Medication costs by glucose tolerance stage in younger and older women and men: results from the population-based KORA survey in Germany.

To estimate medication costs in individuals with diagnosed diabetes, undetected diabetes, impaired glucose regulation and normal blood glucose values in a population-based sample by age and sex.Using the KORA F4 follow-up survey, conducted in 2006-2008 (n=2611, age 40-82 years), we identified individuals' glucose tolerance status by means of an oral glucose tolerance test. We assessed all medications taken regularly, calculated age-sex specific medication costs and estimated cost ratios for total, total without antihyperglycemic drugs, and cardiovascular medication, using multiple 2-part regression models.Compared to individuals with normal glucose values, costs were increased in known diabetes, undetected diabetes and impaired glucose regulation, which was more pronounced in participants aged 40-59 years than in those aged 60-82 years (cost ratios for all medications: 40-59 years: 2.85; 95%-confidence interval: 1.78-4.54, 2.00; 1.22-3.29 and 1.53; 1.12-2.09; 60-82 years: 2.04; 1.71-2.43, 1.17; 0.90-1.51 and 1.09; 0.94-1.28). Compared to individuals with diagnosed diabetes, costs were significantly lower among individuals with impaired glucose regulation across all age and sex strata, also when antihyperglycemic medication was excluded (40-59 years: 0.60; 0.36-0.98, 60-82 years: 0.74; 0.60-0.90; men: 0.72; 0.56-0.93; women: 0.72; 0.54-0.96).We could quantify age- and sex-specific medication costs and cost ratios in individuals with diagnosed diabetes, undetected diabetes and impaired glucose regulation compared to those with normal glucose values, using data of a population-based sample, with oral glucose tolerance test-based identification of diabetes states. These results may help to validly estimate cost-effectiveness of screening and early treatment or prevention of diabetes.

Serum potassium is associated with prediabetes and newly diagnosed diabetes in hypertensive adults from the general population: the KORA F4-study.

AIMS/HYPOTHESIS: Evidence suggests that low serum potassium concentrations or hypokalaemia induced by the intake of diuretics are associated with incident diabetes and increased risk for diabetes in persons with hypertension. We examined a possible association between serum potassium and prediabetes (defined as isolated impaired fasting glucose [i-IFG], isolated impaired glucose tolerance [i-IGT] or combined IFG/IGT), as well as known and newly diagnosed diabetes (NDD), in 32- to 81-year-old men and women with and without hypertension. METHODS: This cross-sectional analysis was based on 2,948 participants in the Cooperative Health Research in the Region of Augsburg (KORA) F4 study conducted in 2006-2008 in southern Germany. Serum concentrations of potassium were measured by indirect potentiometry. RESULTS: In the total sample there was no association between serum potassium concentrations and prediabetes. In hypertensive persons however serum potassium levels in the first and second quartile compared with the highest quartile were independently significantly associated with prediabetes after multivariable adjustment (OR for prediabetes, 2.02 [95% CI 1.27, 3.21] for quartile 2 and 2.00 [95% CI 1.27, 3.15] for quartile 1), while in persons without hypertension no association was found. In multinomial logistic regression analysis these findings could be confirmed. In hypertensive participants after multivariable adjustment the associations were statistically significant for i-IGT and NDD (i-IGT OR 1.23; NDD OR 1.41). However, in non-hypertensive persons, all associations between serum potassium levels and each of the categories of impaired glucose regulation were non-significant. CONCLUSIONS/INTERPRETATION: Serum potassium levels were independently associated with prediabetes and NDD in hypertensive adults from the general population.

The use of porcine acellular dermal matrix in silicone implant-based breast reconstruction.

INTRODUCTION: The most frequently occurring long-term complication in implant-based breast reconstruction is fibrotic capsule formation at the recipient site, with concurrent dysesthesia and poor aesthetic results. Using porcine acellular dermal matrix (PADM) as a connective tissue graft material is supposed to improve the quality and quantity of soft tissue in implant-based breast reconstruction. This study investigates the indications for and the results and the costs of using PADM for the correction or prevention of implant-associated breast deformities. MATERIALS AND METHODS: This study reviewed a single surgeon's experience in the correction or prevention of implant-associated breast deformities with PADM in breast cancer-related breast reconstruction from 2009 to 2011. A total of 23 patients (27 breasts) were included in the study. The aesthetic outcome, the incidence and the type of complication were analysed. Twenty-three women underwent breast cancer-related breast reconstruction: 19 women underwent single-breast reconstruction and four women underwent bilateral reconstruction. RESULTS: Of the 23 patients who underwent breast reconstruction, 18 (78%) were "satisfied" with the aesthetic and haptic outcome after implant-based reconstruction with PADM. One patient (one breast) required another breast operation because of ipsilateral breast cancer recurrence during the follow-up period. PADM-assisted implant-based breast reconstruction has a satisfactory safety profile. CONCLUSION: The use of PADM as an interface matrix for implant-based breast reconstruction yielded predictable and acceptable aesthetic and haptic results by preventing capsular contracture, rippling, implant malposition, soft-tissue thinning and failure of the silicone implant-based breast augmentation.

Age at menarche is associated with prediabetes and diabetes in women (aged 32-81 years) from the general population: the KORA F4 Study.

AIMS/HYPOTHESIS: The aim of this study was to examine the association between age at menarche and prediabetes as well as diabetes, considering confounding factors and the possible mediating role of adult obesity. METHODS: This cross-sectional study analysed data on 1,503 women aged 32-81 years from the German population-based KORA (Cooperative Health Research in the Region of Augsburg, South Germany) F4 Study (2006-2008). Data were collected by standardised interviews, physical examinations, and whole blood and serum measurements, including administration of an OGTT in non-diabetic participants. RESULTS: Of the 1,503 women, 226 showed a prediabetic state (impaired fasting glucose and/or impaired glucose tolerance) and 140 persons had diabetes (45 participants with previously undiagnosed diabetes and 95 with known diabetes). In Poisson regression analysis, age at menarche was significantly inversely associated with prediabetes or diabetes after adjustment for year of birth (RR 0.88; 95% CI 0.82, 0.94, p < 0.0001 per additional year of menarche) and after additional adjustment for a number of confounding factors (RR 0.88; 95% CI 0.83, 0.94, p = 0.0001). Further adjustment for current BMI slightly attenuated the association with prediabetes or diabetes (RR 0.89; 95% CI 0.83, 0.95, p = 0.0009), but the association remained clearly significant. CONCLUSIONS/INTERPRETATION: Age at menarche seems to be inversely associated with prediabetes and diabetes independent of confounding factors including current BMI. Women at risk for diabetes might be identified by a history of young age at menarche.

Validation of 5 routine assays for serum free testosterone with a candidate reference measurement procedure based on ultrafiltration and isotope dilution-gas chromatography-mass spectrometry.

BACKGROUND/METHOD: The analytical validity of free testosterone (FTe) analog immunoassays is subject to much controversy. We revisited the validation of 4 analog assays and 1 FTe calculation procedure with a metrologically traceable reference measurement procedure (RMP) based on ultrafiltration and isotope dilution-mass spectrometry for direct measurement of Te in the ultrafiltrate. To this end, we performed split-sample measurements of 40 male sera. RESULTS: Deming regression showed that 3 of the immunoassays had moderate to good correlation (0.8474 < or = r < or = 0.9241) with the RMP; however, the slope was markedly below 1. The FTe calculation procedure was in good agreement with this result. The Sy/x values for all assays were higher than the combined imprecision values, which indicate their susceptibility to matrix-related effects. CONCLUSIONS: The study demonstrated substantial differences in analytical quality of FTe assays; however, the results suggested that after extending the validation with a larger variety of samples, recalibration of some analog assays might be worth further investigation.

Trueness verification in European external quality assessment schemes: time to care about the quality of the samples.

An external quality assessment (EQA) survey on 14 fresh-frozen, single-donation sera assigned with reference measurement procedure (RMP) values revealed a mean bias of + 5.2% and + 3.7% for the cholesterol oxidase and the photometric glucose oxidase procedure groups, respectively. Conversely, on lyophilized sera, the same procedure groups showed almost bias-free results, the differences from the RMP values being only -0.8% for cholesterol and + 0.7% for glucose. These data, which are in fairly good agreement with the literature, suggest the existence of artificial matrix effects in processed materials. Therefore they indicate that, currently, assessment of trueness is hampered in many European EQA schemes, as most of them use lyophilized sera. This approach may give a false impression about the trueness of laboratory results as well as carrying the risk that laboratories calibrated on the RMP values of the survey samples could make errors in patient testing. Consequently, if European EQA is willing to fulfil a post-market vigilance function of the performance of in vitro diagnostic medical devices, then the time has come to tackle the problem of the quality of the survey samples. EQA organizers urgently need to make an effort to seek out materials that analytically behave like authentic clinical specimens. In the meantime, alternative approaches should be used. Although not ideal, the special survey described in this article is one of the possibilities. Naturally, it implies logistic problems and increased costs for the individual EQA schemes. However, both can be overcome with the cooperation of the predominantly nationally organized schemes.

The ionized fraction of serum total magnesium in hemodialysis patients: is it really lower than in healthy subjects?

AIM OF THE STUDY: Based on data in the literature, it remains unclear whether the ionized fraction of serum total magnesium (Mg) is lower in chronic hemodialysis (HD) patients compared to healthy subjects. PATIENTS AND METHODS: The ionized fraction of serum total Mg was investigated in 49 HD patients, pre- and post-dialysis, and compared to 30 healthy controls. The quality of the analytical performance of the Mg measurements has been emphasized by applying a reference method and/or rigorous internal quality control (IQC). In addition, the ionized fraction of serum total calcium (Ca) was measured in both populations, because the results for Mg should be related to those of Ca. RESULTS: In HD patients, the ionized fraction of serum total Mg was on average 65% (pre-dialysis 64.2% and post-dialysis 66.2%). In healthy controls, the ionized fraction was 64.9%. When the analytical variability was taken into account, no significant differences (p > 0.05) were observed between pre- and post-dialysis samples and controls. For Ca, an ionized fraction of 55.3% was found in HD patients, which was not significantly different from the fraction obtained in the control group (55.7%). CONCLUSION: The present study demonstrates that, compared to healthy controls, the ionized fraction of serum total Mg is not different in hemodialysis patients.

Strategies for determination of insulin with tandem electrospray mass spectrometry: implications for other analyte proteins?

Using human insulin (MW 5808 Da) as a model compound, the possible strategies towards optimization of sensitivity and selectivity of measurement by electrospray ionization with a standard triple quadrupole mass spectrometer were investigated. For measurement in selected ion-monitoring (SIM) mode, these strategies involved systematic variation of instrumental parameters and spray pH. In this investigation four different operating modes were used corresponding to positive/negative ionization modes with acidic/basic sprays and pH reversed (hereafter termed 'wrong-way-round' operation); the cone voltage was optimized for each mode of operation. When collision-activated dissociation (CAD) is employed, two additional operation modes are possible: namely, low collision energies (10-35 eV, CAD-l) for the generation of sequence-specific fragments and high collision energies (>80 eV, CAD-h) for the generation of nonspecific fragments. Overall, this results in twelve different modes of operation. Loop-injection of aqueous insulin standards were run for each of the twelve operating modes and measurements made for five different charge states (n = 2-6) observable with our instrument that has an upper mass limit of m/z 4000. The signal/noise (S/N) ratio was optimized for each charge state, resulting in 60 measurements. The best S/N ratios (20 000) were achieved under positive SIM conditions with charge state 6 (m/z 969) and under 'wrong-way-round' negative SIM conditions with charge state 3 (m/z 1935). Lower S/N ratios were observed under positive CAD-h conditions with charge state 5 (m/z 1163, S/N 15 000) and positive CAD-l conditions with charge state 6 (m/z 969, S/N 10 000). All other operating modes gave maximum S/N ratios of 4000. For measurement of insulin standards, the results obtained show SIM to give the best S/N ratio. However, for samples in complex matrices, our general experience suggests CAD to be the preferable operating mode. Consequently, for the development of a quantitative method for proteins in general, it might be advocated that all of the twelve operating modes and all relevant charge states be investigated to find the optimum S/N ratio.

Models for combining random and systematic errors. assumptions and consequences for different models.

A series of models for handling and combining systematic and random variations/errors are investigated in order to characterize the different models according to their purpose, their application, and discuss their flaws with regard to their assumptions. The following models are considered 1. linear model, where the random and systematic elements are combined according to a linear concept (TE = absolute value(bias) + z x sigma), where TE is total error, bias is the systematic error component, sigma is the random error component (standard deviation or coefficient of variation) and z is the probability factor; 2. squared model with two sub-models of which one is the classical statistical variance model and the other is the GUM (Guide to Uncertainty in Measurements) model for estimating uncertainty of a measurement; 3. combined model developed for the estimation of analytical quality specifications according to the clinical consequences (clinical outcome) of errors. The consequences of these models are investigated by calculation of the functions of transformation of bias into imprecision according to the assumptions and model calculations. As expected, the functions turn out to be rather different with considerable consequences for these types of transformations. It is concluded that there are at least three models for combining systematic and random variation/errors, each created for its own specific purpose, with its own assumptions and resulting in considerably different results. These models should be used according to their purposes.

Quantitative analysis of urinary C-peptide by liquid chromatography-tandem mass spectrometry with a stable isotopically labelled internal standard.

We describe the first results of a quantitative LC-tandem mass spectrometry method for urinary C-peptide with the use of [2H14]C-peptide as internal standard. LC was based on gradient elution of a Hypersil PEP C18 column. Mass spectrometry was performed in the negative electrospray ionization mode and by monitoring of the transitions at m/z 1514/1334 ([2H14]C-peptide) and 1507/1320 (C-peptide). For sample preparation, we applied ultrafiltration. The analytical performance of the method in terms of measurement precision gave an RSD of <2% (n=10). The overall imprecision was investigated from independent analysis of two urine samples in six-fold and resulted in an RSD<5%. The limit of detection, expressed as signal-to-noise ratio 3, was approximately 0.15 ng C-peptide injected. Analysis of 10 random urine samples from laboratory volunteers showed interference-free ion chromatograms at a signal-to-noise ratio of approximately 75 on average. The C-peptide concentrations calculated from quantification by the bracketing calibration technique ranged from 32 to 165 ng/ml.

Evaluation of intrinsic and routine quality of serum total magnesium measurement.

We investigated the intrinsic (as delivered by the manufacturer) and routine quality of four systems for measurement of serum total magnesium (t-Mg(2+)) by method comparison with an ion chromatography reference method. The results of the study were interpreted on the basis of analytical quality specifications derived from the biological variation of t-Mg(2+), expanded by the analytical uncertainty of the reference measurements. This resulted in limits for systematic error of 2.1% and for total error of 4.3%. The study demonstrated that those limits were challenging for all routine systems. Most of them met the total error criterium just borderline and one showed a considerable systematic error (-5.2%). Concerning the measurement quality in the routine laboratories, the study showed that many were unable to preserve the intrinsic quality of the respective manufacturer. Consequently, loss of system performance in the routine laboratory mostly led to violation of the analytical specifications. Most strikingly, the study revealed enormous quality differences between routine laboratories. This indicates that, still, many routine laboratories do not make adequate use of currently available internal and external quality control tools. Moreover, some laboratories considerably expanded the high end of the reference interval, thereby reducing the diagnostic potential of t-Mg(2+).

pH dependency of serum ionised calcium.

Measurement by ion selective electrode showed that the pH dependency of serum ionised calcium is better described by an inversely S-shaped third-degree function than by the conventionally used logarithmic function.

Survey of serum potassium reference measurements.

We compared the quality of reference measurements for serum potassium in four reference laboratories from three different European countries, using a panel of 60 native patients' samples. The reference methods were based on either ion chromatography (one laboratory) or flame atomic emission spectrometry (three laboratories). Performance specifications for serum potassium measurements were defined as a maximum overall coefficient of variation (CV) of 1.5%, a maximum bias of 0.65% and a maximum total error of 3.0%. The overall imprecision for all laboratories was in the range of 0.7 to 1.3%, and was thus below the proposed specification of 1.5%. However, two laboratories reported 12 and 13 quadruplicates with CVs exceeding this limit. The mean bias (expressed as deviation from the overall mean of all laboratories) for all reference laboratories was < 0.65%. In the lower concentration range, however, one laboratory exceeded this limit. No laboratory measured samples with a total error above 3.0%. From these results, it can be concluded that the reference measurements, and, thus, also the reference methodologies, based on ion chromatography and flame atomic emission spectrometry were equivalent, and able to satisfy current analytical specifications for serum potassium measurements.