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Objectives: To evaluate a virtual reality (VR) application for gestational sac fluid volume (GSFV) measurements in first-trimester pregnancies and to study the correlation between different embryonic growth parameters. Methods: This was a prospective cohort study analyzing 180 three-dimensional (3D) ultrasound scans of 42 healthy women, performed between 5 + 5 and 12 + 6 weeks' gestational age (GA). The 3D datasets were transferred to the I-Space immersive VR system. The V-Scope application was used to create a 'hologram' of the ultrasound image, allowing depth perception and interaction with the rendered objects. Volumes were measured semi-automatically using a segmentation algorithm. In addition to the GSFV, the total gestational sac volume (GSV) and its diameter (GSD) were measured. The GSV was also calculated using the ellipsoid formula. Previously obtained measurements of embryonic volume and crown-rump length (CRL) were included in the study. The outcomes were analyzed using repeated-measures analysis of variance. Results: The GSFV was measured in 78 scans, and varied from 434 to 81 491 mm(3). A positive correlation between GSFV and GA, CRL and GSD was found. Comparison of the GSD formula constructed in our study in relation to GA with a formula that is commonly used clinically showed an increasing difference with increasing GA either side of 8 + 5 weeks. The GSFV/embryonic volume ratio showed a decrease with GA. The GSV calculated using the ellipsoid formula was on average 19.8% larger compared with the GSV measured in VR. Conclusion: New charts for first-trimester GSFV were constructed using VR. These growth charts could be promising tools for studying normal and abnormal embryonic development. [ABSTRACT FROM AUTHOR]

Background: Incarceration of inguinal, umbilical and cicatricial hernias is a frequent problem. However, little is known about the relationship between the use of mesh and outcome after surgery. The goal of this study was to describe the relationship between the use of mesh in incarcerated hernia and the clinical outcome.Patients and Methods: Correspondence, operation reports and patient files between January 1995 and December 2005 of patients presented at one academic and one teaching hospital in Rotterdam were searched for the following keywords: incarceration, strangulation and hernia. The patient characteristics, clinical presentation, pre-operative findings and clinical course were scored and analysed.Results: A total of 203 patients could be identified: 76 inguinal, 52 umbilical, 39 incisional, 14 epigastric, 14 femoral, five trocar and three spigelian hernias. In the statistical analysis, epigastric, femoral, trocar and spigelian hernias were pooled, due to their small group sizes. One patient was excluded from the analysis because the hernia was not corrected during operation. In total, 99 hernias were repaired using mesh versus 103 primary suture repairs. Twenty-five wound infections were registered (12.3%). One mesh was removed during a reintervention for anastomotic leakage, although no signs of wound infection were present. Nine patients died, none of them due to wound-related problems [one cardiovascular, one ruptured aneurysm, two anastomotic leakage, two sepsis e causa incognita (e.c.i.), three pulmonary complications]. Univariate analysis showed that female patients (P = 0.007), adipose patients (P = 0.016), patients with an umbilical hernia (P = 0.01) and patients who underwent a bowel resection (P = 0.015) had a significantly higher rate of wound infections. The type of repair (e.g. primary suture or mesh), use of antibiotic prophylaxis, gender, ASA class and age showed no significant relation with post-operative wound infection. After logistic regression analysis, only bowel resection (P = 0.020) showed a significant relation with post-operative wound infection.Conclusions: Wound infection rates are high after the correction of acute hernia, but clinical consequences are relatively low. Mesh correction of an acute hernia seems to be safe and should be considered in every incarcerated hernia. [ABSTRACT FROM AUTHOR]

BACKGROUND & AIMS: Children admitted to the hospital are at risk of developing malnutrition. The aim of the present study was to investigate the feasibility and value of a new nutritional risk screening tool, called STRONG(kids), in a nationwide study. METHODS: A Prospective observational multi-centre study was performed in 44 Dutch hospitals (7 academic and 37 general), over three consecutive days during the month of November 2007. The STRONG(kids) screening tool consisted of 4 items: (1) subjective clinical assessment, (2) high risk disease, (3) nutritional intake, (4) weight loss. Measurements of weight and length were performed. SD-scores <-2 for weight-for-height and height-for-age were considered to indicate acute and chronic malnutrition respectively. RESULTS: A total of 424 children were included. Median age was 3.5 years and median hospital stay was 2 days. Sixty-two percent of the children were classified 'at risk' of developing malnutrition by the STRONG(kids) tool. Children at risk had significantly lower SD-scores for weight-for-height, a higher prevalence of acute malnutrition and a longer hospital stay compared to children with no nutritional risk. CONCLUSIONS: The nutritional risk screening tool STRONG(kids) was successfully applied to 98% of the children. Using this tool, a significant relationship was found between having a 'high risk' score, a negative SD-score in weight-for-height and a prolonged hospital stay. [ABSTRACT FROM AUTHOR]

Objective Nationwide prevalence studies on malnutrition in hospitalised children have not been done. This study aimed to investigate the prevalence of malnutrition of all newly admitted children in The Netherlands during 3 consecutive days. Design Prospective observational study. Setting Paediatric wards of 44 hospitals (7 academic and 37 general). Participants A total of 424 children aged>30 days and hospitalised for > 1 day were included, 63% male, 86% non-white. Median age was 3.5 years and median hospital stay was 2 days. Main outcome measures SD scores ,22 for weight for height and height for age were considered to indicate acute and chronic malnutrition, respectively. Results Overall 19% of the children had acute and/or chronic malnutrition at admission (academic 22% and general 17%). The proportion of children with chronic malnutrition was significantly higher in academic hospitals (14% vs 6%). Logistic regression analysis allowing for age, underlying disease, ethnicity, surgery and type of centre showed a significant relation between the presence of malnutrition at admission and underlying disease (odds ratio (OR) 2.2). For chronic malnutrition both underlying disease and non-white ethnicity were significantly related to a higher prevalence (OR 3.7 and OR 2.8, respectively). Multiple regression analysis showed that children with acute malnutrition stayed on average 45% longer (95% CI 7% to 95%) in the hospital than children without such malnutrition. Conclusions This unique nationwide study shows that 19% of children admitted to Dutch hospitals are malnourished at admission. This high prevalence underlines the need for routine screening and treatment of malnutrition in hospitalised children. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Intravenous immunoglobulin (IVIg) is the first choice treatment for Guillain-Barré syndrome (GBS). All patients initially receive the same arbitrary dose of 2g per kg body weight. Not all patients, however, show a good recovery after this standard dose. IVIg clearance may depend on disease severity and vary between individuals, implying that this dose is suboptimal for some patients. In this study, we determined whether the pharmacokinetics of IVIg is related to outcome in GBS. METHODS: We included 174 GBS patients who had previously participated in 2 randomized clinical trials. At entry, all patients were unable to walk unaided and received a standard dose of IVIg. Total IgG levels in serum samples obtained immediately before and 2 weeks after the start of IVIg administration were determined by turbidimetry and related to clinical outcome at 6 months. RESULTS: The increase in serum IgG (DeltaIgG) 2 weeks after IVIg treatment varied considerably between patients (mean, 7.8g/L; standard deviation, 5.6g/L). Patients with a low DeltaIgG recovered significantly more slowly, and fewer reached the ability to walk unaided at 6 months (log-rank p < 0.001). In multivariate analysis adjusted for other known prognostic factors, a low DeltaIgG was independently associated with poor outcome (p = 0.022). INTERPRETATION: After a standard dose of IVIg treatment, GBS patients show a large variation in pharmacokinetics, which is related to clinical outcome. This may indicate that patients with a small increase in serum IgG level may benefit from a higher dosage or second course of IVIg. Ann Neurol 2009;66:597-603. [ABSTRACT FROM AUTHOR]

RATIONALE: Asthma treatment might improve when inhaled steroids are titrated on airway inflammation. Fractional exhaled nitric oxide (FeNO0.05), a marker of eosinophilic airway inflammation, can be measured at home. OBJECTIVES: We assessed daily FeNO0.05 telemonitoring in the management of childhood asthma. METHODS: Children with atopic asthma (n = 151) were randomly assigned to two groups: FeNO0.05 plus symptom monitoring, or monitoring of symptoms only. All patients scored asthma symptoms in an electronic diary over 30 weeks; 77 received a portable nitric oxide (NO) analyzer. Data were transmitted daily to the coordinating centers. Patients were phoned every 3 weeks and their steroid dose was adapted according to FeNO0.05 and symptoms, or according to symptoms. Children were seen at 3, 12, 21, and 30 weeks for examination and lung function testing. The primary end point was the proportion of symptom-free days in the last 12 study weeks. MEASUREMENTS AND MAIN RESULTS: Telemonitoring was feasible with reliable FeNO0.05 data for 86% of days, and valid diary entries for 79% of days. Both groups showed an increase in symptom-free days, improvement of FEV1 and quality of life, and a reduction in steroid dose. None of the changes from baseline differed between groups. The difference in symptom-free days over the last 12 weeks was 0.3% (P = 0.95; 95% confidence interval, -10 to 11%). There was a trend for fewer exacerbations in the FeNO0.05 group. CONCLUSIONS: Thirty weeks of daily FeNO0.05 and symptom telemonitoring was associated with improved asthma control and a lower steroid dose. We found no added value of daily FeNO0.05 monitoring compared with daily symptom monitoring only. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the effect of carrying the apolipoprotein epsilon 4 (APOE-in4) allele on global functional outcome, on activity limitations and participation restrictions, and on community integration at 3, 6, 12, 18, 24 and 36 months after traumatic brain injury.Method: The Glasgow Outcome Scale (GOS), the Sickness Impact Profile-68 (SIP-68) and the Community Integration Questionnaire (CIQ) were assessed in 79 moderate and severe traumatic brain injury patients at 3, 6, 12, 18, 24 and 36 months post injury. Repeated measures analyses of variance were performed with APOE-in4 status and time of measurement as independent variables and the GOS, SIP-68 and CIQ as dependent variables. Analyses were adjusted for baseline age, gender and Glasgow Coma Scale.Results: Patients with the APOE-in4 allele had a significantly better global functional outcome on the GOS than patients without the APOE-in4 allele. No significant associations were found between APOE-in4 status and the SIP-68 and CIQ.Discussion: In contrast to other studies, we found that carrying the APOE-in4 allele had a protective influence on outcome. Multiple mechanisms, and in some cases competitive mechanisms, may explain the variable relation between the APOE-in4 allele and outcome after traumatic brain injury. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of one single bolus of etomidate used for intubation on adrenal function in children with meningococcal sepsis.Design: Retrospective study conducted between 1997 and 2004.Setting: University-affiliated paediatric intensive care unit (PICU).Patients and Participants: Sixty children admitted to the PICU with meningococcal sepsis, not treated with steroids.Interventions: Adrenal hormone concentrations were determined as soon as possible after PICU admission, and after 12h and 24h. To assess disease severity, PRISM score and selected laboratory parameters were determined.Measurements and Main Results: On admission, before blood was drawn, 23 children had been intubated with etomidate, 8 without etomidate and 29 were not intubated. Children who were intubated had significantly higher disease severity parameters than those not intubated, whereas none of these parameters significantly differed between children intubated with or without etomidate. Children who received etomidate had significantly lower cortisol, higher ACTH and higher 11-deoxycortisol levels than those who did not receive etomidate. Arterial glucose levels were significantly lower in children who were intubated with etomidate than in non-intubated children. When children were intubated with etomidate, cortisol levels were 3.2 times lower for comparable 11-deoxycortisol levels. Eight children died, seven of whom had received etomidate. Within 24h cortisol/ACTH and cortisol/11-deoxycortisol ratios increased significantly in children who received etomidate, but not in children who did not, resulting in comparable cortisol/ACTH ratios with still significantly lowered cortisol/11-deoxycortisol ratios 24h after admission.Conclusions: Our data imply that even one single bolus of etomidate negatively influences adrenal function for at least 24h. It might therefore increase risk of death. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Telemedicine applications carry the potential to enhance the quality of life of patients, but studies evaluating telemedicine applications are still scarce. The evidence regarding the effectiveness of telemedicine is limited and not yet conclusive. This study investigated whether telemedicine could be beneficial to the quality of life of cancer patients. DESIGN AND MEASUREMENTS: Between 1999 and 2002, we conducted a prospective controlled trial evaluating the effects of a telemedicine application on the quality of life of patients with cancer involving the head and neck, using quality of life questionnaires that covered 22 quality of life parameters. All patients had undergone surgery for head and neck cancer at the Erasmus MC, a tertiary university hospital in The Netherlands. Patients in the intervention group were given access to an electronic health information support system for a period of six weeks, starting at discharge from the hospital. RESULTS: In total, we included 145 patients in the control group and 39 in the intervention group. At 6 weeks, the end of the intervention, the intervention group had significantly improved QoL in 5 of the 22 studied parameters. Only one of these five quality of life parameters remained significantly different at 12 weeks. CONCLUSIONS: This study adds to the sparse evidence that telemedicine may be beneficial for the quality of life of cancer patients. [ABSTRACT FROM AUTHOR]

Rationale: Corticosteroids are the antiinflammatory treatment of choice in asthma. Treatment guidelines are mainly symptom-driven but symptoms are not closely related to airway inflammation. The fraction of nitric oxide in exhaled air (FE[NO]) is a marker of airway inflammation in asthma.Objective: We evaluated whether titrating steroids on FE[NO] improved asthma management in children.Methods: Eighty-five children with atopic asthma, using inhaled steroids, were allocated to a FE[NO] group (n = 39) in which treatment decisions were made on both FE[NO] and symptoms, or to a symptom group (n = 46) treated on symptoms only. Children were seen every 3 months over a 1-year period.Measurements: Symptoms were scored during 2 weeks before visits and 4 weeks before the final visit. FE[NO] was measured at all visits, and airway hyperresponsiveness and FEV[1] were measured at the start and end of the study. Primary endpoint was cumulative steroid dose.Results: Changes in steroid dose from baseline did not differ between groups. In the FE[NO] group, hyperresponsiveness improved more than in the symptom group (2.5 vs. 1.1 doubling dose, p = 0.04). FEV[1] in the FE[NO] group improved, and the change in FEV[1] was not significantly different between groups. The FE[NO] group had 8 severe exacerbations versus 18 in the symptom group. The change in symptom scores did not differ between groups. FE[NO] increased in the symptom group; the change in FE[NO] from baseline differed between groups (p = 0.02).Conclusion: In children with asthma, 1 year of steroid titration on FE[NO] did not result in higher steroid doses and did improve airway hyperresponsiveness and inflammation. [ABSTRACT FROM AUTHOR]

Rationale: In cystic fibrosis (CF), chronic bacterial infection and inflammation lead to progressive airway wall thickening and lumen dilatation. Objectives: To quantify airway wall thickening and lumen dilatation in children with CF over a 2-year interval. Methods: Children with CF (n = 23) who had two computed tomography (CT) scans (CT(cf1) and CT(cf2)) combined with pulmonary function tests (PFTs), with a 2-year interval between measurements, were compared with control subjects (n = 21) who had one CT (CT(controls)). On cross-sectional cut airway-artery pairs, airway wall area (WA), airway lumen area (LA) and perimeter, and arterial area (AA) were quantified. LA/AA (= marker of bronchiectasis), airway wall thickness (AWT), and WA/AA (= markers of wall thickness) were calculated. CT scans were scored using four different scoring systems. PFTs were expressed as percent predicted. Results: Airway WA-to-AA ratio was 1.45 (p < 0.001) and airway LA-to-AA ratio was 1.92 times higher (p < 0.001) in children with CF compared with age-matched control subjects. LA/AA and WA/AA remained unchanged from CT(cf1) to CT(cf2) and did not increase with age. AWT as a function of airway size increased from CT(cf1) to CT(cf2) by 2% (0.03 mm; p = 0.02). The change in AWT was inversely related to the change in forced expiratory flow between 25 and 75% of expiratory VC (p = 0.002). Conclusions: In CF, quantitative measurements of airways on CT scans show an increased ratio between airway LA and AA and progressive airway wall thickening. Scoring systems show progression of bronchiectasis but unchanged AWT. PFTs remained stable. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to assess the effect of intravenous (IV) insulin administration in children with severe acute asthma (SAA) and hyperglycemia on IV salbutamol consumption and length of stay (LOS) in a pediatric intensive care unit (PICU)., Methods: Retrospective, descriptive study of the clinical course before and after implementation of an insulin protocol for the treatment of hyperglycemia (i.e. blood glucose >8 mmol/L or 144 mg/dL, respectively) in the PICU of a tertiary care university hospital. Admissions between 1994 and 2010 were reviewed. The insulin protocol was introduced in 2006., Results: A total of 131 pediatric patients with SAA complicated by hyperglycemia requiring IV salbutamol were included. Severity of illness before and after implementation of the insulin protocol did not significantly differ. The insulin-treated patient group had significantly higher maximum blood glucose levels and higher cumulative IV salbutamol dose than the non-treated group. There were no differences between these groups in the duration of IV salbutamol administration and LOS., Conclusions: In view of the lack of difference in outcomes and considering that the insulin protocol is labor-intensive, the question is whether this protocol is efficacious for the treatment of pediatric SAA associated with hyperglycemia.

Background: In this study, we evaluated long-term survival in patients treated with and without mechanical bowel preparation (MBP) before colorectal surgery for cancer., Methods: Long-term outcome of patients of 2 main participating hospitals in a prior multicenter randomized trial comparing clinical outcome of MBP versus no MBP was reviewed. Primary endpoint was cancer-related mortality and secondary endpoint was all-cause mortality., Results: A total of 382 patients underwent potentially curative surgery for colorectal cancer. One hundred seventy-seven (46%) patients were treated with MBP and 205 (54%) were not before surgery. Median follow-up was 7.6 years (mean 6.6, range .01 to 12.73). There was no significant difference in both cancer-related mortality and all-cause mortality in patients treated with MBP and without MBP (P = .76 and P = .36, respectively). Multivariate analysis, taking account of age, sex, AJCC cancer stage, and ASA classification, also showed no survival difference., Conclusions: Our results indicate that MBP does not seem to influence long-term survival in patients surgically treated for colorectal cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To investigate changes in trapped air volume and distribution over time and compare computed tomography (CT) with pulmonary function tests for determining trapped air., Methods: Thirty children contributed two CTs and pulmonary function tests over 2 years. Localized changes in trapped air on CT were assessed using image analysis software, by deforming the CT at timepoint 2 to match timepoint 1, and measuring the volume of stable (TAstable), disappeared (TAdisappeared) and new (TAnew) trapped air as a proportion of total lung volume. We used the difference between total lung capacity measured by plethysmography and helium dilution, residual volume to total lung capacity ratio, forced expiratory flow at 75% of vital capacity, and maximum mid-expiratory flow as pulmonary function test markers of trapped air. Statistical analysis included Wilcoxon's signed rank test and Spearman correlation coefficients., Results: Median (range) age at baseline was 11.9 (5-17) years. Median (range) of trapped air was 9.5 (2-33)% at timepoint 1 and 9.0 (0-25)% at timepoint 2 (p=0.49). Median (range) TAstable, TAdisappeared and TAnew were respectively 3.0 (0-12)%, 5.0 (1-22)% and 7.0 (0-20)%. Trapped air on CT correlated statistically significantly with all pulmonary function measures (p<0.01), other than residual volume to total lung capacity ratio (p=0.37)., Conclusion: Trapped air on CT did not significantly progress over 2 years, may have a substantial stable component, and is significantly correlated with pulmonary function markers., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Asthma guidelines recommend monitoring of asthma control. However, in a substantial proportion of children, asthma is poorly controlled and the best monitoring strategy is not known., Objectives: We studied two monitoring strategies for their ability to improve asthma outcomes in comparison with standard care (SC): web-based monthly monitoring with the (Childhood) Asthma Control Test (ACT or C-ACT) and 4-monthly monitoring of FENO., Methods: In this randomised controlled, partly blinded, parallel group multicentre trial with a 1-year follow-up, children aged 4-18 with a doctor's diagnosis of asthma treated in seven hospitals were randomised to one of the three groups. In the web group, treatment was adapted according to ACT obtained via a website at 1-month intervals; in the FENO group according to ACT and FENO, and in the SC group according to the ACT at 4-monthly visits. The primary endpoint was the change from baseline in the proportion of symptom-free days (SFD)., Results: Two-hundred and eighty children (mean age 10.4 years, 66% boys) were included; 268 completed the study. Mean changes from baseline in SFD were similar between the groups: -2.1% (web group, n=90), +8.9% (FENO group, n=91) versus 0.15% (SC, n=87), p=0.15 and p=0.78. Daily dose of inhaled corticosteroids (ICS) decreased more in the web-based group compared with both other groups (-200 μg/day, p<0.01), while ACT and SFD remained similar., Conclusions: The change from baseline in SFD did not differ between monitoring strategies. With web-based ACT monitoring, ICS could be reduced substantially while control was maintained., Trial Registration Number: NTR 1995., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To investigate the stability throughout the day of the protein to creatinine ratio (PCR) in spot urine, to demonstrate whether the PCR is a valid alternative for 24-hour protein investigation in pregnant women., Design: Prospective study., Setting: Tertiary referral university centre., Population: Women suspected of having pre-eclampsia, admitted to the Erasmus Medical Centre., Methods: Twenty-four-hour urine collections and simultaneously three single voided 5-ml aliquots were obtained at 8 a.m., 12 a.m. (noon) and 5 p.m. A PCR was measured in each specimen and compared with the 24-hour protein excretion., Main Outcome Measures: The 24-hour proteinuria and PCR measured in spontaneous voids., Results: The PCRs correlated strongly with each other and with the 24-hour protein excretion but did show variation throughout the day (mean coefficient of variation 36%; 95% confidence interval 31-40%). The coefficient of variation was unrelated to the degree of 24-hour proteinuria. Receiver operating characteristics curves to discriminate between values below and greater than or equal to the threshold of 0.3 g protein per 24-hour had an area under the curve of respectively 0.94 (8 a.m.), 0.96 (noon) and 0.97 (5 p.m.). Sensitivities at 8 a.m., noon and 5 p.m. were respectively 89%, 96% and 94%; specificities were 75%, 78% and 78% with the proposed PCR cut-off of 30 mg/mmol (0.26 g/g) (National Institute for Health and Care Excellence guidelines).There is no evidence of a difference between the three measurement times regarding the sensitivities and specificities., Conclusion: The PCR determined in spot urine varies throughout the day but is a valid alternative for 24-hour urine collections in pregnant women. It is especially useful to rapidly identify clinically relevant proteinuria., (© 2014 Royal College of Obstetricians and Gynaecologists.)

We prospectively studied the incidence and clinical course of hypertriglyceridemia and hypercholesterolemia during very prolonged use of asparaginase in relation to levels of asparaginase activity in children with acute lymphoblastic leukemia. We also evaluated the incidence of pancreatitis, thrombosis, hyperammonemia and central neurotoxicity and their association with asparaginase activity levels. Eighty-nine patients were treated according to the Dutch Childhood Oncology Group Acute Lymphoblastic Leukemia 10 medium-risk intensification protocol, which includes 15 doses of PEGasparaginase (2,500 IU/m(2)) over 30 weeks. Erwinia asparaginase (20,000 IU/m(2)) was administered when allergy to or silent inactivation of PEGasparaginase occurred. Triglyceride, cholesterol and ammonia levels increased rapidly in children treated with PEGasparaginase and remained temporarily elevated, but normalized after administration of the last asparaginase dose. Among the patients treated with PEGasparaginase, hypertriglyceridemia and hypercholesterolemia (grade 3/4) were found in 47% and 25%, respectively. The correlation between PEGasparaginase activity levels and triglyceride levels was strongest at week 5 (Spearman correlation coefficient = 0.36, P = 0.005). The triglyceride levels were higher in children ≥ 10 years old than in younger patients (<10 years old) after adjustment for type of asparaginase preparation: median 4.9 mmol/L versus 1.6 mmol/L (P<0.001). In patients receiving Erwinia asparaginase, triglyceride levels increased in the first weeks as well, but no grade 3/4 dyslipidemia was found. Hyperammonemia (grade 3/4) was only found in patients treated with Erwinia asparaginase (9%). Thrombosis occurred in 4.5%, pancreatitis in 7%, and central neurotoxicity in 9% of patients using either of the two agents; these toxicities were not related to levels of asparaginase activity or to triglyceride levels. In conclusion, severe dyslipidemia occurred frequently, but was temporary and was not associated with relevant clinical events and should not, therefore, be considered a reason for modifying asparaginase treatment. Dyslipidemia was the only toxicity related to levels of asparaginase activity., (Copyright© Ferrata Storti Foundation.)

Background: In chronic obstructive pulmonary disease (COPD), there is a poor correlation between forced expiratory volume in 1 s (FEV1) and dyspnea following bronchodilator use. Better correlations have been observed between inspiratory lung function parameters (ILPs) and dyspnea, which drives our interest in ILPs. However, the acute and prolonged effects of long-acting bronchodilators and oral corticosteroids on ILPs have not been well investigated. Therefore, the aim of this study was to investigate the effects of these treatments on the ILPs, FEV1, dyspnea (visual analog scale (VAS)) and clinical COPD questionnaire (CCQ)., Methods: Twenty-eight stable COPD patients had their ILPs and FEV1 measured both before and 2 h after the use of a single dose of 18 mcg bronchodilator tiotropium and 50 mcg salmeterol. Thereafter, the patients were randomized to 2 weeks of treatment with 30 mg oral prednisolone once daily or oral placebo in combination with daily treatment with these two bronchodilators. Four weeks after the cessation of the randomized treatment, the ILPs and FEV1 were again measured. After each intervention, any change in the VAS score was assessed., Results: With both bronchodilators, significant improvements in ILPs were demonstrated (p < 0.005), with the exception of changes in ILPs inspiratory capacity (IC) and forced inspiratory flow at 50% of the vital capacity (FIF50) after tiotropium inhalation. After 2 weeks of treatment with prednisolone, significant differences were found for ILP forced inspiratory volume in 1 s (FIV1) and FEV1 compared with placebo. These differences were no longer present 4 weeks after the cessation of prednisolone. Significant relationships between ILPs and VAS scores were only found after 2 weeks of treatment with prednisolone or placebo., Conclusions: After a single dose of long-acting bronchodilator salmeterol, significant improvements are observed in all ILPs and in FIV1 and PIF after tiotropium. Two weeks of oral corticosteroid treatment improved the FIV1 and FEV1. The dyspnea VAS score was only significantly correlated with the ILPs after 2 weeks of oral corticosteroid treatment., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess the effect of red blood cell (RBC) transfusion on quality of life in acutely anaemic women after postpartum haemorrhage., Design: Randomised non-inferiority trial., Setting: Thirty-seven Dutch university and general hospitals., Population: Women with acute anaemia (haemoglobin 4.8-7.9 g/dl [3.0-4.9 mmol/l] 12-24 hours postpartum) without severe anaemic symptoms or severe comorbidities., Methods: Women were allocated to RBC transfusion or non-intervention., Main Outcome Measures: Primary outcome was physical fatigue 3 days postpartum (Multidimensional Fatigue Inventory, scale 4-20; 20 represents maximal fatigue). Non-inferiority was demonstrated if the physical fatigue difference between study arms was maximal 1.3. Secondary outcomes were health-related quality of life and physical complications. Health-related quality of life questionnaires were completed at five time-points until 6 weeks postpartum., Results: In all, 521 women were randomised to non-intervention (n = 262) or RBC transfusion (n = 259). Mean physical fatigue score at day 3 postpartum, adjusted for baseline and mode of delivery, was 0.8 lower in the RBC transfusion arm (95% confidence interval: 0.1-1.5, P = 0.02) and at 1 week postpartum was 1.06 lower (95% confidence interval: 0.3-1.8, P = 0.01). A median of two RBC units was transfused in the RBC transfusion arm. In the non-intervention arm, 33 women received RBC transfusion, mainly because of anaemic symptoms. Physical complications were comparable., Conclusions: Statistically, non-inferiority could not be demonstrated as the confidence interval crossed the non-inferiority boundary. Nevertheless, with only a small difference in physical fatigue and no differences in secondary outcomes, implementation of restrictive management seems clinically justified., (© 2014 Royal College of Obstetricians and Gynaecologists.)

The aim of this cross-sectional study was to analyze the incidence of incisional hernia after liver transplantation (LT), to determine potential risk factors for their development, and to assess their impact on health-related quality of life (HRQoL). Patients who underwent LT through a J-shaped incision with a minimum follow-up of three months were included. Follow-up was conducted at the outpatient clinic. Short Form 36 (SF-36) and body image questionnaire (BIQ) were used for the assessment of HRQoL. A total of 140 patients was evaluated. The mean follow-up period was 33 (SD 20) months. Sixty patients (43%) were diagnosed with an incisional hernia. Multivariate analysis revealed surgical site infection (OR 5.27, p = 0.001), advanced age (OR 1.05, p = 0.003), and prolonged ICU stay (OR 1.54, p = 0.022) to be independent risk factors for development of incisional hernia after LT. Patients with an incisional hernia experienced significantly diminished HRQoL with respect to physical, social, and mental aspects. In conclusion, patients who undergo LT exhibit a high incidence of incisional hernia, which has a considerable impact on HRQoL. Development of incisional hernia was shown to be related to surgical site infection, advanced age, and prolonged ICU stay., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This study prospectively analyzed the efficacy of very prolonged courses of pegylated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. Patients received 15 PEGasparaginase infusions (2500 IU/m(2) every 2 weeks) in intensification after receiving native E coli asparaginase in induction. In case of allergy to or silent inactivation of PEGasparaginase, Erwinia asparaginase (20 000 IU/m(2) 2-3 times weekly) was given. Eighty-nine patients were enrolled in the PEGasparaginase study. Twenty (22%) of the PEGasparaginase-treated patients developed an allergy; 7 (8%) showed silent inactivation. The PEGasparaginase level was 0 in all allergic patients (grade 1-4). Patients without hypersensitivity to PEGasparaginase had serum mean trough levels of 899 U/L. Fifty-nine patients were included in the Erwinia asparaginase study; 2 (3%) developed an allergy and none silent inactivation. Ninety-six percent had at least 1 trough level ≥100 U/L. The serum asparagine level was not always completely depleted with Erwinia asparaginase in contrast to PEGasparaginase. The presence of asparaginase antibodies was related to allergies and silent inactivation, but with low specificity (64%). Use of native E coli asparaginase in induction leads to high hypersensitivity rates to PEGasparaginase in intensification. Therefore, PEGasparaginase should be used upfront in induction, and we suggest that the dose could be lowered. Switching to Erwinia asparaginase leads to effective asparaginase levels in most patients. Therapeutic drug monitoring has been added to our ALL-11 protocol to individualize asparaginase therapy.

Background: In adult patients who are critically ill and mechanically ventilated, daily interruption of sedation (DSI) is an effective method of improving sedation management, resulting in a decrease of the duration of mechanical ventilation, the length of stay in the intensive care unit (ICU) and the length of stay in the hospital. It is a safe and effective approach and is common practice in adult ICUs. For critically ill children it is unknown if DSI is effective and feasible. The aim of this multicenter randomized controlled trial is to evaluate the safety and efficacy of daily sedation interruption in critically ill children., Methods/design: Children between 0 and 18 years of age who require mechanical ventilation, with an expected duration of at least 48 h and need for sedative infusion, will be included. After enrollment patients will be randomly assigned to DSI in combination with protocolized sedation (intervention group) or protocolized continuous sedation (control group). A sedation protocol that contains an algorithm for increasing and weaning of sedatives and analgesics will be used. The sedative infusion will be restarted if the patient becomes uncomfortable or agitated according to the sedation protocol. The primary endpoint is the number of ventilator-free days at 28 days., Trial Registration: NTR2030.

Objective: To compare microcirculatory perfusion in women with severe pre-eclampsia against that in healthy pregnant women, and secondly in women with severe pre-eclampsia with or without HELLP syndrome (haemolysis, elevated liver enzymes, and low platelets)., Design: Case-control study., Setting: University Hospital Rotterdam, the Netherlands., Population: Twenty-three women with severe pre-eclampsia and 23 healthy pregnant controls, matched for maternal and gestational age. Out of the 23 women with severe pre-eclampsia, ten presented with HELLP syndrome., Methods: Microcirculation was analysed sublingually by a non-invasive sidestream dark-field imaging device (SDF)., Main Outcome Measures: Perfused vessel density (PVD), microcirculatory flow index (MFI), and heterogeneity index (HI) were calculated for both small vessels (∅ < 20 μm; capillaries) and non-small vessels (∅ > 20 μm; venules and arterioles)., Results: There were no significant differences between women with severe pre-eclampsia and healthy controls. Women with pre-eclampsia and HELLP syndrome showed a reduced PVD (P = 0.045), MFI (P = 0.008), and increased HI (P = 0.002) for small vessels, as compared with women with pre-eclampsia but without HELLP syndrome., Conclusions: Sidestream dark-field is a novel, promising technique in obstetrics that permits the non-invasive evaluation of microcirculation. We did not observe major differences in sublingual microcirculatory perfusion between women with severe pre-eclampsia and healthy pregnant controls. In women with severe pre-eclampsia, the presence of HELLP syndrome is characterised by impaired capillary perfusion., (© 2013 Royal College of Obstetricians and Gynaecologists.)

Introduction: Small airway obstruction is important in the pathophysiology of cystic fibrosis (CF) lung disease. Additionally, many CF patients lose lung function in the long term as a result of respiratory tract exacerbations (RTEs). No trials have been performed to optimize mucolytic therapy during a RTE. We investigated whether specifically targeting dornase alfa to the small airways improves small airway obstruction during RTEs., Methods: In a multi-center, double-blind, randomized controlled trial CF patients hospitalized for a RTE and on maintenance treatment with dornase alfa were switched to a smart nebulizer. Patients were randomized to small airway deposition (n = 19) or large airway deposition (n = 19) of dornase alfa for at least 7 days. Primary endpoint was forced expiratory flow at 75% of forced vital capacity (FEF75 )., Main Results: Spirometry parameters improved significantly during admission, but the difference in mean change in FEF75 between treatment groups was not significant: 0.7 SD, P = 0.30. FEF25-75 , FEV1 , nocturnal oxygen saturation and diary symptom scores also did not differ between groups., Conclusions: This study did not detect a difference if inhaled dornase alfa was targeted to small versus large airways during a RTE. However, the 95% confidence interval for the change in FEF75 was wide. Further studies are needed to improve the effectiveness of RTE treatment in CF., (© 2013 Wiley Periodicals, Inc.)

Little is known about long-term effects of neonatal intensive care on exercise capacity, physical activity, and fatigue in term borns. We determined these outcomes in 57 young adults, treated for neonatal respiratory failure; 27 of them had congenital diaphragmatic hernia with lung hypoplasia (group 1) and 30 had normal lung development (group 2). Patients in group 2 were age-matched, with similar gestational age and birth weight, and similar neonatal intensive care treatment as patients in group 1. All patients were born before the era of extracorporeal membrane oxygenation, nitric oxide administration, and high frequency ventilation. Exercise capacity was measured by cycle ergometry, daily physical activity with an accelerometry-based activity monitor, and fatigue by the fatigue severity scale. Median (range) VO2peak in mL/kg/min was 35.4 (19.6-55.0) in group 1 and 37.6 (15.7-52.7) in group 2. There was a between-group P-value of 0.65 for exercise capacity. Daily activity and fatigue were also similar in both groups. So, residual lung hypoplasia did not play an important role in this cohort. There were no significant associations between exercise capacity and perinatal characteristics. Future studies need to elucidate whether exercise capacity is impaired in patients with more severe lung hypoplasia who nowadays survive., (© 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To elucidate incidence and risk factors of bone mineral density and fracture risk in children with Acute Lymphoblastic Leukemia (ALL)., Methods: Prospectively, cumulative fracture incidence, calculated from diagnosis until one year after cessation of treatment, was assessed in 672 patients. This fracture incidence was compared between subgroups of treatment stratification and age subgroups (Log-Rank test). Serial measurements of bone mineral density of the lumbar spine (BMDLS) were performed in 399 ALL patients using dual energy X-ray absorptiometry. We evaluated risk factors for a low BMD (multivariate regression analysis). Osteoporosis was defined as a BMDLS≤-2 SDS combined with clinical significant fractures., Results: The 3-year cumulative fracture incidence was 17.8%. At diagnosis, mean BMDLS of ALL patients was lower than of healthy peers (mean BMDLS=-1.10 SDS, P<0.001), and remained lower during/after treatment (8months: BMDLS=-1.10 SDS, P<0.001; 24months: BMDLS=-1.27 SDS, P<0.001; 36months: BMDLS=-0.95 SDS, P<0.001). Younger age, lower weight and B-cell-immunophenotype were associated with a lower BMDLS at diagnosis. After correction for weight, height, gender and immunophenotype, stratification to the high risk (HR)-protocol arm and older age lead to a larger decline of BMDLS (HR group: β=-0.52, P<0.01; age: β=-0.16, P<0.001). Cumulative fracture incidences were not different between ALL risk groups and age groups. Patients with fractures had a lower BMDLS during treatment than those without fractures. Treatment-related bone loss was similar in patients with and without fractures (respectively: ΔBMDLS=-0.36 SDS and ΔBMDLS=-0.12 SDS; interaction group time, P=0.30). Twenty of the 399 patients (5%) met the criteria of osteoporosis., Conclusion: Low values of BMDLS at diagnosis and during treatment, rather than the treatment-related decline of BMDLS, determine the increased fracture risk of 17.8% in children with ALL., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Vitamin A is a multifunctional vitamin that can inhibit the formation of Th17 cells, which are probably involved in the development of relapses in MS. Furthermore, it promotes Treg formation. Therefore, vitamin A can be hypothesized to be lower in patients than in healthy controls, and to decrease relapse risk in relapsing-remitting MS (RRMS) patients., Objective: To compare vitamin A levels in MS patients and controls, and to investigate whether vitamin A levels are associated with relapse risk., Methods: In a case-control study all-trans-retinol levels were compared between 31 RRMS patients and 29 matched controls. In a prospective longitudinal study in 73 RRMS patients, serum samples for all-trans-retinol measurements were taken every eight weeks. Associations between all-trans-retinol concentrations and relapse rates were calculated using Poisson regression with the individual serum levels as time-dependent variable. Associations between vitamin A and vitamin D were calculated., Results: Mean vitamin A levels were lower in patients (2.16μmol/l) than in controls (2.44μmol/l) but with borderline significance (p=0.05). In the longitudinal study, during follow-up (mean 1.7 years), 58 patients experienced a total of 139 relapses. Monthly moving averages of all-trans retinol levels were categorized into tertiles: a low (<2.9μmol/l), medium (2.9-3.7μmol/l) and high level (>3.7μmol/l). Relapse rates were not associated with serum all-trans retinol levels (p>0.2), in univariate nor in multivariate analysis. Serum concentrations of all-trans-retinol and 25-OH-vitamin D were positively correlated, although this correlation was weak (r=0.15)., Conclusion: We did not find evidence for a role for vitamin A in the disease course of RRMS. We did find an association between vitamin A and D levels in the RRMS patients, possibly explained by dietary products that contain both fat-soluble vitamins., (Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.)