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Background and purpose: Brain health is essential for health, well-being, productivity and creativity across the entire life. Its definition goes beyond the absence of disease embracing all cognitive, emotional, behavioural and social functions which are necessary to cope with life situations. Methods: The European Academy of Neurology (EAN) Brain Health Strategy responds to the high and increasing burden of neurological disorders. It aims to develop a non-disease-, non-age-centred holistic and positive approach (‘one brain, one life, one approach’) to prevent neurological disorders (e.g., Alzheimer's disease and other dementias, stroke, epilepsy, headache/migraine, Parkinson's disease, multiple sclerosis, sleep disorders, brain cancer) but also to preserve brain health and promote recovery after brain damage. Results: The pillars of the EAN Brain Health Strategy are (1) to contribute to a global and international brain health approach (together with national and subspecialty societies, other medical societies, the World Health Organization, the World Federation of Neurology, patients' organizations, industry and other stakeholders); (2) to support the 47 European national neurological societies, healthcare and policymakers in the implementation of integrated and people-centred campaigns; (3) to foster research (e.g., on prevention of neurological disorders, determinants and assessments of brain health); (4) to promote education of students, neurologists, general practitioners, other medical specialists and health professionals, patients, caregivers and the general public; (5) to raise public awareness of neurological disorders and brain health. Conclusions: By adopting this ‘one brain, one life, one approach’ strategy in cooperation with partner societies, international organizations and policymakers, a significant number of neurological disorders may be prevented whilst the overall well-being of individuals is enhanced by maintaining brain health through the life course.

Background: Incisional hernia is a frequent complication following loop ileostomy reversal. Incisional hernias are associated with morbidity, loss of health-related quality of life and costs and warrants the investigation of prophylactic measures. Prophylactic mesh implantation at the time of surgical stoma reversal has shown to be a promising and safe method to prevent incisional hernias in this setting. However, the efficacy of this method has not yet been investigated in a large multicentre RCT with adequate external validity. The P.E.L.I.O.N. trial will evaluate the efficacy of prophylactic mesh reinforcement after loop ileostomy closure in decreasing the rate of incisional hernia versus standard closure alone Methods: P.E.L.I.O.N. is a multicentre, prospective, randomized, patient- and observer-blind trial. Patients undergoing loop ileostomy closure will undergo intraoperative 1:1 randomization into either abdominal wall closure with a continuous slowly absorbable suture in small stitch technique without mesh reinforcement (control group) or abdominal wall closure with an additional reinforcement with a retromuscular non-absorbable, macro-pore (pore size ³ 1000 μm or effective porosity >0%) light-weight monofilament or mixed structure mesh. A total of 304 patients (152 per group) will need to be randomised in the study. Based on inclusion and exclusion criteria, 1014 patients are expected to be screened for eligibility in order to recruit the necessary number of patients. Primary endpoint will be the frequency of incisions hernias within 24 months according to the European Hernia Society definition. Secondary endpoints will be the frequency of surgical site occurrences (including surgical site infections, wound seromas and hematomas and enterocutaneous fistulas), postoperative pain, the number of revisions surgeries and health-related quality of life. Safety will be assessed by measuring postoperative complications ≥ grade 3 according to the Dindo-Clavien Classification. Discussion: Depending on the results of the P.E.L.I.O.N. trial prophylactic mesh implantation could become the new standard for loop ileostomy reversal. Trial registration: DRKS00027921, U1111-1273-4657

ZUSAMMENFASSUNGNeozytolyse bezeichnet die bevorzugte Zerstörung von jungen roten Blutzellen (Neozyten), wenn zu viele Erythrozyten vorhanden sind. Das kommt in der Raumfahrt oder beim Abstieg nach langem Höhenaufenthalt vor. Mit dem Ziel, die Existenz von Neozytolyse erstmals zu beweisen, haben wir in der Forschungsstation Jungfraujoch (3450 Hm) eine prospektive Studie durchgeführt. Neu gebildete Erythrozyten von 12 männlichen Probanden wurden durch Einnahme von nichtradioaktivem Glyzin mit seltenen Isotopen markiert: in Heidelberg (110 Hm) und während eines 19-tägigen Aufenthalts (3450 Hm). Die Eliminationsdynamik für Erythrozyten, die in Normoxie und in großer Höhe produziert wurden, unterschied sich nicht. Zusammen mit Änderungen der Retikulozytenzahlen konnte damit das Konzept der Neozytolyse nicht bestätigt werden.

Introduction: donor-derived modified immune cells (MIC) induced long-term specific immunosuppression against the allogeneic donor in preclinical models of transplantation. In a phase I clinical trial (TOL-1 Study), MIC treatment resulted in a cellular phenotype that was directly and indirectly suppressive to the recipient's immune system allowing for reduction of conventional immunosuppressive therapy. Here, we describe a protocol for a randomised controlled, multicentre phase-IIb clinical trial of individualised immunosuppression with intravenously administered donor MIC compared with standard-of-care (SoC) in living donor kidney transplantation (TOL-2 Study). Methods and analysis: sixty-three living donor kidney transplant recipients from six German transplant centres are randomised 2:1 to treatment with MIC (MIC group, N=42) or no treatment with MIC (control arm, N=21). MIC are manufactured from donor peripheral blood mononuclear cells under Good Manufacturing Practice conditions. The primary objective of this trial is to determine the efficacy of MIC treatment together with reduced conventional immunosuppressive therapy in terms of achieving an operational tolerance-like phenotype compared with SoC 12 months after MIC administration. Key secondary endpoints are the number of patient-relevant infections as well as a composite of biopsy-proven acute rejection, graft loss, graft dysfunction or death. Immunosuppressive therapy of MIC-treated patients is reduced during follow-up under an extended immunological monitoring including human leucocyte antigen-antibody testing, and determination of lymphocyte subsets, for example, regulatory B lymphocytes (Breg) and antidonor T cell response. A Data Safety Monitoring Board has been established to allow an independent assessment of safety and efficacy. Ethics and dissemination: ethical approval has been provided by the Ethics Committee of the Medical Faculty of the University of Heidelberg, Heidelberg, Germany (AFmu-580/2021, 17 March 2022) and from the Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Institute, Langen, Germany (Vorlage-Nr. 4586/02, 21 March 2022). Written informed consent will be obtained from all patients and respective donors prior to enrolment in the study. The results from the TOL-2 Study will be published in peer-reviewed medical journals and will be presented at symposia and scientific meetings. Trial registration number NCT05365672., Preparation of the study was funded by the Federal Ministry of Education and Research, Berlin, Germany (FKZ 161B0560A, 161B0560B, and FKZ 031B0560A, 031B0560B), and TolerogenixX GmbH, Heidelberg, Germany (N/A). Conduct of the study is funded by TolerogenixX GmbH (N/A).

Background Randomized controlled trials in pediatric kidney transplantation are hampered by low incidence and prevalence of kidney failure in children. Real-World Data from patient registries could facilitate the conduct of clinical trials by substituting a control cohort. However, the emulation of a control cohort by registry data in pediatric kidney transplantation has not been investigated so far. Methods In this multicenter comparative analysis, we emulated the control cohort (n = 54) of an RCT in pediatric kidney transplant patients (CRADLE trial; ClinicalTrials.gov NCT01544491) with data derived from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, using the same inclusion and exclusion criteria (CERTAIN cohort, n = 554). Results Most baseline patient and transplant characteristics were well comparable between both cohorts. At year 1 posttransplant, a composite efficacy failure end point comprising biopsy-proven acute rejection, graft loss or death (5.8% ± 3.3% vs. 7.5% ± 1.1%, P = 0.33), and kidney function (72.5 ± 24.9 vs. 77.3 ± 24.2 mL/min/1.73 m2P = 0.19) did not differ significantly between CRADLE and CERTAIN. Furthermore, the incidence and severity of BPAR (5.6% vs. 7.8%), the degree of proteinuria (20.2 ± 13.9 vs. 30.6 ± 58.4 g/mol, P = 0.15), and the key safety parameters such as occurrence of urinary tract infections (24.1% vs. 15.5%, P = 0.10) were well comparable. Conclusions In conclusion, usage of Real-World Data from patient registries such as CERTAIN to emulate the control cohort of an RCT is feasible and could facilitate the conduct of clinical trials in pediatric kidney transplantation. Graphical abstract

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.

BACKGROUND AND AIMS Continuous erythropoietin receptor activator—methoxy polyethylene glycol epoetin beta (C.E.R.A.) is a long-acting erythropoiesis-stimulating agent (ESA) approved for the treatment of anaemia associated with chronic kidney disease (CKD) in adults. In June 2018, the Food and Drug Administration approved the use of C.E.R.A. administered intravenously in patients on haemodialysis aged 5– METHOD This was a non-interventional real-world study of patients from the International Paediatric Peritoneal Dialysis Network (IPPN) and the International Paediatric Hemodialysis Network (IPHN) registries. Demographics, clinical characteristics, dialysis information, treatment, laboratory parameters, number and causes of hospitalization events and deaths were reported in patients treated with C.E.R.A. from both registries (IPPN: 2007–2021; IPHN: 2013–2021). RESULTS Overall, 229 patients had at least one observation while being treated with C.E.R.A. and were analysed in this study; 177 on peritoneal dialysis (PD) (median age 10.6 years, interquartile range [IQR] 4.2–14.6) and 52 on haemodialysis (HD) (median age 14.1 years, IQR 10.4-16.2). The median observation time under C.E.R.A. exposure was 6 months (IQR 0–12.5) for PD patients and 12 months (0–18) for HD patients. 121 PD patients (68%) and 36 HD patients (69%) had ≥ 1 hospitalization, of whom 102/121 (84%) and 32/36 (89%), respectively, had non-elective hospitalizations. Median hospitalization surveillance time/patient was 13.5 months in the PD and 18.3 months in the HD cohorts. The most frequent causes for non-elective hospitalization were infections, reported as a cause in 56/177 (32%) patients in the PD cohort and 14/52 (27%) in the HD cohort and technique complications, in 41/177 (23%) patients in the PD cohort and 20/52 (38%) in the HD cohort. There were seven deaths (PD: 5 patients; HD: 2 patients), corresponding to an overall mortality rate of 19.8 cases per 1000 observation years. Causes of death were infections (n = 2), intracranial bleeding (n = 2), congestive heart failure (n = 2) and one case of sudden death at home. Hb levels remained stable over time with 47% of PD patients and 48% of HD patients having a Hb value within the range of 10–12 g/dL at their last observation. Mean [standard deviation (SD)] Hb levels at last observation were 10.9 (1.7) g/dL in the PD and 10.4 (1.7) g/dL in the HD cohort. The median monthly dose of C.E.R.A. at first visit was 100 (IQR 50–120) µg in the PD and 107 (80–129) µg in the HD cohort, while at last visit it was 100 (50–150) µg (PD) and 80 (54–129) µg (HD). While absolute C.E.R.A. dose increased with age, weight-related doses decreased substantially with age in both cohorts: in groups aged CONCLUSION Real-world data from the IPPN and IPHN registries indicated that C.E.R.A. treatment is associated with efficient maintenance of Hb levels in paediatric patients with CKD on dialysis. C.E.R.A. appeared to have a favourable safety profile; analysis of hospitalization rate and causes as well as patient mortality did not reveal any safety signals.

International Society for Peritoneal Dialysis. Baxter Health Care. Fresenius Medical Care, Germany. Ipsen. Medical Faculty of University of Cologne. Marga and Walter Boll-Foundation. Federal Ministry of Education & Research (BMBF): 01GM1515. European Rare Kidney Disease Reference Network (ERKNet).

Purpose: Many students have difficulties in public speaking because of their use of filled pauses (e.g., utterances like “um”; misuse of the word “like”). Mancuso and Miltenberger used habit reversal to decrease filled pauses in public speaking. The present study aimed at replicating this study as a student project. Method: Participants were four undergraduate students of social work. The training phase and total number of sessions were shortened compared to the original study. Results: The mean number of responses (filled pauses) per minute decreased throughout the study and during follow-up measurement. Discussion: Nevertheless, the replication of experimental control wasn’t successful because three of the four participants showed a decrease in response frequency already during the baseline. As a project, the study demonstrates that students of social work with only rudimentary training in single systems research methods can implement evidence-based practice procedures in their work with clients.

BACKGROUND Clinical trials are of central importance for the evaluation and comparison of treatments. The transparency and intelligibility of the treatment effect under investigation is an essential matter for physicians, patients, and health-care authorities. The estimand framework has been introduced because many trials are deficient in this respect. METHODS Introduction, definition, and application of the estimand framework on the basis of an example and a selective review of the literature. RESULTS The estimand framework provides a systematic approach to the definition of the treatment effect under investigation in a clinical trial. An estimand consists of five attributes: treatment, population, variable, population-level summary, and handling of intercurrent events. Each of these attributes is defined in an interdisciplinary discussion during the trial planning phase, based on the clinical question being asked. Special attention is given to the handling of intercurrent events (ICEs): these are events-e.g., discontinuation or modification of treatment or the use of emergency medication-that can occur once the treatment has begun and might affect the possibility of observing the endpoints or their interpretability. There are various strategies for the handling of ICEs; these can, for example, also reflect the existing intentionto- treat (ITT) principle. Per-protocol analyses, in contrast, are prone to bias and cannot be represented in a sensible manner by an estimand, although they may be performed as a supplementary analysis. The discussion of potential intercurrent events and how they should appropriately be handled in view of the aim of the trial must already take place in the planning phase. CONCLUSION Use of the estimand framework should make it easier for both physicians and patients to understand what trials reveal about the efficacy of treatment, and to compare the results of different trials.

Background and ObjectivesTo investigate the prevalence of burnout profiles and their contributing factors in European neurology residents, junior neurologists, and research fellows.MethodsThe members of the Resident and Research Fellow Section (RRFS) of the European Academy of Neurology were surveyed using standardized instruments for burnout, job satisfaction, social support, depression, work-related fatigue, work-life integration, and impact of life events, from September 1, 2020, to January 6, 2021.ResultsThe response rate was 23.1% (332 responders of 1,439 contacted RRFS members); the median age of participants 30 years, with 61.5% being female. Our analysis revealed that 73.9% of the responders showed a perturbation in the Maslach Burnout Inventory dimensions, thus fulfilling the criteria for a dysfunctional phenotype within the burnout spectrum: burnout (22.6%), overextended (26.1%), ineffective (21.0%), and disengaged (4.1%). Multivariate logistic regression analysis indicated that elevated number of night shifts per month, work-related fatigue, and low professional satisfaction are independent risk factors for burnout. Being a certified neurologist, working in an academic environment, and a higher job satisfaction are associated with the engaged profile, a productive state characterized by high energy, strong involvement, and a sense of efficacy.DiscussionBurnout experience is highly prevalent among neurology residents, junior neurologists, and research fellows in Europe. The profile-based approach in this survey captures the multifaceted nature of burnout experience, therefore highlighting mitigating strategies that can be tailored to the distinct dysfunctional burnout profile.

IntroductionPancreatic resections are an important field of surgery worldwide to treat a variety of benign and malignant diseases. Postoperative pancreatic fistula (POPF) remains a frequent and critical complication after partial pancreatectomy and affects up to 50% of patients. POPF increases mortality, prolongs the postoperative hospital stay and is associated with a significant economic burden. Despite various scientific approaches and clinical strategies, it has not yet been possible to develop an effective preventive tool. The SmartPAN indicator is the first surgery-ready medical device for direct visualisation of pancreatic leakage already during the operation. Applied to the surface of pancreatic tissue, it detects sites of biochemical leak via colour reaction, thereby guiding effective closure and potentially mitigating POPF development.Methods and analysisThe ViP trial is a prospective single-arm, single-centre first in human study to collect data on usability and confirm safety of SmartPAN. A total of 35 patients with planned partial pancreatectomy will be included in the trial with a follow-up of 30 days after the index surgery. Usability endpoints such as adherence to protocol and evaluation by the operating surgeon as well as safety parameters including major intraoperative and postoperative complications, especially POPF development, will be analysed.Ethics and disseminationFollowing the IDEAL-D (Idea, Development, Exploration, Assessment, and Long term study of Device development and surgical innovation) framework of medical device development preclinical in vitro, porcine in vivo, and human ex vivo studies have proven feasibility, efficacy and safety of SmartPAN. After market approval, the ViP trial is the IDEAL Stage I trial to investigate SmartPAN in a clinical setting. The study has been approved by the local ethics committee as the device is used exclusively within its intended purpose. Results will be published in a peer-reviewed journal. The study will provide a basis for a future randomised controlled interventional trial to confirm clinical efficacy of SmartPAN.Trial registration numberGerman Clinical Trial Register DRKS00027559, registered on 4 March 2022.

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−1, P = 0.002). Using Youden index, we derived the optimal threshold value for association with MACCE to be 0.027 Tregs nl−1. 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−1 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−1 predicted perioperative MACCE and can be measured to increase accuracy of established preoperative cardiac risk stratification in coronary heart disease patients undergoing noncardiac surgery.

Introduction Comprehensive treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major clinical challenge. The current therapy gold standard is aciclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains around 20% and a majority of survivors suffer from severe disability. Experimental research and recent retrospective clinical observations suggest a favourable therapy response to adjuvant dexamethasone. Currently there is no randomized clinical trial evidence, however, to support the routine use of adjuvant corticosteroid treatment in HSVE. Methods The German trial of Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE) studied the effect of adjuvant dexamethasone versus placebo on top of standard aciclovir treatment in adult patients aged 18 up to 85 years with proven HSVE in German academic centers of Neurology in a randomized and double blind fashion. The trial was open from November 2007 to December 2012. The initially planned sample size was 372 patients with the option to increase to up to 450 patients after the second interim analysis. The primary endpoint was a binary functional outcome after 6 months assessed using the modified Rankin scale (mRS 0–2 vs. 3–6). Secondary endpoints included mortality after 6 and 12 months, functional outcome after 6 months measured with the Glasgow outcome scale (GOS), functional outcome after 12 months measured with mRS and GOS, quality of life as measured with the EuroQol 5D instrument after 6 and 12 months, neuropsychological testing after 6 months, cranial magnetic resonance imaging findings after 6 months, seizures up to day of discharge or at the latest at day 30, and after 6 and 12 months. Results The trial was stopped prematurely for slow recruitment after 41 patients had been randomized, 21 of them treated with dexamethasone and 20 with placebo. No difference was observed in the primary endpoint. In the full analysis set (n = 19 in each group), 12 patients in each treatment arm achieved a mRS of 0–2. Similarly, we did not observe significant differences in the secondary endpoints (GOS, mRS, quality of life, neuropsychological testing). Conclusion GACHE being prematurely terminated demonstrated challenges encountered performing randomized, placebo-controlled trials in rare life threatening neurological diseases. Based upon our trial results the use of adjuvant steroids in addition to antiviral treatment remains experimental and is at the decision of the individual treating physician. Unfortunately, the small number of study participants does not allow firm conclusions. Trial registration EudraCT-Nr. 2005–003201-81.

Aims Total haemoglobin mass (tot-Hb) increases during high-altitude acclimatization. Normalization of tot-Hb upon descent is thought to occur via neocytolysis, the selective destruction of newly formed erythrocytes. Because convincing experimental proof of neocytolysis is lacking, we performed a prospective study on erythrocyte survival after a stay at the Jungfraujoch Research Station (JFJRS; 3450 m). Methods Newly formed erythrocytes of 12 male subjects (mean age 23.3 years) were age cohort labelled in normoxia (110 m) and during a 19-day high-altitude sojourn by ingestion of 13 C2- and 15 N-labelled glycine respectively. Elimination dynamics for erythrocytes produced in normoxia and at high altitude were measured by isotope ratio mass spectrometry of haem, by determining tot-Hb, reticulocyte counts, erythrocyte membrane protein 4.1a/4.1b ratio and by mathematical modelling. Results Tot-Hb increased by 4.7% ± 2.7% at high altitude and returned to pre-altitude values within 11 days after descent. Elimination of 13 C- (normoxia) and 15 N- (high altitude) labelled erythrocytes was not different. Erythropoietin levels and counts of CD71-positive reticulocytes decreased rapidly after descent. The band 4.1a/4.1b ratio decreased at altitude and remained low for 3-4 days after descent and normalized slowly. There was no indication of haemolysis. Conclusion We confirm a rapid normalization of tot-Hb upon descent. Based on the lack of accelerated removal of age cohorts of erythrocytes labelled at high altitude, on patterns of changes in reticulocyte counts and of the band 4.1a/4.1b ratio and on modelling, this decrease did not occur via neocytolysis, but by a reduced rate of erythropoiesis along with normal clearance of senescent erythrocytes.

To investigate the effect of daily whole-body bathing (WBB) using disposable washcloth wipes/caps impregnated with an antiseptic solution containing the quaternary ammonium base compound didecyl dimethyl ammonium chloride (DDAC).A prospective double-blind randomized crossover trial was conducted to compare WBB of adult intensive care unit (ICU) patients with washcloth wipes/caps impregnated with either regular cleanser/shampoo or the antiseptic DDAC. The clinical trial was performed in a medical ICU (MICU) and a surgical ICU (SICU). The study period was divided into two 6-month intervals with alternating treatment regimens.A total of 1540 ICU patients (total length of ICU stay 10 470 days) were included in the trial. Compared to controls, DDAC bathing was found to be associated with reduced incidence rates per 1000 patient days for central-venous-line-associated infections (CLAIs) caused by Gram-positive bacteria (GPB) from 16.39 (95%CI 13.1-20.3) in the control group to 7.28 (95%CI 5.2-9.9) in the intervention group (p 0.01). A stratified analysis by unit showed that the incidence rates of CLAI due to GPB were reduced by the intervention in both the MICU and the SICU from 21.2 (95%CI 15.8-27.7) to 9.3 (95%CI 5.8-14.1) (p 0.01) and from 12.1 (95%CI 8.3-17.0) to 5.7 (95%CI 3.4-9.1) (p 0.01), respectively. There was a trend towards reduction in catheter-related bloodstream infections (CRBSIs) and bloodstream infections (BSIs); however, this did not reach statistical significance due to carry-over effects and small numbers.Given the growing need for new concepts to prevent and control healthcare-associated infections, DDAC may be a new and promising agent for WBB of ICU patients.

Background Non-HLA antibodies against endothelial targets have been implicated in the pathogenesis of antibody-mediated rejection (ABMR), but data in pediatric patients are scarce. Methods We retrospectively analyzed a carefully phenotyped single-center (University Children’s Hospital Heidelberg, Germany) cohort of 62 pediatric kidney transplant recipients (mean age at transplantation, 8.6 ± 5.0 years) at increased risk of graft function deterioration. Patients had received their transplant between January 1, 1999, and January 31, 2010. We examined at time of late index biopsies (more than 1-year post-transplant, occurring after January 2004) the association of antibodies against the angiotensin II type 1 receptor (AT1R), the endothelin type A receptor (ETAR), the MHC class I chain-like gene A (MICA), and vimentin in conjunction with overall and complement-binding donor-specific HLA antibodies (HLA-DSA) with graft histology and function. Results We observed a high prevalence (62.9%) of non-HLA antibody positivity. Seventy-two percent of HLA-DSA positive patients showed additional positivity for at least one non-HLA antibody. Antibodies against AT1R, ETAR, and MICA were associated with the histological phenotype of ABMR. The cumulative load of HLA-DSA and non-HLA antibodies in circulation was related to the degree of microinflammation in peritubular capillaries. Non-HLA antibody positivity was an independent non-invasive risk factor for graft function deterioration (adjusted hazard ratio 6.38, 95% CI, 2.11–19.3). Conclusions Our data indicate that the combined detection of antibodies to HLA and non-HLA targets may allow a more comprehensive assessment of the patients’ immune responses against the kidney allograft and facilitates immunological risk stratification.

BACKGROUND: Preclinical 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. METHODS: In this phase I trial, patients received either 1.5 × 10(6) MICs per kg BW on day –2 (n = 3, group A), or 1.5 × 10(8) 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. RESULTS: MIC 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 × 10(10) 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(+)CD24(hi)CD38(hi) 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. CONCLUSION: MIC administration was safe and could be a future tool for the targeted induction of tolerogenic Bregs. TRIAL REGISTRATION: EudraCT number: 2014-002086-30; ClinicalTrials.gov identifier: NCT02560220. FUNDING: Federal Ministry for Economic Affairs and Technology, Berlin, Germany, and TolerogenixX GmbH, 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-SR30). 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.Este ensayo controlado aleatorizado tuvo como finalidad probar la terapia sistémica (TS) estandarizada y monitoreada recientemente desarrollada para el trastorno de ansiedad social en comparación con la terapia cognitivo-conductual (TCC) estandarizada y monitoreada. Realizamos un ensayo controlado aleatorizado prospectivo, multicentro y con enmascaramiento para el evaluador en 38 pacientes ambulatorios (CIE F40.1; Entrevista Clínica Estructurada para los trastornos del DSM (SCID); Escala de Ansiedad Social de Liebowitz, LSAS-SR30). El resultado principal fue el nivel de ansiedad social (LSAS-SR) al final del tratamiento. Se evaluó a un total de 252 personas, 38 pacientes fueron aleatorizados y comenzaron la terapia (TCC: 20 pacientes; TS: 18 pacientes; edad: promedio= 36 años, desviación estándar = 14). Los análisis intragrupales, de efecto simple, con intención de tratar demostraron una reducción significativa del LSAS-SR (TCC: d = 1.04; TS: d = 1.67), mientras que el análisis de varianza de diseño mixto con intención de tratar demostró la ventaja de la TS (d = 0.81). Los análisis por protocolo respaldaron estos resultados. La remisión basada en los índices de cambio fiable también demostró una diferencia significativa (LSAS-SR: 15% en la TCC; 39% en la TS; h: 0.550), respaldada por diferencias casi significativas en las valoraciones con enmascaramiento para los evaluadores de aquellos que completaron la terapia (SCID; 45% en la TCC, 78% en la TS, p = 0.083). No se informaron efectos adversos. Tanto la TCC como la TS reducen la ansiedad social y respaldan la mejora de los pacientes con la terapia sistémica recientemente desarrollada para los trastornos de ansiedad social; esto aun debe verificarse en un ensayo controlado aleatorizado confirmatorio posterior.本研究中的随机控制试验(RCT)是一个对新开发的系统治疗(ST)的初步研究,该系统治疗是针对社交恐惧症(SAD)的有指导性和监控性的疗法 ,文中与之比较的是有指导性和监控性的认知行为疗法(CBT)。我们的研究对象是38个门诊病人(ICD F40.1;对DSM的结构性临床访谈(SCID);列博维茨社交恐惧等级量表,LSAS-SR在30以上),他们接受了预期的多中心的,测评者身份不告知的随机控制实验(RCT)。主要结果查看的是治疗结束后的社交焦虑LSAS-SR水平。252个人接受筛查,38个病人被随机安排接受治疗(认知行为疗法CBT: 20 个病人; 系统治疗ST: 18个病人; age: 年龄中位数 M = 36 岁, 标准方差 SD = 14)。在群组内,目的导向治疗意向性分析表明 LSAS-SR (CBT: d = 1.04; ST: d = 1.67)有显著性降低,而ITT混合设计方差分析证明ST的优势(d = 0.81)。符合计划人群分析结果支持了以上结论。基于可信改变指数RCI的变小也证实了显著性差异性(LSAS-SR: 15% in CBT; 39% in ST; h: 0.550),这个类似的显著性差异也被那些完成了治疗后的匿名诊断测评的结果支持(SCID; 45% in CBT, 78% in ST, p = 0.083)。尚未出现报告的逆向性的事件。认知行为治疗CBT和系统治疗ST都可以降低社交焦虑,通过新开发的针对社交恐惧症SAD的系统治疗ST促进了病人的好转 ;但是,这还需要在接下来的证实性的“随机控制试验” (RCT)中得到进一步证明。.

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

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.

In diesem Kapitel soll anhand der Daten, die fur die nachfolgenden Auswertungen herangezogen werden, das Vorgehen beim Importieren von Exceldaten in SPSS erlautert und auf die Bearbeitung bzw. Berechnung neuer Variablen eingegangen werden.

Der primare Endpunkt in einer klinischen Studie ist jenes Zielkriterium bzw. Outcome, anhand dessen der Erfolg der Studie (z.B. Nachweis der Wirksamkeit einer neuen Therapie) beurteilt wird. Zur Analyse des primaren Endpunkts stehen zum einen deskriptive, zum anderen konfirmatorische Methoden zur Verfugung. Mittels konfirmatorischer Methoden sollen Ruckschlusse auf die interessierende Grundgesamtheit gezogen und die Studienergebnisse somit verallgemeinert werden.

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.

OBJECTIVE: To identify prenatal, perinatal, and postnatal risk factors for dialysis within the first year of life in children with autosomal recessive polycystic kidney disease (ARPKD) as a basis for parental counseling after prenatal and perinatal diagnosis. STUDY DESIGN: A dataset comprising 385 patients from the ARegPKD international registry study was analyzed for potential risk markers for dialysis during the first year of life. RESULTS: Thirty-six out of 385 children (9.4%) commenced dialysis in the first year of life. According to multivariable Cox regression analysis, the presence of oligohydramnios or anhydramnios, prenatal kidney enlargement, a low Apgar score, and the need for postnatal breathing support were independently associated with an increased hazard ratio for requiring dialysis within the first year of life. The increased risk associated with Apgar score and perinatal assisted breathing was time-dependent and vanished after 5 and 8 months of life, respectively. The predicted probabilities for early dialysis varied from 1.5% (95% CI, 0.5%-4.1%) for patients with ARPKD with no prenatal sonographic abnormalities to 32.3% (95% CI, 22.2%-44.5%) in cases of documented oligohydramnios or anhydramnios, renal cysts, and enlarged kidneys. CONCLUSIONS: This study, which identified risk factors associated with onset of dialysis in ARPKD in the first year of life, may be helpful in prenatal parental counseling in cases of suspected ARPKD. ispartof: JOURNAL OF PEDIATRICS vol:199 pages:22-+ ispartof: location:United States status: published

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.

Children with chronic inflammatory diseases suffer from severe growth failure associated with resistance toward the anabolic action of insulin-like growth factor I (IGF-I). We hypothesized that proinflammatory cytokines interfere with IGF-I signaling. We used the mesenchymal chondrogenic cell line RCJ3.1C5.18 as a model of the growth plate. Cell proliferation was assessed by [3H]-thymidine-uptake and differentiation by gene expression (quantitative reverse-transcriptase PCR) of specific differentiation markers. Key signaling molecules of the respective IGF-I–related intracellular pathways were determined by western immunoblotting. Coincubation of the proinflammatory cytokines interleukin (IL)-1β (10 ng/ml), IL-6 (100 ng/ml), or tumor necrosis factor-α (50 ng/ml) with IGF-I inhibited IGF-I–driven cell proliferation by 50%, while baseline cell proliferation was not altered. These cytokines attenuated the IGF-I–induced phosphorylation of AKT as a key signaling molecule of the phosphatidylinositol-3 kinase pathway by 30–50% and the phosphorylation of ERK as a key signaling molecule of the mitogen-activated protein kinase/extracellular signal–regulated kinase pathway by 50–75%. Also, IGF-I–enhanced chondrocyte differentiation was inhibited by these proinflammatory cytokines. The insensitivity toward the anabolic action of IGF-I in the growth plate in conditions of chronic inflammation is partially due to inhibition of IGF-I–specific signaling pathways by proinflammatory cytokines, which affect both IGF-I–driven chondrocyte proliferation and differentiation.

Summary Concerns have been raised that mammalian target of rapamycin inhibitors in pediatric transplant recipients might interfere with longitudinal bone growth by inhibition of growth factor signaling and growth plate chondrocyte proliferation. We therefore undertook a prospective nested, case-control study on longitudinal growth over 2 years in steroid-free pediatric renal transplant recipients. Fourteen patients on a steroid-free maintenance immunosuppressive regimen consisting of low-dose everolimus (EVR) in conjunction with low-dose cyclosporine (CsA) were compared to a matched cohort of 14 steroid-free patients on a standard dose mycophenolate mofetil (MMF) regimen in conjunction with a standard dose calcineurin inhibitor (CNI). The mean change in height standard deviation (SD) score in the first study year was 0.31 ± 0.71 SD score in the EVR group compared to 0.31 ± 0.64 SD score in the MMF group (P = 0.20). For the entire study period of 2 years, the change in height SD score in the EVR group was 0.43 ± 0.81 SDS compared to 0.75 ± 0.85 SDS in the MMF group (P = 0.32). The percentage of prepubertal patients experiencing catch-up growth, defined as an increase in height SD score ≥0.5 in 2 years, was similar in the EVR group (5/8, 65%) and the MMF group (6/8, 75%; P = 1.00). Longitudinal growth over 2 years in steroid-free pediatric patients on low-dose EVR and CsA is not different to that of a matched steroid-free control group on an immunosuppressive regimen with standard-dose CNI and MMF. Hence, low-dose EVR does not appear to negatively impact short-term growth in pediatric renal transplant recipients.

Pediatric Nephrology, like many disciplines within the field of Pediatrics, requires further clinical research effort to foster advancement in care quality and improvement in patient outcomes. Clinical research conditions within pediatric medicine are distinctive and high-quality care requires a comprehensive knowledge of research methodology, analytic technique, and ethical considerations. This chapter provides the framework for conducting clinical research, highlighting both basic and advanced concepts. While the chapter was designed with the Pediatric Nephrologist in mind, its principles will be useful for academic pediatricians across all disciplines.

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.

Background Insufficient bone height in the posterior maxilla is caused by bone atrophy after tooth extraction and continued pneumatization of the maxillary sinus. To allow for implant placement in this area, external sinus-floor elevations are performed. For this indication, the application of various bone graft materials can be a reliable alternative to autologous bone. Purpose The aim of this study was to analyze a nanoporous bone graft material under the condition of early implant treatment in sinus floor elevations. Materials and Methods Sixty-six patients received 94 individual external sinus-floor elevations as a precondition for implant surgery. As grafting material, a synthetic, nanoporous bone graft material consisting of a mixture of nano-hydroxyapatite and nano-β-tricalciumphosphate crystals, combined with blood from the defect side, was used. Depending on the remaining vertical bone height, implant placement was performed either simultaneously with bone augmentation or consecutively in a delayed approach. After a 4-month healing period, the patients received 218 implants and were followed up clinically, radiographically, and histologically. To quantify the bone situation at implant placement, immunohistochemical analysis using tenascin-C was performed. Results We achieved an average vertical bone increase of 8.28 mm (SD, 2.59) for the one-stage approach and 10.99 mm (SD, 1.73) for the two-stage approach after sinus-floor elevation. The augmented areas showed mean resorption rates of 10.32% (one stage) and 10.82% (two stages) of vertical graft during the observation period. Immunohistochemical analysis after 4 months of healing showed high tenascin activity, indicating bone growth. Good primary stability was achieved during implant placement. Mean peri-implant marginal bone loss was 0.45 mm (SD, 0.31). Conclusion After a mean observation time of 21.45 months, the biomaterial showed good osseointegration and bone stability radiographically. Adding to this the positive histological and immunohistochemical findings, we conclude that, after a relatively short 4-month healing period, the biomaterial showed predictable results.