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Claudia Zemmrich,1 Peter Bramlage,2 Philipp Hillmeister,3 Mesud Sacirovic,3 Ivo Buschmann3 1Deutsche Angiologie-CRO, Berlin, Germany; 2Institute for Pharmacology and Preventive Medicine, Cloppenburg, Germany; 3Department of Angiology, Medical University Brandenburg, Brandenburg, GermanyCorrespondence: Claudia ZemmrichDeutsche Angiologie CRO (DA-CRO), Straubinger Strasse 20, Berlin, 12683, GermanyTel +49 178 7152405Email claudia.zemmrich@da-cro.deIntroduction: Coronary artery disease (CAD) and peripheral arterial disease (PAD) account for significant morbidity and mortality in Germany and are more prevalent in rural, non-metropolitan areas. The goal of this study is to screen patients for their current atherosclerotic status, initiate treatment according to the latest scientific findings using a standardised multimodal approach and track their atherosclerotic status over one year.Methods and Analysis: This manuscript describes the study protocol of a prospective, multicentre registry of 500 sequential patients with CAD and/or PAD in rural, non-metropolitan regions of Germany. Patients, who visit the “WalkByLab” at the Brandenburg Medical School, Brandenburg, Germany, will be assessed by using our structured, multimodal risk factor management (SMART) tool to evaluate cardiovascular morbidity data, collect information on care and deliver multimodal therapy. The study’s primary objective is a cross-sectional examination of the risk profile, diagnostic and therapeutic status in this patient group. Secondary objectives include the assessment of risk factor correlations as well as changes in risk-factor profile and therapy adherence. Patients will be examined at baseline and followed up at three-monthly intervals for one year. Over this time, atherosclerotic risk factors and patient adherence to defined therapeutic strategies will be evaluated. Study completion is estimated to be December 2021. An expansion of this concept into other rural, non-metropolitan neighbouring regions is planned.Ethics and Dissemination: This registry was assessed and approved by the ethics committee of the Brandenburg State Medical Association, Brandenburg, Germany, and conducted in accordance with the Declaration of Helsinki. The study findings will be disseminated through usual academic channels including meeting presentations and peer-reviewed publications.Protocol Version: 1.0.Keywords: coronary artery disease, peripheral arterial disease, atherosclerosis, rural, risk factor, quality improvement

Stephan Kress,1 Anja Borck,2 Ariel Zisman,3 Peter Bramlage,4,5 Thorsten Siegmund6 1Diabeteszentrum, Vinzentius-Krankenhaus, Landau, Germany; 2Medical Department, Sanofi, Berlin, Germany; 3The Endocrine Center of Aventura, Aventura, FL, USA; 4Institute for Pharmacology and Preventive Medicine, Cloppenburg, Germany; 5Department for Angiology, Brandenburg Medical School, Campus Brandenburg/Havel, Brandenburg, Germany; 6Diabetes- Hormon- Und Stoffwechselzentrum Am Isar Klinikum München, München, GermanyCorrespondence: Stephan KressDiabeteszentrum, Vinzentius Krankenhaus, Cornichonstr. 4, Landau, 76829, GermanyTel +49 6341 172208Email kress.innere@vinzentius.deAim: In the present analysis, we characterised the efficacy and safety of adding a single daily injection of insulin glulisine to optimised basal-supported oral therapy (BOT) in patients with a high BeAM value, defined as a more than 50 mg/dl difference between bedtime and pre-breakfast blood glucose.Methods: The BeAM value was retrospectively calculated for patients pooled from two clinical trials that supplemented BOT with glulisine. Data regarding changes in HbA1c, fasting plasma glucose (FPG), and postprandial glucose (PPG) levels from observation periods of 3 to 6 months were assessed.Results: Out of 358 patients that received BOT/glulisine, 182 had a high BeAM value. Patients with a high BeAM value were older and had a longer diabetes duration than patients with a medium BeAM value. Significant reductions in HbA1c (7.5% to 7.2% [59 to 55 mmol/mol], p< 0.0001) and PPG (202 to 143 mg/dl, p< 0.0001) levels were documented. The proportion of patients with a high BeAM value achieving an HbA1c < 7% [53 mmol/mol], alone or in combination with no hypoglycaemia, was lower than that of patients with a medium BeAM value.Conclusion: The analysis indicates that the supplementation of BOT with a single daily injection of prandial insulin is safe and effective for reducing HbA1c and PPG levels in patients with a high BeAM value (more than 50 mg/dl). However, patients with a medium BeAM value also responded well, which suggests that they should also be considered candidates for this change in therapy.Keywords: basal-plus, prandial insulin, type-2 diabetes, glulisine, glargine

Peter Bramlage,1 Eva-Maria Fronk,2 Wolf-Peter Wolf,3 Rüdiger Smolnik,3 Gemma Sutton,1 Roland E Schmieder4 1Institut für Pharmakologie und präventive Medizin, Mahlow, Germany; 2Daiichi Sankyo Europe GmbH, Munich, Germany; 3Daiichi Sankyo Deutschland GmbH, Munich, Germany; 4Abteilung für Nephrologie und Hypertensiologie, Universitätsklinikum Erlangen, Erlangen, Germany Background: Clinical trials indicate that the use of fixed-dose combinations (FDCs) is associated with a higher level of treatment adherence and prolonged blood pressure (BP) control. The aim of this study was to document the safety and effectiveness of the FDC olmesartan/amlodipine/hydrochlorothiazide in patients with essential hypertension in clinical practice. Methods: This multicenter, prospective, 24-week, noninterventional study enrolled 5,831 patients from primary care offices in Germany and Austria. Inclusion criteria were a diagnosis of essential hypertension and newly initiated treatment with the FDC. Results: The mean age of patients was 63.5 years, almost 50% of patients had a time since diagnosis of essential hypertension of over 5 years, and approximately 70% of patients had at least one cardiovascular risk factor, including 29.4% of patients with diabetes mellitus. Following approximately 24 weeks of treatment, the mean reduction in systolic/diastolic BP was 29.0/14.0 mmHg, a BP response was observed by 94.2% of patients, and a target BP of

Peter Bramlage,1 Cornelia Deutsch,1 Ralf Krüger,1 Andreas Wolf,2 Peter Müller,2 Thomas Zwingers,1,4 Beate Beime,1 Thomas Mengden31Institut für Pharmakologie und Präventive Medizin, Cloppenburg, 2Müller and Sebastiani, Ottobrunn, 3Kerckhoff-Klinik, Bad Nauheim, 4Estimate, Augsburg, GermanyObjective: The aim of the present study was to validate the custo screen 400 ambulatory blood pressure-monitoring (ABPM) device according to the 2010 International Protocol revision of the European Society of Hypertension (ESH-IP). The device can be used for ABPM for up to 72 hours.Materials and methods: Systolic and diastolic blood pressure (SBP and DBP, respectively) were sequentially measured in 33 adult subjects (13 males and 20 females) and compared with a standard mercury sphygmomanometer (two observers). A total of 99 comparison pairs were obtained.Results: The custo screen 400 met the requirements of parts 1 and 2 of the ESH-IP revision 2010. The mean difference between the device and reference sphygmomanometer readings was −0.5±4.5 mmHg for SBP and −0.1±3.3 mmHg for DBP. All but one measurement were within the absolute difference of 10 mmHg between the device and the observers for SBP and DBP. The number of absolute differences between the device and the observers within a range of 5 mmHg was 84 of 99 readings for SBP, and 93 of 99 readings for DBP.Conclusion: The custo screen 400 ABPM device met the requirements of the 2010 ESH-IP revision, and hence can be recommended for ABPM in adults. To our knowledge, the custo screen 400 is the first device to pass the revised ESH-IP 2010.Keywords: validation, ambulatory blood pressure monitoring, ESH

Sami T Azar,1 Hadi Abu Hantash,2 Selim Jambart,3 Mohammad M El-Zaheri,4 Rachoin Rachoin,5 Amal Chalfoun,6 Layla Lahoud,6 Osama Okkeh,2 Peter Bramlage,7 Philippe Brudi,8 Baishali M Ambegaonkar81American University of Beirut Medical Center, Beirut, Lebanon; 2Istishari Hospital, Amman, Jordan; 3St Joseph University Faculty of Medicine, Beirut, Lebanon; 4Jordan Hospital, Amman, Jordan; 5Notre Dame des Secours Hospital, Jbeil, Lebanon; 6MSD Levant, Beirut, Lebanon; 7Institut für Pharmakologie und präventive Medizin, Mahlow, Germany; 8Merck and Co, Inc., Whitehouse Station, NJ, USABackground: Cardiovascular disease is the leading cause of death and disability worldwide. Therefore, as part of the Dyslipidemia International Study (DYSIS), we have analyzed the prevalence of lipid abnormalities and risk factors for dyslipidemia in statin-treated patients in Lebanon and Jordan.Methods: This cross-sectional, multicenter study enrolled 617 patients at 13 hospitals in Lebanon and Jordan. Patients were at least 45 years old and had been treated with statins for at least 3 months. Multivariate logistic regression analysis was used to determine patient characteristics contributing to dyslipidemia during statin therapy.Results: Our findings indicated that 55.9% of statin-treated patients (mean age 60.3 years, 47% female) in Lebanon and Jordan did not achieve goal levels for low-density lipoprotein cholesterol which were dependent on Systematic Coronary Risk Evaluation (SCORE) risk, and 70% of patients (76% men and 63.3% of women) were at very high cardiovascular risk. Low-density lipoprotein cholesterol goals were not achieved in 67.2% of those with very high cardiovascular risk. The most commonly prescribed statin was atorvastatin (44.6%), followed by simvastatin (27.7%), rosuvastatin (21.2%), fluvastatin (3.3%), pravastatin (3%), and lovastatin (0.2%). Approximately half of the population was treated with a statin dose potency of 4, equaling 40 mg of simvastatin. In Lebanon and Jordan, the strongest independent associations with low-density lipoprotein cholesterol not at goal were current smoking (odds ratio [OR] 1.96; 95% confidence [CI] 1.25–3.08), diabetes mellitus (OR 2.53; 95% CI 1.70–3.77), and ischemic heart disease (OR 2.26; 95% CI 1.45–3.53), while alcohol consumption was associated with reduced risk (OR 0.12; 95% CI 0.03–0.57).Conclusion: We observed that many patients in Lebanon and Jordan experienced persistent dyslipidemia during statin treatment, supporting the notion that novel lipid-lowering strategies need to be developed. Also, social programs aimed at combating the extremely high rates of tobacco use and obesity in Lebanon and Jordan are critical for combating cardiovascular disease in these countries.Keywords: cardiovascular disease, lipid abnormalities, statins, low-density lipoprotein cholesterol

Jochen Seufert,1 Katrin Pegelow,2 Peter Bramlage3 1Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Freiburg, 2Sanofi Aventis Deutschland GmbH, Berlin, 3Institut für Pharmakologie und Präventive Medizin, Mahlow, Germany Background: For patients with type 2 diabetes who are uncontrolled on a combination of two oral antidiabetic agents, addition of the long-acting basal insulin glargine is a well established treatment option. However, data on the efficacy and safety of a combination of metformin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and insulin glargine are limited in real-world settings. Therefore, the aim of this study was to analyze blood glucose control, rates of hypoglycemia and body weight in a large cohort of patients with type 2 diabetes treated with this combination therapy in real practice. Methods: This noninterventional, multicenter, prospective, observational trial with a follow-up of 20 weeks enrolled insulin-naïve patients who had been on a stable fixed dose of metformin and a DPP-4 inhibitor for at least 3 months, and had a glycosylated hemoglobin (HbA1c) between 7.5% and 10%. Patients were selected at the investigators' discretion for initiation of insulin glargine at baseline. A total of 1,483 patients were included, of whom 1,262 were considered to be the efficacy set. Primary efficacy parameters were HbA1c and fasting plasma glucose. Secondary outcome measures included achievement of glycemic targets, body weight, rates of hypoglycemia, and other safety parameters, as well as resource consumption. Results: Upon initiation of insulin glargine, mean HbA1c decreased from 8.51% to 7.36% (-1.15%±0.91%; 95% confidence interval [CI] -1.20 to -1.10). An HbA1c level

Peter Bramlage,1 Claudia Zemmrich,1 Reinhard Ketelhut,2 Wolf-Peter Wolf,3 Eva-Maria Fronk,4 Roland E Schmieder5 1Institut für Pharmakologie und Präventive Medizin, Mahlow, Germany; 2Institut für Sportmedizin, Universitätsklinikum Charité, Humboldt Universität zu Berlin, Berlin, Germany; 3Daiichi Sankyo Deutschland GmbH, Munich, Germany; 4Daiichi Sankyo Europe GmbH, Munich, Germany; 5Universitätsklinikum Erlangen, Klinik für Nephrologie und Hypertensiologie, Erlangen, Germany Background: The safety and efficacy of olmesartan 40 mg and hydrochlorothiazide (HCTZ) as a fixed-dose combination has been investigated in clinical trials leading to its approval. The aims of the present study were to confirm these data in an unselected patient population in daily practice and to determine the impact of physical activity on blood pressure control. Methods: In a multicenter, noninterventional study, 3,333 patients with either insufficient blood pressure control on olmesartan 40 mg alone or on a fixed/free combination of olmesartan 40 mg and HCTZ 12.5/25 mg were primarily assessed for safety and tolerability of the fixed-dose combination of olmesartan 40 mg and HCTZ 12.5/25 mg at 24 ± 2 weeks. Secondary objectives were blood pressure reduction, treatment compliance, and impact of physical activity as measured by the sum of weekly energy costs. Results: The mean patient age was 63.2 ± 11.46 years, mean baseline blood pressure was 159.6 ± 15.28/93.5 ± 9.52 mmHg, and 70.9% had at least one additional cardiovascular risk factor. Adverse drug reactions were rare (n = 19), and no serious adverse drug reactions occurred. Compliance with drug therapy was at least sufficient in more than 99% of patients at the end of the study. Blood pressure at the last available visit was reduced by 26.1 ± 15.5/13.0 ± 10.1 mmHg versus baseline (P < 0.0001), but had reduced effectiveness in patients ≥75 years with diabetes or impaired renal function. In 69% of patients, blood pressure was normalized (

Alexandre Rey,1 Martin Thoenes,1,2 Rolf Fimmers,3 Christoph A Meier,4 Peter Bramlage51Sanofi Aventis, Medical Department, Meyrin, Switzerland; 2Institute for Clinical Pharmacology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Germany; 3Institut für Medizinische Biometrie, Informatik und Epidemiologie, Universität Bonn, Germany; 4Klinik für Innere Medizin, Stadtspital Triemli, Zürich, Switzerland; 5Institut für Pharmakologie und präventive Medizin, Mahlow, GermanyBackground: Diabetes represents one of the major health challenges in Switzerland, and early diagnosis and treatment is mandatory to prevent or delay diabetes-related morbidity and mortality. For the purpose of identifying affected individuals, early screening in pharmacies is a valuable option. In this survey, we aimed to determine blood glucose and metabolic control in an unselected population of individuals visiting Swiss pharmacies.Methods: The subjects responded to a short questionnaire and underwent a single capillary blood glucose test for screening purposes. They were classified as normal, indeterminate, impaired fasting glucose, and diabetes according to predefined blood glucose levels.Results: A total of 3135 individuals (mean age 56 years) in 18 cantons were screened in November 2010; of these, 4.2% (95% confidence interval [CI] 3.5–4.9) had previously been diagnosed with diabetes. Diabetes was newly diagnosed in 1.9% (95% CI 1.5–2.4), and 11.5% (95% CI 10.4–12.6) had impaired fasting glucose. Subjects with impaired glucose control had an increased body mass index, a frequent family history of diabetes, hypertension, hypercholesterolemia, smoking, and a low level of physical activity. Prevalence of impaired glucose control was different between the French/Italian-speaking part of Switzerland (new diabetes 4.9%; impaired fasting glucose 12.7%) and the German-speaking part (new diabetes 1.9%; impaired fasting glucose 10.3%).Conclusion: Our study shows a 6.1% prevalence of diabetes, of which about a third (1.9%) was previously undiagnosed, and 11.5% had impaired fasting glucose. Therefore, screening initiatives in pharmacies may be suitable for detecting people with undiagnosed diabetes.Keywords: diabetes, pharmacy, epidemiology, screening

Roland E Schmieder 1, Matthias Goebel2, Peter Bramlage31Nephrology and Hypertension, University Hospital Erlangen, Germany; 2AstraZeneca GmbH, Medical Department, Wedel, Germany; 3Institut für Pharmakologie und präventive Medizin, Mahlow, GermanyBackground and purpose: Despite the availability of risk engines to determine cardiovascular risk, risk factor control is suboptimal. Using EURIKA data we compared risk factor control in Germany with that of 11 other European countries (rest of Europe [ROE]) to identify differences and opportunities for improvement.Methods: EURIKA was a multinational, cross-sectional study in 12 European countries including Germany from May 2009 to January 2010. Physicians' attitudes to risk factor control based on the 2007 European guidelines on cardiovascular disease (CVD) prevention in a representative cohort of 7641 primary care outpatients aged ≥50 years with no CV disease and at least one major CV risk factor were determined.Results: Compared to the ROE, German physicians were more frequently male (72.7% vs 62.6%), had a higher mean age (51.7 ± 8.4 vs 47.0 ± 9.7 years), faced higher patient loads (37.9% vs 16.5% had >199 patients/week), and involved other health sector professionals (dieticians, psychologists) less (31.8% vs 41.0% in the ROE). The European Society of Cardiology (ESC) guidelines on CVD prevention were more important for German physicians (60.6% vs 55.9%), while those who didn't use them gave reasons for nonuse as too many (62.5% vs 46.2%), too confusing, unrealistic, or not applicable to their patients. Risk engines were used less (54.5% vs 70.7%), with perceived lack of time (65.5% vs 60.2%) a frequent reason for nonuse. Risk factor control in German patients was inadequate (control rates: hypertension 36.3%, dyslipidemia 30.4%, type 2 diabetes 40.6%, obesity 28.8%) but largely comparable to other ROE countries; however, physicians tended to overestimate control rates.Conclusion: EURIKA provides comprehensive data on the status of primary prevention of CVD in clinical practice in Germany and reveals considerable potential for improving the primary prevention of CVD.Keywords: cardiovascular risk factor, primary care

Thomas Mengden1, Reinhold Hübner2, Peter Bramlage31Kerckhoff-Klinik GmbH, Bad Nauheim, 2Takeda Pharma GmbH, Aachen, 3Institut für Kardiovaskuläre Pharmakologie und Epidemiologie, Mahlow, GermanyBackground: Fixed-dose combinations of candesartan 32 mg and hydrochlorothiazide (HCTZ) have been shown to be effective in clinical trials. Upon market entry we conducted a noninterventional study to document the safety and effectiveness of this fixed-dose combination in an unselected population in primary care and to compare blood pressure (BP) values obtained during office measurement (OBPM) with ambulatory blood pressure measurement (ABPM).Methods: CHILI CU Soon was a prospective, noninterventional, noncontrolled, open-label, multicenter study with a follow-up of at least 10 weeks. High-risk patients aged ≥18 years with previously uncontrolled hypertension were started on candesartan 32 mg in a fixed-dose combination with either 12.5 mg or 25 mg HCTZ. OBPM and ABPM reduction and adverse events were documented.Results: A total of 4131 patients (52.8% male) with a mean age of 63.0 ± 11.0 years were included. BP was 162.1 ± 14.8/94.7 ± 9.2 mmHg during office visits at baseline. After 10 weeks of candesartan 32 mg/12.5 mg or 25 mg HCTZ, mean BP had lowered to 131.7 ± 10.5/80.0 ± 6.6 mmHg (P < 0.0001 for both comparisons). BP reduction was comparable irrespective of prior or concomitant medication. In patients for whom physicians regarded an ABPM to be necessary (because of suspected noncontrol over 24 hours), ABP at baseline was 158.2/93.7 mmHg during the day and 141.8/85.2 mmHg during the night. At the last visit, BP had significantly reduced to 133.6/80.0 mmHg and 121.0/72.3 mmHg, respectively, resulting in 20.8% being normotensive over 24 hours (

Gerd Bönner1, Bernhard Landers2, Peter Bramlage31Park-Klinikum Bad Krozingen, Germany; 2Internal Medicine Practice, Diabetes Center, Mayen, Germany; 3Institute for Cardiovascular Pharmacology and Epidemiology, Mahlow, GermanyBackground: Candesartan cilexetil has been shown to effectively reduce blood pressure and cardiovascular risk. Whether it is advantageous to combine candesartan cilexetil with low-dose hydrochlorothiazide (HCTZ) or uptitrate it in cases of insufficient blood pressure control has not been fully investigated under routine clinical conditions.Methods: CHILI Triple T is a prospective, noninterventional, observational study. Patients with uncontrolled hypertension and added cardiovascular risk received a fixed-dose combination of candesartan cilexetil 16 mg and HCTZ 12.5 mg (combination therapy group) or high-dose monotherapy with candesartan cilexetil 32 mg (high-dose monotherapy group).Results: A total of 4600 patients with a mean age of 63.1 ± 11.0 years, of which 44.7% were female, was included. The combination therapy group had 3337 patients, and the high-dose monotherapy group 1263 patients. Patients in both treatment groups were comparable with respect to age and gender, but patients receiving high-dose monotherapy had a slightly higher mean systolic blood pressure, more prior revascularizations, renal insufficiency, diabetic nephropathy, peripheral artery disease, and a lower ankle brachial index. The use of combination therapy resulted in a blood pressure reduction of -28.5 ± 13.8/-14.2 ± 9.4 mm Hg (P < 0.001 vs 160.2 ± 13.3/94.5 ± 8.2 mm Hg at baseline). The use of high-dose monotherapy reduced blood pressure by -29.73 ± 15.3/-14.1 ± 9.6 mm Hg (P < 0.001 vs 162.4 ± 14.7/94.7 ± 8.7 mm Hg at baseline). Differences in subgroups of patients defined by age, gender, body mass index, dyslipidemia, waist circumference, smoking, prior cardiovascular event, glomerular filtration rate, and microalbuminuria were minor, although partially significant. Tolerability was excellent, with only 28 out of 3358 patients (0.8%) in the combination therapy group and 15 out of 1273 patients (1.2%) in the high-dose monotherapy group experiencing any adverse event, of which one in each group was considered to be serious (

Background & aimsType 2 diabetes (T2D) is a growing problem in children. Children with NAFLD are at potentially high risk for developing T2D; however, the incidence of T2D in this population is unknown. This study aimed to determine the incidence of T2D in children with NAFLD and identify associated risk factors.MethodsChildren with NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network were followed longitudinally. Incidence of T2D was determined by using clinical history and fasting laboratory values. Cumulative incidence curves were developed for time to T2D. A Cox regression multivariable model was constructed using best subsets Akaike's Information Criteria selection.ResultsThis study included 892 children with NAFLD and with a mean age of 12.8 years (2.7) followed for 3.8 years (2.3) with a total 3234 person-years at risk. The incidence rate of T2D was 3000 new cases per 100,000 person-years at risk. At baseline, 63 children had T2D, and during follow-up, an additional 97 children developed incident T2D, resulting in a period prevalence of 16.8%. Incident T2D was significantly higher in females versus males (hazard ratio [HR], 1.8 [1.0-2.8]), associated with BMI z-score (HR, 1.8 [1.0-3.0]), and more severe liver histology including steatosis grade (HR, 1.3 [1.0-1.7]), and fibrosis stage (HR, 1.3 [1.0-1.5]).ConclusionsChildren with NAFLD are at high risk for existing and incident T2D. In addition to known risk factors for T2D (female and BMI z-score), severity of liver histology at the time of NAFLD diagnosis was independently associated with T2D development. Targeted strategies to prevent T2D in children with NAFLD are needed.

BackgroundPediatric metabolic-associated fatty liver disease (MAFLD) is a global health problem, with lifestyle modification as its major therapeutic strategy. Rigorous characterization of dietary content on MAFLD in children is lacking. We hypothesized an objectively measured healthier diet would positively modulate MAFLD.MethodsDiet was assessed using the Nutrition Data System for Research in children enrolled from 10 tertiary clinical centers to determine the Healthy Eating Index (HEI, 0-100) and individual food components.ResultsIn all, 119 children were included (13.3 ± 2.7 y), 80 (67%) male, 67 (18%) White, and 90 (76%) Hispanic, with an average body mass index Z-score of 2.2 ± 0.5. Diet was classified as low HEI < 47.94 (n = 39), mid HEI ≥ 47.94 and < 58.89 (n = 41), or high HEI ≥ 58.89 (n=39). Children with high HEI (healthier diet) had lower body weight (p = 0.005) and more favorable lipids. Mean serum triglycerides for low, mid, and high HEI were 163, 148, and 120 mg/dL, respectively; p = 0.04 mid versus high, p = 0.01 low versus high. Mean HDL was 38, 41 and 43 mg/dL; p = 0.02 low vs high. Less severe steatosis was noted with added sugar ≤ 10% of calories (p = 0.03). Higher lobular inflammation is associated with a higher percentage of calories from fat (OR (95% CI) = 0.95 (0.91-1.00), p = 0.04).ConclusionsIn children with MAFLD, high HEI is associated with lower body weight and more favorable lipids, while added sugar and fat intake has individual histologic features. Differential consumption of major dietary components may modify both metabolic risk factors and histologic liver injury, highlighting the importance of objective diet assessments in children with MAFLD.

Background & aimsNonalcoholic fatty liver disease (NAFLD) is the most common pediatric chronic liver disease. Little is known about outcomes in recognized youth.MethodsWe compared paired liver biopsies from 122 of 139 children with NAFLD (74% male; 64% white; 71% Hispanic; mean age, 13 ± 3 years; age range, 8-17 years) who received placebo and standard of care lifestyle advice in 2 double-blind, randomized clinical trials within the nonalcoholic steatohepatitis (NASH) clinical research network from 2005 through 2015. We analyzed histologic changes with respect to baseline and longitudinal change in clinical variables using regression analysis.ResultsAt enrollment, 31% of the children had definite NASH, 34% had borderline zone 1 NASH, 13% had borderline zone 3 NASH, and 21% had fatty liver but not NASH. Over a mean period of 1.6 ± 0.4 years, borderline or definite NASH resolved in 29% of the children, whereas 18% of the children with fatty liver or borderline NASH developed definite NASH. Fibrosis improved in 34% of the children but worsened in 23%. Any progression to definite NASH and/or in fibrosis was associated with adolescent age, and higher waist circumference, levels of alanine or aspartate aminotransferase, total and low-density lipoprotein cholesterol at baseline (

Recurring reports indicate that doctoral and postdoctoral students are regularly confronted with tasks that exceed contractually agreed duties and responsibilities. Research shows that such unreasonable tasks are dysfunctional to both the individual and the organization. However, there is a lack of reliable knowledge about more complex interconnections between unreasonable tasks and their consequences. The paper therefore investigates the mechanisms by which unreasonable tasks relate to doctoral and postdoctoral students' experience of their working conditions. The research model is tested using structural equation modelling (SEM) and data from 1053 doctoral and postdoctoral students at randomly selected German universities. The results reveal that unreasonable tasks have extensive and diverse negative effects on quantitative role overload, effort-reward imbalance, exhaustion, and intention to leave academia. In this way, the paper demonstrates how unreasonable tasks trigger sequences of negative effects that lead to the (post)doctoral students' intention to leave academia. The occurrence of unreasonable tasks is thus problematic not only for the individual, but also for the university as an organization.

BACKGROUND AND PURPOSE: External counterpulsation improves cerebral perfusion velocity in acute stroke and may stimulate collateral artery growth. However, whether (non-acute) at-risk patients with high-grade carotid artery disease may benefit from counterpulsation needs to be validated. METHODS: Twenty-eight patients (71 ± 6.5 years, five women) with asymptomatic unilateral chronic severe internal carotid artery stenosis (>70%) or occlusion were randomized to receive 20 min active counterpulsation followed by sham treatment or vice versa. Cerebral blood flow velocity (CBFV) (measured bilaterally by transcranial middle cerebral artery Doppler), tissue oxygenation index (TOI) (measured over the bilateral prefrontal cortex by near-infrared spectroscopy) and cerebral hemodynamic parameters, such as relative pulse slope index (RPSI), were monitored. RESULTS: Ipsilateral mean CBFV (ΔVmean +3.5 ± 1.2 cm/s) and tissue oxygenation (ΔTOI +2.86 ± 0.8) increased significantly during active counterpulsation compared to baseline, whilst the sham had little effect (ΔVmean +1.13 ± 1.1 cm/s; ΔTOI +1.25 ± 0.65). On contralateral sides, neither counterpulsation nor sham control had any effect on either parameter. During counterpulsation, early dynamic changes in ΔRPSI of the ipsilateral CBFV signal predicted improved tissue oxygenation during counterpulsation (odds ratio 1.179, 95% confidence interval 1.01-1.51), whilst baseline cerebrovascular reactivity to hypercapnia failed to show an association. CONCLUSIONS: In patients with high-grade carotid disease, ipsilateral cerebral oxygenation and blood flow velocity are increased by counterpulsation. This is a necessary condition for the stimulation of regenerative collateral artery growth and thus a therapeutic concept for the prevention of cerebral ischaemia. This study provides a rationale for further clinical investigations on the long-term effects of counterpulsation on cerebral hemodynamics and collateral growth.

ObjectiveTo determine the percentage of children with nonalcoholic fatty liver disease (NAFLD) in whom intervention for low-density lipoprotein cholesterol or triglycerides was indicated based on National Heart, Lung, and Blood Institute guidelines.Study designThis multicenter, longitudinal cohort study included children with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. Fasting lipid profiles were obtained at diagnosis. Standardized dietary recommendations were provided. After 1 year, lipid profiles were repeated and interpreted according to National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction. Main outcomes were meeting criteria for clinically actionable dyslipidemia at baseline, and either achieving lipid goal at follow-up or meeting criteria for ongoing intervention.ResultsThere were 585 participants, with a mean age of 12.8 years. The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention. Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications.ConclusionsMore than one-half of children with NAFLD met intervention thresholds for dyslipidemia. Based on the burden of clinically relevant dyslipidemia, lipid screening in children with NAFLD is warranted. Clinicians caring for children with NAFLD should be familiar with lipid management.

Background & aimsFocal zone 1 steatosis, although rare in adults with nonalcoholic fatty liver disease (NAFLD), does occur in children with NAFLD. We investigated whether focal zone 1 steatosis and focal zone 3 steatosis are distinct subphenotypes of pediatric NAFLD. We aimed to determine associations between the zonality of steatosis and demographic, clinical, and histologic features in children with NAFLD.MethodsWe performed a cross-sectional study of baseline data from 813 children (age

ObjectivesTo examine the distribution of birth weight in children with nonalcoholic fatty liver disease (NAFLD) compared with the general US population, and to investigate the relationship between birth weight and severity of NAFLD.Study designA multicenter, cross-sectional study of children with biopsy-proven NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network Database. Birth weight was categorized as low birth weight (LBW), normal birth weight (NBW), or high birth weight (HBW) and compared with the birth weight distribution in the general US population. The severity of liver histology was assessed by birth weight category.ResultsChildren with NAFLD (n = 538) had overrepresentation of both LBW and HBW compared with the general US population (LBW, 9.3%; NBW, 75.8%; HBW, 14.9% vs LBW, 6.1%; NBW, 83.5%; HBW 10.5%; P

BACKGROUND Arrhythmia recurrence after pulmonary vein isolation (PVI) is common. We conducted a multicenter, randomized trial to determine the impact of increased physical activity on atrial fibrillation recurrence after PVI. METHODS: From 2018 to 2020, we randomly assigned 200 patients with atrial fibrillation to the ACTION or NO-ACTION group in 4 different centers in the local country of Brandenburg, Germany. Patients were eligible if they were scheduled to undergo PVI, aged ≥50 to ≤77 years, body mass index ≥23 to ≤35 kg/m², and accepted wearing an activity tracker allowing 24-hour activity monitoring via mobile app. Patients in the ACTION group were actively remote-controlled via transmitted activity data by a physiotherapist, and individual motivational interviewing call sessions were scheduled with each ACTION patient every 2 weeks. The primary end point was the composite of recurrence of any atrial arrhythmia >30 seconds, additional ablation procedure, cardioversion, and new onset of antiarrhythmic drugs earliest after 90 days after index PVI over 12 months. RESULTS Overall, the median age of patients was 66 (interquartile range, 61-71) years, 33.5% were women, and 52% had persistent atrial fibrillation. The number of steps per day increased in both groups of patients from baseline to 12 months (P<0.001). The absolute increase in steps per day did not differ between patients in the ACTION group with +3205 steps (597-4944) compared with those in the NO-ACTION group +2423 steps (17-4284), P=0.325. Unadjusted intention-to-treat analysis showed no difference in the primary composite end point in the ACTION group (27.3%) versus the NO-ACTION group (32.7%), P=0.405. CONCLUSIONS: Physical activity improved in patients after PVI. The present randomized controlled trial shows that activity tracker and motivational calls to increase physical activity versus activity tracker alone did not reduce the occurrence of the primary composite end point of atrial fibrillation recurrence or the absolute increase in steps per day. [ABSTRACT FROM AUTHOR]

Background & aimsNo treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD.MethodsWe performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ≤65 kg, 375 mg for patients weighing >65 to 80 kg, and 450 mg for patients weighing >80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran-Mantel-Haenszel analysis.ResultsThere was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8-2.1; P = .34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P = .02) and aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P = .008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1-2.9; P = .03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3-12.3; P = .005).ConclusionsIn a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.