Direct costs in impaired glucose regulation: results from the population-based Heinz Nixdorf Recall study.

OBJECTIVE: For the first time, this population-based study sought to analyze healthcare utilization and associated costs in people with normal fasting glycemia (NFG), impaired fasting glycemia (IFG), as well as previously undetected diabetes and previously diagnosed diabetes linking data from the prospective German Heinz Nixdorf Recall (HNR) study with individual claims data from German statutory health insurances. RESEARCH DESIGN AND METHODS: A total of 1709 participants of the HNR 5-year follow-up (mean age (SD) 64.9 (7.5) years, 44.5% men) were included in the study. Age-standardized and sex-standardized healthcare utilization and associated costs (reported as € for the year 2008, perspective of the statutory health insurance) were stratified by diabetes stage defined by the participants' self-report and fasting plasma glucose values. Cost ratios (CRs) were estimated using two-part regression models, adjusting for age, sex, sociodemographic variables and comorbidity. RESULTS: The mean total direct healthcare costs for previously diagnosed diabetes, previously undetected diabetes, IFG, and NFG were €2761 (95% CI 2378 to 3268), €2210 (1483 to 4279), €2035 (1732 to 2486) and €1810 (1634 to 2035), respectively. Corresponding age-adjusted and sex-adjusted CRs were 1.53 (1.30 to 1.80), 1.16 (0.91 to 1.47), and 1.09 (0.95 to 1.25) (reference: NFG). Inpatient, outpatient and medication costs varied in order between people with IFG and those with previously undetected diabetes. CONCLUSIONS: The study provides claims-based detailed cost data in well-defined glucose metabolism subgroups. CRs of individuals with IFG and previously undetected diabetes were surprisingly low. Data are important for the model-based evaluation of screening programs and interventions that are aimed either to prevent diabetes onset or to improve diabetes therapy as well.

Clinically high-risk prostate cancer patients comprise a relevant number of cancers with overall favorable tumor characteristics.

PURPOSE: We hypothesized that a relevant number of patients with clinically high-risk prostate cancer (PCA) indeed harbor overall favorable tumor characteristics (OFTC) (i.e., pT2a-c and Gleason score ≤3 + 4 = 7 and pN0/X) and that in these patients radical prostatectomy (RP) alone is most likely curative. METHODS: Between June 1, 1997, and October 31, 2011, 2,346 patients with biopsy-detected PCA underwent RP. According to D'Amico, 1,767 patients presented low-/intermediate-risk PCA, and 579 presented high-risk PCA. We compared the incidence of OFTC between low-/intermediate-risk and high-risk patients, and between high-risk patients with different risk factor constellations. Furthermore, overall survival (OS), cancer-specific survival (CSS) and biochemical progression-free survival (BFS) were calculated for low-/intermediate-risk and high-risk patients with and without OFTC. RESULTS: High-risk patients were less likely to harbor OFTC (17.3 vs. 58.2 %; p < 0.001). That means, however, that nearly one in five patients with clinically high-risk PCA indeed had OFTC. Particularly, the subgroup with PSA >20 ng/ml or cT2c-3 tumor as sole high-risk factor showed a considerable proportion of OFTC in 30.2 and 26.1 % of cases, respectively. While the entire high-risk group had shorter OS, CSS and BFS than the low-/intermediate-risk group, high-risk patients with OFTC had comparably good OS, CSS and BFS as low-/intermediate-risk patients with OFTC. CONCLUSIONS: Nearly, one in five patients assumed to have high-risk PCA indeed had OFTC. Particularly, patients with PSA >20 ng/ml or cT2c-3 tumor as sole high-risk factor were often misclassified. However, these misclassified patients achieve excellent survival and have a reasonable chance of cure with RP alone.

Cardiac risk in patients with treatment naïve, first-line medically controlled and first-line surgically cured acromegaly in comparison to matched data from the general population.

INTRODUCTION: Coronary risk factors in patients with acromegaly after first-line transsphenoidal surgery (TSS) or first-line somatostatine analogue (SSA) treatment have rarely been examined. Aim of this study was an evaluation of cardiovascular risk factors and left ventricular hypertrophy (LVH) in 3 different patient groups with treatment naïve, active (ACT), first-line medically controlled (MED) and first-line surgically treated (SUR) acromegaly and a calculation of the Framingham Weibull Risk Score (FS). DESIGN: Retrospective comparative matched case-control study. PATIENTS & METHODS: 40 acromegalic patients (cases aged 45-74 years, 23 men) were matched with respect to age and gender to 200 controls from the general population. 13 patients had treatment-naïve acromegaly (ACT), 12 patients were SSA treated (MED) and 15 patients were operated by TSS (SUR). Coronary risk factors were assessed after 12 months of treatment by interviews and direct laboratory measurements. Only patients normalized for IGF-I in MED and SUR group were included. FS and odds ratios (OR) from multiple conditional logistic regression (matched for age and gender, adjusted for BMI) were calculated. RESULTS: Compared to matched controls ACT patients had higher HbA1c levels (6.9±1.4 vs. 5.5±0.7% (p<0.0001)) and an increased prevalence of left ventricular hypertrophy (LVH) (30.8 vs. 3.2% (p=0.007). MED and SUR groups were similar for gender, age, disease duration and IGF-I levels at diagnosis. Compared to matched controls, MED patients had a significantly increased diastolic blood pressure (89±9 vs. 79±11 mmHg (p=0.001), prevalence of LVH (41.7 vs. 1.7% (p<0.0001), prevalence of diabetes mellitus (33.3 vs. 10.0% (p=0.03)), higher HbA1c levels (6.8±1.3 vs. 5.5±0.7% (p=0.0005)) and a higher FS (21.2±9.7 vs. 12.4±7.7% (p=0.002), OR 1.11 [1.02-1.21] (p=0.01)) while in the SUR group only higher prevalences of LVH (40.0 vs. 4.1% (p<0.0001)) and HbA1c levels (6.4±1.2 vs. 5.5±0.8% (p=0.006)) were found compared to controls. CONCLUSION: When comparing treatment naive, medically treated and surgically cured patients with acromegaly to age- and gender-matched subjects from the general population, we have found an increased cardiovascular risk in patients at 12 months after first-line SSA treatment but not in patients after first-line surgery.

[Distribution of carotid intima media thickness in men and women with and without coronary heart disease. Cross-sectional data of the Heinz Nixdorf Recall Study]. / Verteilung der karotidalen Intima-Media-Dicke bei Männern und Frauen mit und ohne koronare Herzerkrankung : Querschnittsdaten aus der Heinz Nixdorf Recall Studie.

PURPOSE: The aim of this study was to introduce population-based sex and age-stratified distributions of carotid intima media thickness (CIMT), to compare fixed cut-off and percentile values for subjects with and without known coronary heart disease (CHD) and to describe CIMT percentiles. METHODS: Between 2000 and 2003, a total of 4,814 subjects aged 45-75 years were recruited into the Heinz Nixdorf recall study (HNR). Ultrasound examination of extracranial arteries was performed and the CIMT was measured manually over a distance of 1 cm proximal to the bulb in the common carotid artery (CCA). Both sides were measured and the average of the right and left artery were calculated (mean CIMT). RESULTS: The CIMT was measured for 1,749 men and 1,802 women without prevalent CHD and 177 men and 50 women with prevalent CHD. Mean CIMT values were higher in men compared to women (men 0.71 ± 0.14 mm vs. women 0.65 ± 0.11 mm, p ≤ 0.0001) and in subjects with CHD compared to those without (men with and without CHD: 0.76 ± 0.14 mm and 0.70 ± 0.14 mm, p ≤ 0.0001, respectively; women with and without CHD: 0.73 ± 0.15 mm and 0.64 ± 0.11 mm, p ≤ 0.0001, respectively). In men the mean CIMT increased from 0.62 ± 0.10 mm in the youngest (45-49 years old) up to 0.79 ± 0.13 mm in the highest age group (≥ 70 years) (0.57 ± 0.08 mm up to 0.71 ± 0.12 mm in women, p ≤ 0.0001 for both). CONCLUSIONS: Compared to international studies similar CIMT distributions were found in this study using both continuous and percentile distributions. However, lower CIMT values were observed in older participants, which can be explained by exclusion of carotid plaque formation in CIMT measurements.

Impact of smoking on the course of Graves' disease after withdrawal of antithyroid drugs.

Cigarette smoking has been reported to alter relapse rate in patients with Graves' disease (GD). However, the predictive effect of smoking in GD patients after withdrawal of antithyroid drug treatment (ATDT) is still controversial. A prospective multicenter trial has previously identified smoking as an independent risk factor for relapse. Based on this study, the present paper gives a more detailed analysis of the impact of smoking on the long-term course of GD after ATDT withdrawal. To this end, 86 smokers and 177 non-smokers were followed during two years after ATDT cessation. At the end of ATDT (visit 1) and four weeks later (visit 2) smokers had significant higher TSH receptor antibody (TRAb) levels than non-smokers (10.0 IU/L+/-1.6; mean+/-SEM vs. 6.4 IU/L+/-0.9; 11.0 IU/L+/-1.8 vs. 6.8 IU/L+/-0.8, p < 0.01, respectively). During follow-up, Kaplan Meier analysis showed a significantly higher relapse rate in smokers than non-smokers. A subset of GD patients with TRAb levels >10 IU/L had the highest risk to develop relapse during follow-up. Among them, smokers more often relapsed than non-smokers irrespective of TRAb levels, p < 0.01. Thus, in smokers with TRAb levels > or =10 IU/L the predictive values of a positive and negative test for relapse was 68% and 73%, respectively (specificity 95%). In conclusion, we identified two effects by which smoking alters the course of GD. First, smoking is implicated to elevate TRAb levels and therefore increase the risk for relapse during follow-up. Second, smoking is an independent risk factor to worsen the clinical course of both, GD patients with low and high immunological risk to experience relapse after a successful outcome of ATDT. Thus, our data suggest that smoking has modifying immunological consequences and an adverse impact on the course of GD after withdrawal of ATDT. Therefore, patients should be encouraged to stop smoking.

Binding, stimulating and blocking TSH receptor antibodies to the thyrotropin receptor as predictors of relapse of Graves' disease after withdrawal of antithyroid treatment.

TSH-receptor autoantibodies (TRAbs) are a valuable diagnostic tool for confirming a diagnosis of Graves' disease (GD). While there is evidence that high TRAb levels are associated with relapse of GD, whether a discrimination of TRAb into stimulating (TSAb) and blocking (TBAb) autoantibodies would benefit the clinician in terms of outcome prediction remains unclear. To address this issue, we have determined TRAb, TSAb and TBAb levels in serum samples of ninety-six euthyroid patients with GD taken four weeks after antithyroid drug withdrawal (ATDT). Forty-seven patients (49 %) underwent relapse of GD within two years. Amongst those, forty-one (87 %) had been positive for TRAb and thirty-five (74 %) for TSAb after treatment. All patients except one were negative for TBAb. The correlation between TRAb and TSAb in those treated GD patients was relatively weak (r = 0.268, p < 0.001). Based on a cut-off limit of 1.5 IU/l, the positive and negative predictive values with respect to prediction of relapse were too low for any clinical relevance (TRAb: 49 % and 54 %; TSAb: 51 % and 55 %). However, when a cut-off level above 10 IU/l was used, the positive and negative predictive values increased to 83 % and 62 %. The additional measurement of TSAb or TBAb in those samples after therapy did not add additional information, even at higher decision thresholds. In conclusion, differentiation of TRAb into TSAb and TBAb is of no help in the prediction of relapse of GD in euthyroid patients at the end of ATDT, and only high TRAb levels are associated with relapse.

Long-term follow-up of thyroid nodule growth.

Benign thyroid nodules are common in iodine deficient countries. Although many recent studies have addressed the molecular basis and short-term outcome of treatment in nodular thyroid disease, data on the long-term follow-up of thyroid nodule growth are widely lacking. The aim of the present study was to evaluate the long-term behaviour of benign thyroid nodules growth. We followed 109 consecutive patients seen at yearly intervals in our Outpatient Clinic for at least 3 years (range 3-12 years, mean 4.9 +/- 2.6 years) presenting with 139 benign nodules in uni- or multinodular goiters. The size of the nodules and thyroid glands was analysed retrospectively. The study included a spectrum of benign thyroid nodules, 86 functioning and 53 non-functioning. 27 patients were treated with levothyroxine, 8 with iodide and 16 with a combination of both. 58 patients were not treated mainly because of thyroid functional autonomy. Patients with overt hyperthyroidism or suspected malignancy by fine-needle aspiration were excluded from the study. The nodules and glands were assessed by ultrasonography at yearly intervals and documented by photoprints. Relevant growth was defined as an increase in nodule volume of at least 30%. For statistical analyses, Cox Proportional Hazard Model and life-table analyses according to Kaplan-Meier were performed. Most thyroid nodules grew slowly but continuously during follow-up. After about 3 years, half of the nodules had increased their volume by at least 30%. Growth of the nodules was significantly faster than of the corresponding thyroid glands (p < 0.0001). Age and sex of the patients and size or function of the nodules at initial presentation were not significantly related to their growth. Suppression of TSH did not affect growth of the nodules irrespective of the source of thyroid hormones, endogenous or by administration of levothyroxine. In conclusion, benign thyroid nodules have a slow intrinsic growth potential, which is apparently higher than that of the non-nodular tissue. In this study, not only nodular but even non-nodular goiter growth continues in the majority of patients. Exogeneous factors, including therapy with levothyroxine and/or iodide, appear to have little effect on the growth behaviour.

Transient stimulatory effects on pituitary-thyroid axis in patients treated with interleukin-2.

It has been shown that various cytokine therapies may influence thyroid hormone parameters that may lead to serious side effects including nonthyroidal illness. Interleukin-2 is effective in increasing CD4-T cell numbers in human immunodeficiency virus (HIV)-infected patients and it is used in the treatment of various malignant tumours. However, the association of interleukin-2 (IL-2) therapy and thyroid function is not clearly established as serial systematic measurements of thyroid parameters have not been performed with interleukin-2 as the sole therapeutic agent. Therefore, it was the aim of this study to examine prospectively the impact of a 5-day interleukin-2 therapy on thyroid parameters in asymptomatic HIV-infected patients. Twenty male euthyroid patients (mean age, 42.6 +/- 3.2 years; body weight, 73.4 +/- 3.0 kg) received 9,000,000 IU/d interleukin-2. Thyroid function was evaluated by measurements of serum thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4), free thyroxine (FT4), reverse T3 (rT3), thyroglobulin (Tg), thyroxine-binding globulin (TBG), and anti-thyroid-peroxidase (TPO)-antibodies from day 1-4 and on days 7, 14, 20, 40, 60, 80, and 100. All results are given as mean +/- SD. On day 4, we observed a significant increase that was still within normal range of T4 and T3 (p < 0.05). TSH increased from 1.33 +/- 0.57 to 4.53 +/- 1.39 mU/l (p = 0.0001) and FT4 from 18.1 +/- 4.2 to 48.9 +/- 10.9 pmol/L (p = 0.0001) on day 4 with a gradual decrease thereafter. Normalization to baseline levels for TSH (1.45 +/- 0.75 mU/L) and FT4 (18.1 +/- 3.0 pmol/L) was achieved only on day 14. The increase of FT4 was more pronounced (well in the hyperthyroid range) than the increase in total T4 in the presence of normal TBG and albumin concentrations whereas TBG was not affected. We did not observe changes in anti-TPO-antibody levels up to day 100. Our data clearly demonstrate that the administration of interleukin-2 has a stimulatory effect on the pituitary-thyroid axis. The increase of TSH suggests a central stimulation directed by the action of IL-2 as the major mechanism.

Long-term survival after induction therapy with idarubicin and cytosine arabinoside for de novo acute myeloid leukemia.

We treated 153 patients with de novo acute myeloid leukemia (AML) with two induction courses of conventional-dose cytosine arabinoside (ara-C) and idarubicin (AIDA) followed by either a third course of AIDA, high-dose ara-C or bone-marrow transplantation. The complete remission (CR) rate for all patients was 63.4%, with a higher CR rate for patients with a normal (versus unfavorable) karyotype (73.2% vs 52.5%; P=0.038). The probability of overall survival (OS) was 30.7% after 5 years (26.3% after 7 years). Improved OS at 5 years could be observed for patients up to 50 years old versus patients older than 50 years of age (37.6% vs 19.9%; P=0.001) and patients with a normal (versus unfavorable) karyotype (42.9% vs 14.1%; P=0.0016). Disease-free survival (DFS) after 5 years was 33.2% for all 97 CR patients and was significantly better for patients with a normal (versus unfavorable) karyotype (44.3% vs 12.3%; P= 0.003). Multivariate analysis revealed that the age for OS (P < 0.02) and the karyotype for both OS (P<0.03) and DFS (P< 0.05) were independent prognostic factors. In conclusion, AIDA is an effective and well-tolerated induction regimen (even in elderly patients) with a 5-year survival of more than 30% when combined with ara-C-containing postremission therapy. The karyotype is the most powerful prognostic factor for predicting the outcome of patients treated with this protocol.

Differences in blood pressure values by simultaneous auscultation of Korotkoff sounds inside the cuff and in the antecubital fossa.

To elucidate whether auscultation of the Korotkoff sounds inside the cuff and in the antecubital fossa leads to different blood pressure (BP) values we measured BP at both sites simultaneously with identical flat stethoscopes in a same-arm test design (part A) in 64 normotensive (N: 32 men, 32 women; mean age: 38.7 +/- 15.1 years) and 67 hypertensive subjects (H: 36 men, 31 women; mean age: 44.6 +/- 12.9 years), and additionally in a same- and opposite-arm test design (part B) in 20 normotensive young women. While in part A systolic BP measured inside the cuff was only slightly higher (N: +1. 6 +/- 3.2 mm Hg; H: +1.0 +/- 1.4 mm Hg), diastolic BP was considerably lower (N: -10.6 +/- 5.6 mm Hg; H: -8.4 +/- 4.9 mm Hg). This result was corroborated by part B with differences in systolic/diastolic BP of +0.8 +/- 1.0/-8.5 +/- 2.2 mm Hg in the same-arm test and +0.4 +/- 4.8/-10.6 +/- 5.2 mm Hg in the opposite-arm test. Subject's age was the main variable determining differences in diastolic BP with significantly higher differences in younger than in older subjects, indicating that the elastic properties of arteries may be responsible for these differences. Our results demonstrate that a modification in the auscultatory technique of BP measurement produces significantly different diastolic BP values, the magnitude of which is important for our conceptions of threshold and target values in diagnosing and treating hypertension.

[What is the value of determining walking distance in peripheral arterial occlusive disease on the treadmill and in daily life? Prospective correlation study]. / Was bedeuten Gehstreckenbestimmungen bei peripherer arterieller Verschlusskrankheit auf dem Laufband und im Alltag? Prospektive Korrelationsuntersuchung.

AIM: To investigate the question whether and how walking distances measured under standardized conditions on the treadmill and on the level correlate with the patients walking ability under everyday conditions. PATIENTS AND METHOD: In 49 patients (33 men, 16 women, age 34 to 84 years) with Fontaine Stage II peripheral arterial occlusive disease the pain-free and absolute walking distance on the treadmill were measured under standardized conditions, as also the walking distance on the level at freely selected speed. RESULT: It was found that the pain-free walking distance under everyday conditions was about 2 to 3 times longer than that measured under standardized conditions on the treadmill.

Devices for blood pressure self measurement: tested in comparison.

OBJECTIVE: Comparative clinical evaluation of instruments designed for the self-measurement of blood pressure. METHOD: The usefulness of 27 different, exclusively oscillometric, automated devices were tested on a single group of 24 test persons without pressure-reducing arterial stenoses in the upper extremity. The cuff was to be put on the upper arm with 20 devices, on the wrist with five devices and on the left index finger with two devices. Per device and test person, six sequential comparative measurements were carried out using automated self-measurement and standard method with a double stethoscope in the same arm. RESULTS: On average, the devices measured the systolic pressure between 13.2 mmHg lower and 3.5 mmHg higher than the standard procedure; the diastolic pressure was measured between 17.4 and 0.2 mmHg lower. Using a scoring system, in which a device only got points for a comparative measurement if the differences to the control in systolic and diastolic measurement both were < or = 10 mmHg, the devices gained between 67 and 259 out of a maximum of 576 points. If each of the test persons had opted to buy just those devices which revealed a mean systolic and diastolic error of < or = 5 mmHg in his or her case, younger test persons would have found zero to five suitable devices older persons three to 13. The site of cuff application had no significant influence on results. CONCLUSIONS: Standard measurements and measurements with automated blood pressure self-measurement devices can differ considerably. In young test persons less suitable instruments are found than for older persons.

Breakpoint localization within the M-bcr and clinical course do not correlate in patients with chronic myelogenous leukemia undergoing alfa interferon therapy.

The breakpoint localization was analyzed in 61 patients with Philadelphia chromosome (Ph) positive chronic myelogenous leukemia to compare the breakpoint localization and clinical course. All patients were treated with interferon alfa (IFN alpha) or IFN alpha plus IFN gamma at the time of the study. Thirty-three of the patients had been pretreated with other cytostatic drugs. Sixty-nine per cent of the breakpoints were located in the 5' region of the major breakpoint cluster region (M-bcr), 29% in the 3' part. There was no significant difference between these two groups with respect to response to IFN(s), clinical course or conversion to blast crisis, nor survival.

[Cross-sectional study of elementary school children for assessing suspected effects of regional hemato-toxic environmental pollutants]. / Querschnittsuntersuchung an Grundschulkindern zur Klärung eines Verdachts auf Auswirkungen von regionalen hämatotoxischen Umweltnoxen.

To investigate the suspicion of an increased incidence of leukopenia in school children living in the more industrialised northern region of the city of Essen, blood counts of these children were compared to those of pupils from the southern region in a two-phased study. In 469 1st and 2nd grade children, neither the mean leukocyte count nor the number of individual abnormal results differ between the two regional groups. A difference in the mean hemoglobin value found in the first series of investigations could not be reproduced in a control study of 255 children, the analysis of the data pointing to a methodological reason for the difference. Feasibility, planning and interpretation of results of such a cross-sectional study are discussed.