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BACKGROUND: At Eurotransplant (ET), kidneys are transferred to "rescue allocation" (RA), whenever the standard allocation (SA) algorithms Eurotransplant Kidney Allocation System (ETKAS) and Eurotransplant Senior Program (ESP) fail. We analyzed the outcome of RA. METHODS: Retrospective patient clinical and demographic characteristics association analyses were performed with graft outcomes for 2422 recipients of a deceased donor renal transplantation (DDRT) after RA versus 25 481 after SA from 71 centers across all ET countries from 2006 to 2018. RESULTS: Numbers of DDRTs after RA increased over the time, especially in Germany. RA played a minor role in ESP versus ETKAS (2.7% versus 10.4%). RA recipients and donors were older compared with SA recipients and donors, cold ischemia times were longer, waiting times were shorter, and the incidence of primary nonfunction was comparable. Among ETKAS recipients, HLA matching was more favorable in SA (mean 3.7 versus 2.5). In multivariate modeling, the incidence of graft loss in ETKAS recipients was reduced in RA compared with SA (subdistribution hazard ratio, 0.80; 95% confidence interval [0.70-0.91], P

Background The pathophysiology of neurological dysfunction in severe chronic kidney disease (CKD) in children and young adults is largely unknown. We aimed to investigate brain volumes and white matter integrity in this population and explore brain structure under different treatment modalities. Methods This cross-sectional study includes 24 patients with severe CKD (eGFR n = 7; dialysis, n = 7; transplanted, n = 10) and 21 healthy controls matched for age, sex, and parental educational level. Neuroimaging targeted brain volume using volumetric analysis on T1 scans and white matter integrity with tract-based spatial statistics and voxel-wise regression on diffusion tensor imaging (DTI) data. Results CKD patients had lower white matter integrity in a widespread cluster of primarily distal white matter tracts compared to healthy controls. Furthermore, CKD patients had smaller volume of the nucleus accumbens relative to healthy controls, while no evidence was found for abnormal volumes of gray and white matter or other subcortical structures. Longer time since successful transplantation was related to lower white matter integrity. Exploratory analyses comparing treatment subgroups suggest lower white matter integrity and smaller volume of the nucleus accumbens in dialysis and transplanted patients relative to healthy controls. Conclusions Young CKD patients seem at risk for widespread disruption of white matter integrity and to some extent smaller subcortical volume (i.e., nucleus accumbens). Especially patients on dialysis therapy and patients who received a kidney transplant may be at risk for disruption of white matter integrity and smaller volume of the nucleus accumbens. Graphical abstract

Nephrotic syndrome in childhood is a common entity in the field of pediatric nephrology. The optimal treatment of children with nephrotic syndrome is often debated. Previously conducted studies have shown significant variability in nephrotic syndrome management, especially in the choice of steroid-sparing drugs. In the Netherlands, a practice guideline on the management of childhood nephrotic syndrome has been available since 2010. The aim of this study was to identify practice variations and opportunities to improve clinical practice of childhood nephrotic syndrome in the Netherlands. A digital structured survey among Dutch pediatricians and pediatric nephrologists was performed, including questions regarding the initial treatment, relapse treatment, kidney biopsy, additional immunosuppressive treatment, and supportive care. Among the 51 responses, uniformity was seen in the management of a first presentation and first relapse. Wide variation was found in the tapering of steroids after alternate day dosing. Most pediatricians and pediatric nephrologists (83%) would perform a kidney biopsy in case of steroid-resistant nephrotic syndrome, whereas for frequent relapsing and steroid-dependent nephrotic syndrome this was 22% and 41%, respectively. Variation was reported in the steroid-sparing treatment. Finally, significant differences were present in the supportive treatment of nephrotic syndrome.Conclusion: Substantial variation was present in the management of nephrotic syndrome in the Netherlands. Differences were identified in steroid tapering, use of steroid coverage during stress, choice of steroid-sparing agents, and biopsy practice. To promote guideline adherence and reduce practice variation, factors driving this variation should be assessed and resolved. What is Known:• National and international guidelines are available to guide the management of childhood nephrotic syndrome.• Several aspects of the management of childhood nephrotic syndrome, including the choice of steroid-sparing drugs and biopsy practice, are controversial and often debated among physicians.What is New:• Significant practice variation is present in the management of childhood nephrotic syndrome in the Netherlands, especially in the treatment of FRNS, SDNS, and SRNS.• The recommendation on the steroid treatment of a first episode of nephrotic syndrome in the KDIGO guideline leaves room for interpretation and is likely the cause of substantial differences in steroid-tapering practices among Dutch pediatricians and pediatric nephrologists.

Transition in medical care is a high-risk period in adolescence and young adulthood. To date, data on transition policy, its application in practice, and transition procedures in patients with rare, hereditary kidney diseases in Europe is scarce. An online survey was developed and was distributed within the paediatric centres of the European Reference Network for Rare Kidney Diseases (ERKNet) aiming to assess the transition-relevant structures from the providers' perspectives. Its items were based on the consensus statement on transition published by the International Society of Nephrology (ISN) and the International Paediatric Nephrology Association (IPNA) in 2011. Forty-six paediatric experts based at 28/32 ERKNet university hospitals participated. Annually, a median number of 14 patients (1-80) are transferred to adult based care. One centre continued to care for paediatric kidney transplant recipients throughout their entire lifespan. Choosing this option terminated the survey and no further data was obtained from this centre. 29/45 experts confirmed the application of an-at least unwritten-transition procedure (64%). Transition clinics are offered by 23 experts. Most physicians (40%) transfer patients at age 18-19, 10 experts at age

Background: Hyperparathyroidism persists in up to 50% of pediatric kidney transplant recipients. The aims of this study were to describe the evolution of parathyroid hormone (PTH) in the first year after transplantation and to identify factors associated with hyperparathyroidism. Methods: This retrospective study included children who underwent kidney transplantation at the University Hospitals of Ghent, Leuven, Rotterdam, or Amsterdam. Data from 149 patients were collected before and up to 12 months after transplantation. Severe hyperparathyroidism was defined as PTH 2-fold above the reference value. Factors associated with hyperparathyroidism and severe hyperparathyroidism were identified using multivariate logistic regression analysis. Results: Before transplantation, 97 out of 137 patients (71%) had hyperparathyroidism. The probability of hyperparathyroidism and severe hyperparathyroidism declined from 0.49 and 0.17 to 0.29 and 0.09 at 3 and 12 months after transplantation, respectively. BMI SDS (β: 0.509; p = 0.011; 95% CI: 1.122–2.468), eGFR (β: − 0.227; p = 0.030; 95% CI: 0.649–0.978), and pre-transplant hyperparathyroidism (β: 1.149; p = 0.039; 95% CI: 1.062–9.369) were associated with hyperparathyroidism 12 months after transplantation. Pre-transplant hyperparathyroidism (β: 2.115; p = 0.044; 95% CI: 1.055–65.084), defined as intact parathormone (iPTH) levels > 65 ng/l (6.9 pmol/l) or 1-84 PTH > 58 ng/l (6.2 pmol/l), was associated with severe hyperparathyroidism at 3 months. Only eGFR (β: − 0.488; p = 0.010; 95% CI: 0.425–0.888) was inversely associated with severe hyperparathyroidism at 9 months after transplantation. Conclusions: Allograft function remains the main determinant of severe hyperparathyroidism after transplantation. Our findings emphasize the importance of BMI and pre-transplant PTH control.

One of the main objectives of the European health policy framework is to ensure equitable access to high-quality health services across Europe. Here we examined country-specific kidney transplantation and graft failure rates in children and explore their country- and patient-level determinants. Patients under 20 years of age initiating kidney replacement therapy from January 2007 through December 2015 in 37 European countries participating in the ESPN/ERA-EDTA Registry were included in the analyses. Countries were categorized as low-, middle-, and high-income based on gross domestic product. At five-years of follow-up, 4326 of 6909 children on kidney replacement therapy received their first kidney transplant. Overall median time from kidney replacement therapy start to first kidney transplantation was 1.4 (inter quartile range 0.3-4.3) years. The five-year kidney transplantation probability was 48.8% (95% confidence interval: 45.9-51.7%) in low-income, 76.3% (72.8-79.5%) in middle-income and 92.3% (91.0-93.4%) in high-income countries and was strongly associated with macro-economic factors. Gross domestic product alone explained 66% of the international variation in transplantation rates. Compared with high-income countries, kidney transplantation was 76% less likely to be performed in low-income and 58% less likely in middle-income countries. Overall five-year graft survival in Europe was 88% and showed little variation across countries. Thus, despite large disparities transplantation access across Europe, graft failure rates were relatively similar. Hence, graft survival in low-risk transplant recipients from lower-income countries seems as good as graft survival among all (low, medium, and high risk) graft recipients from high-income countries.

Objectives To develop a consensus statement on current best practice of active surveillance (AS) in the UK, informed by patients and clinical experts. Subjects and Methods A consensus statement was drafted on the basis of three sources of data: systematic literature search of national and international guidelines; data arising from a Freedom of Information Act request to UK urology departments regarding their current practice of AS; and survey and interview responses from men with localized prostate cancer regarding their experiences and views of AS. The Prostate Cancer UK Expert Reference Group (ERG) on AS was then convened to discuss and refine the statement. Results Guidelines and protocols for AS varied significantly in terms of risk stratification, criteria for offering AS, and protocols for AS between and within countries. Patients and healthcare professionals identified clinical, emotional and process needs for AS to be effective. Men with prostate cancer wanted more information and psychological support at the time of discussing AS with the treating team and in the first 2 years of AS, and a named healthcare professional to discuss any questions or concerns they had. The ERG agreed 30 consensus statements regarding best practice for AS. Statements were grouped under headings: ‘Inclusion/Exclusion Criteria’; ‘AS follow-up protocol’ and ‘When to stop AS’. Conclusion Significant variation currently exists in the practice of AS in the UK and internationally. Men have clear views on the level of involvement in treatment decisions and support from their treating professionals when receiving AS. The Prostate Cancer UK AS ERG has developed a set of consensus statements for best practice in AS. Evidence for best practice in AS, and the use of multiparametric magnetic resonance imaging in AS, is still evolving, and further studies are needed to determine how to optimize AS outcomes

CONTEXTIdiopathic nephrotic syndrome (INS) in children is a disease with considerable morbidity, yet the incidence and risk for relapse have not been systematically reviewed.OBJECTIVETo estimate the overall pooled weighted incidence and risk for relapse of INS in children.DATA SOURCESMedline and Embase (until December 2020).STUDY SELECTIONAll studies reporting incidence (per 100 000 children per year) and/or risk for relapse (the proportion of patients who experience ≥1 relapse) of INS in children (age: DATA EXTRACTIONAfter quality assessment, data were extracted: study (design, localization, and sample size) and patient (age, sex, steroid response, and ethnicity) characteristics, incidence, and risk for relapse.RESULTSAfter screening, 73 studies were included for analysis (27 incidence, 54 relapse). The overall pooled weighted estimate and corresponding prediction interval (PI) of the incidence was 2.92 (95% PI: 0.00–6.51) per 100 000 children per year. Higher incidences were found in non-Western countries (P < .001). Incidence tended to be lower in white children, but this was not significant. The overall pooled weighted estimate of the risk for relapse was 71.9% (95% PI: 38.8–95.5). Between 1945 and 2011, incidence did not change (P = .39), yet the risk for relapse decreased significantly (P = .024), from 87.4% to 66.2%.LIMITATIONSThere was no full-text availability (n = 33), considerable heterogeneity, and limited studies from Africa, Latin America, and Asia.CONCLUSIONSINS has a low incidence with ethnic variation but high risk for relapse. Although corticosteroids have significantly reduced the risk for relapse, it remains unacceptably high, underscoring the need for alternative treatment strategies.

Recurrence of primary disease is one of the major risks for allograft loss after pediatric RTx. The risk of recurrence of FSGS/SRNS after pediatric RTx in particular can be up to 86% in idiopathic cases. There is a need for consensus recommendations on its prevention and treatment. The CERTAIN study group has therefore performed a thorough literature search based on the PICO model of clinical questions to formulate educated statements to guide the clinician in the process of decision-making. A set of educated statements on prevention and treatment of FSGS/SRNS after pediatric RTx has been generated after careful evaluation of available evidence and thorough panel discussion. We do not recommend routine nephrectomy prior to transplantation; neither do we recommend abstaining from living donation. Special attendance needs to be given to those patients who had already experienced graft loss due to FSGS/SRNS recurrence. Early PE or IA with or without high-dose CsA and/or rituximab seems to be most promising to induce remission. The educated statements presented here acknowledge that FSGS/SRNS recurrence after pediatric RTx remains a major concern and is associated with shorter graft survival or even graft loss. The value of any recommendation needs to take into account that evidence is based on cohorts that differ in ethnicity, pre-transplant history, immunosuppressive regimen, definition of recurrence (eg, clinical and/or histological diagnosis) and treatment modalities of recurrence.

In genetic frontotemporal dementia, cross-sectional studies have identified profiles of presymptomatic neuroanatomical loss for C9orf72 repeat expansion, MAPT, and GRN mutations. In this study, we characterize longitudinal gray matter (GM) and white matter (WM) brain changes in presymptomatic frontotemporal dementia. We included healthy carriers of C9orf72 repeat expansion (n = 12), MAPT (n = 15), GRN (n = 33) mutations, and related noncarriers (n = 53), that underwent magnetic resonance imaging at baseline and 2-year follow-up. We analyzed cross-sectional baseline, follow-up, and longitudinal GM and WM changes using voxel-based morphometry and cortical thickness analysis in SPM and tract-based spatial statistics in FSL. Compared with noncarriers, C9orf72 repeat expansion carriers showed lower GM volume in the cerebellum and insula, and WM differences in the anterior thalamic radiation, at baseline and follow-up. MAPT mutation carriers showed emerging GM temporal lobe changes and longitudinal WM degeneration of the uncinate fasciculus. GRN mutation carriers did not show presymptomatic neurodegeneration. This study shows distinct presymptomatic cross-sectional and longitudinal patterns of GM and WM changes across C9orf72 repeat expansion, MAPT, and GRN mutation carriers compared with noncarriers.

ispartof: PEDIATRIC NEPHROLOGY vol:35 issue:10 pages:1867-1870 ispartof: location:Germany status: published

Levamisole has been considered the least toxic and least expensive steroid-sparing drug for preventing relapses of steroid-sensitive idiopathic nephrotic syndrome (SSINS). However, evidence for this is limited as previous randomized clinical trials were found to have methodological limitations. Therefore, we conducted an international multicenter, placebo-controlled, double-blind, randomized clinical trial to reassess its usefulness in prevention of relapses in children with SSINS. The efficacy and safety of one year of levamisole treatment in children with SSINS and frequent relapses were evaluated. The primary analysis cohort consisted of 99 patients from 6 countries. Between 100 days and 12 months after the start of study medication, the time to relapse (primary endpoint) was significantly increased in the levamisole compared to the placebo group (hazard ratio 0.22 [95% confidence interval 0.11–0.43]). Significantly, after 12 months of treatment, six percent of placebo patients versus 26 percent of levamisole patients were still in remission. During this period, the most frequent serious adverse event (four of 50 patients) possibly related to levamisole was asymptomatic moderate neutropenia, which was reversible spontaneously or after treatment discontinuation. Thus, in children with SSINS and frequent relapses, levamisole prolonged the time to relapse and also prevented recurrence during one year of treatment compared to prednisone alone. However, regular blood controls are necessary for safety issues., SCOPUS: ar.j, info:eu-repo/semantics/published

Frontotemporal dementia is a highly heritable and devastating neurodegenerative disease. About 10–20% of all frontotemporal dementia is caused by known pathogenic mutations, but a reliable tool to predict clinical conversion in mutation carriers is lacking. In this retrospective proof-of-concept case-control study, we investigate whether MRI-based and cognition-based classifiers can predict which mutation carriers from genetic frontotemporal dementia families will develop symptoms (‘convert’) within 4 years. From genetic frontotemporal dementia families, we included 42 presymptomatic frontotemporal dementia mutation carriers. We acquired anatomical, diffusion-weighted imaging, and resting-state functional MRI, as well as neuropsychological data. After 4 years, seven mutation carriers had converted to frontotemporal dementia (‘converters’), while 35 had not (‘non-converters’). We trained regularized logistic regression models on baseline MRI and cognitive data to predict conversion to frontotemporal dementia within 4 years, and quantified prediction performance using area under the receiver operating characteristic curves. The prediction model based on fractional anisotropy, with highest contribution of the forceps minor, predicted conversion to frontotemporal dementia beyond chance level (0.81 area under the curve, family-wise error corrected P = 0.025 versus chance level). Other MRI-based and cognitive features did not outperform chance level. Even in a small sample, fractional anisotropy predicted conversion in presymptomatic frontotemporal dementia mutation carriers beyond chance level. After validation in larger data sets, conversion prediction in genetic frontotemporal dementia may facilitate early recruitment into clinical trials., MRI-based classification combining anatomical, structural connectivity and functional connectivity measures may aid early frontotemporal dementia diagnosis. Feis et al. report that MRI-based classification using fractional anisotropy predicts frontotemporal dementia onset within 4 years beyond chance level in frontotemporal dementia mutation carriers., Graphical Abstract Graphical Abstract

Background Echocardiography is the most frequently used non -invasive diagnostic tool to evaluate cardiac anatomy and function in domestic species but increasingly also in non -domestic species, especially since cardiac disease is being recognized as an important cause of death in captive primates. The purpose of this cross -sectional study was to investigate the feasibility of transthoracic echocardiography in healthy squirrel monkeys as well as to provide species specific normal values for standard echocardiographic measurements. A secondary aim was to determine plasma and serum levels of the cardiac biomarkers, N -terminal pro -brain natriuretic peptide (NT -proBNP) and cardiac troponin T (cTnT). Furthermore, a commercial, non -invasive, smartphone -based ECG (AliveCor Vet TM) monitoring device was used to evaluate the heart rate and rhythm and to diagnose possible arrhythmias. Results In this study, transthoracic echocardiography of 14 squirrel monkeys was performed in right and left lateral recumbency. Similar standard right parasternal and left apical images were obtained as in dogs and cats and normal values for routine two -dimensional, time motion mode and Doppler mode measurements were generated. Thirteen animals were considered healthy and one squirrel monkey was identified with significant aortic dilation and regurgitation and consequently values obtained from this animal were not used when species specific normal values were calculated. NT -ProBNP and cTnT concentrations were available for 7 of the 13 healthy monkeys with NT -proBNP concentrations below detection limit in all animals and a mean cTnT concentration of 0.049 ng/mL. Electrocardiography was performed in all squirrel monkeys. The mean heart rate was 172 bpm. Frequent supraventricular premature beats were diagnosed in the squirrel monkey suffering from significant aortic dilation and regurgitation. Conclusion This study presents echocardiographic normal values and additional cardiovascular data in anaesthetised Saimiri monkeys, fundamental from both the perspective of zoo animal health care as well as scientific research, since the squirrel monkey is often used as an animal model for human disease.

BackgroundMultimodal MRI-based classification may aid early frontotemporal dementia (FTD) diagnosis. Recently, presymptomatic FTD mutation carriers, who have a high risk of developing FTD, were separated beyond chance level from controls using MRI-based classification. However, it is currently unknown how these scores from classification models progress as mutation carriers approach symptom onset. In this longitudinal study, we investigated multimodal MRI-based classification scores between presymptomatic FTD mutation carriers and controls. Furthermore, we contrasted carriers that converted during follow-up (‘converters’) and non-converting carriers (‘non-converters’).MethodsWe acquired anatomical MRI, diffusion tensor imaging and resting-state functional MRI in 55 presymptomatic FTD mutation carriers and 48 healthy controls at baseline, and at 2, 4, and 6 years of follow-up as available. At each time point, FTD classification scores were calculated using a behavioural variant FTD classification model. Classification scores were tested in a mixed-effects model for mean differences and differences over time.ResultsPresymptomatic mutation carriers did not have higher classification score increase over time than controls (p=0.15), although carriers had higher FTD classification scores than controls on average (p=0.032). However, converters (n=6) showed a stronger classification score increase over time than non-converters (pConclusionsOur findings imply that presymptomatic FTD mutation carriers may remain similar to controls in terms of MRI-based classification scores until they are close to symptom onset. This proof-of-concept study shows the promise of longitudinal MRI data acquisition in combination with machine learning to contribute to early FTD diagnosis.

As age and Parkinson's disease (PD) both play a role in the degeneration of brain white matter, we aimed to investigate a possible interaction effect of age and disease presence on white matter integrity in patients with PD. We studied white matterhyperintensity volume, global fractional anisotropy, mean diffusivity and mean magnetization transfer ratio of normal appearing white matter in 163 patients with PD and 218 age- and gender-matched healthy control subjects. We investigated the relationship between age and these parameters in both groups, and interaction between age and disease presence. Patients with PD had a higher load of white matter hyperintensities with a preferential periventricular and anterior distribution as compared with healthy control subjects. Visuospatial functioning was related to total and postural instability and gait difficultywas related to periventricular white matter hyperintensity volume in patients with PD. The age-related decline of white matter integrity was similar for both groups. Global microstructural integrity of the normal appearing white matter did not differ betweenpatients and healthy control subjects, suggesting that PD-specific changes do not exceed normal age-associated change in white matter without lesions. (C) 2019 The Authors. Published by Elsevier Inc.

Early and accurate mild cognitive impairment (MCI) detection within a heterogeneous, nonclinical population is needed to improve care for persons at risk of developing dementia. Magnetic resonance imaging (MRI)‐based classification may aid early diagnosis of MCI, but has only been applied within clinical cohorts. We aimed to determine the generalizability of MRI‐based classification probability scores to detect MCI on an individual basis within a general population. To determine classification probability scores, an AD, mild‐AD, and moderate‐AD detection model were created with anatomical and diffusion MRI measures calculated from a clinical Alzheimer's Disease (AD) cohort and subsequently applied to a population‐based cohort with 48 MCI and 617 normal aging subjects. Each model's ability to detect MCI was quantified using area under the receiver operating characteristic curve (AUC) and compared with an MCI detection model trained and applied to the population‐based cohort. The AD‐model and mild‐AD identified MCI from controls better than chance level (AUC = 0.600, p = 0.025; AUC = 0.619, p = 0.008). In contrast, the moderate‐AD‐model was not able to separate MCI from normal aging (AUC = 0.567, p = 0.147). The MCI‐model was able to separate MCI from controls better than chance (p = 0.014) with mean AUC values comparable with the AD‐model (AUC = 0.611, p = 1.0). Within our population‐based cohort, classification models detected MCI better than chance. Nevertheless, classification performance rates were moderate and may be insufficient to facilitate robust MRI‐based MCI detection on an individual basis. Our data indicate that multiparametric MRI‐based classification algorithms, that are effective in clinical cohorts, may not straightforwardly translate to applications in a general population.

Introduction Primary FSGS is an important cause of ESRD in children. FSGS recurrence after kidney transplantation is associated with early graft loss. No guidelines for treatment of FSGS recurrence exist. We conducted a survey to gain insight into variation of treatment between centers. Methods A survey was sent to all members of the ESPN on behalf of the "Renal Transplantation" and "Idiopathic Nephrotic Syndrome" working groups. Results Fifty-nine nephrologists from 31 countries responded, reporting 807 FSGS patients, with 241 (30%) FSGS recurrences after transplantation. Recurrence varied from 0% to 100% between respondents. Native nephrectomy before or during transplantation was performed, respectively, always (37%), never (39%), or on clinical indication (17%). Half of the respondents started preventive treatment before transplantation, using PF (n = 10); R (n = 4); PF or IA, plus R (n = 9); cyclosporine (n = 2); or unknown (n = 4). Immunosuppressive therapy for patients without known mutations consisted of a combination of steroids, tacrolimus/cyclosporine, and MMF, with or without IL-2R-blockade in, respectively, 61% and 86% of the respondents. Sixty-three percent applied a similar regimen to patients with known mutations. FSGS recurrence was treated with PF or IA, plus R by 66% of respondents; 54% observed no response. Complete remission in >50% of patients was reported by 41% of the respondents. Discussion FSGS recurrence after transplantation is common, but varies greatly between centers. We found great variability in preventive and therapeutic treatment regimens. Future research should focus on predisposing factors, including biopsy findings and genetic mutations, and standardized treatment.

The necessity of post-transplant monitoring for donor-specific antibodies (DSAs) is unclear. This study evaluates the clinical relevance of post-transplantation donor-specific HLA antibodies in pediatric renal transplant recipients, aiming at better stratification of patients at risk of graft dysfunction and better recommendations for post-transplant monitoring. A cohort of 68 pediatric kidney recipients, involving 76 transplantations between 2004 and 2014, was studied retrospectively. All patients were screened for HLA antibodies at 1, 3, 6, and 12 months after transplantation and yearly thereafter. Samples testing positive were further analyzed to detect DSA. A biopsy was performed on clinical indication. We studied the baseline characteristics of the patients with biopsy, with DSA, and with rejection. We assessed the effect of post-transplant DSA on clinical outcome, including antibody-mediated acute rejection and GFR decrease. In our cohort, the prevalence of DSA was 19% (13/68 transplantations). Most patients with HLA antibodies after transplantation were DSA-positive (76%; 13/17). A clear association between DSA and subsequent rejection was found. At the end of the study period, a significantly lower GFR was found in patients with biopsy, DSA, or rejection. Based on our observations, we recommend routine post-transplantation screening for HLA and DSA. The presence of DSA justifies a renal biopsy even in the absence of clinical signs of rejection.

Background: The European Randomised Study of Prostate Cancer Screening has shown a 21% relative reduction in prostate cancer mortality at 13 years. The causes of death can be misattributed, particularly in elderly men with multiple comorbidities, and therefore accurate assessment of the underlying cause of death is crucial for valid results. To address potential unreliability of end-point assessment, and its possible impact on mortality results, we analysed the study outcome adjudication data in six countries. Methods: Latent class statistical models were formulated to compare the accuracy of individual adjudicators, and to assess whether accuracy differed between the trial arms. We used the model to assess whether correcting for adjudication inaccuracies might modify the study results. Results: There was some heterogeneity in adjudication accuracy of causes of death, but no consistent differential accuracy by trial arm. Correcting the estimated screening effect for misclassification did not alter the estimated mortality effect of screening. Conclusions: Our findings were consistent with earlier reports on the European screening trial. Observer variation, while demonstrably present, is unlikely to have materially biased the main study results. A bias in assigning causes of death that might have explained the mortality reduction by screening can be effectively ruled out.

Cardiac disease has been recognized as a major cause of death in captive nonhuman primates, which necessitates diagnostic (imaging) techniques to screen for and diagnose preclinical and clinical stages of possible cardiac conditions. Echocardiography is currently the most commonly used diagnostic tool for evaluation of cardiac anatomy and function. Complete with thoracic radiography and blood levels of two cardiac biomarkers, N-terminal probrain natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT), it gives an extensive examination of the cardiorespiratory system. The purpose of this cross-sectional cohort study is to describe normal thoracic anatomy using thoracic radiography, and to provide normal values for echocardiographic measurements in 20 ring-tailed lemurs (Lemur catta). Additionally, cardiac biomarkers were determined. Three radiographic projections of the thoracic cavity and a complete transthoracic echocardiography were performed in 20 clinically healthy ring-tailed lemurs during their annual health examinations. Similar standard right parasternal and left apical echocardiographic images were obtained as described in dogs and cats and normal values for routine two-dimensional (2D-), time-motion (M-) and Doppler mode measurements were generated. Furthermore, a noninvasive smartphone base ECG recording and blood concentrations of cardiac biomarkers were obtained. Other radiographic measurements are provided for the skeletal and respiratory systems such as the trachea to inlet ratio and tracheal inclination. Knowledge of the normal radiographic thoracic and echocardiographic anatomy and function are fundamental for the diagnosis and follow-up of cardiac disease in affected individuals and for species screening, and will be of added value in future research in and conservation of this endangered species.

Background Cerebral amyloid angiopathy ( CAA ) is a major cause of lobar intracerebral hemorrhage in elderly adults; however, presymptomatic diagnosis of CAA is difficult. Hereditary cerebral hemorrhage with amyloidosis–Dutch type ( HCHWA ‐D) is a rare autosomal‐dominant disease that leads to pathology similar to sporadic CAA . Presymptomatic HCHWA ‐D mutation carriers provide a unique opportunity to study CAA ‐related changes before any symptoms have occurred. In this study we investigated early CAA ‐related alterations in the white matter. Methods and Results We investigated diffusion magnetic resonance imaging ( dMRI ) data for 15 symptomatic and 11 presymptomatic HCHWA ‐D mutation carriers and 30 noncarrier control participants using 4 different approaches. We looked at (1) the relation between age and global dMRI measures for mutation carriers versus controls, (2) voxel‐wise d MRI , (3) independent component‐clustered dMRI measures, and (4) structural connectomics between presymptomatic or symptomatic carriers and controls. Fractional anisotropy decreased, and mean diffusivity and peak width of the skeletonized mean diffusivity increased significantly over age for mutation carriers compared with controls. In addition, voxel‐wise and independent component‐wise fractional anisotropy, and mean diffusivity, and structural connectomics were significantly different between HCHWA ‐D patients and control participants, mainly in the periventricular frontal and occipital regions and in the occipital lobe. We found no significant differences between presymptomatic carriers and control participants. Conclusions The d MRI technique is sensitive in detecting alterations in symptomatic HCHWA ‐d carriers but did not show alterations in presymptomatic carriers. This result indicates that d MRI may be less suitable for identifying early white matter changes in CAA .

Background and Purpose— We evaluated deep learning algorithms’ segmentation of acute ischemic lesions on heterogeneous multi-center clinical diffusion-weighted magnetic resonance imaging (MRI) data sets and explored the potential role of this tool for phenotyping acute ischemic stroke. Methods— Ischemic stroke data sets from the MRI-GENIE (MRI-Genetics Interface Exploration) repository consisting of 12 international genetic research centers were retrospectively analyzed using an automated deep learning segmentation algorithm consisting of an ensemble of 3-dimensional convolutional neural networks. Three ensembles were trained using data from the following: (1) 267 patients from an independent single-center cohort, (2) 267 patients from MRI-GENIE, and (3) mixture of (1) and (2). The algorithms’ performances were compared against manual outlines from a separate 383 patient subset from MRI-GENIE. Univariable and multivariable logistic regression with respect to demographics, stroke subtypes, and vascular risk factors were performed to identify phenotypes associated with large acute diffusion-weighted MRI volumes and greater stroke severity in 2770 MRI-GENIE patients. Stroke topography was investigated. Results— The ensemble consisting of a mixture of MRI-GENIE and single-center convolutional neural networks performed best. Subset analysis comparing automated and manual lesion volumes in 383 patients found excellent correlation (ρ=0.92; P 3 (0.9–16.6 cm 3 ). Patients with small artery occlusion stroke subtype had smaller lesion volumes ( P Conclusions— Automated accurate clinical diffusion-weighted MRI lesion segmentation using deep learning algorithms trained with multi-center and diverse data is feasible. Both lesion volume and topography can provide insight into stroke subtypes with sufficient sample size from big heterogeneous multi-center clinical imaging phenotype data sets.

IntroductionIdiopathic nephrotic syndrome (INS) is characterised by a high relapse rate up to 80% after initial response to standard therapy with corticosteroids. Steroid toxicity is common and causes a great burden of disease that negatively influences the health-related quality of life (HRQoL). Recently, studies have shown that levamisole, an anthelminthic drug, significantly improves relapse-free survival in children with frequent relapses or steroid dependency. Compared with other steroid-sparing drugs, levamisole has relatively few side effects. We hypothesise that adding levamisole to standard therapy with corticosteroids in children with a first episode of INS will prevent relapses, decrease cumulative dosage of steroids used and improve HRQoL. This paper presents the study protocol for the LEARNS study (LEvamisole as Adjuvant therapy to Reduce relapses of Nephrotic Syndrome).Methods and analysisAn international, double-blind, placebo-controlled randomised trial will be conducted in 20 participating hospitals in the Netherlands and Belgium. Participants (n=92) with a first episode of INS, aged 2–16 years, who achieve remission after 4 weeks of oral prednisolone will be randomly assigned (1:1) to receive either levamisole 2.5 mg/kg alternate day or placebo added to prednisolone (18-week tapering schedule) for a total of 24 weeks. Follow-up will be until 2 years after first presentation. Additionally, parents and/or children will fill out five HRQoL questionnaires. Primary outcome of the LEARNS study is occurrence of relapses within 12 months after first presentation. Secondary outcomes include time to first relapse, cumulative steroid dose after 2 years, safety parameters and quality of life scores.Ethics and disseminationThe trial was approved by the Medical Ethical Committee. Results of the study will be published in a peer-reviewed journal.Trial registration numberNL6826, 2017-001025-41

Background and purposeFunctional outcomes after ischaemic stroke are worse in women, despite adjusting for differences in comorbidities and treatment approaches. White matter microvascular integrity represents one risk factor for poor long-term functional outcomes after ischaemic stroke. The aim of the study is to characterise sex-specific differences in microvascular integrity in individuals with acute ischaemic stroke.MethodsA retrospective analysis of subjects with acute ischaemic stroke and brain MRI with diffusion-weighted (DWI) and dynamic-susceptibility contrast-enhanced (DSC) perfusion-weighted imaging obtained within 9 hours of last known well was performed. In the hemisphere contralateral to the acute infarct, normal-appearing white matter (NAWM) microvascular integrity was measured using the K2 coefficient and apparent diffusion coefficient (ADC) values. Regression analyses for predictors of K2 coefficient, DWI volume and good outcome (90-day modified Rankin scale (mRS) score Results105 men and 79 women met inclusion criteria for analysis. Despite no difference in age, women had increased NAWM K2 coefficient (1027.4 vs 692.7×10–6/s; p=0.006). In women, atrial fibrillation (β=583.6; p=0.04) and increasing NAWM ADC (β=4.4; p=0.02) were associated with increased NAWM K2 coefficient. In multivariable regression analysis, the K2 coefficient was an independent predictor of DWI volume in women (β=0.007; p=0.01) but not men.ConclusionsIn women with acute ischaemic stroke, increased NAWM K2 coefficient is associated with increased infarct volume and chronic white matter structural integrity. Prospective studies investigating sex-specific differences in white matter microvascular integrity are needed.

Achieving normal growth is one of the most challenging problems in the management of children with chronic kidney disease (CKD). Treatment with recombinant human growth hormone (GH) promotes longitudinal growth and likely enables children with CKD and short stature to reach normal adult height. Here, members of the European Society for Paediatric Nephrology (ESPN) CKD–Mineral and Bone Disorder (MBD), Dialysis and Transplantation working groups present clinical practice recommendations for the use of GH in children with CKD on dialysis and after renal transplantation. These recommendations have been developed with input from an external advisory group of paediatric endocrinologists, paediatric nephrologists and patient representatives. We recommend that children with stage 3–5 CKD or on dialysis should be candidates for GH therapy if they have persistent growth failure, defined as a height below the third percentile for age and sex and a height velocity below the twenty-fifth percentile, once other potentially treatable risk factors for growth failure have been adequately addressed and provided the child has growth potential. In children who have received a kidney transplant and fulfil the above growth criteria, we recommend initiation of GH therapy 1 year after transplantation if spontaneous catch-up growth does not occur and steroid-free immunosuppression is not a feasible option. GH should be given at dosages of 0.045–0.05 mg/kg per day by daily subcutaneous injections until the patient has reached their final height or until renal transplantation. In addition to providing treatment recommendations, a cost-effectiveness analysis is provided that might help guide decision-making., This Evidence-Based Guideline developed by members of the European Society for Paediatric Nephrology CKD-MBD, Dialysis and Transplantation working groups presents clinical practice recommendations for the use of growth hormone in children with chronic kidney disease on dialysis and after renal transplantation.

Background Classification models based on magnetic resonance imaging (MRI) may aid early diagnosis of frontotemporal dementia (FTD) but have only been applied in established FTD cases. Detection of FTD patients in earlier disease stages, such as presymptomatic mutation carriers, may further advance early diagnosis and treatment. In this study, we aim to distinguish presymptomatic FTD mutation carriers from controls on an individual level using multimodal MRI-based classification. Methods Anatomical MRI, diffusion tensor imaging (DTI) and resting-state functional MRI data were collected in 55 presymptomatic FTD mutation carriers (8 microtubule-associated protein Tau, 35 progranulin, and 12 chromosome 9 open reading frame 72) and 48 familial controls. We calculated grey and white matter density features from anatomical MRI scans, diffusivity features from DTI, and functional connectivity features from resting-state functional MRI. These features were applied in a recently introduced multimodal behavioural variant FTD (bvFTD) classification model, and were subsequently used to train and test unimodal and multimodal carrier-control models. Classification performance was quantified using area under the receiver operator characteristic curves (AUC). Results The bvFTD model was not able to separate presymptomatic carriers from controls beyond chance level (AUC = 0.570, p = 0.11). In contrast, one unimodal and several multimodal carrier-control models performed significantly better than chance level. The unimodal model included the radial diffusivity feature and had an AUC of 0.646 (p = 0.021). The best multimodal model combined radial diffusivity and white matter density features (AUC = 0.680, p = 0.005). Conclusions FTD mutation carriers can be separated from controls with a modest AUC even before symptom-onset, using a newly created carrier-control classification model, while this was not possible using a recent bvFTD classification model. A multimodal MRI-based classification score may therefore be a useful biomarker to aid earlier FTD diagnosis. The exclusive selection of white matter features in the best performing model suggests that the earliest FTD-related pathological processes occur in white matter., Highlights • MRI-based classification was performed on presymptomatic FTD gene carriers and controls. • Presymptomatic carriers were separated from controls significantly better than chance-level. • The best performing model was based on white matter features from structural and diffusion scans. • Multimodal MRI-based classification scores may be useful to aid earlier FTD diagnosis.

Objective Posterior circulation ischemic stroke (PCiS) constitutes 20–30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. Methods Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. Results PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p .05; male sex 68% vs. 58%, p p p p Conclusion Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.

Reproductive monitoring for captive breeding in giant pandas is based on behavioural observation and non-invasive hormone analysis. In urine, interpretation of results requires normalisation due to an animal's changing hydration. Correction of urinary concentrations based on creatinine is the gold standard. In this study, a largely unexplored, easy-to-perform normalisation technique, based on urinary specific gravity (USpG), was examined and compared to creatinine. To this extent, six cycles from two female pandas (SB741(1) and SB569 (5)) were monitored through urine analysis for oestrogen, progesterone, ceruloplasmin and 13,14-dihydro-15-keto-PGF2a (PGFM). The Pearson's correlation between creatinine and USpG was high (r = 0.805-0.894; p < 0.01), indicative for a similar performance of both normalisation methods. However, generally lower values were observed during pro-oestrus and primary (progesterone) rise. This could be associated with huge shifts in appetite, monitored by faecal output (kg) with an averaged > 50% decrease during oestrus and > 50% increase during primary progesterone rise. In parallel, respectively highest and lowest creatinine and USpG levels, were measured, with creatinine obviously more affected as a result of linkage with muscle tissue metabolism affected by reproductive hormones. As a consequence, metabolite levels were significantly different between both corrected datasets with significantly higher oestrogen peak levels during oestrus ranging from 2.13-86.93 and 31.61-306.45 ng/mL (USpG correction) versus 2.33-31.20 and 36.36-249.05 ng/mL Cr (creatinine correction) for SB569 and SB741 respectively, and significant lower progesterone levels during primary progesterone rise ranging from 0.35-3.21 and 0.85-6.80 ng/mL (USpG correction) versus 0.52-10.31 and 2.10-272.74 ng/mL Cr (creatinine correction) for SB569 and SB741 respectively. Consequently, USpG correction rendered unbiased profiles, less subject to variation and metabolic artefacts and therefore allowed a more straightforward identification of peak oestrogen and onset of secondary progesterone rise, being potentially advantageous for future studies unravelling key giant panda reproductive events, including (delayed) implantation. The alternative application of USpG as a normalisation factor was further supported by its easy application and environmental and technical robustness.

Item does not contain fulltext BACKGROUND: The aim of this study was to develop a population pharmacokinetic model of tacrolimus in paediatric patients at least 1 year after renal transplantation and simulate individualised dosage regimens. PATIENTS AND METHODS: We included 54 children with median age of 11.1 years (range 3.8-18.4 years) with 120 pharmacokinetic profiles performed over 2 to 4 h. The pharmacokinetic analysis was performed using the non-linear mixed-effects modelling software (NONMEM((R))). The impact of covariates including concomitant medications, age, the cytochrome P450 (CYP) CYP3A5*3 gene and the adenosine triphosphate binding cassette protein B1 (ABCB1) 3435 C-->T gene polymorphism on tacrolimus pharmacokinetics was analysed. The final model was externally validated on an independent dataset and dosing regimens were simulated. RESULTS: A two-compartment model adequately described tacrolimus pharmacokinetics. Apparent oral clearance (CL/F) was associated with weight (allometric scaling) but not age. Children with lower weight and CYP3A5 expressers required higher weight-normalised tacrolimus doses. CL/F was inversely associated with haematocrit (P < 0.05) and gamma-glutamyl transpeptidase (gammaGT) (P < 0.001) and was increased by 45 % in carriers of the CYP3A5*1 allele (P < 0.001). CL/F was not associated with concomitant medications. Dose simulations show that a daily tacrolimus dose of 0.2 mg/kg generates a pre-dose concentration (C 0) ranging from 5 to 10 microg/L depending on the weight and CYP3A5 polymorphism. The median area under the plasma concentration-time curve (AUC) corresponding with a tacrolimus C 0 of 4-8 microg/L was 97 h.microg/L (interquartile range 80-120). CONCLUSIONS: In patients beyond the first year after transplantation, there is a cumulative effect of CYP3A5*1 polymorphism and weight on the tacrolimus C 0. Children with lower weight and carriers of the CYP3A5*1 allele have higher weight-normalised tacrolimus dose requirements.

The pattern of vascular remodelling in relation to recovery after stroke remains largely unclear. We used steady-state contrast-enhanced magnetic resonance imaging to assess the development of cerebral blood volume and microvascular density in perilesional and exofocal areas from (sub)acutely to chronically after transient stroke in rats. Microvascular density was verified histologically after infusion with Evans Blue dye. At day 1, microvascular cerebral blood volume and microvascular density were reduced in and around the ischemic lesion (intralesional borderzone: microvascular cerebral blood volume = 72 ± 8%; microvascular density = 76 ± 8%) (P

Estimation of hemorrhagic transformation (HT) risk is crucial for treatment decision–making after acute ischemic stroke. We aimed to determine the accuracy of multiparametric MRI-based predictive algorithms in calculating probability of HT after stroke. Spontaneously, hypertensive rats were subjected to embolic stroke and, after 3 h treated with tissue plasminogen activator (Group I: n = 6) or vehicle (Group II: n = 7). Brain MRI measurements of T2, T2*, diffusion, perfusion, and blood–brain barrier permeability were obtained at 2, 24, and 168 h post-stroke. Generalized linear model and random forest (RF) predictive algorithms were developed to calculate the probability of HT and infarction from acute MRI data. Validation against seven-day outcome on MRI and histology revealed that highest accuracy of hemorrhage prediction was achieved with a RF-based model that included spatial brain features (Group I: area under the receiver-operating characteristic curve (AUC) = 0.85 ± 0.14; Group II: AUC = 0.89 ± 0.09), with significant improvement over perfusion- or permeability-based thresholding methods. However, overlap between predicted and actual tissue outcome was significantly lower for hemorrhage prediction models (maximum Dice’s Similarity Index (DSI) = 0.20 ± 0.06) than for infarct prediction models (maximum DSI = 0.81 ± 0.06). Multiparametric MRI-based predictive algorithms enable early identification of post-ischemic tissue at risk of HT and may contribute to improved treatment decision-making after acute ischemic stroke.

Dense deposit disease (DDD), a subtype of C3 glomerulopathy, is a rare disease affecting mostly children. Treatment options are limited. Debate exists whether eculizumab, a monoclonal antibody against complement factor C5, is effective in DDD. Reported data are scarce, especially in children. The authors analyzed clinical and histologic data of five pediatric patients with a native kidney biopsy diagnosis of DDD. Patients received eculizumab as therapy of last resort for severe nephritic or nephrotic syndrome with alternative pathway complement activation; this therapy was given only when the patients had not or only marginally responded to immunosuppressive therapy. Outcome measures were kidney function, proteinuria, and urine analysis. In all, seven disease episodes were treated with eculizumab (six episodes of severe nephritic syndrome [two of which required dialysis] and one nephrotic syndrome episode). Median age at treatment start was 8.4 (range, 5.9-13) years. For three treatment episodes, eculizumab was the sole immunosuppressive treatment. In all patients, both proteinuria and renal function improved significantly within 12 weeks of treatment (median urinary protein-to-creatinine ratio of 8.5 [range, 2.2-17] versus 1.1 [range, 0.2-2.0] g/g, P

We sought to investigate the relationship between blood–brain barrier (BBB) permeability and microstructural white matter integrity, and their potential impact on long-term functional outcomes in patients with acute ischemic stroke (AIS). We studied 184 AIS subjects with perfusion-weighted MRI (PWI) performed

Cribriform and intraductal prostate cancer are both associated with an adverse outcome after radical prostatectomy. We included all patients with prostate cancer from the first screening round of the European Randomized Study of Screening for Prostate Cancer (ERSPC). All available slides were revised and scored for presence of cribriform and/or intraductal prostate cancer. Outcome measurements were biochemical recurrence and disease-specific survival. In total, 486 patients had Gleason score (GS) 6 (47%) and 545 GS ≥7 (53%). The disease-specific survival and biochemical-recurrence-free survival of CR/IDC−-GS3+4 patients did not differ significantly from those with GS 6, while patients with CR/IDC+-GS3+4-patients had a significant poorer outcome. Conclusion: The presence of cribriform and intraductal growth in prostate cancer, is a strong clinical prognostic marker with potential. The use of this variable in a clinical setting could contribute to reducing overtreatment of prostate cancer.

IntroductionOral corticosteroids are the first-line treatment for idiopathic childhood nephrotic syndrome. Most children experience several relapses, needing repeated courses of corticosteroid therapy. This exposes them to side effects and long-term complications. For most patients, long-term prognosis is for complete resolution of the disease over time and maintenance of normal kidney function. Therefore, it is vital to focus on minimising adverse events of the disease and its therapy. Unfortunately, no randomised controlled trials are available to determine the optimal corticosteroid treatment of an infrequent relapse of nephrotic syndrome. Recent studies show that treatment schedules for the first episode can safely be shortened to 2 months. The hypothesis of the REducing STEroids in Relapsing Nephrotic syndrome (RESTERN) study is that a 4-week reduction of alternate-day steroids after inducing remission is effective and safe, reduces steroid exposure by 35% on average and is therefore preferable.Methods and analysisThe RESTERN study is a nationwide, double-blind, randomised, placebo-controlled, non-inferiority intervention study. Children aged 1–18 years with a relapse of steroid-sensitive nephrotic syndrome are eligible for this study. Study subjects (n=144) will be randomly assigned to either current standard therapy in the Netherlands or a reduced prednisolone schedule. The primary outcome of the RESTERN study is the time to first relapse after the final prednisolone dose. The secondary outcomes are the number or relapses, progression to frequent relapsing or steroid dependent nephrotic syndrome and the cumulative dosage of prednisolone during the study period.Ethics and disseminationThis non-inferiority trial will be performed in accordance with the Declaration of Helsinki and has been approved by the medical ethical committee of Arnhem-Nijmegen and the Dutch Competent Authority (Central Committee on Research Involving Human Subjects, CCMO). After completion of this study, results will be published in national and international peer-reviewed scientific journals. Papers will be published according to CCMO guidelines. The final report will be made available to trial participants.Trial registration numberNTR5670, EudraCT no 2016-002430-76.

Background: Multimodal MRI may support single-subject differentiation diagnosis of Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Yet, what MRI modality combinations maximize classification accuracy is not yet known. We analyzed various MRI modality combinations to determine what combinations suit single-subject classification of AD patients, bvFTD patients, and control subjects best. Methods: Thirty-seven patients with probable AD, 28 patients with bvFTD, and 40 cognitively normal subjects (Controls) (Table 1) underwent diffusion tensor imaging (DTI), resting-state functional, and T1-weighted structural MRI at 3T. From each T1-w image, probabilistic gray matter (GM) maps were calculated and used to estimate local GM density (GMD) within 96 Harvard-Oxford cortical and 14 deep GM regions. 20 tracts of the Johns-Hopkins-University tractography atlas were used to determine local white matter density (WMD) values and, after projection on the study-specific skeleton calculated with tract-based spatial statistics, local measures of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity. Seventy rs-fMRI components, derived from a temporally concatenated independent component analysis, were used to calculate the components' pairwise correlations and partial correlations. These features were used to establish classification accuracy using nested cross-validation classification analyses with elastic net classifiers. Individual and combinations of MRI modalities were step-wise evaluated to determine classification accuracy, expressed as area under the receiver operating characteristic curves (AUC). A three-group classification model was used to determine the accuracy for differentiating between AD, bvFTD, and Control subjects. Three two-group models were calculated to differentiate AD from Controls, bvFTD from Controls, and AD from bvFTD subjects. Results: Classification accuracy for three-group and AD versus Control classifications were highest with GMD-based features ((AUC [min-max]) 0.7±5[0.711-0.847] and 0.933[0.886- 0.963]) (Table 2). bvFTD versus Control and AD versus bvFTD classification models were most accurate using DTI-based features (FA: 0.860[0.807-0.913], MD: 0.693[0.614-0.821]). Overall, rsfMRI features did not improve classification accuracy. Conclusions: MRI-based differentiation of dementia forms may depend on dementia- type and MRI modality. T1-w-based measures particularly supported AD classifications, whereas DTI-based measurements facilitated bvFTD classifications. Functional connectivity measures and multimodal combinations did not substantially improve dementia- type discrimination. For MRI-based differential dementiatype diagnosis careful selection of MRI modalities is warranted.

Magnetic resonance imaging (MRI) provides a powerful (neuro)imaging modality for the diagnosis and outcome prediction after (acute) stroke. Since MRI allows noninvasive, longitudinal, and three-dimensional assessment of vessel occlusion (with magnetic resonance angiography (MRA)), tissue injury (with T1-, T2-, T2∗-, and/or diffusion-weighted MRI), and hemodynamics (with perfusion MRI), it offers a valuable tool for (pre)clinical and experimental studies on stroke pathology, treatment, and recovery. Combined MRI protocols that inform of different aspects of stroke pathophysiology enable the delineation of irreversibly damaged tissue and, potentially salvageable, tissue at risk of infarction, based on concepts like the perfusion-diffusion mismatch, or by predictive modeling of infarct probability. These approaches can aid in the selection of patients who could respond favorably to thrombolysis or thrombectomy. Furthermore, structural and functional MRI of the progression of affected tissue may contribute to the monitoring and characterization of effects of (experimental) therapeutic interventions aimed at improving outcome after stroke.

We present a case of diabetic ketoacidosis, known as one of the most serious metabolic complications of diabetes. We were confronted with rapid neurological deterioration and unseen glycaemic values, which reached almost 110 mmol/L, subsequently resulting in hyperkalaemia and life-threatening dysrhythmias. This is the first reported live case with such high values of blood glucose and a favourable outcome.

The use of patient reported outcomes (PROs) in pediatric practice is effective in increasing discussion about emotional and psychosocial functioning. This finding forms the basis for implementing KLIK: a web-based program using electronic PROs (ePROs). The aim of this article is to describe the KLIK implementation in line with the 8 methodological recommendations composed by the International Society for Quality of Life Research (ISOQOL). (1) Goal of KLIK: to monitor and screen children (aged 0–18) with chronic illnesses over extended periods of time. (2) Children aged 8–18 complete the questionnaires themselves. Parents complete the questionnaires for young children. (3) The basis is a generic HRQOL questionnaire. Disease-specific HRQOL and psychosocial questionnaires are also available. (4) A web-based mode was selected. (5) The questionnaires in KLIK are available prior to a consultation. Pediatricians retrieve the ePROfile from the website (www.hetklikt.nu) and discuss it with the patients. The ePROfile consists of a literal representation of the answers and a graphic presentation. (6) Various tools are used to aid in its interpretation. (7) All members of the multidisciplinary team receive training in how to use the website and how to adequately respond to the patient’s ePROfile. (8) Improvements to and evaluation of KLIK are ongoing. Since implementation began, 17 patient groups, 160 professionals and >1,450 patients have started using KLIK. The implementation of KLIK appears to be feasible and workable. Many pediatricians have shown an interest in using KLIK and it is therefore being expanded and adapted for different patient groups and hospitals. (PsycINFO Database Record (c) 2014 APA, all rights reserved)

Aminsharifi et al present their study on the predictive accuracy of PSAD for prostate cancer grade group 2 or greater. The study cohort consisted of 2,162 men with PSA in the diagnostic gray zone of 4 to 10 ng/ml, of whom 1,210 (56%) were African American. Interestingly the predictive accuracy of PSAD was independent of race and BMI. Stratification using a PSAD cutoff of 0.08 ng/ml/cc could have avoided 273 of 2,162 biopsies (13%), missing 48 of 622 grade group 1 cancers (8%) and 10 of 499 grade group 2 or greater cancers (2%). This study confirms what we have known for a while. PSAD is the strongest predictor of prostate cancer and it can be used to avoid unnecessary biopsies. The strength of PSAD is confirmed in the latest prediction models, including omics. Recently it was shown that prostate volume was the strongest predictor in the Stockholm-3 model, including PSA and its subforms (reference 1 in article). Nevertheless, parameters such as DRE, previous biopsy status, patient age and family history add to the predictive accuracy of all PSAD based models like the PCPT 2.0 (reference 12 in article) and ERSPC (reference 16 in article) risk calculators. In the current study it is important to realize the fact of calibration in the comparison between PSAD and the PCPT 2.0 risk calculator (reference 12 in article). The performance of PSAD was directly derived from the institutional cohort while risk calculators were developed in different study cohorts. Without doubt the performance of these risk calculators would be better after a simple calibration step. Therefore, we acknowledge the strength of PSAD to predict the biopsy outcome but think that ignoring other relevant information is not the way to go.

Introduction: Although antiplatelet therapy is a mainstay of post–percutaneous coronary intervention therapy, pharmacogenetic (PGt) considerations of therapy are often ignored despite related Food and Drug Administration warnings. Pharmacists are well situated to provide PGt guidance, and the community pharmacy is one setting where PGt testing, interpretation, and recommendations can take place to ensure optimal therapeutic outcomes. Case Report: A 65-year-old man who had a myocardial infarction that was treated with PCI and stent placement was determined by a community pharmacist to be a candidate for PGt testing to ensure optimal antiplatelet therapy. The patient was seen in the pharmacy as a part of a medication therapy management encounter and underwent genetic testing. Results of the genetic testing indicated the need for modification of therapy. The community pharmacist interpreted the results and made the appropriate recommendation to the cardiologist who in turn modified antiplatelet therapy appropriately. Conclusion: This case describes the potential for collaboration between pharmacists and physicians to optimize antiplatelet therapy through PGt testing. Points of consideration for others looking to implement related PGt services are also discussed.

Aim: Presacral lesions are uncommon and represent a diagnostic and surgical challenge. The aim of this study is to present our experience with Kraske’s transsacral resection and to review current literature. Methods: Seven patients who had a transsacral resection between 2001 and 2013 were reviewed retrospectively. Results: Two men and five women with a mean age of 39 (range 17 - 60) years were diagnosed with a presacral lesion. The clinical presentation was nonspecific; pain was the most common symptom. All lesions were palpable on digital rectal examination. Magnetic resonance imaging (MRI) was necessary to assess the tumor’s extent, biological behavior and relationship to adjacent structures. MRI predicted malignancy with 100% accuracy. All lesions were located below S3 and underwent a transsacral resection. Pathological examination revealed four tailgut cysts, two epidermoid cysts and one chordoma. Postoperative complications included wound infections (two cases) and spasms of the gluteus muscle (one case). We reported no recurrence or mortality. Conclusion: Clinical awareness, the use of MRI in the routine work-up and avoidance of an incisional biopsy result in a good outcome after surgical resection of presacral lesions. Kraske’s approach can be used for presacral lesions below S3, resulting in low morbidity, no recurrence and no mortality.

Vascular occlusion sites largely determine the pattern of cerebral tissue damage and likelihood of subsequent reperfusion after acute ischemic stroke. We aimed to elucidate relationships between flow obstruction in segments of the internal carotid artery (ICA) and middle cerebral artery (MCA), and (1) profiles of acute ischemic lesions and (2) probability of subsequent beneficial reperfusion. Embolic stroke was induced by unilateral intracarotid blood clot injection in normotensive ( n=53) or spontaneously hypertensive ( n=20) rats, followed within 2 hours by magnetic resonance (MR) angiography (MRA), diffusion- (DWI) and perfusion-weighted magnetic resonance imaging (MRI) (PWI). In a subset of animals ( n=9), MRI was repeated after 24 and 168 hours to determine the predictive value of the occlusion pattern on benefit of reperfusion. The extent of cerebral perfusion and diffusion abnormality was related to the pattern of flow obstruction in ICA and MCA segments. Hypertensive animals displayed significantly larger cortical perfusion lesions. Acute perfusion-diffusion lesion mismatches were detected in all animals that subsequently benefitted from reperfusion. Yet, the presence of an angiography-diffusion mismatch was more specific in predicting reperfusion benefit. Combination of DWI, PWI, and MRA exclusively informs on the impact of arterial occlusion profiles after acute ischemic stroke, which may improve prognostication and subsequent treatment decisions.

Background: Impaired glomerular function is one of the health problems affecting childhood cancer survivors (CCS). It is unclear whether glomerular function deteriorates or recovers. We investigated time trends and predictors of glomerular function in CCS. Methods: We evaluated repeated observations of estimated glomerular filtration rate (GFR) and glomerular dysfunction (GFR Results: At a median follow-up of 21 years after diagnosis, glomerular function was assessed in 1,122 CCS aged ≥18 years. CCS treated with potentially nephrotoxic therapy had a significantly lower GFR and higher glomerular dysfunction probability up to 35 years after cancer diagnosis compared with CCS treated without nephrotoxic therapy (P < 0.001). Especially ifosfamide, cisplatin, and nephrectomy were associated with worse glomerular function that persisted during the entire follow-up period (P < 0.001). Glomerular function deteriorated over time in all CCS (P < 0.001). CCS treated with higher doses of cisplatin seem to have a higher deterioration rate as compared with other CCS (P < 0.005). Conclusions: The loss in glomerular function starts early, especially for CCS treated with ifosfamide, higher doses of cisplatin, and nephrectomy, and seems to be persistent. We have an indication that CCS treated with higher doses of cisplatin experience faster decline than other CCS. Impact: As glomerular function continues to deteriorate, CCS are at risk for premature chronic renal failure. Cancer Epidemiol Biomarkers Prev; 22(10); 1736–46. ©2013 AACR.

Item does not contain fulltext Many children receiving a kidney transplant are seronegative for CMV and therefore, highly susceptible to a primary CMV infection. This study aims at evaluating incidence, time of occurrence, and severity of CMV infection in the first year post-transplantation in relation to different types of CMV prophylaxis. Transplantations in three centers in the Netherlands between 1999 and 2010 were included. Retrospective, observational, multicenter study. Clinical data and PCR measurements of CMV were collected. Prophylaxis in high-risk patients (CMV serostatus D+R-) consisted of (val)ganciclovir during three months, or acyclovir plus CMV immunoglobulin at a former stage. Intermediate-risk patients (R+) received (val)acyclovir, or acyclovir plus CMV immunoglobulin at a former stage. Low-risk patients (D-R-) did not receive prophylaxis. Infection was defined as CMV PCR above 50 geq/mL plasma or whole blood, a clinically relevant infection above 1000 geq/mL. One hundred and fifty-nine transplantations were included. CMV infection was documented for 41% of high-risk, 24% of intermediate-risk, and 13% of low-risk patients, in the latter two groups typically during the first three months. The infection rate was highest in the high-risk group after cessation of valganciclovir prophylaxis. Valganciclovir provided better protection than did acyclovir + CMV immunoglobulin. Adding an IL2-receptor blocker to the immunosuppressive regimen did not affect the infection rate. Acute graft rejection was not related with CMV infection. Valganciclovir prophylaxis effectively prevents CMV infection in high-risk pediatric kidney recipients, but only during prophylaxis. Valacyclovir prophylaxis in intermediate-risk patients is less effective. 01 september 2013

Background: In acute ischemic stroke (AIS), therapeutic decisions are increasingly being based upon the volume of likely-unsalvageable brain tissue, which is often estimated using DWI. Deep learning algorithms, e.g. convolutional neural networks (CNN), have been employed for chronic stroke lesion segmentation. Here we investigate the applicability of CNN for DWI lesion measurement in acute stroke. Methods: 50 AIS patients underwent DWI < 12h from last known well. Apparent diffusion coefficient maps, T2WI, and DWI were used as covariates in a 2D CNN (5-fold cross validation). Including convolutional, inception and fully connected dense layers, a CNN of 15 layers was trained using manually outlined DWI lesions. To avoid overfitting, statistical dropout, L1- and L2-regularization and batch-normalization were used. Automatically segmented lesion volumes (ALV) using a 50% risk threshold were compared to the manual lesion volumes (MLV) using Dice similarity index (DSI, a measure of overlap) and Spearman’s correlation coefficient. Subset analysis was performed evaluating results between small ( Results: The figure shows examples of CNN segmentation. The median [IQR] measured lesion volume and DSI were 25 [13-46] mL and 66% [35-75%], respectively. The correlation of MLV with ALV was 86% (P Discussion: Automatic DWI lesion segmentation for large lesions is feasible using CNN. CNN tended to overestimate the volumes of small lesions. Prior methods have used a priori heuristics or morphometric operations to remove artifacts. CNN methods show promise for “learning” to discriminate artifacts from real lesions.