Publications by authors named "Anja Sander"

44 Publications

Protocol for a randomised controlled trial to compare postoperative complications between minimally invasive and open DIStal PAnCreaTectomy (DISPACT-2 trial).

BMJ Open 2021 Feb 22;11(2):e047867. Epub 2021 Feb 22.

The Study Center of the German Society of Surgery (SDGC), University of Heidelberg, Heidelberg, Germany.

Introduction: In recent years, minimally invasive distal pancreatectomy (MIDP) has been used with increasing frequency to accelerate patient recovery. Distal pancreatectomy has an overall morbidity rate of 30%-40%. The known advantages of minimally invasive techniques must be rigorously compared with those of open surgery before they can be completely implemented into clinical practice.

Methods And Analysis: DISPACT-2 is a multicentre randomised controlled trial comparing minimally invasive (conventional laparoscopic or robotic assisted) with open distal pancreatic resection in patients undergoing elective surgery for benign as well as malign diseases of the pancreatic body and tail. After screening for eligibility and obtaining informed consent, a total of 294 adult patients will be preoperatively randomised in a 1:1 ratio. The primary hypothesis is that MIDP is non-inferior to open distal pancreatectomy in terms of postoperative mortality and morbidity expressed as the Comprehensive Complication Index (CCI) within 3 months after index operation, with a non-inferiority margin of 7.5 CCI points. Secondary endpoints include pancreas-specific complications, oncological safety and patient reported outcomes. Follow-up for each individual patient will be 2 years.

Ethics And Dissemination: The DISPACT-2 trial has been approved by the Ethics Committee of the medical faculty of Heidelberg University (S-693/2017). Results of the primary endpoint will be available in 2024 and will be published at national and international meetings. Full results will be made available in an open access, peer-reviewed journal. The website www.dispact.de contains up-to-date information regarding the trial.

Trial Registration Number: DRKS00014011.
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http://dx.doi.org/10.1136/bmjopen-2020-047867DOI Listing
February 2021

Evaluation of the 2020 EAN Virtual Congress: transition from a face-to-face to a virtual meeting.

Eur J Neurol 2020 Dec 28. Epub 2020 Dec 28.

Department of Neurology, Inselspital, Bern, University Hospital, University of Bern, Switzerland.

Background: Due to the COVID-19 pandemic, scientific congresses are increasingly being organised as virtual congresses. In May 2020, the European Academy of Neurology (EAN) held a VC, free-of-charge. In the absence of systematic studies on this topic, the aim of this study is to evaluate the attendance and perceived quality of the 2020 EAN virtual congress (VC) compared to the 2019 EAN face-to-face congress (FFC).

Methods: Analysis of demographic data of participants obtained from the online registration collected. Comparison of the two congresses based on a survey with questions on the perception of speakers' performance, quality of networking, and other aspects.

Results: Of 43,596 registered participants, 20,694 active participants attended the VC. Compared to 2019, the number of participants tripled (6916 in 2019) and the cumulated number of participants attending the sessions was five times higher (169,334 in 2020 vs 33,024 in 2019). Out of active participants 55% were from outside Europe, 42% were board-certified neurologists (FFC: 80%), and 21% were students (FFC: 0.6%). The content of the congress was evaluated as 'above expectation' by 56% of the attendees (FFC: 41%). Out of the respondents who had been exposed to earlier EAN congresses 73% preferred the FFC congress compared to the VC (17%).

Conclusion: The VC fulfilled the main mission of organizing high quality EAN congresses despite the restrictions of the impersonal format. The geographical distribution of the participants prove the expected higher inclusivity of a VC. The large participation of students and neurologists in training opens new educational potentials for the EAN.
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http://dx.doi.org/10.1111/ene.14702DOI Listing
December 2020

Randomized clinical trial to compare efficacy and safety of repeated courses of rituximab to single-course rituximab followed by maintenance mycophenolate-mofetil in children with steroid dependent nephrotic syndrome.

BMC Nephrol 2020 11 30;21(1):520. Epub 2020 Nov 30.

Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.

Background: Approximately 30% of children with idiopathic nephrotic syndrome develop a complicated course with frequent relapses or steroid dependency. Rituximab, a B cell depleting monoclonal antibody, is a safe and effective alternative to steroids or other immunosuppressants for achieving and maintaining remission in this population at short term. Despite the good initial response relapses inevitably occur after regeneration of B lymphocytes, necessitating either repeat courses of rituximab or addition of another steroid-sparing immunosuppressant.

Methods: This is a prospective, single-center, open-label, two-parallel-arm randomized controlled phase III study among children with steroid dependent nephrotic syndrome who are maintained in remission with oral steroids. One hundred children will be randomized to either Rituximab and maintenance Mycophenolate mofetil (A) or repeated courses of prophylactic Rituximab only (B). In arm A, mycophenolate mofetil (1200 mg/m per day) will be started 3 months after Rituximab administration. In arm B, Rituximab infusions will be administered at 0, 8 and 16 months if B cell count normalize at the given time points. Prednisolone will be discontinued in both groups 2 weeks following first course of rituximab. Primary aim is to evaluate the difference in 24-month relapse-free survival. Main secondary endpoints are cumulative prednisolone dose, frequency of relapses and changes in anthropometry. Circulating B lymphocyte populations will be studied as biomarkers or predictors of rituximab responsiveness and adverse events will be analysed.

Discussion: The study will provide evidence as to the comparative safety and efficacy of two alternative steroid-sparing therapeutic options in children suffering from steroid dependent nephrotic syndrome. The two-year study design will address the long-term results obtained with the alternative treatment protocols.

Trial Registration: This trial was prospectively registered to the Clinicaltrial.gov ( NCT03899103 dated 02/04/2019; https://clinicaltrials.gov/ ) and Clinical Trials Registry of India ( CTRI/2019/04/018517 dated 09/04/2019).
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http://dx.doi.org/10.1186/s12882-020-02153-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706288PMC
November 2020

Phase I trial of donor-derived modified immune cell infusion in kidney transplantation.

J Clin Invest 2020 05;130(5):2364-2376

Transplantation Immunology, Institute of Immunology.

BACKGROUNDPreclinical experiments have shown that donor blood cells, modified in vitro by an alkylating agent (modified immune cells [MICs]), induced long-term specific immunosuppression against the allogeneic donor.METHODSIn this phase I trial, patients received either 1.5 × 106 MICs per kg BW on day -2 (n = 3, group A), or 1.5 × 108 MICs per kg BW on day -2 (n = 3, group B) or day -7 (n = 4, group C) before living donor kidney transplantation in addition to post-transplantation immunosuppression. The primary outcome measure was the frequency of adverse events (AEs) until day 30 (study phase) with follow-up out to day 360.RESULTSMIC infusions were extremely well tolerated. During the study phase, 10 treated patients experienced a total of 69 AEs that were unlikely to be related or not related to MIC infusion. No donor-specific human leukocyte antigen Abs or rejection episodes were noted, even though the patients received up to 1.3 × 1010 donor mononuclear cells before transplantation. Group C patients with low immunosuppression during follow-up showed no in vitro reactivity against stimulatory donor blood cells on day 360, whereas reactivity against third-party cells was still preserved. Frequencies of CD19+CD24hiCD38hi transitional B lymphocytes (Bregs) increased from a median of 6% before MIC infusion to 20% on day 180, which was 19- and 68-fold higher, respectively, than in 2 independent cohorts of transplanted controls. The majority of Bregs produced the immunosuppressive cytokine IL-10. MIC-treated patients showed the Immune Tolerance Network operational tolerance signature.CONCLUSIONMIC administration was safe and could be a future tool for the targeted induction of tolerogenic Bregs.TRIAL REGISTRATIONEudraCT number: 2014-002086-30; ClinicalTrials.gov identifier: NCT02560220.FUNDINGFederal Ministry for Economic Affairs and Technology, Berlin, Germany, and TolerogenixX GmbH, Heidelberg, Germany.
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http://dx.doi.org/10.1172/JCI133595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190926PMC
May 2020

Physical fitness and health-related quality of life in pediatric renal transplant recipients: An interventional trial with active video gaming.

Pediatr Transplant 2020 02 27;24(1):e13630. Epub 2019 Dec 27.

Medical Clinic, Internal Medicine VII: Sports Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Background: Pediatric renal transplant recipients are at increased risk for cardiovascular diseases, one contributing factor is reduced cardiorespiratory fitness. The purpose was to evaluate cardiorespiratory fitness, motor coordination, muscle strength, daily physical activity, and health-related quality of life and to find out, if active video gaming is effective for improving these items in this patient population.

Methods: Twenty renal transplant recipients (13.5 ± 3.4 years) and 33 matched healthy controls (13.1 ± 3.2 years) performed a spiroergometry, a motor coordination test, and a maximal handgrip strength test. Quality of life was determined with a validated questionnaire, and daily physical activity was recorded with a physical activity monitor. Thirteen patients (12.9 ± 3.4 years) participated in a 6-week home-based exergaming intervention (3×/week for 30 minutes) and repeated all tests after that.

Results: The renal transplant recipients exhibited a substantial impairment compared with the controls in peak oxygen consumption (-31%, P < .001), motor competence (-44%, P < .001), daily physical activity (-33%, P = .001), and quality of life (-12%, P = .017). Handgrip strength was similar in both groups. Despite of low compliance in the intervention group, steps per hour were significantly increased after 6 weeks of exergaming (+31%, P = .043); however, all other measures remained unchanged.

Conclusion: Cardiorespiratory fitness, motor competence, and quality of life are reduced in pediatric renal transplant recipients. Home-based exergaming is not appropriate to improve these items, probably due to a substantially impaired motor competence. However, it provided a stimulus for an increased daily physical activity.
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http://dx.doi.org/10.1111/petr.13630DOI Listing
February 2020

Cluster-randomised trial evaluating a complex intervention to improve mental health and well-being of employees working in hospital - a protocol for the SEEGEN trial.

BMC Public Health 2019 Dec 17;19(1):1694. Epub 2019 Dec 17.

Clinic of Psychosomatic Medicine and Psychotherapy, University Hospital Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.

Background: Health care employees in Germany and worldwide are exposed to a variety of stressors. However, most of the hospitals in Germany lack a systematic workplace health management. Thus, this study aims at the evaluation of the effects of a behavioural as well as organisational (´complex´) intervention on the mental health and well-being of hospital staff.

Methods: Mental health in the hospital workplace (SEElische GEsundheit am Arbeitsplatz KrankeNhaus - SEEGEN) is an unblinded, multi-centred cluster-randomised open trial with two groups (intervention group (IG) and waitlist control group (CG)). Study participants in the intervention clusters will receive the complex intervention; study participants in the waitlist control clusters will receive the complex intervention after the last follow-up measurement. The intervention consists of five behavioural and organisational intervention modules that are specifically tailored to hospital employees at different hierarchical and functional levels. Hospital staff may select one specific module according to their position and specific needs or interests. Towards the end of the intervention roundtable discussions with representatives from all professional groups will be held to facilitate organisational change. Primary outcome is the change in emotional and cognitive strain in the working environment, from baseline (T0) to 6 month-follow up (T1), between IG and CG. In addition, employees who do not participate in the modules are included in the trial by answering shorter questionnaires (cluster participants). Furthermore, using mixed methods, a process evaluation will identify uptake of the intervention, and mediators and moderators of the effect.

Discussion: There seems to be growing psychological strain on people working in the health care sector worldwide. This study will examine whether investing directly in the hospital staff and their interpersonal relationship may lead to measurable benefits in subjective well-being at the workplace and improved economic performance indicators of the hospital. In case of a positive outcome, health promotion strategies looking at behavioural as well as organisational components within the hospital may gain additional importance, especially in regard of the growing financial pressure within the health sector.

Trial Registration Drks: The SEEGEN study is registered at the German Clinical Trial Register (DRKS) under the DRKS-ID DRKS00017249. Registered 08 October 2019, URL. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00017249.
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http://dx.doi.org/10.1186/s12889-019-7909-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918673PMC
December 2019

Comparing Cognitive Behavioral Therapy and Systemic Therapy for Social Anxiety Disorder: Randomized Controlled Pilot Trial (SOPHO-CBT/ST).

Fam Process 2020 12 27;59(4):1389-1406. Epub 2019 Oct 27.

Institute of Medical Psychology, Center for Psychosocial Medicine, University Hospital Heidelberg, Heidelberg, Germany.

This randomized controlled trial (RCT) aimed to pilot the newly developed manualized and monitored systemic therapy (ST) for social anxiety disorder (SAD), as compared to manualized and monitored cognitive behavioral therapy (CBT). We conducted a prospective multicenter, assessor-blind pilot RCT on 38 outpatients (ICD F40.1; Structured Clinical Interview for DSM (SCID); Liebowitz Social Anxiety Scale, LSAS-SR >30). The primary outcome was level of social anxiety (LSAS-SR) at the end of treatment. A total of 252 persons were screened, and 38 patients were randomized and started therapy (CBT: 20 patients; ST: 18 patients; age: M = 36 years, SD = 14). Within-group, simple-effect intent-to-treat analyses (ITT) showed significant reduction in LSAS-SR (CBT:d = 1.04; ST:d = 1.67), while ITT mixed-design ANOVA demonstrated the advantage of ST (d = 0.81). Per-protocol analyses supported these results. Remission based on reliable change indices also demonstrated significant difference (LSAS-SR: 15% in CBT; 39% in ST;h: 0.550), supported by blind diagnosticians' ratings of those who completed therapy (SCID; 45% in CBT, 78% in ST,p = .083). No adverse events were reported. CBT and ST both reduced social anxiety, supporting patient improvement with the newly developed ST for SAD; this has yet to be verified in a subsequent confirmatory RCT.
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http://dx.doi.org/10.1111/famp.12492DOI Listing
December 2020

Frontline Science: Low regulatory T cells predict perioperative major adverse cardiovascular and cerebrovascular events after noncardiac surgery.

J Leukoc Biol 2020 05 15;107(5):717-730. Epub 2019 Sep 15.

Department of Anesthesiology, University Hospital Heidelberg, Heidelberg, Germany.

Immune cells drive atherosclerotic lesion progression and plaque destabilization. Coronary heart disease patients undergoing noncardiac surgery are at risk for perioperative major adverse cardiac and cerebrovascular events (MACCE). It is unclear whether differential leukocyte subpopulations contribute to perioperative MACCE and thereby could aid identification of patients prone to perioperative cardiovascular events. First, we performed a hypothesis-generating post hoc analysis of the LeukoCAPE-1 study (n = 38). We analyzed preoperative counts of 6 leukocyte subpopulations in coronary heart disease patients for association with MACCE (composite of cardiac death, myocardial infarction, myocardial ischemia, myocardial injury after noncardiac surgery, thromboembolic stroke) within 30 d after surgery. Regulatory T cells (Tregs) were the only leukocyte subgroup associated with MACCE. We found reduced Tregs in patients experiencing MACCE versus no-MACCE (0.02 [0.01; 0.03] vs. 0.04 [0.03; 0.05] Tregs nl , P = 0.002). Using Youden index, we derived the optimal threshold value for association with MACCE to be 0.027 Tregs nl . Subsequently, we recruited 233 coronary heart disease patients for the prospective, observational LeukoCAPE-2 study and independently validated this Treg cutoff for prediction of MACCE within 30 d after noncardiac surgery. After multivariate logistic regression, Tregs < 0.027 cells nl remained an independent predictor for MACCE (OR = 2.54 [1.22; 5.23], P = 0.012). Tregs improved risk discrimination of the revised cardiac risk index based on ΔAUC (area under the curve; ΔAUC = 0.09, P = 0.02), NRI (0.26), and IDI (0.06). Preoperative Treg levels below 0.027 cells nl predicted perioperative MACCE and can be measured to increase accuracy of established preoperative cardiac risk stratification in coronary heart disease patients undergoing noncardiac surgery.
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http://dx.doi.org/10.1002/JLB.5HI1018-392RRDOI Listing
May 2020

Prostate bed irradiation with alternative radio-oncological approaches (PAROS) - a prospective, multicenter and randomized phase III trial.

Radiat Oncol 2019 Jul 10;14(1):122. Epub 2019 Jul 10.

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.

Background: For patients with treatment-naïve carcinoma of the prostate, hypofractionated irradiation becomes more and more popular. Due to the low α/β value of prostate cancer, increased single dose leading to a shortened treatment period seems to be safe and feasible. However, reliable data is lacking for post-prostatectomy patients so far. Further, the role of proton therapy is still under debate. Two prospective phase II trials with both, hypofractionated photon and proton therapy, provided promising results.

Methods/ Design: The PAROS trial is a prospective, multicenter and randomized phase III trial for men with localized prostate carcinoma after surgery. Post-prostatectomy patients will be randomized to either normofractionated radiotherapy (nRT) with photons (70.0/ 2.0 Gy), or hypofractionated radiotherapy (hRT) with photons (57.0/ 3.0 Gy) or hRT with protons (57.0/ 3.0 Gy relative biological effectiveness [RBE]). Block randomization is stratified by Gleason Score (≤ 7 vs. > 7) and treatment indication (adjuvant vs. salvage). The trial is planned to enroll 897 patients. The primary objective is to show an improvement in the bowel-score according to EORTC QLQ-PR25 after proton therapy compared to photon irradiation (week 12 vs. baseline). Secondary aims are non-inferiority of hRT compared to nRT with regard to biochemical progression-free survival (bPFS), overall survival (OS), quality of life and toxicity.

Discussion: The present study aims to evaluate the role of hypofractionated radiotherapy to the prostate bed with photons and protons leading to significant impact on future management of operated men with prostate cancer.

Trial Registration: Deutsches Register klinischer Studien: DRKS00015231 ; registered 27 September 2018.
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http://dx.doi.org/10.1186/s13014-019-1325-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617634PMC
July 2019

What do parents expect from a genetic diagnosis of their child with intellectual disability?

J Appl Res Intellect Disabil 2019 Sep 15;32(5):1129-1137. Epub 2019 Apr 15.

Section for Neuropediatrics and Inborn Errors of Metabolism, University Children's Hospital, Clinic I, Heidelberg, Germany.

Background: Caring for a child with intellectual disability (ID) has been associated with increased social and psychological burdens. Diagnostic and prognostic uncertainty may enhance emotional stress in families.

Method: The present authors assessed the motivations, expectations, mental health, physical health and the quality of life of 194 parents whose children with intellectual disability were undergoing a genetic diagnostic workup.

Results: Most parents considered a diagnosis highly relevant for their own emotional relief, their child's therapies and education, or family planning. Parental mental health was significantly lower compared with the normative sample, but physical health was not different. The severity of the child's intellectual disability correlated negatively with their parents' mental and physical health, quality of life, and positively with parental anxiety.

Conclusion: Healthcare providers should be aware of the disadvantages facing families with intellectually disabled children. Receiving practical, social and psychological support as well as genetic testing might be particularly relevant for families with severely disabled children.
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http://dx.doi.org/10.1111/jar.12602DOI Listing
September 2019

Global Variation of Nutritional Status in Children Undergoing Chronic Peritoneal Dialysis: A Longitudinal Study of the International Pediatric Peritoneal Dialysis Network.

Sci Rep 2019 03 20;9(1):4886. Epub 2019 Mar 20.

Children's Mercy Hospital, Kansas City, MO, USA.

While children approaching end-stage kidney disease (ESKD) are considered at risk of uremic anorexia and underweight they are also exposed to the global obesity epidemic. We sought to investigate the variation of nutritional status in children undergoing chronic peritoneal dialysis (CPD) around the globe. The distribution and course of body mass index (BMI) standard deviation score over time was examined prospectively in 1001 children and adolescents from 35 countries starting CPD who were followed in the International Pediatric PD Network (IPPN) Registry. The overall prevalence of underweight, and overweight/obesity at start of CPD was 8.9% and 19.7%, respectively. Underweight was most prevalent in South and Southeast Asia (20%), Central Europe (16.7%) and Turkey (15.2%), whereas overweight and obesity were most common in the Middle East (40%) and the US (33%). BMI SDS at PD initiation was associated positively with current eGFR and gastrostomy feeding prior to PD start. Over the course of PD BMI SDS tended to increase on CPD in underweight and normal weight children, whereas it decreased in initially overweight patients. In infancy, mortality risk was amplified by obesity, whereas in older children mortality was markedly increased in association with underweight. Both underweight and overweight are prevalent in pediatric ESKD, with the prevalence varying across the globe. Late dialysis start is associated with underweight, while enteral feeding can lead to obesity. Nutritional abnormalities tend to attenuate with time on dialysis. Mortality risk appears increased with obesity in infants and with underweight in older children.
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http://dx.doi.org/10.1038/s41598-018-36975-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426856PMC
March 2019

Are we preparing future doctors to deal with emotionally challenging situations? Analysis of a medical curriculum.

Patient Educ Couns 2019 07 25;102(7):1304-1312. Epub 2019 Feb 25.

Department of General Internal and Psychosomatic Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Electronic address:

Objective: Skilful communication by doctors is necessary for healthcare delivery during emotionally challenging situations. This study analyses a medical curriculum for the frequency and intensity of teaching content on communication in emotionally challenging situations.

Methods: A questionnaire with 31 questions ("EmotCog31") was used to evaluate teaching sessions at 17 departments of a medical school for one semester.

Results: Teaching content on communication in emotionally challenging situations was observed in 62 of 724 (∼nine percent) teaching sessions. Fifty-six percent of these sessions were within psychosocial specialisations. Lecturers used mental diseases as teaching topics four times more than somatic diseases. Forty-two percent of the 62 sessions were large-group while fifty-eight percent were small-group, interactive sessions. Clinical examples were used in sixty-nine percent of these sessions. Eighty-one percent of the handouts provided and sixty-six percent of simulated patient scenarios used were rated as helpful. Two-thirds of teaching sessions were rated positively when they included practical context.

Conclusion: There was a considerable lack of teaching on communication skills in an emotional context. Teaching was limited to psychosocial specialties, reducing the impact of available knowledge for other medical specialties.

Practice Implications: More interactive, practically oriented teaching methods are useful for teaching emotional communication skills.
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http://dx.doi.org/10.1016/j.pec.2019.02.024DOI Listing
July 2019

Initial treatment of steroid-sensitive idiopathic nephrotic syndrome in children with mycophenolate mofetil prednisone: protocol for a randomised, controlled, multicentre trial (INTENT study).

BMJ Open 2018 10 10;8(10):e024882. Epub 2018 Oct 10.

Department of Pediatrics, University Children's Hospital Köln, University Hospital Köln, Köln, Germany.

Introduction: Idiopathic nephrotic syndrome is the most common glomerular disease in childhood with an incidence of 1.8 cases per 100 000 children in Germany. The treatment of the first episode implies two aspects: induction of remission and sustainment of remission. The recent Kidney Disease Improving Global Outcomes, American Academy of Pediatrics and German guidelines for the initial treatment of the first episode of a nephrotic syndrome recommend a 12-week course of prednisone. Despite being effective, this treatment is associated with pronounced glucocorticoid-associated toxicity due to high-dose prednisone administration over a prolonged period of time. The aim of the INTENT study (Initial treatment of steroid-sensitive idiopathic nephrotic syndrom in children with mycophenolate mofetil versus prednisone: protocol for a randomised, controlled, multicentre trial) is to show that an alternative treatment regimen with mycophenolic acid is not inferior regarding sustainment of remission, but with lower toxicity compared with treatment with glucocorticoids only.

Methods And Design: The study is designed as an open, randomised, controlled, multicentre trial. 340 children with a first episode of steroid-sensitive nephrotic syndrome and who achieved remission by a standard prednisone regimen will be enrolled in the trial and randomised to one of two treatment arms. The standard care group will be treated with prednisone for a total of 12 weeks; in the experimental group the treatment is switched to mycophenolate mofetil, also for a total of 12 weeks in treatment duration. The primary endpoint is the occurrence of a treated relapse within 24 months after completion of initial treatment.

Ethics And Dissemination: Ethics approval for this trial was granted by the ethics committee of the Medical Faculty of the University of Heidelberg (AFmu-554/2014). The study results will be published in accordance with the Consolidated Standards of Reporting Trials statement and the Standard Protocol Items: Recommendations for Interventional Trials guidelines. Our findings will be submitted to major international paediatric nephrology and general paediatric conferences and submitted for publication in a peer-reviewed, open-access journal.

Trial Registration Number: DRKS0006547; EudraCT2014-001991-76; Pre-result.

Date Of Registration: 30 October 2014; 24 February 2017.
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http://dx.doi.org/10.1136/bmjopen-2018-024882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252704PMC
October 2018

Cognitive and Behavioral Consequences of Pediatric Delirium: A Pilot Study.

Pediatr Crit Care Med 2018 10;19(10):e531-e537

Division of Neuropediatrics and Metabolic Medicine, Department of General Pediatrics, Centre for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Objectives: To investigate the long-term impact of postoperative delirium in children.

Design: Single-center point prevalence study.

Setting: Twenty-two bed PICU.

Patients: Forty-seven patients 1-16 years old.

Interventions: Standardized neuropsychologic follow-up investigation after a mean time of 17.7 ± 2.9 months after PICU discharge.

Measurements And Main Results: Pediatric delirium did not have significant long-term impact on global cognition, executive functions, or behavior. Severity of delirium did not influence the outcome. Different predictors were identified for later cognitive functioning, executive functions, and behavioral problems. Younger age was confirmed to be a relevant risk factor for delirium as well as for the cognitive and behavioral outcome.

Conclusions: Contrary to the findings in adults, there was no clear association between pediatric delirium and long-term cognition or behavior in this cohort. However, this is a first pilot study with several limitations that should promote more comprehensive prospective trials.
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http://dx.doi.org/10.1097/PCC.0000000000001686DOI Listing
October 2018

Efficacy of Rituximab vs Tacrolimus in Pediatric Corticosteroid-Dependent Nephrotic Syndrome: A Randomized Clinical Trial.

JAMA Pediatr 2018 08;172(8):757-764

Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.

Importance: Calcineurin inhibitors are an established first-line corticosteroid-sparing therapy for patients with corticosteroid-dependent nephrotic syndrome (CDNS), whereas B-lymphocyte-depleting therapy is mostly used as a rescue for calcineurin inhibitor-resistant cases. The positive efficacy and safety profile of rituximab raises the question of whether it could be used as a first-line alternative to calcineurin inhibitor therapy.

Objective: To compare the efficacy of rituximab and tacrolimus in maintaining relapse-free survival among children with CDNS.

Design, Setting, And Participants: A parallel-arm, open-label, randomized clinical trial was performed from May 8, 2015, to September 20, 2016, with 1-year follow-up in a single-center, tertiary care unit. A total of 176 consecutive children aged 3 to 16 years with CDNS not previously treated with corticosteroid-sparing agents were screened for eligibility.

Interventions: The children received either tacrolimus (along with tapering alternate-day prednisolone) for 12 months or a single course of rituximab (2 infusions of 375 mg/m2).

Main Outcomes And Measures: Twelve-month relapse-free survival in the intention-to-treat population.

Results: Of the 176 children screened for eligibility, 120 were randomized and all but 3 patients completed 1 year of follow-up. The groups were comparable, with mean (SD) age of 7.2 (2.8) years, 32 boys (53.3%) in each group, mean (SD) disease duration of 2.5 (1.5) years and 2.3 (1.7) in the tacrolimus and rituximab groups, respectively, disease duration less than 1 year among 15 children (25.0%) in each group, median (interquartile range) of 4 (3-5) relapses in each group, and mean (SD) cumulative prednisolone dose of 246 (48) mg/kg and 239 (52) mg/kg in the prestudy year in the tacrolimus and rituximab groups, respectively. Rituximab therapy was associated with a higher 12-month relapse-free survival rate than tacrolimus (54 [90.0%] vs 38 [63.3%] children; P < .001; odds ratio, 5.21; 95% CI, 1.93-14.07). Among the patients who experienced relapse, median time to first relapse was 40 weeks in the rituximab group and 29 weeks in the tacrolimus group. Only 2 patients in the rituximab group had more than 1 relapse during the study period compared with 10 patients in the tacrolimus group. The cumulative corticosteroid dose during the 12-month study period was lower with rituximab compared with tacrolimus (mean [SD], 25.8 [27.8] vs 86.3 [58.0] mg/kg). Although both treatments were well tolerated, mild to moderate infections were twice as common in the tacrolimus group (26 [43.3%] vs 13 [21.7%] events).

Conclusions And Relevance: In children with CDNS, rituximab appears to be more effective than tacrolimus in maintaining disease remission and minimizing corticosteroid exposure and, given its good tolerability and lack of nephrotoxic effects, may be considered as first-line corticosteroid-sparing therapy.

Trial Registration: ClinicalTrials.gov Identifier: NCT02438982; Clinical Trial Registry of India: CTRI/2014/01/004355.
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http://dx.doi.org/10.1001/jamapediatrics.2018.1323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142920PMC
August 2018

Effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism in children with chronic kidney disease.

Nephrol Dial Transplant 2018 12;33(12):2208-2217

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.

Background: We investigated the effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism, i.e. serum levels of fibroblast growth factor 23 (FGF23), Klotho, bone alkaline phosphatase (BAP) and sclerostin, in two cohorts with chronic kidney disease (CKD).

Methods: In all, 80 vitamin D-deficient children were selected: 40 with mild to moderate CKD from the ERGO study, a randomized trial of ergocalciferol supplementation [estimated glomerular filtration rate (eGFR) 55 mL/min/1.73 m2], and 40 with advanced CKD from the observational Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study (eGFR 24 mL/min/1.73 m2). In each study, vitamin D supplementation was started in 20 children and 20 matched children not receiving vitamin D served as controls. Measures were taken at baseline and after a median period of 8 months. Age- and gender-related standard deviation scores (SDSs) were calculated.

Results: Before vitamin D supplementation, children in the ERGO study had normal FGF23 (median 0.31 SDS) and BAP (-0.10 SDS) but decreased Klotho and sclerostin (-0.77 and -1.04 SDS, respectively), whereas 4C patients had increased FGF23 (3.87 SDS), BAP (0.78 SDS) and sclerostin (0.76 SDS) but normal Klotho (-0.27 SDS) levels. Vitamin D supplementation further increased FGF23 in 4C but not in ERGO patients. Serum Klotho and sclerostin normalized with vitamin D supplementation in ERGO but remained unchanged in 4C patients. BAP levels were unchanged in all patients. In the total cohort, significant effects of vitamin D supplementation were noted for Klotho at eGFR 40-70 mL/min/1.73 m2.

Conclusions: Vitamin D supplementation normalized Klotho and sclerostin in children with mild to moderate CKD but further increased FGF23 in advanced CKD.
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http://dx.doi.org/10.1093/ndt/gfy012DOI Listing
December 2018

Association of angiotensin II type 1 receptor antibodies with graft histology, function and survival in paediatric renal transplant recipients.

Nephrol Dial Transplant 2018 06;33(6):1065-1072

Department of Paediatrics I, University Children's Hospital, Heidelberg, Germany.

Background: We analysed in a carefully phenotyped cohort of paediatric patients the association of serum angiotensin II type 1 receptor antibodies (AT1R-Ab) with specific histological lesions and with graft function and survival in conjunction with overall and complement-binding donor-specific human leucocyte antigen donor-specific antibodies (HLA-DSA).

Methods: Sera of 62 patients at the time of renal graft biopsy for clinical indication >1 year post-transplant were assessed for AT1R-Ab by enzyme-linked immunosorbent assay (ELISA) and for DSA and C1q-fixing DSA by single-antigen bead technology.

Results: Serum AT1R-Ab concentration was significantly higher in antibody-mediated rejection (ABMR) than in T-cell-mediated rejection or control. By receiver operating characteristic (ROC) curve analysis, the optimal AT1R-Ab cut-off value discriminating between patients with features of ABMR and those without was 9.5 U/mL. A total of 6 of 28 patients (21.4%) with ABMR were only positive for AT1R-Ab. Patients with AT1R-Ab and HLA-DSA double positivity had a significantly higher vascular micro-inflammation score than DSA-negative patients. The 5-year graft survival was only 59% in the AT1R-Ab-positive group compared with 87% in the AT1R-Ab-negative group. Patients with AT1R-Ab and HLA-DSA double positivity tended to have a more rapid decline of estimated glomerular filtration rate (eGFR) than patients who were only positive for AT1R-Ab or HLA-DSA. In a multivariate Cox regression model of non-invasive factors, C1q-positive HLA-DSA, eGFR and AT1R-Ab positivity were significantly associated with accelerated graft function decline.

Conclusions: Serum AT1R-Ab positivity in the context of an indication biopsy >1 year post-transplant is associated with the histopathology of ABMR and is an independent non-invasive risk factor for adverse graft outcome.
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http://dx.doi.org/10.1093/ndt/gfy008DOI Listing
June 2018

Early Effects of Renal Replacement Therapy on Cardiovascular Comorbidity in Children With End-Stage Kidney Disease: Findings From the 4C-T Study.

Transplantation 2018 03;102(3):484-492

Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.

Background: The early impact of renal transplantation on subclinical cardiovascular measures in pediatric patients has not been widely investigated. This analysis is performed for pediatric patients participating in the prospective cardiovascular comorbidity in children with chronic kidney disease study and focuses on the early effects of renal replacement therapy (RRT) modality on cardiovascular comorbidity in patients receiving a preemptive transplant or started on dialysis.

Methods: We compared measures indicating subclinical cardiovascular organ damage (aortal pulse wave velocity, carotid intima media thickness, left ventricular mass index) and evaluated cardiovascular risk factors in 166 pediatric patients before and 6 to 18 months after start of RRT (n = 76 transplantation, n = 90 dialysis).

Results: RRT modality had a significant impact on the change in arterial structure and function: compared to dialysis treatment, transplantation was independently associated with decreases in pulse wave velocity (ß = -0.67; P < 0.001) and intima media thickness (ß = -0.40; P = 0.008). Independent of RRT modality, an increase in pulse wave velocity was associated with an increase in diastolic blood pressure (ß = 0.31; P < 0.001). Increasing intima media thickness was associated with a larger increase in body mass index (ß = 0.26; P = 0.003) and the use of antihypertensive agents after RRT (ß = 0.41; P = 0.007). Changes in left ventricular mass index were associated with changes in systolic blood pressure (ß = 1.47; P = 0.01).

Conclusions: In comparison with initiating dialysis, preemptive transplantation prevented further deterioration of the subclinical vascular organ damage early after transplantation. Classic cardiovascular risk factors, such as hypertension and obesity are of major importance for the development of cardiovascular organ damage after renal transplantation.
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http://dx.doi.org/10.1097/TP.0000000000001948DOI Listing
March 2018

Cardiovascular Phenotypes in Children with CKD: The 4C Study.

Clin J Am Soc Nephrol 2017 01 8;12(1):19-28. Epub 2016 Nov 8.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background And Objectives: Cardiovascular disease is the most important comorbidity affecting long-term survival in children with CKD.

Design, Setting, Participants, & Measurements: The Cardiovascular Comorbidity in Children with CKD Study is a multicenter, prospective, observational study in children ages 6-17 years old with initial GFR of 10-60 ml/min per 1.73 m. The cardiovascular status is monitored annually, and subclinical cardiovascular disease is assessed by noninvasive measurements of surrogate markers, including the left ventricular mass index, carotid intima-media thickness, and central pulse wave velocity. We here report baseline data at study entry and an explorative analysis of variables associated with surrogate markers.

Results: A total of 737 patients were screened from October of 2009 to August of 2011 in 55 centers in 12 European countries, and baseline data were analyzed in 688 patients. Sixty-four percent had congenital anomalies of the kidney and urinary tract; 26.1% of children had uncontrolled hypertension (24-hour ambulatory BP monitoring; n=545), and the prevalence increased from 24.4% in CKD stage 3 to 47.4% in CKD stage 5. The prevalence of left ventricular hypertrophy was higher with each CKD stage, from 10.6% in CKD stage 3a to 48% in CKD stage 5. Carotid intima-media thickness was elevated in 41.6%, with only 10.8% of patients displaying measurements below the 50th percentile. Pulse wave velocity was increased in 20.1%. The office systolic BP SD score was the single independent factor significantly associated with all surrogate markers of cardiovascular disease. The intermediate end point score (derived from the number of surrogate marker measurements >95th percentile) was independently associated with a diagnosis of congenital anomalies of the kidney and urinary tract, time since diagnosis of CKD, body mass index, office systolic BP, serum phosphorus, and the hemoglobin level.

Conclusions: The baseline data of this large pediatric cohort show that surrogate markers for cardiovascular disease are closely associated with systolic hypertension and stage of CKD.
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http://dx.doi.org/10.2215/CJN.01090216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220645PMC
January 2017

Genetic, Environmental, and Disease-Associated Correlates of Vitamin D Status in Children with CKD.

Clin J Am Soc Nephrol 2016 07 16;11(7):1145-53. Epub 2016 Jun 16.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background And Objectives: Vitamin D deficiency is endemic in children with CKD. We sought to investigate the association of genetic disposition, environmental factors, vitamin D supplementation, and renal function on vitamin D status in children with CKD.

Design, Setting, Participants, & Measurements: Serum 25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, and 24,25-dihydroxy-vitamin D concentrations were measured cross-sectionally in 500 children from 12 European countries with CKD stages 3-5. All patients were participants of the Cardiovascular Comorbidity in Children with Chronic Kidney Disease Study, had CKD stage 3-5, and were age 6-18 years old. Patients were genotyped for single-nucleotide polymorphisms in the genes encoding 25-hydroxylase, vitamin D binding protein, 7-dehydrocholesterol reductase, and 24-hydroxylase. Associations of genetic status, season, local solar radiation, oral vitamin D supplementation, and disease-associated factors with vitamin D status were assessed.

Results: Two thirds of patients were vitamin D deficient (25-hydroxy-vitamin D <16 ng/ml). 25-Hydroxy-vitamin D concentrations varied with season and were twofold higher in vitamin D-supplemented patients (21.6 [14.1] versus 10.4 [10.1] ng/ml; P<0.001). Glomerulopathy, albuminuria, and girls were associated with lower 25-hydroxy-vitamin D levels. 24,25-dihydroxy-vitamin D levels were closely correlated with 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D (r=0.87 and r=0.55; both P<0.001). 24,25-dihydroxy-vitamin D concentrations were higher with higher c-terminal fibroblast growth factor 23 and inversely correlated with intact parathyroid hormone. Whereas 25-hydroxy-vitamin D levels were independent of renal function, 24,25-dihydroxy-vitamin D levels were lower with lower eGFR. Vitamin D deficiency was more prevalent in Turkey than in other European regions independent of supplementation status and disease-related factors. Single-nucleotide polymorphisms in the vitamin D binding protein gene were independently associated with lower 25-hydroxy-vitamin D and higher 24,25-dihydroxy-vitamin D.

Conclusions: Disease-related factors and vitamin D supplementation are the main correlates of vitamin D status in children with CKD. Variants in the vitamin D binding protein showed weak associations with the vitamin D status.
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http://dx.doi.org/10.2215/CJN.10210915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4934841PMC
July 2016

Blinded sample size recalculation in clinical trials with binary composite endpoints.

J Biopharm Stat 2017 13;27(4):705-715. Epub 2016 Jun 13.

a Institute of Medical Biometry and Informatics , University of Heidelberg , Heidelberg , Germany.

We consider clinical trials with a binary composite endpoint where the trial is successful when a significant result is achieved for the composite or one prespecified main component. Appropriate sample size planning is challenging in this situation, as in addition to the Type I error rate, power, and target difference the overall event rates and the correlation between the test statistics have to be defined. Reliable estimates of these quantities, however, are usually hard to obtain and therefore there is a high risk to not achieve the intended power in a fixed sample size design. In this article, we propose an internal pilot study design where the nuisance parameters are estimated in a blinded way at an interim stage and where the sample size is then revised accordingly. We investigate the characteristics of the proposed design with respect to the actual Type I error rate, power, and sample size. The application of this design is illustrated by a clinical trial example.
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http://dx.doi.org/10.1080/10543406.2016.1198371DOI Listing
January 2018

Comparing systemic therapy and cognitive behavioral therapy for social anxiety disorders: study protocol for a randomized controlled pilot trial.

Trials 2016 Mar 31;17:171. Epub 2016 Mar 31.

Center for Psychosocial Medicine, Institute for Medical Psychology, Heidelberg University Hospital, Bergheimer Straße 20, D-69115, Heidelberg, Germany.

Background: Social anxiety disorders are among the most prevalent anxiety disorders in the general population. The efficacy of cognitive behavioral therapy (CBT) for social anxiety disorders is well demonstrated. However, only three studies point to the efficacy of systemic therapy (ST) in anxiety disorders, and only two of them especially focus on social anxiety disorders. These ST studies either do not use a good comparator but minimal supportive therapy, they do not use a multi-person ST but a combined therapy, or they do not especially focus on social anxiety disorders but mood and anxiety disorders in general. Though ST was approved as evidence based in Germany for a variety of disorders in 2008, evidence did not include anxiety disorders. This is the first pilot study that will investigate multi-person ST, integrating a broad range of systemic methods, specifically for social anxiety disorders and that will compare ST to the "gold standard" CBT.

Design: This article describes the rationale and protocol of a prospective, open, interventive, balanced, bi-centric, pilot randomized controlled trial (RCT). A total of 32 patients with a primary SCID diagnosis of social anxiety disorder will be randomized to either CBT or ST. Both treatments will be manualized. The primary outcome will include social anxiety symptoms at the end of therapy. Therapy will be restricted to no more than 26 hours (primary endpoint). Secondary outcomes will include psychological, social systems and interpersonal functioning, symptom adjustment, and caregiver burden, in addition to change measures, therapist variables and treatment adherence. At the secondary endpoints, 9 and 12 months after the beginning of therapy, we will again assess all outcomes.

Discussion: The study is expected to pilot test a RCT which will be the first to directly compare CBT and multi-person ST, integrating a broad range of systemic methods, for social anxiety disorders, and it will provide empirical evidence for the calculation of the number of patients needed for a confirmatory RCT.

Trial Registration: ClinicalTrials.gov: NCT02360033 ; date of registration: 21 January 2015.
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http://dx.doi.org/10.1186/s13063-016-1252-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815062PMC
March 2016

Association of C1q-fixing DSA with late graft failure in pediatric renal transplant recipients.

Pediatr Nephrol 2016 07 29;31(7):1157-66. Epub 2016 Feb 29.

Department of Pediatrics I, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.

Background: We investigated the prognostic value of overall and complement-binding donor-specific HLA antibodies (DSA) in pediatric patients undergoing clinically indicated graft biopsies and their association with graft outcome and specific histological lesions.

Methods: Sera of 62 patients at time of indication biopsy ≥1 year posttransplant were assessed for DSA and C1q-fixing DSA by single-antigen bead (SAB) technology.

Results: Twenty-six patients (42 %) were DSA-positive at time of indication biopsy and nine (15 %) were C1q-positive. At 4 years postbiopsy, patients with C1q-positivity had a low graft survival (11 %) compared to DSA-positive, C1q-negative patients (82 %, p = 0.001) and to DSA-negative patients (88 %, p < 0.001). The majority (89 %) of C1q-positive patients were diagnosed with active chronic antibody-mediated rejection (ABMR). C1q DSA-positivity [adjusted hazard ratio (HR) 6.35], presence of transplant glomerulopathy (HR 9.54), and estimated glomerular filtration rate (eGFR) at the time of indication biopsy (HR 0.91) were risk factors for subsequent graft loss.

Conclusions: The presence of C1q-positive DSA in the context of an indication biopsy identifies a subgroup of pediatric renal transplant recipients with a markedly increased risk of subsequent graft loss. Because a fraction of DSA-positive patients escape rejection or graft dysfunction, the C1q assay increases the specificity of a positive DSA result regarding unfavorable transplant outcome.
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http://dx.doi.org/10.1007/s00467-016-3322-8DOI Listing
July 2016

Influx of multidrug-resistant organisms by country-to-country transfer of patients.

BMC Infect Dis 2015 Oct 28;15:466. Epub 2015 Oct 28.

Department of Infectious Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 324, D-69120, Heidelberg, Germany.

Background: Multidrug-resistant organisms (MDRO) are a worldwide problem. International migration and travel facilitate the spread of MDRO. Therefore the goal of our study was to assess the risk of influx of MDRO from patients transferred to one of Central Europe's largest hospitals from abroad.

Methods: A mono-centre study was conducted. All patients transferred from other countries were screened; additional data was collected on comorbidities, etc. Presence of carbapenemases of multidrug-resistant Gram-negatives was confirmed by PCR. The association between length of stay, being colonized and/or infected by a MDRO, country of origin, diagnosis and other factors was assessed by binomial regression analyses.

Results: From 2012 to 2013, one fifth of all patients were colonized with MDRO (Methicillin-resistant Staphylococcus aureus [4.1 %], Vancomycin-resistant Enterococci [2.9 %], multidrug-resistant Gram-negatives [12.8 %] and extensively drug-resistant Gram-negatives [3.4 %]). The Gram-negatives carried a variety of carbapenemases including OXA, VIM, KPC and NDM. The length of stay was significantly prolonged by 77.2 % in patients colonized with a MDRO, compared to those not colonized (p<0.0001).

Conclusions: Country-to-Country transfer of patients to European hospitals represents a high risk of introduction of MDRO and infection control specialists should endorse containment and screening measures.
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http://dx.doi.org/10.1186/s12879-015-1173-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624670PMC
October 2015

Rationale, design and objectives of ARegPKD, a European ARPKD registry study.

BMC Nephrol 2015 Feb 18;16:22. Epub 2015 Feb 18.

Department of Pediatrics, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.

Background: Autosomal recessive polycystic kidney disease (ARPKD) is a rare but frequently severe disorder that is typically characterized by cystic kidneys and congenital hepatic fibrosis but displays pronounced phenotypic heterogeneity. ARPKD is among the most important causes for pediatric end stage renal disease and a leading reason for liver-, kidney- or combined liver kidney transplantation in childhood. The underlying pathophysiology, the mechanisms resulting in the observed clinical heterogeneity and the long-term clinical evolution of patients remain poorly understood. Current treatment approaches continue to be largely symptomatic and opinion-based even in most-advanced medical centers. While large clinical trials for the frequent and mostly adult onset autosomal dominant polycystic kidney diseases have recently been conducted, therapeutic initiatives for ARPKD are facing the challenge of small and clinically variable cohorts for which reliable end points are hard to establish.

Methods/design: ARegPKD is an international, mostly European, observational study to deeply phenotype ARPKD patients in a pro- and retrospective fashion. This registry study is conducted with the support of the German Society for Pediatric Nephrology (GPN) and the European Study Consortium for Chronic Kidney Disorders Affecting Pediatric Patients (ESCAPE Network). ARegPKD clinically characterizes long-term ARPKD courses by a web-based approach that uses detailed basic data questionnaires in combination with yearly follow-up visits. Clinical data collection is accompanied by associated biobanking and reference histology, thus setting roots for future translational research.

Discussion: The novel registry study ARegPKD aims to characterize miscellaneous subcohorts and to compare the applied treatment options in a large cohort of deeply characterized patients. ARegPKD will thus provide evidence base for clinical treatment decisions and contribute to the pathophysiological understanding of this severe inherited disorder.
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http://dx.doi.org/10.1186/s12882-015-0002-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359504PMC
February 2015

Risk factors for loss of residual renal function in children treated with chronic peritoneal dialysis.

Kidney Int 2015 Sep 15;88(3):605-13. Epub 2015 Apr 15.

Pediatric Nephrology Division, Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany.

In dialyzed patients, preservation of residual renal function is associated with better survival, lower morbidity, and greater quality of life. To analyze the evolution of residual diuresis over time, we prospectively monitored urine output in 401 pediatric patients in the global IPPN registry who commenced peritoneal dialysis (PD) with significant residual renal function. Associations of patient characteristics and time-variant covariates with daily urine output and the risk of developing oligoanuria (under 100 ml/m(2)/day) were analyzed by mixed linear modeling and Cox regression analysis including time-varying covariates. With an average loss of daily urine volume of 130 ml/m(2) per year, median time to oligoanuria was 48 months. Residual diuresis significantly subsided more rapidly in children with glomerulopathies, lower diuresis at start of PD, high ultrafiltration volume, and icodextrin use. Administration of diuretics significantly reduced oligoanuria risk, whereas the prescription of renin-angiotensin system antagonists significantly increased the risk oligoanuria. Urine output on PD was significantly associated in a negative manner with glomerulopathies (-584 ml/m(2)) and marginally with the use of icodextrin (-179 ml/m(2)) but positively associated with the use of biocompatible PD fluid (+111 ml/m(2)). Children in both Asia and North America had consistently lower urine output compared with those in Europe perhaps due to regional variances in therapy. Thus, in children undergoing PD, residual renal function depends strongly on the cause of underlying kidney disease and may be modifiable by diuretic therapy, peritoneal ultrafiltration, and choice of PD fluid.
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http://dx.doi.org/10.1038/ki.2015.108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558567PMC
September 2015

Screening for respiratory syncytial virus and isolation strategies in children hospitalized with acute respiratory tract infection.

Medicine (Baltimore) 2014 Nov;93(25):e144

From the Center for Childhood and Adolescent Medicine (General Pediatrics and Pediatric Neurology), University Hospital Heidelberg (JP, MR, JG-H); German Center for Infectious Diseases (DZIF) (JP); Department of Infectious Diseases, Virology, University Hospital Heidelberg (JT, PS); and Institute of Medical Biometry and Informatics, University of Heidelberg (AS), Heidelberg, Germany.

Nosocomial infection with respiratory syncytial virus (RSV) is an important health risk in pediatric care but is largely preventable by efficient infection control measures. Commonly applied rapid antigen detection tests (RADTs) miss a considerable number of RSV-infected patients. The objective of our analysis was to evaluate whether readily available host parameters are associated with false-negative RADT, and to assess how these parameters could be applied in an optimized RSV isolation strategy.We retrospectively analyzed a cohort of 242 children under the age of 2 years hospitalized with acute respiratory tract infection to identify host parameters associated with false-negative RADT test result. We subsequently simulated the outcome of different isolation strategies based on RADT result and host parameters in view of the overall isolation efficacy.Out of 242 hospitalized patients, 134 (55%) patients were found RSV-positive by RT-PCR, whereas 108 (45%) patients were tested negative. The performance of the RADT was compared with the result obtained by reverse transcription polymerase chain reaction on the identical nasopharyngeal wash. Overall, we found that 85 patients (35%) were tested true positive, 108 (45%) were tested true negative, whereas a false-negative test result was obtained in 49 patients (20%). Duration of respiratory symptoms for >3 days and a respiratory admission diagnosis are associated with false-negative RADT result. In comparison with RADT alone, consideration of these clinical parameters and RADT result can decrease the rate of nonisolated RSV-infected patients from approximately 24% to 8% (65% RSV pretest probability).Consideration of both RADT and clinical parameters associated with false-negative RADT can result in an optimized RSV infection control policy.
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http://dx.doi.org/10.1097/MD.0000000000000144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4616380PMC
November 2014

Influence of insulin and glargine on outgrowth and number of circulating endothelial progenitor cells in type 2 diabetes patients: a partially double-blind, randomized, three-arm unicenter study.

Cardiovasc Diabetol 2014 Oct 11;13:137. Epub 2014 Oct 11.

Department of Medicine I and Clinical Chemistry, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg, 69120, Germany.

Background: Endothelial progenitor cells (EPC) are bone marrow-derived cells which can undergo differentiation into endothelial cells and participate in endothelial repair and angiogenesis. Insulin facilitates this in vitro mediated by the IGF-1 receptor. Clinical trials showed that the number of circulating EPCs is influenced by glucose control and EPC are a predictor of cardiovascular death. To study direct effects of insulin treatment on EPCs in type 2 diabetes patients, add-on basal insulin treatment was compared to an escalation of oral medication aiming at similar glucose control between the groups.

Methods: 55 patients with type 2 diabetes (61.6±5.9 years) on oral diabetes medication were randomized in a 2:2:1 ratio in 3 groups. Patients were treated additionally with insulin glargine (n=20), NPH insulin (n=22) or escalated with oral medication (n=13). Number of circulating EPC, EPC-outgrowth, intima media thickness, skin microvascular function and HbA1c were documented at baseline and/or after 4 weeks and 4 months.

Results: HbA1c at baseline was, 7.3+/-0.7% in the oral group, 7.3+/-0.9% and 7.5+/-0.7% in the glargine and NPH insulin respectively (p=0.713). HbA1c after 4 months decreased to 6.8+/-0.8%, 6.6+/-0.7% and 6.7+/-0.6%, in the oral, glargine and NPH insulin group respectively (p=0.61). FACS analysis showed no difference in number of circulating EPC between the groups after 4 weeks and 4 months. However, the outgrowth of EPCs as detected by colony forming assay was increased in the NPH insulin and glargine groups (29.2+/-6.4 and 29.4+/- 6.7 units respectively) compared to the group on oral medication (23.2+/-6.3, p=0.013) after 4 months of treatment. A significant decrease of IMT from 0.80mm (+/-0.14) at baseline to 0.76mm (+/-0.12) after 4 months could be observed in all patients only (p=0.03) with a trend towards a reduction of IMT after 4 months when all patients on insulin treatment were compared to the oral treatment group (p=0.06). Skin microvascular function revealed no differences between the groups (p=0.74).

Conclusion: The study shows that a 4-month treatment with add-on insulin significantly increases the outgrowth of EPC in patients with type 2 diabetes mellitus.

Trial Registration: (Clinical Trials Identifier: NCT00523393).
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http://dx.doi.org/10.1186/s12933-014-0137-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195950PMC
October 2014

Effect of delayed CNI-based immunosuppression with Advagraf® on liver function after MELD-based liver transplantation [IMUTECT].

BMC Surg 2014 Sep 1;14:64. Epub 2014 Sep 1.

Department of General, Visceral and Transplant Surgery, Heidelberg, Germany.

Background: MELD-based allocation for liver transplantation follows the "sickest-patient-first" strategy. The latter patients present with both, decreased immune competence and poor kidney function which is further impaired by immunosuppressants.

Methods/design: In this prospective observational study, 50 patients with de novo low-dose standard Advagraf®-based immunosuppression consisting of Advagraf®, Mycophenolat-mofetil and Corticosteroids after liver transplantation will be evaluated. Advagraf® trough levels of 7-10 μg/l will be reached at the end of the first postoperative week. Immunostatus, infectious complications, graft and kidney function are compared between patients with a pretransplant calculated MELD-score of ≤20 and >20. Each group comprises of 25 consecutive patients. Prior to liver transplantation and on the postoperative days 1, 3 and 7, the patients' graft function (LiMAx test) will be evaluated. On the postoperative days 3, 5 and 7 the patients' immune status will be evaluated by the measurement of their monocytic HLA-DR status.Infectious complications (CMV-reactivation, wound infection, urinary tract infection, and pneumonia), graft- and kidney function will be analysed on day 0, within the first week, and 1, 3, 6, 9 and 12 months after liver transplantation.

Discussion: This study was designed to assess the effect of a standard low-dose Calcineurin inhibitor-based immunosuppression regime with Advagraf® on the rate of infectious complications, graft and renal function after liver transplantation.

Trial Registration: The trial is registered at "Clinical Trials" (http://www.clinicaltrials.gov), NCT01781195.
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http://dx.doi.org/10.1186/1471-2482-14-64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160448PMC
September 2014