Klaus Straßburger

Sudden and unexpected deaths after the administration of hexavalent vaccines (diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, Haemophilius influenzae type b): is there a signal?

Deaths in temporal association with vaccination of hexavalent vaccines have been recently reported. The objective of this paper is to assess whether these temporal associations can be attributed to chance. Standardised mortality ratios (SMR) for deaths within 1 to 28 days after administration of either of the two hexavalent vaccines in the 1st and 2nd year of life were determined using the respective annual rates for sudden unexpected deaths (SUDs) from the national vital statistics. The distribution of SUD cases and the vaccination uptake by month were estimated from surveys and sales figures for the individual vaccines. Sensitivity analyses were performed to account for limitations in the data sources. For one of the vaccines, Vaccine B, all SMRs were well below one. For the other, Vaccine A, SMRs exceeded one insignificantly on the 1st day after vaccination in the 1st year of life. In the 2nd year of life, however, the SMRs for SUD cases within 1 day of vaccination with vaccine A were 31.3 (95% CI 3.8–113.1; two cases observed; 0.06 cases expected) and 23.5 (95% CI 4.8–68,6) for within 2 days after vaccination (three cases observed; 0.13 cases expected). Extensive sensitivity analyses could not attribute these findings to limitations of the data sources. Conclusion: These findings based on spontaneous reporting do not prove a causal relationship between vaccination and sudden unexpected deaths. However, they constitute a signal for one of the two hexavalent vaccines which should prompt intensified surveillance for unexpected deaths after vaccination.

Indirect calorimetry in humans: a postcalorimetric evaluation procedure for correction of metabolic monitor variability

BACKGROUND Indirect calorimetry (IC) with metabolic monitors is widely used for noninvasive assessment of energy expenditure and macronutrient oxidation in health and disease. OBJECTIVE To overcome deficiencies in validity and reliability of metabolic monitors, we established a procedure that allowed correction for monitor-specific deviations. DESIGN Randomized comparative IC (canopy mode) with the Deltatrac MBM-100 (Datex) and Vmax Encore 29n (SensorMedix) was performed in postabsorptive (overnight fast >8 h) healthy subjects (n = 40). In vitro validation was performed by simulation of oxygen consumption (VO2) and carbon dioxide output (VCO2) rates by using mass-flow regulators and pure gases. A simulation-based postcalorimetric calibration of cart readouts [individual calibration control evaluation (ICcE)] was established in adults (n = 24). RESULTS The comparison of carefully calibrated monitors showed marked differences in VCO2 and VO2 (P < 0.01) and derived metabolic variables [resting energy expenditure (REE), respiratory quotient (RQ), glucose/carbohydrate oxidation (Gox), and fat oxidation (Fox); P < 0.001]. Correlations appeared to be acceptable for breath gas rates and REE (R(2) ~ 0.9) but were unacceptable for RQ (R(2) = 0.3), Gox, and Fox (R(2) = 0.2). In vitro simulation experiments showed monitor-dependent interferences for VCO2 and VO2 as follows: 1) within series, nonlinear and variable deviations of monitor readouts at different exchange rates; 2) between series, differences and unsteady variability; and 3) differences in individual monitor characteristics (eg, rate dependence, stability, imprecision). The introduction of the postcalorimetric recalibration by ICcE resulted in an adjustment of gas exchange rates and the derived metabolic variables with reasonable correlations (R(2) > 0.9). CONCLUSIONS Differential, metabolic, monitor-specific deviations are the primary determinants for lack of accuracy, comparability, and transferability of results. This problem can be overcome by the present postcalorimetric ICcE procedure.

Comparison of liver fat indices for the diagnosis of hepatic steatosis and insulin resistance.

Context Hepatic steatosis, defined as increased hepatocellular lipid content (HCL), associates with visceral obesity and glucose intolerance. As exact HCL quantification by 1H-magnetic resonance spectroscopy (1H-MRS) is not generally available, various clinical indices are increasingly used to predict steatosis. Objective The purpose of this study was to test the accuracy of NAFLD liver fat score (NAFLD-LFS), hepatic steatosis index (HSI) and fatty liver index (FLI) against 1H-MRS and their relationships with insulin sensitivity and secretion. Design, Setting and Participants Ninety-two non-diabetic, predominantly non-obese humans underwent clinical examination, 1H-MRS and an oral glucose tolerance test (OGTT) to calculate insulin sensitivity and β-cell function. Accuracy of indices was assessed from the area under the receiver operating characteristic curve (AROC). Results Median HCL was 2.49% (0.62;4.23) and correlated with parameters of glycemia across all subjects. NAFLD-LFS, FLI and HSI yielded AROCs of 0.70, 0.72, and 0.79, respectively, and related positively to HCL, insulin resistance, fasting and post-load β-cell function normalized for insulin resistance. Upon adjustment for age, sex and HCL, regression analysis revealed that NAFLD-LFS, FLI and HSI still independently associated with both insulin sensitivity and β-cell function. Conclusion The tested indices offer modest efficacy to detect steatosis and cannot substitute for fat quantification by 1H-MRS. However, all indices might serve as surrogate parameters for liver fat content and also as rough clinical estimates of abnormal insulin sensitivity and secretion. Further validation in larger collectives such as epidemiological studies is needed.

Health-Related Quality of Life Among German Youths With Early-Onset and Long-Duration Type 1 Diabetes

OBJECTIVE To evaluate self- and parent reports of general health status and health-related quality of life (QoL) in children and adolescents with early-onset and long-lasting type 1 diabetes compared with the general population in Germany. RESEARCH DESIGN AND METHODS A total of 629 subjects aged 11 to 17 years, with a type 1 diabetes onset occurring from age 0 to 4 years during the years 1993–1999, and their parents, completed questionnaires, including the generic KINDL-R Questionnaire for Measuring Health-Related Quality of Life in Children and Adolescents, revised version, to assess QoL. The comparison group (n = 6,813) was a representative sample from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) study. Regression analyses were conducted using sociodemographic and health-related covariates. RESULTS Intensified insulin therapy was used to treat 93% of children and adolescents with type 1 diabetes. They reported “excellent” general health as often as peers (adjusted OR 0.83 [95% CI 0.66–1.04] for an “excellent” rating), but the parent-rated general health was worse than that in the general population (OR 0.60 [0.48–0.74]). The patients reported increased self-esteem (adjusted difference β = 4.39 [SE 0.82]; P < 0.001) and well-being at school (β = 3.41 [0.77]; P < 0.001) but lower well-being within their families (β = –2.42 [0.80]; P = 0.002). The self- and parent-reported total QoL did not differ between the patient group and the general population. The adjusted difference (SE) between the two samples in total QoL was β = 0.89 (0.52; P = 0.087) in the self-reports and β = –0.98 (0.53; P = 0.066) in the parent-reports. CONCLUSIONS Compared with the general population, the QoL and general health status were not impaired among those aged 11–17 years with early-onset type 1 diabetes, despite the challenges of modern therapy.

Testing and Selecting for Equivalence with Respect to a Control

Abstract The problem of equivalence assessment of several treatments with a control is considered. The first approach uses a hypothesis testing formulation in which the alternative states global equivalence. With respect to a family of distributions with location parameter, a test based on a two-sided many-one statistic is proposed. Least favorable parameter configuration results are presented as being necessary to evaluate critical values and to determine sample sizes implied by certain power requirements when planning experiments. The second approach concerns a stepwise selection procedure. The goal is to select a subset of treatments containing all those actually equivalent to the control in the absence of global equivalence. The normal case is dealt with in detail for randomized block designs as well as for one-way layouts. Concerning the test problem, optimal allocations of total sample sizes are determined to guarantee specified power requirements for the one-way layout.

Quality of life in intensively treated youths with early-onset type 1 diabetes: a population-based survey

To evaluate factors associated with self‐reported generic, chronic‐generic, and condition‐specific quality of life (QoL) impairments in intensively treated patients with early‐onset and long‐duration type 1 diabetes.

Is disordered eating behavior more prevalent in adolescents with early-onset type 1 diabetes than in their representative peers?

OBJECTIVE Despite modern therapeutic regimens, youths with Type 1 diabetes may be at increased risk of mental and behavioral disorders. In this study, the prevalence of disordered eating behavior (DEB) in intensely treated children and adolescents with early-onset Type 1 diabetes and peers from the general population was compared. METHOD Data from 629 patients from a population-based, nationwide survey (54.1% male, mean age 15.3 years) with early-onset Type 1 diabetes of at least 10 years duration were compared with data from 6,813 participants of the German KiGGS study (51.3% male, mean age 14.6 years). The generic SCOFF questionnaire was used as screening instrument to identify participants with symptoms of DEB. Both groups were compared with multivariable regression analysis adjusting for sociodemographic covariates. RESULTS 31.2% of the female and 11.7% of the male diabetic patients and 28.9% of the females and 15.2% of the males in the comparison group were SCOFF-positive (SCOFF score ≥2; p > .05). The odds for symptoms of eating disorders were 3.7% higher in female and 4.3% lower in male patients with diabetes than in the comparison group, but the differences were not significant. 20.5% of the female and 18.5% of the male diabetic patients reported insulin restriction at least three times per week. DISCUSSION Children and adolescents with early-onset Type 1 diabetes of long duration do not seem to be more frequently SCOFF-positive than peers. However, as insulin restriction is practiced in a substantial portion of patients, attention for insulin restriction in diabetes care is essential.

Lower Fasting Muscle Mitochondrial Activity Relates to Hepatic Steatosis in Humans

OBJECTIVE Muscle insulin resistance has been implicated in the development of steatosis and dyslipidemia by changing the partitioning of postprandial substrate fluxes. Also, insulin resistance may be due to reduced mitochondrial function. We examined the association between mitochondrial activity, insulin sensitivity, and steatosis in a larger human population. RESEARCH DESIGN AND METHODS We analyzed muscle mitochondrial activity from ATP synthase flux (fATP) and ectopic lipids by multinuclei magnetic resonance spectroscopy from 113 volunteers with and without diabetes. Insulin sensitivity was assessed from M values using euglycemic-hyperinsulinemic clamps and/or from oral glucose insulin sensitivity (OGIS) using oral glucose tolerance tests. RESULTS Muscle fATP correlated negatively with hepatic lipid content and HbA1c. After model adjustment for study effects and other confounders, fATP showed a strong negative correlation with hepatic lipid content and a positive correlation with insulin sensitivity and fasting C-peptide. The negative correlation of muscle fATP with age, HbA1c, and plasma free fatty acids was weakened after adjustment. Body mass, muscle lipid contents, plasma lipoproteins, and triglycerides did not associate with fATP. CONCLUSIONS The association of impaired muscle mitochondrial activity with hepatic steatosis supports the concept of a close link between altered muscle and liver energy metabolism as early abnormalities promoting insulin resistance.

Inflammatory markers are associated with cardiac autonomic dysfunction in recent-onset type 2 diabetes

Objective Cardiovascular autonomic neuropathy is a common but underestimated diabetes-related disorder. Associations between cardiovascular autonomic dysfunction and subclinical inflammation, both risk factors of diabetic comorbidities and mortality, have been proposed in non-diabetic populations, while data for type 1 and type 2 diabetes are conflicting. Our aim was to investigate associations between inflammation-related biomarkers and cardiac autonomic dysfunction in patients with diabetes. Methods We characterised the associations between seven biomarkers of subclinical inflammation and cardiac autonomic dysfunction based on heart rate variability and cardiovascular autonomic reflex tests (CARTs) in 161 individuals with type 1 and 352 individuals with type 2 diabetes (time since diagnosis of diabetes <1 year). Analyses were adjusted for age, sex, anthropometric, metabolic and lifestyle factors, medication and cardiovascular comorbidities. Results In individuals with type 2 diabetes, higher serum interleukin (IL)-18 was associated with lower vagal activity (p≤0.015 for association with CARTs), whereas higher levels of total and high-molecular-weight adiponectin showed associations with very low frequency power, an indicator of reduced sympathetic activity (p≤0.014). Higher levels of soluble intercellular adhesion molecule-1 were associated with indicators of both lower vagal (p=0.025) and sympathetic (p=0.008) tone, soluble E-selectin with one indicator of lower vagal activity (p=0.047). Serum C-reactive protein and IL-6 were also related to cardiac autonomic dysfunction, but these associations were explained by confounding factors. No consistent associations were found in individuals with type 1 diabetes. Conclusions Biomarkers of inflammation were differentially associated with diminished cardiac autonomic dysfunction in recent-onset type 2 diabetes.

Adiponectin, markers of subclinical inflammation and nerve conduction in individuals with recently diagnosed type 1 and type 2 diabetes

OBJECTIVE Subclinical inflammation has been implicated in the development of diabetic sensorimotor polyneuropathy (DSPN), but studies using electrophysiological assessment as outcomes are scarce. Therefore, we aimed to investigate associations of biomarkers reflecting different aspects of subclinical inflammation with motor and sensory nerve conduction velocity (NCV) in individuals with diabetes. DESIGN AND METHODS Motor and sensory NCV was assessed in individuals with recently diagnosed type 2 (n=352) or type 1 diabetes (n=161) from the baseline cohort of the observational German Diabetes Study. NCV sum scores were calculated for median, ulnar and peroneal motor as well as median, ulnar and sural sensory nerves. Associations between inflammation-related biomarkers, DSPN and NCV sum scores were estimated using multiple regression models. RESULTS In type 2 diabetes, high serum interleukin (IL)-6 was associated with the presence of DSPN and reduced motor NCV. Moreover, higher levels of high-molecular weight (HMW) adiponectin, total adiponectin and their ratio were associated with prevalent DSPN and both diminished motor and sensory NCV, whereas no consistent associations were observed for C-reactive protein, IL18, soluble intercellular adhesion molecule-1 and E-selectin. In type 1 diabetes, only HMW and total adiponectin showed positive associations with motor NCV. CONCLUSIONS Our results point to a link between IL6 and both DSPN and slowed motor NCV in recently diagnosed type 2 diabetes. The reverse associations between adiponectin and NCV in type 1 and type 2 diabetes are intriguing, and further studies should explore whether they may reflect differences in the pathogenesis of DSPN in both diabetes types.