Fatigue in adults with spinal muscular atrophy under treatment with nusinersen.

5q-Associated spinal muscular atrophy is a hereditary neuromuscular disease leading to progressive muscle weakness in which fatigue occurs and affects quality of life. Treatment with the antisense oligonucleotide nusinersen has been shown to improve motor function. Fatigue can be measured within the Fatigue Severity Scale (FSS). FSS is a self-reported questionnaire consisting of nine items to quantify fatigue severity within the last week. Higher values indicating a higher severity. Using the FSS, fatigue was measured in 28 adult patients, subdivided into ambulatory and non-ambulatory, suffering from a genetically confirmed 5q-SMA under treatment with nusinersen in accordance with the label. Correlations were performed among FSS and motor scales, 6-minute walk test (6MWT) and Hammersmiths Functional Motor Scale Expanded (HFMSE). Evaluation was performed prior to treatment initiation and after 6 and 10 months. The mean FSS score for all 28 patients at baseline was 4.61 ± 1.44. After 6 months mean FSS score significantly reduced to 3.92 ± 1.35. After 10 months mean FSS score had not differed from baseline, 3.84 ± 1.25. A moderate negative correlation of the difference of FSS and 6MWT after 6 months compared to baseline conditions was measured. Nusinersen reduces fatigue as measured by the FSS in adult patients with 5q-SMA transiently after initiation of treatment. There was no reduction of FSS 10 months after the beginning of treatment when compared to baseline.

Good Medicine and Good Healthcare Demand Good Information (Systems).

The demand for evidence-based health informatics and benchmarking of 'good' information systems in health care gives an opportunity to continue reporting on recent papers in the German journal GMS Medical Informatics, Biometry and Epidemiology (MIBE) here. The publications in focus deal with a comparison of benchmarking initiatives in German-speaking countries, use of communication standards in telemonitoring scenarios, the estimation of national cancer incidence rates and modifications of parametric tests. Furthermore papers in this issue of MIM are introduced which originally have been presented at the Annual Conference of the German Society of Medical Informatics, Biometry and Epidemiology. They deal as well with evidence and evaluation of 'good' information systems but also with data harmonization, surveillance in obstetrics, adaptive designs and parametrical testing in statistical analysis, patient registries and signal processing.

How to use information technology to improve medication safety.

The publication of a memorandum on improving medication safety by information technology in both the German journal GMS Medical Informatics, Biometry and Epidemiology (MIBE) and the journal Methods of Information in Medicine (MIM) gives reason to strengthen cooperation of MIBE and MIM and to report on more publications of MIBE here. The publications in focus deal with simulation-based optimization of emergency processes, handling of research data in publications, open access to research metadata, reliability of digital patient records in medical research, assessment methods for physical activity, using of insurance databases for epidemiological studies, certificates for epidemiological professionals, regression models, computer based training, and performance management in Swiss hospitals. Finally determining factors for scientific careers are discussed.

Treatment adherence and persistence in adult ADHD: results from a twenty-four week controlled clinical trial with extended release methylphenidate.

PURPOSE: The aim of this analysis is to describe medication adherence, and treatment persistence, in adults with attention deficit/hyperactivity disorder (ADHD) treated for 24 weeks with extended release methylphenidate (MPH-ER). Additionally, patient-, disorder- and treatment-related factors associated with adherence and persistence will be identified. METHOD: Post-hoc analysis of the active treatment group of a placebo-controlled, randomised, 24 week trial with MPH-ER with univariate description and multiple logistic regression models and Hosmer and Lemeshow tests. RESULTS: In the sample of 241 adults with ADHD (mean age of 35.2 ± 10.1 years), 9.4% of the patients were non-adherent, taking less than 80% of the dispensed medication. Factors associated with non-adherence included age<25 years, education level lower than secondary education, lacking family history of ADHD, lower ADHD baseline severity and lower self- and observer-rated medication efficacy. Lacking family history of ADHD, lower education level and lower self-rated medication efficacy, predicted non-adherence with a prediction accuracy of 16%. Seventeen percent of the patients discontinued early with most discontinuing within the first five weeks of the MPH-ER titration phase. Mean persistence in the discontinuing group was 63.4 ± 49.4 days. Factors associated with discontinuation included male gender, lower education level, lacking family history of ADHD and lower self- and observer-rated medication efficacy. Treatment non-response, male gender and lower education level predicted treatment discontinuation with a prediction accuracy of 22.7%. CONCLUSION: Male adults without relatives with ADHD, with lower educational level and lower self- and observer-rated medication efficacy, who are newly treated with MPH-ER, are at increased risk of non-adherence and treatment discontinuation. Patients are at increased risk of treatment discontinuation during the medication titration phase.

More than four decades of medical informatics education for medical students in Germany. New recommendations published.

The publication of German competency-based learning objectives "Medical Informatics" for undergraduate medical education gives reason to report on more publications of the German journal GMS Medical Informatics, Biometry and Epidemiology ( MIBE ) in Methods. The publications in focus deal with support of medical education by health and biomedical informatics, hospital information systems and their relation to medical devices, transinstitutional health information systems and the need of national eHealth strategies, epidemiological research on predicting high consumption of resources, and with the interaction of epidemiologists and medical statisticians in examining mortality risks in diabetes, in genome wide association studies and in dealing with limits and thresholds. This report is the beginning of an annual series intending to support better international cooperation to achieve good information as a basis for good medicine and good healthcare.

Randomized comparison of synchronous CABG and carotid endarterectomy vs. isolated CABG in patients with asymptomatic carotid stenosis: the CABACS trial.

RATIONALE: High-grade carotid artery stenosis is present in 6-8% of patients undergoing coronary artery bypass graft surgery. Many cardiovascular surgeons advocate staged or synchronous carotid endarterectomy to reduce the high perioperative and long-term risk of stroke associated with multivessel disease. However, no randomized trial has assessed whether a combined synchronous or staged carotid endarterectomy confers any benefit compared with isolated coronary artery bypass grafting in these patients. AIMS: The objective of this study is to compare the safety and efficacy of isolated coronary artery bypass grafting vs. synchronous coronary artery bypass grafting and carotid endarterectomy in patients with asymptomatic high-grade carotid artery stenosis. DESIGN: Coronary Artery Bypass graft surgery in patients with Asymptomatic Carotid Stenosis (CABACS) is a randomized, controlled, open, multicenter, group sequential trial with two parallel arms and outcome adjudication by blinded observers. Patients with asymptomatic high-grade carotid stenosis scheduled for elective coronary artery bypass grafting will be assigned to either isolated coronary artery bypass grafting or synchronous coronary artery bypass grafting and carotid endarterectomy by 1 : 1 block-stratified randomization with three different stratification factors (age, gender, modified Rankin scale). STUDY: The trial started in December 2010 aiming at recruiting 1160 patients in 25 to 30 German cardiovascular centers. The composite primary efficacy end point is the number of strokes and deaths from any cause (whatever occurs first) within 30 days after operation. A 4·5% absolute difference (4% compared to 8·5%) in the 30-day rate of the above end points can be detected with >80% power. OUTCOMES: The results of this trial are expected to provide a basis for defining an evidence-based standard and will have a wide impact on managing this disease.

Long-acting methylphenidate has an effect on aggressive behavior in children with attention-deficit/hyperactivity disorder.

INTRODUCTION: Aggression is frequently observed in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to assess the efficacy with regard to oppositional and aggressive behavior of a new long-acting methylphenidate preparation (Medikinet retard, MPH-MR), with equal portions of the immediate-release and the sustained-release active substance, and especially to look at correlations between either teacher or parent assessment of aggression and ADHD sub-symptomatology. METHODS: Eighty five children and adolescents (6-16 years) were investigated in a double-blind, randomized, clinical trial over 5 weeks under a treatment with MPH-MR using symptom checklists for ADHD, oppositional-defiant and conduct disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). RESULTS: A total of 64.9% of the children showed oppositional defiant disorder/conduct disorder (ODD/CD) symptoms. A statistically significant effect was found in the group treated with MPH (verum-group). On the basis of Cohen's criteria, high effects were found for aggressive symptoms in school (d = 1.0), but not in the afternoon (d = 0.4). There were also lower effect sizes for more severe aggressive symptoms. We found characteristic correlations between ODD/CD symptoms and the ADHD subscale hyperactivity/impulsivity compared to the subscale inattention. CONCLUSIONS: Long-acting MPH is effective in the treatment of oppositional-defiant and aggressive behavior, especially concerning milder symptoms. The expected correlation between impulsivity and aggressiveness could be confirmed.

Risk factors for venous thromboembolic events in cancer patients.

BACKGROUND: Cancer patients of the Department of Internal Medicine (Cancer Research) of the Essen University Medical School (Tumor Clinics), Germany, were examined and questioned with the aim of identifying those who run a high risk of deep vein thrombosis (DVT). PATIENTS AND METHODS: Between September 2002 and April 2003, cancer therapy and DVT risk factors of 507 cancer patients (53% males, 47% females, mean age 56+/-12 years) were documented. During a mean follow-up of 8+/-5 months, 60 patients (12%) suffered from new venous thromboembolic events (VTE): 28 at the lower limb, 25 at the upper limb and 13 pulmonary embolisms. RESULTS: The following factors were considered as predictive for an increased VTE risk: inpatient treatment (P<0.0001), prior DVT in medical history (P=0.0275), DVT in family (P=0.0598), chemotherapy (P=0.0080), fever (P=0.0093) and CRP (P<0.001). After combining factors in one variable (number of factors) the predicted VTE risk increased with the number of factors in both outpatients (OR 1.85, 95% CI 1.18-2.88, P=0.0071) and inpatients (OR 2.34, 95% CI 1.63-3.36, P

Risk factors for varicose veins.

AIM: To determine the prevalence of varicose veins in the German population and specify possible risk factors the data of the Duesseldorf/Essen civil servants study were analysed. METHODS: From December 1989 to July 1993 a total of 9 935 employees were recruited. All volunteers filled out a questionnaire regarding family history and risk factors and were clinically examined. Venous findings were classified and adapted to the CEAP-classification. For the analysis of risk factors only volunteers classified as CEAP-class 0 or as CEAP-class II were considered: 4 250 men, 10% belonged to CEAP-class II and 2 380 women including 16% CEAP-class II. RESULTS: In general, age and gender were the most relevant risk factors for varicose veins. Odds ratio age: male: 3.4 (95%-CI: 2.6-4.4), age female 6.5 (95%-CI: 5.0-8.5), gender 2.3 (95%-CI 1.9-2.7). In addition in females the most frequent risk factors were oral contraception and in both genders a predominately sitting posture at work. Regarding the family history, varicose veins by the mother was most frequent compared to varicose veins by the father or both. After adjusting for age and gender heridity became the most important risk factor with an odds ratio of 5.2 (95%-CI:3.7-7.3-4.50) in case of varicose veins present in both parents, followed by a standing posture at work 2.2 (95%-CI: 1.2-3.9). In contrast, smoking also reached a significant level, but with a decreased odds ratio of 0.66 (95%-CI: 0.57-0.77) indicating a protective effect. CONCLUSION: In addition to age and gender a family history of varicose veins is the most important risk factor in the total population. Despite significant influence of other risk factors their relevance for varicose veins in the investigated population is low either due to low frequencies or low odds ratios.

[Emergency room patients]. / Der Schockraumpatient. Einschätzung ernster Schädelverletzungen anhand der GCS bei vermeintlich leichtem und mittelschwerem Schädel-Hirn-Trauma.

UNLABELLED: The aim of the study was to examine the predictive value of CT for severe intracranial lesions of mild (GCS 15-13) and moderate (12-9) head injuries. Further,we examined the possibility of predicting these lesions by various variables/factors. Data were collected prospectively from the trauma registry of the DGU (Deutsche Gesellschaft für Unfallchirurgie). Patients with a GCS score from 15-13 and from 12-9 were included in this study and examined for intracranial lesions (AIS(head) 3-6). Over a time period from 1993 to 1999, 1778 patients with mild head injury and 235 patients with moderate head injury were analyzed. Severe intracranial lesions were suffered by 18.6% of the patients with mild head injury and 50.4% of the patients with moderate head injuries. Of the predictive variables, heart rate,patients' age,and primary assessment by the emergency physician showed a strong correlation with the later observed intracranial lesions. IN CONCLUSION: (1) independently of the initially good GCS, a high percentage of patients suffered from severe intracranial lesions and (2) besides the GCS only the patients'age and primary assessment by the emergency physician were useful for identifying patients at risk for an intracranial lesion.

Peripheral veins: influence of gender, body mass index, age and varicose veins on cross-sectional area.

To investigate changes in the size of the deep and superficial venous systems associated with gender, age, body mass index and varicose veins, changes to the cross-sectional area of the femoral and the long saphenous veins were analysed in the Duesseldorf/Essen civil servant study population. Between December 1989 and July 1993 a total of 9935 employees were recruited; 9261 were then evaluated for this analysis. Diameters of the long saphenous and femoral veins were determined 2-3 cm distal to the confluence in lying (after 15 min rest) and standing (after 5 min) positions. Cross-sectional areas (CSA) were calculated. A total of 63% of all people were assigned to CEAP (clinical, etiological, anatomical pathophysiological) class 0, 27% to class 1, 8.5% to class 2, while 1.5% belonged to higher CEAP classes. In people without varicose veins (CEAP class 0) the CSA of the femoral and long saphenous veins were smaller in females than in males. In people with a normal body mass index (BMI) (20-25) the mean CSA of the femoral and long saphenous veins in a standing position was similar from the third up to the sixth decade of life. The volume increase due to a standing position expressed as the absolute increase in CSA of the femoral and long saphenous veins was not age-related, either. The relative volume increase expressed as a ratio remained unchanged with age. There was a strong relationship between the CSA of both veins and increasing BMI. In a lying position, the CSA of the femoral and long saphenous veins increased only slightly with increasing CEAP classes. In a standing position, the CSA of both veins increased even in CEAP class 1 (p < 0.001). In a stepwise multivariate regression analysis, the CSA of both veins in a standing position was not age-related but associated with BMI, CEAP classes and gender. The absolute increase in CSA was influenced by all four variables, but BMI and gender were most important. In Conclusion, this study shows that aging is not necessarily associated with an increase in venous CSA of the deep and superficial venous system. BMI is the most important determinant for an increase in CSA in standing position. Varicosity of the superficial venous system is always associated with similar changes in the deep venous system.

Symptoms in individuals with small cutaneous veins.

The clinical relevance of small cutaneous veins (SCV) is still being discussed. In the Duesseldorf/Essen civil servants study, the prevalence of SCV and the individual symptoms and age-dependent changes were analysed. This cross-sectional study recruited 9935 employees; 9100 could be finally evaluated for this analysis. All volunteers were asked to fill out the questionnaire and were clinically examined. Primarily the clinical findings were documented, adapted to the Basel Study and later modified according to the CEAP classification: (a) class 0 - no visible or palpable clinical signs of venous disease, (b) class 1 - small cutaneous veins, (c) class 1 - reticular veins, (d) class 2 - varicose veins. In all, 64% of the volunteers had no signs of venous disease (class 0: age 41+/-10 years); 10% had small cutaneous veins (class 1: age 44+/-10 years). SCV was more frequent in females (25%) than in males (6%). Only 5% of those with SCV had already consulted a physician. A striking result was that individuals with SCV generally complained about more leg symptoms, of which 'leg swelling' and 'muscle cramps during the night' were the most frequent. 'Continual leg swelling' was reported by 24% of individuals with SCV as opposed to 10% of those without. 'Leg cramps' and 'restless legs' also were more often documented in individuals with SCV (29% vs 22% and 10% vs 7%). These findings were all statistically significant (p<0.001). After adjusting for age and sex, though, there were few or no differences between groups (leg swelling: odds ratio (OR) 1.3; 95% confidence interval (95% CI) 1.1-1.6 and cramps: OR 1.1; 95% CI 0.9-1.3). A gender separate estimation of the rates showed that females suffer more often from any symptom. Regarding 'leg cramps', 'restless legs' and 'itching', the OR were not different for females and males. For 'leg swelling' the age-adjusted OR were significant for women (OR 1.4; 95% Cl 1.1-1.7) compared with men (OR 1.1; 95% Cl 0.7-2). Individuals with SCV seem to have more symptoms compared with healthy people. However, this analysis shows that age and sex are the most relevant explanations for these symptoms.

Occurrence of ventricular late potentials in patients with active acromegaly.

OBJECTIVE: Patients with acromegaly have an increased risk of ventricular dysrhythmias and sudden death. Late potentials in a signal-averaged electrocardiogram (SAECG), a predictor of ventricular dysrhythmias, are frequently seen in patients after previous myocardial infarction, but little is known about the prevalence of late potentials in acromegaly. The aim of our study was to investigate the prevalence of late potentials in patients with acromegaly and their relation to the activity of the disease and to myocardial hypertrophy. PATIENTS: The study included 48 patients with acromegaly [27 males, 21 females, mean age 52.3 +/- 14.2 years, 16 active disease, 32 cured or 'well controlled', under treatment with sandostatin analogues (12/32)] and 38 healthy volunteers as a control group. RESULTS: Late potentials were detected in 9/16 (56%) patients with active acromegaly vs. 2/32 (6%) with cured/well controlled acromegaly (P = 0.001), defined as normal age-related IGF-1 levels and GH levels suppressible below 1 microg/l after an oral glucose load (75 g). Late potentials were not related to muscle mass index (127 +/- 35 active vs. 123 +/- 34 g/m2 cured/well controlled). The association of disease activity with the detection of late potentials was independent of age, gender, duration of the disease and body mass index. In comparison to the control group, the prevalence of late potentials was significantly higher in patients with acromegaly (23%) than in the control group (0%; P < 0.001). CONCLUSIONS: Late potentials in the SAECG are frequently seen in active acromegaly and may represent an early and sensitive parameter to detect myocardial injury in acromegaly.

[Changes in central hemodynamics and peripheral circulation in pregnancy]. / Veränderungen der zentralen Hämodynamik und der peripheren Zirkulation in der Schwangerschaft.

Systemic blood pressure, stroke volume, systolic time intervals (measured via impedance cardiography), rheological properties of blood (hematocrit, plasma viscosity and erythrocyte aggregation) and peripheral flow conditions (measured via occlusive impedance plethysmography) were assessed longitudinally in 21 nonpregnant women and in 49 patients from 5th to 41st week of gestation and 4 to 9 days postpartum. Measurements were taken in the left lateral position. The data showed, that dz/dt, stroke volume and cardiac index rose until the 30th week of gestation and decreased throughout the rest of pregnancy. The same changes were observed in the data on diastolic pressure and Heather Index. Peripheral resistance fell during the first trimester and then increased notably throughout the following time of pregnancy. The systolic time intervals become longer in the last trimester of pregnancy, but were characterised by a markedly shortened left ventricular ejection time (LVET). The reduction of stroke volume in the last trimester is due to diminished venous return or venous outflow by obstruction of the inferior vena cava or by abnormalities in the left ventricular function and/or impaired rheological properties of the blood.

[Changes in plasma coagulation and fibrinolysis following cesarean section and relationship to deep venous thrombosis. Results of a randomized prospective comparative study with 6% hydroxyethyl starch 0.62 and low-dose heparin as thrombosis prophylaxis]. / Veränderungen der plasmatischen Gerinnung und der Fibrinolyse nach Kaiserschnitt-Operationen und die Beziehungen zur tiefen Beinvenenthrombose. Ergebnisse einer randomisierten prospektiven Vergleichsstudie mit 6% Hydroxyäthylstärke 0.62 und low dose Heparin als Thromboseprophylaxe.

Routine postoperative monitoring of plasma coagulation and fibrinolysis system values after cesarean delivery in 191 women who did not develop thrombosis and 16 who did revealed a preoperative defect in the fibrinolysis (PAI, TAT) and inhibitor (AT III) systems. Significant postoperative correlations in the drop in antithrombin levels could not be explained solely by hemodilution. Moreover, a disturbance of the equilibrium of the alpha-2 increase and plasminogen was observed, favouring alpha-2 antiplasmin. Hydroxyethyl starch is capable of simultaneously influencing hypercoagulability and postoperative status. The only difference noted between the two groups of drugs was in the course of the PAI concentration (P less than 0.02). It would therefore appear logical in clinical practice to extend preoperative tests to include determination of the plasminogen activator inhibitor and the thrombin-antithrombin complex.

[Perioperative prevention of thrombosis in cesarean section: results of a randomized prospective comparative study with 6% hydroxyethyl starch and 0.62 low dose heparin]. / Die perioperative Thromboseprophylaxe beim Kaiserschnitt: Ergebnisse einer randomisierten prospektiven Vergleichsuntersuchung mit 6% Hydroxyäthylstärke 0.62 und Low-dose-Heparin.

In 207 consecutive randomized women undergoing cesarean section, of whom 104 received 3 X 5000 IE unfractionated heparin and 103 3 X 500 ml hydroxyethylstarch 6% 0.62, the frequency of deep vein thrombosis was evaluated with a non-invasive diagnostic technique-impedance plethysmography. 5.9% of the patients in the hydroxyethylstarch group and 7.8% in the heparin-group developed deep vein thrombosis. Activation of blood coagulation at cesarean section results in an increasing of factor VIIIR:Ag, Fibrinogen and Reptilase clotting time. Hydroxyethylstarch 6% 0.62 produces minor abnormalities of coagulation test results. After 1500 ml infusions HES the following effects were noted: 1. Factor VIIIR:Ag fell by about 20%, a greater decrease than could be explained simply by hemodilution. 2. Reptilase clotting times shortened without a different increase in fibrin activation products (resulting in an increased lysability of the thrombus). 3. Plasma fibrinogen decreased by approximately 7% due to hemodilution caused by plasma volume expansion. For patients with a low risk of deep vein thrombosis (Cesarean section) HES has an excellent safety record in doses not exceeding 1500 ml/24 h.