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Summary Enteroaggregative Escherichia coli (EAEC) induces release of pro-inflammatory markers and disruption of intestinal epithelial barriers in vitro, suggesting an inflammatory aspect to EAEC infection. However, the mechanisms underlying EAEC-induced mucosal inflammatory responses and the extent to which these events contribute to pathogenesis is not well characterized. Employing an established in vitro model we demonstrated that EAEC prototype strain 042 induces migration of polymorphonuclear neutrophils (PMNs) across polarized T84 cell monolayers. This event was mediated through a conserved host cell signalling cascade involving the 12/15-LOX pathway and led to apical secretion of an arachidonic acid-derived lipid PMN chemoattractant, guiding PMNs across the epithelia to the site of infection. Moreover, supporting the hypothesis that inflammatory responses may contribute to EAEC pathogenesis, we found that PMN transepithelial migration promoted enhanced attachment of EAEC 042 to T84 cells. These findings suggest that EAEC-induced PMN infiltration may favour colonization and thus pathogenesis of EAEC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Stereotactic Radiosurgery (SRS) is an emerging alternative to whole-brain radiotherapy (WBRT) for treating multiple brain metastases (BM), reducing toxicity and improving tumor control. The CYBER-SPACE trial compared SRS based on either SPACE or MPRAGE MRI sequence for avoiding or delaying WBRT in patients with 1-10 BM., Methods: Patients with 1-10 untreated BM were randomized 1:1 to receive SRS of all lesions based on either SPACE or MPRAGE MRI sequences. If subsequently new BM occurred, SRS was repeated. WBRT was indicated upon occurrence of >10 new BM, leptomeningeal disease or exhausted SRS-radiotolerance. The primary outcome was freedom from WBRT indication (WBRTi). Secondary outcomes included overall survival (OS), safety, and quality of life., Results: 202 patients were randomized; SPACE n=99, MPRAGE n=103. 12-month WBRTi-free survival was 77.1% (95%-CI: 69.5%-83.1%) overall, 78.5% (95%-CI: 66.7%-86.5%) for SPACE, and 76.0% (95%-CI: 65.2%-83.9%) for MPRAGE (HR=0.84, 95%-CI: 0.43-1.63, p=0.590). Patients with 5-10 BM had shorter WBRTi-free survival (HR=3.13, 95%-CI: 1.53-6.40, p=0.002). Median OS was 13.1 months overall, 10.5 months for SPACE, and 15.2 months for MPRAGE (HR=1.10, 95%-CI: 0.78-1.56, p=0.585). Neurologic death rate was 10.1%. Predictors for longer OS included Karnofsky Performance Status >80% (HR=0.51, 95%-CI: 0.33-0.77, p=0.002) and concurrent immunotherapy (HR=0.34, 95%-CI: 0.23-0.52, p<0.001)., Conclusions: The more sensitive SPACE sequence did not improve outcomes over MPRAGE. SRS with thorough monitoring and immediate re-treatment for new lesions decreases the need for WBRT and achieves low neurologic death rates. SRS should be considered a favorable alternative to WBRT for patients with 1-10 BM., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Dilated cardiomyopathy (DCM) is a leading cause of heart failure, particularly in younger individuals. Low physical strength is a global risk factor for cardiovascular mortality, and physical activity and a healthy lifestyle have been shown to improve outcomes in patients with heart failure. However, inappropriate exercise may increase the risk of arrhythmias in certain individuals with DCM. The determinants for predicting individual risks in this setting are poorly understood, and clinicians are hesitant to recommend sports for cardiomyopathy patients. The activeDCM trial aims to assess the safety and efficacy of a personalized exercise and activity programme for individuals with DCM., Study Design: The activeDCM trial is a prospective, randomized, interventional trial with a 12 month follow-up. Three hundred patients, aged 18-75 years with DCM, left ventricular ejection fraction (LVEF) ≤ 50% and New York Heart Association (NYHA) classes I-III, will be enrolled. The intervention includes a personalized exercise and activity programme. The primary outcome is the increase in peak oxygen uptake (VO 2 max, mL/kg/min) from baseline to 12 months. Secondary endpoints include adherence to personalized activity programmes, freedom from clinically relevant arrhythmia, unplanned hospitalization for heart failure and changes in NYHA class, quality of life scores, 6 min walk distance, muscular strength, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) levels and cardiac function. Advanced research questions include high-density phenome and omics analysis combined with digital biomarkers derived from Apple Watch devices., Discussion: The activeDCM trial will provide valuable insights into the safety and efficacy of personalized exercise training in DCM patients, inform clinical practice and contribute to the development of heart failure management programmes. The study will generate data on the impact of exercise on various aspects of cardiovascular disease, including genetic, metabolic, phenotypic and longitudinal aspects, facilitating the development of future digital tools and strategies, including the incorporation of smart wearable devices., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: Chronic back pain is a widespread medical condition associated with high socioeconomic costs and increasing prevalence. Despite the advanced implementation of multidisciplinary approaches, providing a satisfactory treatment offer for those affected is often not possible. Exposure therapy (EXP) promises to be an effective and economical form of treatment and in a previous pilot study showed to be superior to cognitive behavioral therapy (CBT) in reducing perceived limitations of movement. The current study aims to further compare the efficacy of both treatment methods and identify those patient groups that particularly benefit from EXP., Methods: The general objective of this randomized multicenter clinical trial (targeted N = 380) is to improve and expand the range of treatments available to patients with chronic back pain. As the primary objective of the study, two different psychological treatments (EXP and CBT) will be compared. The primary outcome measure is a clinically significant improvement in pain-related impairment, measured by the QPBDS, from baseline to 6-month follow-up. Secondary outcome measures are absolute changes and clinically significant improvements in variables coping, psychological flexibility, depressiveness, catastrophizing, exercise avoidance and fear of exercise, and intensity of pain. Participants are recruited in five psychological and medical centers in Germany and receive ten sessions of manualized therapy by trained licensed CBT therapists or clinical psychologists, who are currently in their post-gradual CBT training. Potential predictors of each treatment's efficacy will be explored with a focus on avoidance and coping behavior., Conclusion: This study will be the first RCT to compare CBT and EXP in chronic back pain in a large sample, including patients from different care structures due to psychological and medical recruitment centers. By identifying and exploring potential predictors of symptom improvement in each treatment group, this study will contribute to enable a more individualized assignment to treatment modalities and thus improves the care situation for chronic back pain and helps to create a customized treatment program for subgroups of pain patients. If our findings confirm EXP to be an efficacious and efficient treatment concept, it should gain more attention and be further disseminated., Trial Registration: ClinicalTrials.gov NCT05294081. Registered on 02 March 2022., (© 2024. The Author(s).)

Background: This retrospective real-world study used data from two registries, International Pediatric Peritoneal Dialysis Network (IPPN) and International Pediatric Hemodialysis Network (IPHN), to characterize the efficacy and safety of continuous erythropoietin receptor activator (C.E.R.A.) in pediatric patients with chronic kidney disease (CKD) on peritoneal dialysis (PD) or hemodialysis (HD)., Methods: IPPN and IPHN collect prospective data (baseline and every 6 months) from pediatric PD and HD centers worldwide. Demographics, clinical characteristics, dialysis information, treatment, laboratory parameters, number and causes of hospitalization events, and deaths were extracted for patients on C.E.R.A. treatment (IPPN: 2007-2021; IPHN: 2013-2021)., Results: We analyzed 177 patients on PD (median age 10.6 years) and 52 patients on HD (median age 14.1 years) who had ≥ 1 observation while being treated with C.E.R.A. The median (interquartile range [IQR]) observation time under C.E.R.A. exposure was 6 (0-12.5) and 12 (0-18) months, respectively. Hemoglobin concentrations were stable over time; respective means (standard deviation) at last observation were 10.9 (1.7) g/dL and 10.4 (1.7) g/dL. Respective median (IQR) monthly C.E.R.A. doses at last observation were 3.5 (2.3-5.1) µg/kg, or 95 (62-145) µg/m 2 and 2.1 (1.2-3.4) µg/kg, or 63 (40-98) µg/m 2 . Non-elective hospitalizations occurred in 102 (58%) PD and 32 (62%) HD patients. Seven deaths occurred (19.8 deaths per 1000 observation years)., Conclusions: C.E.R.A. was associated with efficient maintenance of hemoglobin concentrations in pediatric patients with CKD on dialysis, and appeared to have a favorable safety profile. The current analysis revealed no safety signals., (© 2023. The Author(s).)

Background: Open partial pancreatoduodenectomy (OPD) represents the current gold standard of surgical treatment of a wide range of diseases of the pancreatic head but is associated with morbidity in around 40% of cases. Robotic partial pancreatoduodenectomy (RPD) is being used increasingly, yet, no randomised controlled trials (RCTs) of RPD versus OPD have been published, leaving a low level of evidence to support this practice., Methods: This investigator-initiated, exploratory RCT with two parallel study arms was conducted at a high-volume pancreatic centre in line with IDEAL recommendations (stage 2b). Patients scheduled for elective partial pancreatoduodenectomy (PD) for any indication were randomised (1:1) to RPD or OPD with a centralised web-based tool. The primary endpoint was postoperative cumulative morbidity within 90 days, assessed via the Comprehensive Complication Index (CCI). Biometricians were blinded to the intervention, but patients and surgeons were not. The trial was registered prospectively (DRKS00020407)., Findings: Between June 3, 2020 and February 14, 2022, 81 patients were randomly assigned to RPD (n = 41) or OPD (n = 40), of whom 62 patients (RPD: n = 29, OPD: n = 33) were analysed in the modified intention to treat analysis. Four patients in the OPD group were randomised, but did not undergo surgery in our department and one patient was excluded in the RPD group due to other reason. Nine patients in the RPD group and 3 patients in the OPD were excluded from the primary analysis because they did not undergo PD, but rather underwent other types of surgery. The CCI after 90 days was comparable between groups (RPD: 34.02 ± 23.48 versus OPD: 36.45 ± 27.65, difference in means [95% CI]: -2.42 [-15.55; 10.71], p = 0.713). The RPD group had a higher incidence of grade B/C pancreas-specific complications compared to the OPD group (17 (58.6%) versus 11 (33.3%); difference in rates [95% CI]: 25.3% [1.2%; 49.4%], p = 0.046). The only complication that occurred significantly more often in the RPD than in the OPD group was clinically relevant delayed gastric emptying. Procedure-related and overall hospital costs were significantly higher and duration of surgery was longer in the RPD group. Blood loss did not differ significantly between groups. The intraoperative conversion rate of RPD was 23%. Overall 90-day mortality was 4.8% without significant differences between RPD and OPD., Interpretation: In the setting of a very high-volume centre, both RPD and OPD can be considered safe techniques. Further confirmatory multicentre RCTs are warranted to uncover potential advantages of RPD in terms of perioperative and long-term outcomes., Funding: Federal Ministry of Education and Research (BMBF: 01KG2010)., Competing Interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© 2024 The Author(s).)

(1) Background: External beam radiotherapy (EBRT) and concurrent chemotherapy, followed by brachytherapy (BT), offer a standard of care for patients with locally advanced cervical carcinoma. Conventionally, large safety margins are required to compensate for organ movement, potentially increasing toxicity. Lately, daily high-quality cone beam CT (CBCT)-guided adaptive radiotherapy, aided by artificial intelligence (AI), became clinically available. Thus, online treatment plans can be adapted to the current position of the tumor and the adjacent organs at risk (OAR), while the patient is lying on the treatment couch. We sought to evaluate the potential of this new technology, including a weekly shuttle-based 3T-MRI scan in various treatment positions for tumor evaluation and for decreasing treatment-related side effects. (2) Methods : This is a prospective one-armed phase-II trial consisting of 40 patients with cervical carcinoma (FIGO IB-IIIC1) with an age ≥ 18 years and a Karnofsky performance score ≥ 70%. EBRT (45-50.4 Gy in 25-28 fractions with 55.0-58.8 Gy simultaneous integrated boosts to lymph node metastases) will be accompanied by weekly shuttle-based MRIs. Concurrent platinum-based chemotherapy will be given, followed by 28 Gy of BT (four fractions). The primary endpoint will be the occurrence of overall early bowel and bladder toxicity CTCAE grade 2 or higher (CTCAE v5.0). Secondary outcomes include clinical feasibility, quality of life, and imaging-based response assessment.

Background: High-level evidence regarding the technique of abdominal wall closure for patients undergoing emergency midline laparotomy is sparse. Therefore, we conducted a randomized controlled trial (RCT) to evaluate the efficacy and safety of two commonly applied abdominal wall closure strategies after primary emergency midline laparotomy., Methods/design: CONTINT was a multi-center pragmatic open-label exploratory randomized controlled parallel trial. Two different abdominal wall closure strategies in patients undergoing primary midline laparotomy for an emergency surgical intervention with a suspected septic focus in the abdominal cavity were compared: the continuous, all-layer suture and the interrupted suture technique. The primary composite endpoint was burst abdomen within 30 days after surgery or incisional hernia within 12 months. As reliable data on this composite primary endpoint were not available for patients undergoing emergency surgery, it was planned to initially recruit 80 patients and conduct an interim analysis after these had completed the 12 months follow-up., Results: From August 31, 2009, to June 28, 2012, 124 patients were randomized of whom 119 underwent surgery and were analyzed according to the intention-to-treat (ITT) principal. The primary composite endpoint did not differ between the continuous suture (C: 27.1%) and the interrupted suture group (I: 30.0%). None of the individual components of the primary endpoint (reoperation due to burst abdomen after 30 days (C: 13.5%, I: 15.1%) and reoperation due to incisional hernia (C: 3.0%, I:11.1%)) differed between groups. Time needed for fascial closure was longer in the interrupted suture group (C: 12.8 ± 4.5 min, I: 17.4 ± 6.1 min). BMI was associated with burst abdomen during the first 30 days with an OR of 1.17 (95% CI 1.04-1.32)., Conclusion: This RCT showed no difference between continuous suture with slowly absorbable suture versus interrupted rapidly absorbable sutures after primary emergency midline laparotomy in rates of postoperative burst abdomen and incisional hernia after one year. However, the trial was stopped after the interim analysis due to futility as there was no chance to show superiority of one suture technique., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: In the Rituximab for Relapse Prevention in Nephrotic Syndrome (RITURNS) trial, we demonstrated superior efficacy of single-course rituximab over maintenance tacrolimus in preventing relapses in children with steroid dependent nephrotic syndrome (SDNS) during a 1-year observation. Here we present the long-term outcomes of all 117 trial completers, who were followed up for another 2 years., Methods: Relapsing patients in the rituximab arm received a second course of rituximab, either with ( n  = 44) or without mycophenolate mofetil (MMF) cotreatment ( n  = 15). In the tacrolimus arm, second line rituximab monotherapy was initiated after relapses ( n  = 32) or electively ( n  = 24)., Results: All 12-month relapse-free patients in the rituximab arm relapsed in the second postexposure year, resulting in similar median relapse-free survival times in the 2 trial arms (62 vs. 59 weeks). Second line rituximab in the tacrolimus arm was less effective than first-line therapy in patients switched to rituximab following a relapse (relapse-free survival 55 vs. 63 weeks, P  < 0.01). B-cell counts 6 months post-rituximab predicted relapse risk both for first and second line therapy. MMF cotreatment yielded much improved 2-year relapse-free survival as compared to rituximab monotherapy (67% vs. 9%, P  < 0.0001). Higher grade 2 adverse event rates were observed post-rituximab versus on tacrolimus (0.87 vs. 0.53 per year)., Conclusion: The superior therapeutic effect of rituximab in SDNS vanishes during the second year post-exposure. Rituximab appears to yield longer remission when applied as first line as compared to second line therapy. Maintenance MMF following rituximab induces long-term disease remission., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

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 m 2 P = 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. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s).)

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 warrant 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 randomised-controlled trial (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, patient- and observer-blind RCT. Patients undergoing loop ileostomy closure will undergo intraoperative 1:1 randomisation 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 ≥ 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, 1,014 patients are expected to be screened for eligibility in order to recruit the necessary number of patients. The primary endpoint will be the frequency of incision 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 revision 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., (© 2023. The Author(s).)

Objective: 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)., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

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 (AT 1 R), the endothelin type A receptor (ET A R), 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 AT 1 R, ET A R, 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: 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.

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., Competing Interests: Competing interests: RE, MRB, JD, AF, JG, DH, BH, PFH, BK, MJK, MK, SL, UQ and AS declare to have no competing interests. BT and LTW have received research grants from Roche Pharma AG and Novartis AG., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 2 . 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., (Copyright © 2016 by the American Society of Nephrology.)

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., (Copyright © 2016 by the American Society of Nephrology.)

Background and Objectives: Double-chamber peritoneal dialysis fluids exert less toxicity by their neutral pH and reduced glucose degradation product content. The role of the buffer compound (lactate and bicarbonate) has not been defined in humans., Design, Setting, Participants, & Measurements: A multicenter randomized controlled trial in 37 children on automated peritoneal dialysis was performed. After a 2-month run-in period with conventional peritoneal dialysis fluids, patients were randomized to neutral-pH, low-glucose degradation product peritoneal dialysis fluids with 35 mM lactate or 34 mM bicarbonate content. Clinical and biochemical monitoring was performed monthly, and peritoneal equilibration tests and 24-hour clearance studies were performed at 0, 3, 6, and 10 months., Results: No statistically significant difference in capillary blood pH, serum bicarbonate, or oral buffer supplementation emerged during the study. At baseline, peritoneal solute equilibration and clearance rates were similar. During the study, 4-hour dialysis to plasma ratio of creatinine tended to increase, and 24-hour dialytic creatinine and phosphate clearance increased with lactate peritoneal dialysis fluid but not with bicarbonate peritoneal dialysis fluid. Daily net ultrafiltration, which was similar at baseline (lactate fluid=5.4±2.6 ml/g glucose exposure, bicarbonate fluid=4.9±1.9 ml/g glucose exposure), decreased to 4.6±1.0 ml/g glucose exposure in the lactate peritoneal dialysis fluid group, whereas it increased to 5.1±1.7 ml/g glucose exposure in the bicarbonate content peritoneal dialysis fluid group (P=0.006 for interaction)., Conclusions: When using biocompatible peritoneal dialysis fluids, equally good acidosis control is achieved with lactate and bicarbonate buffers. Improved long-term preservation of peritoneal membrane function may, however, be achieved with bicarbonate-based peritoneal dialysis fluids.

Unlabelled: BACKGROUND, OBJECTIVES, AND METHODS: Hospitalization and mortality rates in pediatric dialysis patients remain unacceptably high. Although studies have associated the presence of comorbidities with an increased risk for death in a relatively small number of pediatric dialysis patients, no large-scale study had set out to describe the comorbidities seen in pediatric dialysis patients or to evaluate the impact of those comorbidities on outcomes beyond the newborn period. In the present study, we evaluated the prevalence of comorbidities in a large international cohort of pediatric chronic peritoneal dialysis (CPD) patients from the International Pediatric Peritoneal Dialysis Network registry and began to assess potential associations between those comorbidities and hospitalization rates and mortality., Results: Information on comorbidities was available for 1830 patients 0 - 19 years of age at dialysis initiation. Median age at dialysis initiation was 9.1 years [interquartile range (IQR): 10.9], median follow-up for calculation of hospitalization rates was 15.2 months (range: 0.2 - 80.9 months), and total follow-up time in the registry was 2095 patient-years. At least 1 comorbidity had been reported for 602 of the patients (32.9%), with 283 (15.5%) having cognitive impairment; 230 (12.6%), motor impairment; 167 (9.1%), cardiac abnormality; 76 (4.2%), pulmonary abnormality; 212 (11.6%), ocular abnormality; and 101 (5.5%), hearing impairment. Of the 150 patients (8.2%) that had a defined syndrome, 85% had at least 1 nonrenal comorbidity, and 64% had multiple comorbidities. The presence of at least 1 comorbidity was associated with a higher hospitalization rate [hospital days per 100 observation days: 1.7 (IQR: 5.8) vs 1.2 (IQR: 3.9), p = 0.001] and decreased patient survival (4-year survival rate: 73% vs 90%, p < 0.0001)., Conclusions: Nearly one third of pediatric CPD patients in a large international cohort had at least 1 comorbidity, and multiple comorbidities were frequently reported among patients with a defined syndrome. Preliminary analysis suggests an association between comorbidity and poor outcome in those patients. As this powerful international registry matures, further multivariate analyses will be important to more clearly define the impact of comorbidities on hospitalization rates and mortality in pediatric CPD patients.