13.5 years. Girls show an almost continuous decline in their fundamental frequency. Only the Tanner stage showed significant positive relationships with the grade of lowering of the fundamental frequency in both sexes. CONCLUSIONS: It was shown that the investigation of the speaking voice using predefined intensity-levels represents a feasible examination for children and adolescents. This study provides reference data on the range and age-adjusted normative values of the speaking voice.

Serum Uric Acid Levels as an Indicator for Metabolically Unhealthy Obesity in Children and Adolescents.

BACKGROUND: Metabolically healthy obesity (MHO) refers to those individuals who do not show cardiometabolic abnormalities. Our aim was to identify potential clinical and metabolic indicators that may help to distinguish between metabolically healthy and unhealthy individuals amongst overweight and obese children and adolescents. METHODS: The study involved 246 overweight/obese and 212 normal-weight individuals enrolled in the LIFE Child study, aged between 6 and 18 years. Overweight/obese individuals without cardiovascular risk factors (fasting serum lipids, blood pressure, and glucose) were classified as MHO. Individuals meeting 1 or more criteria of cardiovascular risk factors were classified as metabolically unhealthy obesity (MUO). RESULTS: Among the 246 overweight/obese individuals, 173 (70%) were MHO and 73 (30%) were MUO. The MHO individuals were younger, more likely to be male, and had lower BMI SDS. In the logistic regression models, uric acid (UA) SDS (OR 1.61, 95% CI 1.1-2.6, p = 0.004), waist circumference SDS (OR 2.50, 95% CI 1.2-6.4, p = 0.017), and C-peptide (OR 4.05, 95% CI 3.5-91, p = 0.003) were significant indicators of MUO. CONCLUSION: Our results suggest that nearly one-third of overweight/obese children are already identified as MUO. Serum levels of UA can be used as an indicator of unhealthy obesity in youth, where lower levels of UA indicate a lower risk and higher levels suggest a higher risk of MUO. We note that the relevance of identifying potential indicators remains the first most important step in future clinical research.