Use of electronic health records by child primary healthcare providers in Europe.

BACKGROUND: There is limited data on the use and functionality level of electronic health records (EHRs) supporting primary child health care in Europe. Our objective was to determine European primary child healthcare providers' use of EHRs, and functionality level of the systems used. METHODS: European primary care paediatricians, paediatric subspecialists and family doctors were invited by European Academy of Paediatrics Research in Ambulatory Setting Network (EAPRASnet) country coordinators to complete a web-based survey on the use of EHRs and the systems' functionalities. Binomial logistic analysis has been used to evaluate the effect of specialty and type of practice on the use of EHRs. RESULTS: The survey was completed by 679 child primary healthcare providers (response rate 53%). Five hundred and fifty four responses coming from 10 predominant countries were taken for further analysis. EHR use by respondents varied widely between countries, all electronic type use ranging between 7% and 97%. There was no significant difference in EHR use between group practice and solo practitioners, or between family doctors and primary care paediatricians. History and physical examination can be properly recorded by respondents in most countries. However, growth chart plotting capacity in some countries ranges between 22% and 50%. Vaccination recording capacity varies between 50% and 100%, and data exchange capacity with immunization databases is mostly limited, ranging between 0% and 54%. CONCLUSIONS: There is marked heterogeneity in the use and functionalities of EHRs used among child primary child healthcare providers in Europe. More importantly, lack of critical paediatric supportive functionalities like growth tracking and vaccination status has been documented in some countries. There is a need to explore the reasons for these findings, and to develop a cross European paediatric EHR standards.

Behavioral and fMRI evidence of the differing cognitive load of domain-specific assessments.

Standards-referenced educational reform has increased the prevalence of standardized testing; however, whether these tests accurately measure students' competencies has been questioned. This may be due to domain-specific assessments placing a differing domain-general cognitive load on test-takers. To investigate this possibility, functional magnetic resonance imaging (fMRI) was used to identify and quantify the neural correlates of performance on current, international standardized methods of spelling assessment. Out-of-scanner testing was used to further examine differences in assessment results. Results provide converging evidence that: (a) the spelling assessments differed in the cognitive load placed on test-takers; (b) performance decreased with increasing cognitive load of the assessment; and (c) brain regions associated with working memory were more highly activated during performance of assessments that were higher in cognitive load. These findings suggest that assessment design should optimize the cognitive load placed on test-takers, to ensure students' results are an accurate reflection of their true levels of competency.

First results of endocavity evaluation of the microvascularization of malignant prostate tumors using contrast enhanced ultrasound (CEUS) including perfusion analysis: first results.

AIM: Detection of prostate cancer lesions using transrectal contrast enhanced ultrasound (CEUS) of the prostate utilizing quantitative perfusion analysis. METHOD: 20 patients (mean age 63 years, 47-71) with biopsy proven prostate cancer underwent transrectal ultrasound (TRUS) prior to radical prostatectomy by 2 experienced examiners using a multifrequency endocavitary probe (5-9 MHZ, LOGIQ E9, GE Healthcare, Chalfont St Giles, UK) to detect cancer-suspect lesions. CEUS was performed dynamically up to 3 Min after bolus injections of 2.4 ml SonoVue® (BRACCO, Italy). Digital cine loops were analyzed by an independent blinded examiner using perfusion quantification software with colour-coded parametric images in order to define suspect regions based on the perfusion-related parameters early wash in rate (WIR), mean transit time (MTT) and rise time (RT). The results of CEUS perfusion analysis were compared with the histopathology after surgery, obtained from whole mount sections. RESULTS: After prostatectomy and histopathology, 34 prostate cancer foci were found in 20 patients. In 30/34 cases an early enhancement within the tumor was detected by CEUS perfusion analysis without early wash out. By evaluating the MTT and RT tumor detection was possible in 29/34 and 25/34 cases. The highest detection rate of prostate cancers was obtained by analysis of early contrast enhancement (priot to the normal prostate parenchyma), with a sensitivity of 88%, specificity 100%, NPP 60%, PPV 90%, in clinically suspicious cases with good correlation to the postoperative histopathological findings (r = 0.728). CONCLUSION: This pilot study demonstrates, that quantitaive analysis of perfusion parameters obtained with transrectal CEUS could be helpful for characterization of neoplastic microcirculation of prostate cancer, for preoperative localization of cancer-suspect areas and for therapy guidance and management.

[Urinary proteomics: the diagnostic key for urinary tract abnormalities and kidney diseases in children?]. / Urinproteomanalytik : Der Diagnoseschlüssel bei Harntransportstörungen und Nierenerkrankungen im Kindesalter?

Due to its accessibility and availability, ease of collection, and correlation with physiology and pathology, urine is an attractive source for clinical proteomics/peptidomics in urology and nephrology. Here, we review the published findings of a reproducible, high-resolution method for peptidome analysis of naturally occurring human urinary peptides and proteins - ranging from 0.8 to 17.0 kDA - using samples from renal patients analyzed by capillary electrophoresis coupled to mass spectrometry (CE-MS). CE-MS identified children with urodynamically relevant ureteric junction obstruction, vesicoureteric reflux of grades IV and V, glomerulopathies, tubulopathies, and chronic kidney disease. Our analysis revealed that the incorporation of urinary proteome analysis in the initial evaluation of children with urinary tract abnormalities will avoid side effects of radiological imaging techniques, reduce costs, and increase the quality-adjusted life years in this patient population. CE-MS can be recommended for clinical prospective studies on the analysis of naturally occurring urinary peptides in children with urinary tract diseases.

De novo therapy with everolimus, low-dose ciclosporine A, basiliximab and steroid elimination in pediatric kidney transplantation.

The number of acute rejections and infections after pediatric kidney transplantation (KTX) could not be reduced in the last years. To reduce these events, we investigated a new immunosuppressive protocol in a prospective trial. After KTX, 20 children (median age 12 years, range 1-17) were initially treated with Basiliximab, ciclosporine A (CsA) (trough-level = C0 200-250 ng/mL) and prednisolone. After 2 weeks, CsA dose was reduced to 50% (C0 75-100 ng/mL, after 6 months: 50-75 ng/mL) and everolimus (1.6 mg/m²) /day) was started (C0 3-6 ng/mL). Six months after KTX prednisolone was set to alternate dose and stopped 3 months later. All 20 protocol biopsies 6 months after KTX showed no acute rejection or borderline findings. Indication biopsies resulted in no acute rejections and two borderline findings. Mean glomerular filtration rate (GFR) 1 year after KTX was 71 ± 25 mL/min/1.73 m². Without cytomegalovirus (CMV)-prophylaxis, only two primary CMV infections were seen despite a donor/recipient-CMV-constellation pos./neg. in 10/20 children. In pediatric KTX, de novo immunosuppression with low-dose CsA, everolimus and steroid withdrawal after 9 months led to promising results according to numbers of acute rejections and infections. Further follow up is needed. Future larger trials will have to confirm our findings.

Protocol biopsy-driven interventions after pediatric renal transplantation.

The therapeutic value of protocol biopsies (PBs) in renal transplant recipients remains unclear. We performed protocol biopsies in 57 children six months after transplantation. We increased the CNI dose in patients with borderline findings. In cases of Banff grade Ia, six prednisolone IV-pulses were given and the CNI dose was increased. CNI toxicity and polyomavirus nephropathy led to a reduction in the CNI dose. GFR was compared with a control group of 51 children with no PBs transplanted in the same period. Forty-two percent of PBs had no pathological changes, 24% IF/TA. Borderline findings were detected in 11%, Banff grade Ia in 15% (CNI), toxicity in 8%, and one case showed polyomavirus nephropathy. GFR after 1.5 and 2.5 yr was similar in both groups. GFR 3.5 yr after transplantation was significantly higher in the intervention group (57 ± 17 vs. 46 ± 20). Patients treated with low-dose CNI and everolimus had a significantly lower number of pathological findings in PBs. The performance of protocol biopsies followed by a standardized treatment algorithm led to better graft function 3.5 yr after transplantation. Prospective randomized studies to confirm our findings are needed.

Vaso-occlusion in Schimke-immuno-osseous dysplasia: is the NO pathway involved?

Schimke-immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder with the main clinical findings of spondyloepiphyseal dysplasia, nephrotic syndrome, and defective cellular immunity. Vaso-occlusive processes, especially generalized atherosclerosis, are a life-limiting complication in patients with severe SIOD. The nitric oxide synthase (NOS) oxidizes L-arginine to nitric oxide (NO). NO is a potent vasodilator with inhibitory effects on platelet aggregation and the development of atherosclerosis. We hypothesized that reduced NO production due to antagonism of NOS by asymmetric dimethylarginine (ADMA) would be a possible pathophysiological mechanism for vaso-occlusion in SIOD. We tested this hypothesis in 10 patients with SIOD and 10 age-matched healthy controls. Plasma and urine levels of nitrite and nitrate, the indicators of NO synthesis, and of ADMA, an endogenous NOS inhibitor, in children suffering from SIOD were not significantly different from those in the age-matched healthy controls. Our results suggest that the L-arginine/NO pathway is not altered in SIOD. Antagonism of NOS by ADMA does not seem to be the cause of premature general atherosclerosis in SIOD. The underlying pathology of vaso-occlusion in SIOD still remains unclear.

Superior long-term graft function and better growth of grafts in children receiving kidneys from paediatric compared with adult donors.

BACKGROUND: Organs from paediatric donors are often not accepted for paediatric recipients because previous reports suggested inferior graft function for small kidneys transplanted in children. On the other hand, studies have shown that kidneys of adult donors transplanted into children down-regulate filtration after transplantation and may not increase their function to the need of the growing child. METHODS: We assessed 64 male and 35 female (total n = 99) white children aged <10 years (male: mean 5.1 years, SD 2.8; female: mean 5.8 years, SD 3.4) who had received cadaveric kidney transplants at our centre between 1990 and 2005. Mean observation time was 5.9 years, SD 4.0. The children were divided into two groups depending on the kidney donor age: 63 children (mean age 5.0 years, SD 2.9) received an organ of an adult, and 39 (mean age 6.4 years, SD 3.4) of a paediatric donor. Immunosuppression was performed with prednisolone, cyclosporin A microemulsion+/-mycophenolate mofetil. RESULTS: Three to five years after transplantation the calculated glomerular filtration rate corrected to body surface was significantly higher in recipients of paediatric organs. The size of paediatric grafts doubled in the first years after transplantation while adult grafts had a stable size. Graft survival was comparable in both groups during observation time. CONCLUSIONS: We conclude that paediatric donor kidneys should be given preferentially to paediatric recipients due to better long-term function.

Living related kidney donation as an advantage for growth of children independent of glomerular filtration rate.

Seventy-two pediatric kidney recipients of living related donors (LRD) and 145 of cadaveric donors (CAD) were analyzed for height standard deviation scores (Ht-SDS) and glomerular filtration rates (GFR) directly after transplantation and over the following 5 years. GFR was significantly higher immediately after transplantation in LRD compared with CAD recipients; however, GFR was not different during the 5-year follow-up period. Although Ht-SDS was comparable at the time of transplantation in both groups, it was significantly higher among LRD recipients over the next 5 years. Multivariate and covariate analyses showed that Ht-SDS after 5 years was mainly influenced only by CAD vs LRD and not by GFR or other factors, namely, donor age, rejections, time of dialysis, preemptive transplantation, age at transplantation, or immunosuppression. Thus, children receiving grafts from LRD showed a better catch-up growth independent of the GFR than those after CAD transplantation. We concluded that the period of donor death and prolonged cold ischemia in CAD grafts may lead to changes in gene expression of cytokines and other mediator molecules that affect bone metabolism. Better growth seems to be an additional factor supporting the policy of LRD kidney transplantation as the best option in children.

Nodular B-cell aggregates associated with treatment refractory renal transplant rejection resolved by rituximab.

Acute rejection episodes leading to treatment refractory early graft loss are increasingly rare events in living related renal transplantation today. Pathophysiologic pathways often remain unsolved. We report on tubulointerstitial and vascular rejection developing within 2 weeks after transplantation in a 12-year-old boy treated with cyclosporine, mycophenolate, steroids and double blinded basiliximab. Despite steroid pulses, switch to tacrolimus and ATG serum creatinine peaked at 347 micromol/L with imminent graft loss and ongoing C4d negative cellular vascular rejection. Permanent gain of function was only achieved after a single dose of rituximab. Retrospectively CD20+ nodular B-cell aggregates could be demonstrated in all three biopsies obtained prior to rituximab and resolved concomitantly with functional improvement. Our case for the first time demonstrates resolution of nodular CD20+ infiltrates and decline of OX40, NF-kappaB and CTL transcription shortly after rituximab indicating a B-cell facilitated C4d negative pathway. Single dose rituximab may effectively reverse even long-lasting refractory rejection.

Growth in children after kidney transplantation with living related donor graft or cadaveric graft.

The extent to which growth after renal transplantation differs between children with a living related donor graft (LRD) and those with a cadaveric donor graft (CAD) is unclear. We retrospectively studied growth in the 5 years after transplantation in 30 boys who received LRD and 21 who received CAD. Height was similar in both groups after transplantation but was greater in LRD than in CAD recipients during follow-up. LRD recipients were taller at all ages, and had greater growth velocity in infancy and during puberty. Glomerular filtration rate (GFR) was higher immediately after transplantation in LRD than in CAD recipients, but did not differ between the groups during follow-up. GFR and other factors did not affect height 5 years after transplantation. These findings support use of LRD as the preferred option in children.

Long-term follow-up of pediatric transplant recipients: mycophenolic acid trough levels are not a good indicator for long-term graft function.

BACKGROUND: Mycophenolate mofetil (MMF) has the potential of decreasing acute rejection episodes early following renal transplantation. Pharmocokinetic monitoring of mycophenolic acid (MPA) trough levels is performed by many centers. MMF has also proved successful in improving long-term graft function in patients with chronic allograft nephropathy (CAN). However, no data for long-term monitoring of MPA in children have yet been published. METHODS: MMF therapy with a dose of 600 mg/m2 twice daily was initiated in 42 children (median age 9.4 yr, range 1.4-15.1) after a median period of 3.8 yr (range 1.0-10.6) post-transplantation-- according to significant increases in serum creatinine. CAN was diagnosed by renal biopsy and the amount of fibrosis was quantified with PicroSiriusRed staining. MMF therapy was combined with ciclosporin A and prednisolone. MPA-C0-levels, measured by high-pressure liquid chromatography, were tested every 3 months. In 12 children a full MPA area under the curve concentration (AUC) was measured. The glomerular filtration rate (GFR) was calculated at the start of MMF therapy and 2 yr later. RESULTS: After initiation of MMF, the calculated GFR did not decrease further in 22 children and mean GFR remained stable for 2 yr in the whole study group. There was a significant correlation between MPA levels 75 min after administration and the full AUC (r = 0.94, p < 0.001) but no correlation between trough levels and AUC (r = -0.07, p > 0.05). The mean MPA trough level was 2.8 +/- 1.3 ng/mL. The intra-individual coefficient of variation was 2.6 +/- 1.4. There was no correlation between mean MPA trough levels and GFR development after 2 yr (r = 0.03, p > 0.05). In children with an MPA level below 1.2 mg/L (n = 5), the mean GFR decline was no different to those with a higher level (p > 0.05). CONCLUSIONS: Drug monitoring of MPA trough levels had no impact on long-term graft function in kidney recipients. MPA levels taken 75 min after administration showed a high correlation with MPA-AUC whereas C0-levels did not correlate. The value of C75 drug measurements for monitoring renal allograft survival will have to be judged in future studies.

[Bacterial pathogens, resistance patterns and treatment options in community acquired pediatric urinary tract infection]. / Bakterielle Erreger, Resistenzentwicklung und Behandlungsoptionen beim ambulant erworbenen Harnwegsinfekt im Kindesalter.

BACKGROUND: Epidemiology and resistance patterns of bacterial pathogens in pediatric UTI show large interregional variability and rates of bacterial resistances are changing due to different antibiotic treatment. We intended to evaluate data from northern Germany. PATIENTS AND METHODS: In 100 children (53 female, 47 male, mean age 4.4 +/- 4.2 years) with community acquired UTI, who presented in the emergency department of our medical school from 2000 - 2002, urine cultures were performed. Inclusion criteria were: acute voiding symptoms, significant bacteriuria with growth of at least 10 (5) colony-forming units/ml urine, leukocyturia > 50/ micro l. Exclusion criteria were underlying renal diseases, anatomic abnormalities of the urinary tract, age < 2 months and recurrent UTI. RESULTS: Patients presented with a mean rectal temperature of 38.6 +/- 1.3 degrees C, mean CRP of 66 +/- 68 mg/dl, mean WBC 13 500 +/- 5 600/ micro l and mean urinary leukocytes of 425 +/- 363/ micro l. In urine cultures E. coli was found in 47 % of the cases, Enterococcus faecalis 23 %, Proteus mirabilis 8 %, Klebsiella oxytoca 4 %, Pseudomonas aeruginosa 5 % and others 13 %. In 76 % one and in 24 % two different bacterial species (60 % Enterococcus faecalis) were cultured. Mean resistance rates were in all bacteria (in E. coli): Ampicillin 53 % (69 %), Ampicillin and Sulbactam 51 % (61 %), Cefalosporin 1 (st) generation (Cefaclor) 48 % (24 %), Cefalosporin 2 (nd) generation (Cefuroxim) 40 % (3 %), Cefalosporin 3 (rd) generation (Cefuroxim) 33 % (0 %), Tobramycin 30 % (2 %), Ciprofloxacine 0 %, Cotrimoxazole 40 % (42 %), Nitrofurantoin 12 % (0 %). CONCLUSION: The resistance rates to Ampicillin (+/- Sulbactam) did not increase as compared to previous analyses (1990 - 1995), however, resistance rates to Cotrimoxazole and 1 (st) generation Cefalosporines increased about 20 %. We conclude that the policies for treatment of UTI in children should be re-evaluated every 5 years according to local resistance rates.

Cyclosporine in pediatric kidney transplantation.

Before the era of cyclosporine (CsA), immunosuppression with azathioprine and steroids resulted in high rejection rates and severe growth retardation in pediatric renal transplant recipients. In the early 1980s, immunosuppression with CsA was introduced for children. Because of differences in metabolism rates and relation of weight and body surface area, special pediatric dosing regimens and monitoring strategies had to be developed. Use of CsA led to a decreased number of acute rejections and, consequently, to a marked increase in graft survival rates. The growth rates of transplanted children were significantly higher under CsA-based immunosuppression than with classical regimens. This was due to a decreased need of steroid co-administration. Main side effects of CsA in children were nephrotoxicity and hirsutism. The introduction of CsA microemulsion in the 1990s led to more reliable absorption profiles and to a lower interindividual variability of CsA area-under-the-curve concentrations and thus to another improvement in rejection rates. New monitoring strategies, based on CsA levels taken 2 hours' postdose, seem promising. In pediatric transplantation, CsA is often successfully combined with an antibody-induction therapy in order to reduce the number of early acute rejections. Combination with mycophenolate mofetil reduces the appearance of chronic rejection. Additional therapy with ToR inhibitors might enforce a reduction of CsA doses and therefore lead to a reduction of CsA toxic effects.

A single center clinical experience in intensive care management of 104 pediatric renal transplantations between 1998 and 2002.

Only a few publications about the treatment in the intensive care unit (ICU) after pediatric renal transplantation have been published yet. As there are no guidelines, we hereby describe the results and recommendations of our transplant unit. A total of 104 renal transplantations have been performed in 96 children at our center since 1998. The age of the children has ranged from 6 months to 18 yr and their body weight from 6 kg to 110 kg. A special fluid management was performed in order to avoid hypotension and hypoperfusion of the graft. Systolic arterial pressure was kept at elevated levels above 100 mmHg during the first day after transplantation. The children remained on the respirator for 4-8 h after transplantation. Anticoagulation was performed using low dose heparin because of the size mismatch of the anastomosed vessels. The mean time in the ICU for the pediatric patients aged <3 yr was 2 days and for children older than 3 yr was 1 day. The main complications after renal transplantation in the ICU were disorders of electrolytes, acute renal failure because of a non-functioning graft (12%), bleeding from the anastomoses (4%), arterial or venous thrombosis (1%), arterial hypertension and pulmonary edema, defined as radiographic evidence (1%). In case of non-function peritoneal- or hemodialysis were performed in the ICU. Young children were more frequently affected than older children. From 1998-2002 one patient died during the ICU time. The 3 yr graft survival rate was 90%. To sum up, children undergoing renal transplantation should be treated in a specialized unit postoperatively to avoid early non-functioning of the graft and extrarenal complications. General guidelines for postoperative care should be established.

Cyclosporin A monitoring by 2-h levels: preliminary target levels in stable pediatric kidney transplant recipients.

Clinical trials in adults have shown that management of transplanted patients with cyclosporin A (CsA) 2-h levels (C2) lead to superior outcome compared with monitoring of 12-h trough levels (C0). In both adults and children, C2 levels enabled a better estimation of the area under the curve concentration than C0 levels. Therefore, it can be suspected that C2 monitoring might also lead to a better outcome in children. Until now C2 target levels for children have not been defined. We measured C2 levels in 101 stable pediatric kidney recipients with a minimum time of 1 yr after transplantation. C2 levels were compared with changes in glomerular filtration rate (GFR) 6 months later. Median C2 levels in children after renal transplantation were 714 ng/mL (95% confidence interval 654-774). Patients with C2 levels below 750 ng/mL had a significantly higher percentage of decline in GFR than patients with C2 levels above 750 ng/mL (p < 0.05). In children with C2 levels below 500 ng/mL three acute rejections occurred in comparison with no rejection in the remaining patients (p < 0.05). We conclude that the lower C2 target level should be above 750 ng/mL in stable pediatric transplant recipients. An upper target level above 1000 ng/mL should be avoided. The question, whether C2 monitoring in pediatric kidney recipients is superior to C0 monitoring, is yet to be answered.

Adaptation of glutathion-peroxidase activity to oxidative stress occurs in children but not in adult patients with end-stage renal failure undergoing hemodialysis.

Lipid peroxidation (LPO) products formed after reaction of free radicals with membrane lipids are involved in the pathogenesis of cardiac diseases. Also in patients with end-stage renal disease (ESRD) LPO was shown to be accelerated and concentrations of non-enzymatic antioxidants were measured lower than in control subjects. However, up to now only limited knowledge about the role of antioxidant enzymes was available. Whether or not activity of those antioxidants might be induced due to oxidative stress in ESRD patients is not known. To answer the question the activity of 3 enzymatic antioxidants, superoxide dismutase (SOD), catalase (CAT), and glutathion peroxidase (GPx), was measured in red blood cells of the ESRD patients undergoing hemodialysis (2 groups: children and adults) and matching controls. LPO in these subjects was determined by measurement of the LPO product 4-hydroxynonenal (HNE) in blood plasma. Plasma HNE was significantly increased by factor 3 in both patient groups children and adults compared to the control groups. The activity of the enzymatic antioxidants was measured differently. While SOD was significantly lower in patients (children and adults) than in the matching controls this was not the case for catalase and GPx. While GPx activity in adult patients was comparable to that in the control groups (childrens and adults), the GPx in children with ESRD was almost twice as high than in the other groups. Since children were shown to have higher levels of glutathion, activated GPx might be a sign of adaptation of these children to the increased rate of oxidation.