[Alban Köhler (1874-1947): Inventor of grid therapy]

Grid (or sieve) therapy ("Gitter-" oder "Siebtherapie"), spatially fractionated kilo- and megavolt X-ray therapy, was invented in 1909 by Alban Köhler, a radiologist in Wiesbaden, Germany. He tested it on several patients before 1913 using approximately 60-70kV Hittorf-Crookes tubes. Köhler pushed the X-ray tube's lead-shielded housing against a stiff grid of 1 mm-square iron wires woven 3.0-3.5mm on center, taped tightly to the skin over a thin chamois. Numerous islets unshielded by iron in the pressure-blanched skin were irradiated with up to about 6 erythema doses (ED). The skin was then thoroughly cleansed, disinfected, and bandaged; delayed punctate necrosis healed in several weeks. Although grid therapy was disparaged or ignored until the 1930s, it has been used successfully since then to shrink bulky malignancies. Also, advanced cancers in rats and mice have been mitigated or ablated using Köhler's concept since the early 1990s by unidirectional or stereotactic exposure to an array of nearly parallel microplanar (25-75μm-wide) beams of very intense, moderately hard (median energy approximately 100 keV) synchrotron-generated X rays spaced 0.1-0.4mm on center. Such beams maintain sharp edges at high doses well beneath the skin yet confer little toxicity. They could palliate some otherwise intractable malignancies, perhaps in young children too, with tolerable sequelae. There are plans for such studies in larger animals.

A 13-year analysis from Switzerland of non-fatal sledging (sledding or tobogganing) injuries

INTRODUCTION: Winter sports have evolved from an upper class activity to a mass industry. Especially sledging regained popularity at the start of this century, with more and more winter sports resorts offering sledge runs. This study investigated the rates of sledging injuries over the last 13 years and analysed injury patterns specific for certain age groups, enabling us to make suggestions for preventive measures. METHODS: We present a retrospective analysis of prospectively collected data. From 1996/1997 to 2008/2009, all patients involved in sledging injuries were recorded upon admission to a Level III trauma centre. Injuries were classified into body regions according to the Abbreviated Injury Scale (AIS). The Injury Severity Score (ISS) was calculated. Patients were stratified into 7 age groups. Associations between age and injured body region were tested using the chi-squared test. The slope of the linear regression with 95% confidence intervals was calculated for the proportion of patients with different injured body regions and winter season. RESULTS: 4956 winter sports patients were recorded. 263 patients (5%) sustained sledging injuries. Sledging injury patients had a median age of 22 years (interquartile range [IQR] 14-38 years) and a median ISS of 4 (IQR 1-4). 136 (51.7%) were male. Injuries (AIS≥2) were most frequent to the lower extremities (n=91, 51.7% of all AIS≥2 injuries), followed by the upper extremities (n=48, 27.3%), the head (n=17, 9.7%), the spine (n=7, 4.0%). AIS≥2 injuries to different body regions varied from season to season, with no significant trends (p>0.19). However, the number of patients admitted with AIS≥2 injuries increased significantly over the seasons analysed (p=0.031), as did the number of patients with any kind of sledging injury (p=0.004). Mild head injuries were most frequent in the youngest age group (1-10 years old). Injuries to the lower extremities were more often seen in the age groups from 21 to 60 years (p<0.001). CONCLUSION: Mild head trauma was mainly found in very young sledgers, and injuries to the lower extremities were more frequent in adults. In accordance with the current literature, we suggest that sledging should be performed in designated, obstacle-free areas that are specially prepared, and that children should always be supervised by adults. The effect of routine use of helmets and other protective devices needs further evaluation, but it seems evident that these should be obligatory on official runs.

Good agreement between capillary and venous sampling for lectin pathway proteins

Background: The lectin pathway of complement activation, in particular mannose-binding lectin (MBL), has been extensively investigated over recent years. So far, studies were exclusively based on venous samples. The aim of this study was to investigate whether measurements of lectin pathway proteins obtained by capillary sampling are in agreement with venous samples. Methods: Prospective study including 31 infants that were admitted with suspected early-onset sepsis. Lectin pathway proteins were measured in simultaneously obtained capillary and venous samples. Bland–Altman plots of logarithmized results were constructed, and the mean capillary to venous ratios (ratiocap/ven) were calculated with their 95% confidence intervals (CI). Results: The agreement between capillary and venous sampling was very high for MBL (mean ratiocap/ven, 1.01; 95% CI, 0.85–1.19). Similarly, high agreement was observed for H-ficolin (mean ratiocap/ven, 1.02; 95% CI, 0.72–1.44), MASP-2 (1.04; 0.59–1.84), MASP-3 (0.96; 0.71–1.28), and MAp44 (1.01; 0.82–1.25), while the agreement was moderate for M-ficolin (mean ratiocap/ven, 0.78; 95% CI, 0.27–2.28). Conclusions: The results of this study show an excellent agreement between capillary and venous samples for most lectin pathway proteins. Except for M-ficolin, small volume capillary samples can thus be used when assessing lectin pathway proteins in neonates and young children.

Exhaled nitric oxide in symptomatic children at preschool age predicts later asthma

Prediction of asthma in young children with respiratory symptoms is hampered by the lack of objective measures applicable in clinical routine. In this prospective study in a preschool children cohort, we assessed whether the fraction of exhaled nitric oxide (FeNO), a biomarker of airway inflammation, is associated with asthma at school age.

Assessment of bronchodilator responsiveness in preschool children using forced oscillations

BACKGROUND: The forced oscillation technique (FOT) requires minimal patient cooperation and is feasible in preschool children. Few data exist on respiratory function changes measured using FOT following inhaled bronchodilators (BD) in healthy young children, limiting the clinical applications of BD testing in this age group. A study was undertaken to determine the most appropriate method of quantifying BD responses using FOT in healthy young children and those with common respiratory conditions including cystic fibrosis, neonatal chronic lung disease and asthma and/or current wheeze. METHODS: A pseudorandom FOT signal (4-48 Hz) was used to examine respiratory resistance and reactance at 6, 8 and 10 Hz; 3-5 acceptable measurements were made before and 15 min after the administration of salbutamol. The post-BD response was expressed in absolute and relative (percentage of baseline) terms. RESULTS: Significant BD responses were seen in all groups. Absolute changes in BD responses were related to baseline lung function within each group. Relative changes in BD responses were less dependent on baseline lung function and were independent of height in healthy children. Those with neonatal chronic lung disease showed a strong baseline dependence in their responses. The BD response in children with cystic fibrosis, asthma or wheeze (based on both group mean data and number of responders) was not greater than in healthy children. CONCLUSIONS: The BD response assessed by the FOT in preschool children should be expressed as a relative change to account for the effect of baseline lung function. The limits for a positive BD response of -40% and 65% for respiratory resistance and reactance, respectively, are recommended.

Establishing glycaemic control with continuous subcutaneous insulin infusion in children and adolescents with type 1 diabetes: experience of the PedPump Study in 17 countries

AIMS/HYPOTHESIS: To assess the use of paediatric continuous subcutaneous infusion (CSII) under real-life conditions by analysing data recorded for up to 90 days and relating them to outcome. METHODS: Pump programming data from patients aged 0-18 years treated with CSII in 30 centres from 16 European countries and Israel were recorded during routine clinical visits. HbA(1c) was measured centrally. RESULTS: A total of 1,041 patients (age: 11.8 +/- 4.2 years; diabetes duration: 6.0 +/- 3.6 years; average CSII duration: 2.0 +/- 1.3 years; HbA(1c): 8.0 +/- 1.3% [means +/- SD]) participated. Glycaemic control was better in preschool (n = 142; 7.5 +/- 0.9%) and pre-adolescent (6-11 years, n = 321; 7.7 +/- 1.0%) children than in adolescent patients (12-18 years, n = 578; 8.3 +/- 1.4%). There was a significant negative correlation between HbA(1c) and daily bolus number, but not between HbA(1c) and total daily insulin dose. The use of <6.7 daily boluses was a significant predictor of an HbA(1c) level >7.5%. The incidence of severe hypoglycaemia and ketoacidosis was 6.63 and 6.26 events per 100 patient-years, respectively. CONCLUSIONS/INTERPRETATION: This large paediatric survey of CSII shows that glycaemic targets can be frequently achieved, particularly in young children, and the incidence of acute complications is low. Adequate substitution of basal and prandial insulin is associated with a better HbA(1c).

A psychoeducational intervention reduces the need for anesthesia during radiotherapy for young childhood cancer patients

BACKGROUND: Radiotherapy (RT) has become an important treatment modality in pediatric oncology, but its delivery to young children with cancer is challenging and general anesthesia is often needed. METHODS: To evaluate whether a psychoeducational intervention might reduce the need for anesthesia, 223 consecutive pediatric cancer patients receiving 4141 RT fractions during 244 RT courses between February 1989 and January 2006 were studied. Whereas in 154 RT courses corresponding with 2580 RT fractions patients received no psychoeducational intervention (group A), 90 RT courses respectively 1561 RT fractions were accomplished by using psychoeducational intervention (group B). This tailored psychoeducational intervention in group B included a play program and interactive support by a trained nurse according to age to get familiar with staff, equipment and procedure of radiotherapy. RESULTS: Group A did not differ significantly from group B in age at RT, gender, diagnosis, localization of RT and positioning during RT. Whereas 33 (21.4%) patients in group A got anesthesia, only 8 (8.9%) patients in group B needed anesthesia. The median age of cooperating patients without anesthesia decreased from 3.2 to 2.7 years. In both uni- and multivariate analyses the psychoeducational intervention significantly and independently reduced the need for anesthesia. CONCLUSION: We conclude that a specifically tailored psychoeducational intervention is able to reduce the need for anesthesia in children undergoing RT for cancer. This results in lower costs and increased cooperation during RT.

A new standardized treadmill walking test requiring low motor skills in children aged 4-10 years

Exercise intolerance may be reported by parents of young children with respiratory diseases. There is, however, a lack of standardized exercise protocols which allow verification of these reports especially in younger children. Consequently the aims of this pilot study were to develop a standardized treadmill walking test for children aged 4-10 years demanding low sensorimotor skills and achieving high physical exhaustion. In a prospective experimental cross sectional pilot study, 33 healthy Caucasian children were separated into three groups: G1 (4-6 years, n = 10), G2 (7-8 years, n = 12), and G3 (9-10 years, n = 11). Children performed the treadmill walking test with increasing exercise levels up to peak condition with maximal exhaustion. Gas exchange, heart rate, and lactate were measured during the test, spirometry before and after. Parameters were statistically calculated at all exercise levels as well as at 2 and 4 mmol/L lactate level for group differences (Kruskal-Wallis H-test, alpha = 0.05; post hoc: Mann-Whitney U-test with Bonferroni correction alpha = 0.05/n) and test-retest differences (Wilcoxon-rank-sum test) with SPSS. The treadmill walking test could be demonstrated to be feasible with a good repeatability within groups for most of the parameters. All children achieved a high exhaustion level. At peak level under exhaustion condition only the absolute VO2 and VCO2 differed significantly between age groups. In conclusion this newly designed treadmill walking test indicates a good feasibility, safety, and repeatability. It suggests the potential usefulness of exercise capacity monitoring for children aged from early 4 to 10 years. Various applications and test modifications will be investigated in further studies.

Mini-arthrotomy for lateral discoid menisci in children

BACKGROUND: Long-term results after partial, extended, or complete resection of lateral discoid meniscus in children revealed knee arthritis. The purpose of this study was to evaluate whether the operative approach, arthrotomy or arthroscopy, has an impact on the outcome and the development of arthritis. METHODS: A retrospective comparison of 2 well matching groups totaling 40 children with symptomatic lateral discoid meniscus (48 knees, mean age 8.9 years, 13 male and 27 female patients). Meniscus resection was performed via mini-arthrotomy in group 1 (n=17 patients, 20 knees) and arthroscopically in group 2 (n=23 patients, 28 knees). RESULTS: In the follow-up (mean 57 months in group 1, 62 months in group 2), functional results indicated a trend to better results in the International Knee Documentation Committee score (P=0.12) and in the Lysholm score for group 1 (P=0.13) but not in the Ikeuchi score (P=0.48). The comparison of the radiographic arthritis grading in the follow-up showed no significant arthritis in either group (P=0.22). The overall complication rate was similar in both groups (2/20, 10% in group 1; 3/28, 12% in group 2). CONCLUSIONS: Most likely because of the appropriate visualization of the children's joint and the easier instrumentation, the mini-arthrotomy led to slightly superior results compared with those after arthroscopic resection regarding functional outcome and 5 years after surgery. We can recommend the mini-arthrotomy for the resection of lateral discoid meniscus particularly in young children with narrow joint spaces and for surgeons that are not familiar with arthroscopies of small joints. LEVEL OF EVIDENCE: III (therapeutic study, case series with control group).

Comparing the validity and output of the GT1M and GT3X accelerometer in 5- to 9-year-old children

The purpose of this study was to compare the validity and output of the biaxial ActiGraph GT1M and the triaxial GT3X (ActiGraph, LLC, Pensacola, FL, USA)accelerometer in 5- to 9-year-old children. Thirty-two children wore the two monitors while their energy expenditure was measured with indirect calorimetry. They performed four locomotor and four play activities in an exercise laboratory and were further measured during 12 minutes of a sports lesson. Validity evidence in relation to indirect calorimetry was examined with linear regression equations applied to the laboratory data. During the sports lessons predicted energy expenditure according to the regression equations was compared to measured energy expenditure with the Wilcoxon-signed rank test and the Spearman correlation. To compare the output, agreement between counts of the two monitors during the laboratory activities was assessed with Bland-Altman plots. The evidence of validity was similar for both monitors. Agreement between the output of the two monitors was good for vertical counts (mean bias = −14 ± 22 counts) but not for horizontal counts (−17 ± 32 counts). The current results indicate that the two accelerometer models are able to estimate energy expenditure of a range of physical activities equally well in young children. However, they show output differences for movement in the horizontal direction.

Development and validation of energy expenditure prediction models based on GT3X accelerometer data in 5- to 9-year-old children

Background: Accelerometry has been established as an objective method that can be used to assess physical activity behavior in large groups. The purpose of the current study was to provide a validated equation to translate accelerometer counts of the triaxial GT3X into energy expenditure in young children. Methods: Thirty-two children aged 5–9 years performed locomotor and play activities that are typical for their age group. Children wore a GT3X accelerometer and their energy expenditure was measured with indirect calorimetry. Twenty-one children were randomly selected to serve as development group. A cubic 2-regression model involving separate equations for locomotor and play activities was developed on the basis of model fit. It was then validated using data of the remaining children and compared with a linear 2-regression model and a linear 1-regression model. Results: All 3 regression models produced strong correlations between predicted and measured MET values. Agreement was acceptable for the cubic model and good for both linear regression approaches. Conclusions: The current linear 1-regression model provides valid estimates of energy expenditure for ActiGraph GT3X data for 5- to 9-year-old children and shows equal or better predictive validity than a cubic or a linear 2-regression model.

Development and validation of GT3X accelerometer cut-off points in 5- to 9-year-old children based on indirect calorimetry measurements

The ActiGraph accelerometer is commonly used to measure physical activity in children. Count cut-off points are needed when using accelerometer data to determine the time a person spent in moderate or vigorous physical activity. For the GT3X accelerometer no cut-off points for young children have been published yet. The aim of the current study was thus to develop and validate count cut-off points for young children. Thirty-two children aged 5 to 9 years performed four locomotor and four play activities. Activity classification into the light-, moderate- or vigorous-intensity category was based on energy expenditure measurements with indirect calorimetry. Vertical axis as well as vector magnitude cut-off points were determined through receiver operating characteristic curve analyses with the data of two thirds of the study group and validated with the data of the remaining third. The vertical axis cut-off points were 133 counts per 5 sec for moderate to vigorous physical activity (MVPA), 193 counts for vigorous activity (VPA) corresponding to a metabolic threshold of 5 MET and 233 for VPA corresponding to 6 MET. The vector magnitude cut-off points were 246 counts per 5 sec for MVPA, 316 counts for VPA - 5 MET and 381 counts for VPA - 6 MET. When validated, the current cut-off points generally showed high recognition rates for each category, high sensitivity and specificity values and moderate agreement in terms of the Kappa statistic. These results were similar for vertical axis and vector magnitude cut-off points. The current cut-off points adequately reflect MVPA and VPA in young children. Cut-off points based on vector magnitude counts did not appear to reflect the intensity categories better than cut-off points based on vertical axis counts alone.

Pharmacological and non-pharmacological therapy for arrhythmias in the pediatric population: EHRA and AEPC-Arrhythmia Working Group joint consensus statement

In children with structurally normal hearts, the mechanisms of arrhythmias are usually the same as in the adult patient. Some arrhythmias are particularly associated with young age and very rarely seen in adult patients. Arrhythmias in structural heart disease may be associated either with the underlying abnormality or result from surgical intervention. Chronic haemodynamic stress of congenital heart disease (CHD) might create an electrophysiological and anatomic substrate highly favourable for re-entrant arrhythmias. As a general rule, prescription of antiarrhythmic drugs requires a clear diagnosis with electrocardiographic documentation of a given arrhythmia. Risk-benefit analysis of drug therapy should be considered when facing an arrhythmia in a child. Prophylactic antiarrhythmic drug therapy is given only to protect the child from recurrent supraventricular tachycardia during this time span until the disease will eventually cease spontaneously. In the last decades, radiofrequency catheter ablation is progressively used as curative therapy for tachyarrhythmias in children and patients with or without CHD. Even in young children, procedures can be performed with high success rates and low complication rates as shown by several retrospective and prospective paediatric multi-centre studies. Three-dimensional mapping and non-fluoroscopic navigation techniques and enhanced catheter technology have further improved safety and efficacy even in CHD patients with complex arrhythmias. During last decades, cardiac devices (pacemakers and implantable cardiac defibrillator) have developed rapidly. The pacing generator size has diminished and the pacing leads have become progressively thinner. These developments have made application of cardiac pacing in children easier although no dedicated paediatric pacing systems exist.

Early metacognitive abilities: The interplay of monitoring and control processes in 5- to 7-year-old children

The goal of the current investigation was to compare two monitoring processes (judgments of learning [JOLs] and confidence judgments [CJs]) and their corresponding control processes (allocation of study time and selection of answers to maximize accuracy, respectively) in 5- to 7-year-old children (N=101). Children learned the meaning of Japanese characters and provided JOLs after a study phase and CJs after a memory test. They were given the opportunity to control their learning in self-paced study phases, and to control their accuracy by placing correct answers into a treasure chest and incorrect answers into a trash can. All three age groups gave significantly higher CJs for correct compared to incorrect answers, with no age-related differences in the magnitude of this difference, suggesting robust metacognitive monitoring skills in children as young as 5. Furthermore, a link between JOLs and study time was found in the 6- and 7-year-olds, such that children spent more time studying items with low JOLs compared to items with high JOLs. Also, 6- and 7-year-olds but not 5-year-olds spent more time studying difficult items compared to easier items. Moreover, age-related improvements were found in children's use of CJs to guide their selection of answers: although children as young as 5 placed their most confident answers in the treasure chest and least confident answers in the trash can, this pattern was more robust in older children. Overall, results support the view that some metacognitive judgments may be acted upon with greater ease than others among young children.

VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children

BACKGROUND Despite substantial evidence supporting a pharmacogenetic approach to warfarin therapy in adults, evidence on the importance of genetics in warfarin therapy in children is limited, particularly for clinical outcomes. We assessed the contribution of CYP2C9/VKORC1/CYP4F2 genotypes and variation in other genes involved in vitamin K and coagulation pathways to warfarin dose and related clinical outcomes in children. PROCEDURE Clinical and genetic data for 93 children (age ≤ 18 years) who received warfarin therapy were obtained. DNA was genotyped for 93 selected single nucleotide polymorphisms using a custom assay. RESULTS With a median age of 4.8 years, our cohort included more young children than most previous studies. Overall, 76.3% of dose variability was explained by weight, indication, VKORC1-1639G/A and CYP2C9 *2/*3, with genotypes accounting for 21.1% of variability. There was a strong correlation (R(2) = 0.68; P < 0.001) between actual and predicted warfarin dose using a pediatric genotype-based dosing model. VKORC1 genotype had a significant impact on time to therapeutic international normalized ratio (INR) (P = 0.047) and time to over-anticoagulation (INR > 4; P = 0.024) during the initiation of therapy. CYP2C9*3 carriers were also at increased risk of major bleeding while receiving warfarin (adjusted OR = 11.28). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose (P = 0.020) in a multivariate clinical and genetic model. CONCLUSIONS This study confirms the importance of VKORC1/CYP2C9 genotypes for warfarin dosing in a young pediatric cohort and demonstrates an impact of genetic factors on clinical outcomes in children. Furthermore, we identified an additional variant in CYP2C9 of potential relevance for warfarin dosing in children.