Physical training and high-protein diet improved muscle strength, parent-reported fatigue, and physical quality of life in children with Pompe disease.

Exercise has proven to be an effective adjuvant treatment to enzyme replacement therapy (ERT) in mildly affected adult Pompe patients. The aim of this study was to investigate the effects of a 12-week tailored lifestyle intervention, consisting of physical training and a high protein diet (2 grams/kg), in children with Pompe disease. This randomized controlled semi-crossover trial investigated the effects of a lifestyle intervention on the primary outcome: exercise capacity. Secondary outcomes were: muscle strength, core stability, motor function, physical activity levels, quality of life, fatigue, fear of exercise, caloric intake, energy balance, body composition, and safety. Fourteen Pompe patients with a median age of 10.6 [IQR: 7.2-14.5], of whom six classic infantile patients, participated in the lifestyle intervention. At baseline, patients had a lower exercise capacity compared to healthy peers (median 70.3% [IQR: 54.8%-98.6%] of predicted). After the intervention, absolute Peak VO2 improved significantly (1279 mL/min [1012.5-2006] vs. 1352 mL/min [1101.5-2069], p = 0.039), but not compared to the control period. Muscle strength of the hip flexors, hip abductors, elbow extensors, neck extensors, knee extensors, and core stability improved significantly compared to the control period. Children reported a significant increase on the change in health domain of quality of life, parents reported significantly better scores on the quality of life domains: physical functioning, change in health, family cohesion, and fatigue. A 12-week tailored lifestyle intervention for children with Pompe disease seemed safe and led to improvements in muscle strength, core stability, quality of life, and parent-reported fatigue. Pompe patients with a stable disease trajectory seemed to benefit the most from the intervention.

Diagnostic accuracy of nerve excitability and compound muscle action potential scan derived biomarkers in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The lack of reliable early biomarkers still causes substantial diagnostic delays in amyotrophic lateral sclerosis (ALS). The aim was to assess the diagnostic accuracy of a novel electrophysiological protocol in patients with suspected motor neuron disease (MND). METHODS: Consecutive patients with suspected MND were prospectively recruited at our tertiary referral centre for MND in Utrecht, The Netherlands. Procedures were performed in accordance with the Standards for Reporting of Diagnostic Accuracy. In addition to the standard diagnostic workup, an electrophysiological protocol of compound muscle action potential (CMAP) scans and nerve excitability tests was performed on patients' thenar muscles. The combined diagnostic yield of nerve excitability and CMAP scan based motor unit number estimation was compared to the Awaji and Gold Coast criteria and their added value was determined. RESULTS: In all, 153 ALS or progressive muscular atrophy patients, 63 disease controls and 43 healthy controls were included. Our electrophysiological protocol had high diagnostic accuracy (area under the curve [AUC] 0.85, 95% confidence interval [95% CI] 0.80-0.90), even in muscles with undetectable axon loss (AUC 0.78, 95% CI 0.70-0.85) and in bulbar-onset patients (AUC 0.85, 95% CI 0.73-0.95). Twenty-four of 33 (73%) ALS patients who could not be diagnosed during the same visit were correctly identified, as well as 8/13 (62%) ALS patients not meeting the Gold Coast criteria and 49/59 (83%) ALS patients not meeting the Awaji criteria during this first visit. CONCLUSIONS: Our practical and non-invasive electrophysiological protocol may improve early diagnosis in clinically challenging patients with suspected ALS. Routine incorporation may boost early diagnosis, enhance patient selection and generate baseline measures for clinical trials.

Physical Training and Healthy Diet Improved Bowel Symptoms, Quality of Life, and Fatigue in Children With Inflammatory Bowel Disease.

OBJECTIVES: Physical activity programs have been suggested as adjunctive therapy in adult inflammatory bowel disease (IBD) patients. We assessed the effects of a 12-week lifestyle intervention in children with IBD. METHODS: This study was a randomized semi-crossover controlled trial, investigating a 12-week lifestyle program (3 physical training sessions per week plus personalized healthy dietary advice) in children with IBD. Endpoints were physical fitness (maximal and submaximal exercise capacity, strength, and core stability), patient-reported outcomes (quality of life, fatigue, and fears for exercise), clinical disease activity (fecal calprotectin and disease activity scores), and nutritional status (energy balance and body composition). Change in maximal exercise capacity (peak VO 2 ) was the primary endpoint; all others were secondary endpoints. RESULTS: Fifteen patients (median age 15 [IQR: 12-16]) completed the program. At baseline, peak VO 2 was reduced (median 73.3% [58.8-100.9] of predicted). After the 12-week program, compared to the control period, peak VO 2 did not change significantly; exercise capacity measured by 6-minute walking test and core-stability did. While medical treatment remained unchanged, Pediatric Crohn's Disease Activity Index decreased significantly versus the control period (15 [3-25] vs 2.5 [0-5], P = 0.012), and fecal calprotectin also decreased significantly but not versus the control period. Quality of life (IMPACT-III) improved on 4 out of 6 domains and total score (+13 points) versus the control period. Parents-reported quality of life on the child health questionnaire and total fatigue score (PedsQoL Multidimensional Fatigue Scale) also improved significantly versus the control period. CONCLUSIONS: A 12-week lifestyle intervention improved bowel symptoms, quality of life, and fatigue in pediatric IBD patients.

Composite endpoint for ALS clinical trials based on patient preference: Patient-Ranked Order of Function (PROOF).

BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) show considerable variation in symptoms. Treatments targeting an overall improvement in symptomatology may not address what the majority of patients consider to be most important. Here, we propose a composite endpoint for ALS clinical trials that weighs the improvement in symptoms compared with what the patient population actually wants. METHODS: An online questionnaire was sent out to a population-based registry in The Netherlands. Patients with ALS were asked to score functional domains with a validated self-reported questionnaire, and rank the order of importance of each domain. This information was used to estimate variability in patient preferences and to develop the Patient-Ranked Order of Function (PROOF) endpoint. RESULTS: There was extensive variability in patient preferences among the 433 responders. The majority of the patients (62.1%) preferred to prioritise certain symptoms over others when evaluating treatments. The PROOF endpoint was established by comparing each patient in the treatment arm to each patient in the placebo arm, based on their preferred order of functional domains. PROOF averages all pairwise comparisons, and reflects the probability that a patient receiving treatment has a better outcome on domains that are most important to them, compared with a patient receiving placebo. By means of simulation we illustrate how incorporating patient preference may upgrade or downgrade trial results. CONCLUSIONS: The PROOF endpoint provides a balanced patient-focused analysis of the improvement in function and may help to refine the risk-benefit assessment of new treatments for ALS.

The burden of parenting children with frontal lobe epilepsy.

OBJECTIVE: Caring for a child with a chronic illness adds stress to the typical parenting stress in healthy developing children. This stress can place a heavy burden on parents and may increase when a child displays problem behavior. In general, parenting and child's behavior problems are associated. Furthermore, externalizing (more outgoing) behavior is reported frequently in children with frontal lobe epilepsy (FLE). Therefore, in this study, we first investigated the burden of parents of children with FLE, and second, we investigated the relation between the experienced burden and reported behavioral problems. The validity of parents' reports on proxy measures as well as duration of epilepsy is taken into account. METHODS: Thirty-one parents of children with FLE completed validated questionnaires about behavioral problems and burden of parenting. To examine if parents tend to be inconsistent or unusually negative, we used the two validity scales of the Behavioral Rating Inventory of Executive Function (BRIEF) (Negativity and Inconsistency). RESULTS: Only parents of children with FLE who have had epilepsy for 5 years or longer report more problems on the Nijmeegse Vragenlijst voor de Opvoedingssituatie (NVOS) subscales 'Able to manage', 'Child is a burden', and 'Good Interaction' compared with the healthy controls. The subscale 'Child is a burden' significantly predicts scores in about 20% to 49% on the main scales of the Child Behavior Checklist (CBCL), the Global Executive Composite (GEC), and Behavioral Regulation Index (BRI) of the BRIEF. Only 6% of parents scored in the clinical range of the negativity scale of the BRIEF. For the inconsistency scale, this was 45%. CONCLUSION: Parents of children with FLE do not report excessive parental burden. Longer duration of epilepsy might be a risk factor in experiencing burden. The findings suggest a link between parental burden and behavioral problems in children with FLE. Externalizing behavioral problems are the most marked behavioral problems, which relate to the parental burden. Parents tend to be inconsistent in their ratings.

Muscle strength and motor function throughout life in a cross-sectional cohort of 180 patients with spinal muscular atrophy types 1c-4.

BACKGROUND AND PURPOSE: Natural history studies in spinal muscular atrophy (SMA) have primarily focused on infants and children. Natural history studies encompassing all age groups and SMA types are important for the interpretation of treatment effects of recently introduced survival motor neuron gene-augmenting therapies. METHODS: We conducted a cross-sectional study to investigate muscle strength, Hammersmith Functional Motor Scale (Expanded) score and the patterns of muscle weakness in relation to age and SMA type. RESULTS: We included 180 patients with SMA types 1-4 in the age range 1-77.5 years with median disease duration of 18 (range 0-65.8) years. With the exception of the early phases of disease in which children with SMA types 2 and 3 may achieve new motor skills and show a temporary increase in muscle strength, cross-sectional data suggested that declining muscle strength and loss of motor skills over time are characteristic of all SMA types. Mean loss of strength was at least 1 point on the Medical Research Council score and 0.5 point on the Hammersmith Functional Motor Scale (Expanded) score per year. Trend lines compatible with deterioration of motor function and muscle strength started in childhood and continued into adulthood. The age at loss of specific motor skills was associated with disease severity. Triceps, deltoid, iliopsoas and quadriceps were the weakest muscles in all patients. Hierarchical cluster analysis did not show a segmental distribution of muscle weakness as suggested previously. CONCLUSIONS: Progressive muscle weakness and loss of motor function are characteristic of all SMA types and all ages.

The limitations of some European healthcare databases for monitoring the effectiveness of pregnancy prevention programmes as risk minimisation measures.

PURPOSE: Pregnancy prevention programmes (PPPs) exist for some medicines known to be highly teratogenic. It is increasingly recognised that the impact of these risk minimisation measures requires periodic evaluation. This study aimed to assess the extent to which some of the data needed to monitor the effectiveness of PPPs may be present in European healthcare databases. METHODS: An inventory was completed for databases contributing to EUROmediCAT capturing pregnancy and prescription data in Denmark, Norway, the Netherlands, Italy (Tuscany/Emilia Romagna), Wales and the rest of the UK, to determine the extent of data collected that could be used to evaluate the impact of PPPs. RESULTS: Data availability varied between databases. All databases could be used to identify the frequency and duration of prescriptions to women of childbearing age from primary care, but there were specific issues with availability of data from secondary care and private care. To estimate the frequency of exposed pregnancies, all databases could be linked to pregnancy data, but the accuracy of timing of the start of pregnancy was variable, and data on pregnancies ending in induced abortions were often not available. Data availability on contraception to estimate compliance with contraception requirements was variable and no data were available on pregnancy tests. CONCLUSION: Current electronic healthcare databases do not contain all the data necessary to fully monitor the effectiveness of PPP implementation, and thus, special data collection measures need to be instituted.

No association between Borrelia burgdorferi antibodies and amyotrophic lateral sclerosis in a case-control study.

BACKGROUND AND PURPOSE: Previous studies, mostly case reports and uncontrolled studies, provide a low level of evidence for the hypothesized link between Lyme disease and amyotrophic lateral sclerosis (ALS). In order to make evidence-based recommendations regarding testing for Borrelia burgdorferi antibodies in the diagnostic work-up for ALS, the objective of this study was to explore the evidence for an association between these antibodies and ALS in a case-control design including age-, gender- and residency-matched controls. METHODS: A total of 491 patients with ALS were matched to 982 controls. IgG titers against B. burgdorferi were determined by an enzyme-linked immunosorbent assay and, in the case of positivity or borderline results, a western blot was performed. Conditional logistic regression and Fisher's exact tests were used to compare the antibody titers or positivity between patients and controls. RESULTS: No difference in seroprevalence of Borrelia was found between patients (4.1%) and controls (5.9%). Clinical characteristics and survival were similar between seropositive and seronegative patients. Moreover, patients with a spinal onset were not more frequently seropositive compared with patients with a bulbar onset (P = 0.47), and neither were patients with a short diagnostic delay of <6 months compared with controls (P = 0.69). None of the 20 patients with a diagnostic delay of <3 months tested positive for IgM antibodies, suggestive of a recent infection. CONCLUSION: This large case-control study provides evidence for a lack of association between B. burgdorferi antibodies and ALS, and therefore does not support the inclusion of routine testing for these antibodies in the diagnostic work-up in patients with classical ALS.

A comparative study of brachial plexus sonography and magnetic resonance imaging in chronic inflammatory demyelinating neuropathy and multifocal motor neuropathy.

BACKGROUND AND PURPOSE: To compare the performance of neuroimaging techniques, i.e. high-resolution ultrasound (HRUS) and magnetic resonance imaging (MRI), when applied to the brachial plexus, as part of the diagnostic work-up of chronic inflammatory demyelinating neuropathy (CIDP) and multifocal motor neuropathy (MMN). METHODS: Fifty-one incident, treatment-naive patients with CIDP (n = 23) or MMN (n = 28) underwent imaging of the brachial plexus using (i) a standardized MRI protocol to assess enlargement or T2 hyperintensity and (ii) bilateral HRUS to determine the extent of nerve (root) enlargement. RESULTS: We found enlargement of the brachial plexus in 19/51 (37%) and T2 hyperintensity in 29/51 (57%) patients with MRI and enlargement in 37/51 (73%) patients with HRUS. Abnormal results were only found in 6/51 (12%) patients with MRI and 12/51 (24%) patients with HRUS. A combination of the two imaging techniques identified 42/51 (83%) patients. We found no association between age, disease duration or Medical Research Council sum-score and sonographic nerve size, MRI enlargement or presence of T2 hyperintensity. CONCLUSIONS: Brachial plexus sonography could complement MRI in the diagnostic work-up of patients with suspected CIDP and MMN. Our results indicate that combined imaging studies may add value to the current diagnostic consensus criteria for chronic inflammatory neuropathies.

Susceptibility loci for sporadic brain arteriovenous malformation; a replication study and meta-analysis.

BACKGROUND: Case-control studies have reported multiple genetic loci to be associated with sporadic brain arteriovenous malformations (AVMs) but most of these have not been replicated in independent populations. The aim of this study was to find additional evidence for these reported associations and perform a meta-analysis including all previously published results. METHODS: We included 167 Dutch patients and 1038 Dutch controls. Case genotyping was performed by KASPar assays. Controls had been previously genotyped with a genome wide single nucleotide polymorphisms (SNP) array. Differences in genotype frequencies between cases and controls were estimated by χ(2) testing in Plink V.1.07. Meta-analysis was performed in RevMan V.5.3. RESULTS: In our case-control study we found no significant association with brain AVM (BAVM) for previously discovered SNPs near ANGPTL4, IL-1ß, GPR124, VEGFA and MMP-3. The meta-analysis revealed a statistically significant association with BAVMs for the polymorphism rs11672433 near ANGPTL4 (OR 1.39; 95% CI 1.10 to 1.75, p value 0.005). CONCLUSIONS: The results of this study support a role for the previously identified SNP near ANGPTL4 in the pathogenesis of AVMs. Previously found associations with SNPs near IL-1ß, GPR124, VEGFA and MMP-3 genes could not be substantiated in our replication cohort or in the meta-analysis.

Correlation of the patient's reported outcome Inflammatory-RODS with an objective metric in immune-mediated neuropathies.

BACKGROUND AND PURPOSE: There is increasing interest in using patient-reported outcome measures (PROMs) in clinical studies to capture individual changes over time. However, PROMs have also been criticized because they are entirely subjective. Our objective was to examine the relationship between a subjective PROM and an objective outcome tool in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and gammopathy-related polyneuropathy (MGUSP). METHODS: The Inflammatory Rasch-built Overall Disability Scale (I-RODS©, a multi-item scale that examines functionality) was completed by 137 patients with newly diagnosed (or relapsing) GBS (55), CIDP (59) and MGUSP (23) who were serially examined (GBS/CIDP, T0/T1/T3/T6/T12 months; MGUSP, T0/T3/T12). Possible association between the I-RODS findings and the vigorimeter scores, an objective linear instrument to assess grip strength, was examined. RESULTS: A significant correlating trend was found between the I-RODS and grip strength scores for the overall group and in each illness, independently. CONCLUSION: The objectivity of patients' subjective report on their functional state based on a strong correlation between the I-RODS and grip strength in patients with GBS, CIDP and MGUSP has been demonstrated. These findings provide further support to use the I-RODS and grip strength in future clinical studies in these conditions.

Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain.

BACKGROUND: In genome-wide association studies (GWAS) five putative risk loci are associated with intracranial aneurysm. As brain arteriovenous malformations (AVM) and intracranial aneurysms are both intracranial vascular diseases and AVMs often have associated aneurysms, we investigated whether these loci are also associated with sporadic brain AVM. METHODS: We included 506 patients (168 Dutch, 338 American) and 1548 controls, all Caucasians. Controls had been recruited as part of previous GWAS. Dutch patients were genotyped by KASPar assay and US patients by Affymetrix SNP 6.0 array. Associations in each cohort were tested by univariable logistic regression modelling, with subgroup analysis in 205 American cases with aneurysm data. Meta-analysis was performed by a Mantel-Haenszel fixed-effect method. RESULTS: In the Dutch cohort none of the single nucleotide polymorphisms (SNPs) were associated with AVMs. In the American cohort, genotyped SNPs near SOX-17 (OR 0.74; 95% CI 0.56-0.98), RBBP8 (OR 0.76; 95% CI 0.62-0.94) and an imputed SNP near CDKN2B-AS1 (OR 0.79; 95% CI 0.64-0.98) were significantly associated with AVM. The association with SNPs near SOX-17 and CDKN2B-AS1 but not RBBP8 were strongest in patients with AVM with associated aneurysms. In the meta-analysis we found no significant associations between allele frequencies and AVM occurrence, but rs9298506, near SOX-17 approached statistical significance (OR 0.77; 95% CI 0.57-1.03, p=0.08). CONCLUSIONS: Our meta-analysis of two Caucasian cohorts did not show an association between five aneurysm-associated loci and sporadic brain AVM. Possible involvement of SOX-17 and RBBP8, genes involved in cell cycle progression, deserves further investigation.

Prose memory impairment in amyotrophic lateral sclerosis patients is related to hippocampus volume.

BACKGROUND AND PURPOSE: Thirty per cent of amyotrophic lateral sclerosis (ALS) patients have non-motor symptoms, including executive and memory deficits. The in vivo anatomical basis of memory deficits in ALS has not been elucidated. In this observational study, brain atrophy in relation to memory function was investigated in ALS patients and controls. METHODS: Twenty-six ALS patients without dementia and 21 healthy volunteers matched for gender, age and education level underwent comprehensive neuropsychological evaluation and T1- and T2-weighted 3 T magnetic resonance imaging scanning of the brain. Grey and white matter brain volumes were analysed using voxel-based morphometry and age related white matter changes were assessed. The most frequently abnormal memory test (<2 SD below normative data corrected for age, gender and education) was correlated with regional brain volume variations by multiple regression analyses with age, gender and total grey matter volumes as covariates. RESULTS: Immediate and delayed story recall scores were abnormal in 23% of ALS patients and correlated to bilateral hippocampus grey matter volume (r = 0.52 for both memory tests; P < 0.05; corrected for age, gender and total grey matter volume). This correlation was not found in healthy controls with similar age, education, anxiety and depression levels and white matter changes. CONCLUSIONS: Prose memory impairment is a frequent finding in this cohort and is associated with hippocampus volume in ALS patients without dementia. These findings complement previous hippocampus changes in imaging studies in ALS and suggest involvement of the hippocampus in cognitive dysfunction of ALS.

Selective serotonin reuptake inhibitor prescribing before, during and after pregnancy: a population-based study in six European regions.

OBJECTIVE: To explore the prescribing patterns of selective serotonin reuptake inhibitors (SSRIs) before, during and after pregnancy in six European population-based databases. DESIGN: Descriptive drug utilisation study. SETTING: Six electronic healthcare databases in Denmark, the Netherlands, Italy (Emilia Romagna/Tuscany), Wales and the rest of the UK. POPULATION: All women with a pregnancy ending in a live or stillbirth starting and ending between 2004 and 2010. METHODS: A common protocol was implemented across databases to identify SSRI prescriptions issued (UK) or dispensed (non-UK) in the year before, during or in the year following pregnancy. MAIN OUTCOME MEASURES: The percentage of deliveries in which the woman received an SSRI prescription in the year before, during or in the year following pregnancy. We also compared the choice of SSRIs and changes in prescribing over the study period. RESULTS: In total, 721 632 women and 862,943 deliveries were identified. In the year preceding pregnancy, the prevalence of SSRI prescribing was highest in Wales [9.6%; 95% confidence interval (CI95 ), 9.4-9.8%] and lowest in Emilia Romagna (3.3%; CI95 , 3.2-3.4%). During pregnancy, SSRI prescribing had dropped to between 1.2% (CI95 , 1.1-1.3%) in Emilia Romagna and 4.5% (CI95 , 4.3-4.6%) in Wales. The higher UK pre-pregnancy prescribing rates resulted in higher first trimester exposures. After pregnancy, SSRI prescribing increased most rapidly in the UK. Paroxetine was more commonly prescribed in the Netherlands and Italian regions than in Denmark and the UK. CONCLUSIONS: The higher SSRI prescribing rates in the UK, compared with other European regions, raise questions about differences in the prevalence and severity of depression and its management in pregnancy across Europe.

Muscle fiber-type distribution, fiber-type-specific damage, and the Pompe disease phenotype.

Pompe disease is a lysosomal storage disorder caused by acid α-glucosidase deficiency and characterized by progressive muscle weakness. Enzyme replacement therapy (ERT) has ameliorated patients' perspectives, but reversal of skeletal muscle pathology remains a challenge. We studied pretreatment biopsies of 22 patients with different phenotypes to investigate to what extent fiber-type distribution and fiber-type-specific damage contribute to clinical diversity. Pompe patients have the same fiber-type distribution as healthy persons, but among nonclassic patients with the same GAA mutation (c.-32-13T>G), those with early onset of symptoms tend to have more type 2 muscle fibers than those with late-onset disease. Further, it seemed that the older, more severely affected classic infantile patients and the wheelchair-bound and ventilated nonclassic patients had a greater proportion of type 2x muscle fibers. However, as in other diseases, this may be caused by physical inactivity of those patients.

Treatment of respiratory impairment in patients with motor neuron disease in the Netherlands: patient preference and timing of referral.

BACKGROUND AND PURPOSE: We assessed the first evaluation at a large ventilation clinic in the Netherlands to: (i) determine what proportion of patients with motor neuron disease would benefit from earlier referral; and (ii) examine the patient preferences regarding ventilatory support. METHODS: Observational study at a single centre with a catchment area of 7.6 million inhabitants. Data on disease status, the referral process and patients' preferences regarding ventilatory support were collected during the first home ventilation services (HVS) assessment and analysed for correlation with the presence of daytime hypercapnia and suspected nocturnal hypoventilation. The latter conditions require immediate (within 48 h) or subacute (within 3 weeks) initiation of ventilatory support. RESULTS: Vital capacity (in percentage of predicted value, VC%pred) was assessed by referring physicians in 84% of the 217 referred patients; the mean VC%pred was 69% (SD 16). One-hundred and ninety-one patients attended the first HVS assessment without ventilatory support, at a median of 21 days following referral: 18% had respiratory failure (daytime hypercapnia), 19% had normocapnia but were suspected of nocturnal hypoventilation, and 63% had normocapnia without symptoms. Following the HVS assessment, 25 patients (13%) declined home mechanical ventilation; this occurred more often in patients with (14/70) compared with patients without respiratory impairment (11/121; P < 0.05). CONCLUSION: A meaningful proportion of patients who desire ventilatory support are referred to a ventilation clinic after already developing respiratory failure. Future studies could examine means, including more sensitive respiratory measures, to detect those patients who could benefit from earlier referral.

A 12-week lifestyle intervention: effects on fatigue, fear, and nutritional status in children with a Fontan circulation.

Introduction: Children and adolescents with a Fontan circulation are less physically active compared to healthy peers. In the current study, effects of a 12-week lifestyle intervention on fatigue, fears regarding exercise, caloric intake, rest energy expenditure (REE), and body composition were measured in children with a Fontan circulation. Methods: This study was a semi-cross-over randomized controlled trial. The lifestyle intervention consisted of a 12-week high-weight resistance training (three supervised training sessions a week) supported by high-protein diet (>2 g/kg) and tailored recommended caloric intake. Fatigue (measured by the validated PedsQol Multidimensional Fatigue Scale), fears regarding exercise (measured on a fear thermometer), REE (measured using indirect calorimetry), caloric intake and body composition using air displacement plethysmography, and four-skinfold method were measured before and after the intervention and control period. Results: Twenty-seven pediatric Fontan patients, median age 12.9 years (IQR: 10.5-16.2), of the included 28 patients successfully completed the program. Before training, both child- and parent-reported levels of fatigue were significantly worse on all domains (general, sleep/rest, and cognitive fatigue) compared to healthy peers. After training, parent-reported fatigue significantly improved on the general and cognitive fatigue domains [effect size +16 points (7-25), p < 0.001, and +10 points (2-17), p = 0.015, compared to the control period]. Before training, fear regarding exercise scored on the fear thermometer was low for both children and parents (median score 1 and 2, respectively, on a scale of 0-8). After training, child-reported fear decreased further compared to the control period [effect size -1.4 points (-2.3 to -0.6), p = 0.001]. At baseline, children had increased REE +12% compared to reference values, which did not change after exercise. Children ate an average of 637 calories below recommended intake based on REE, caloric deficit became smaller after the intervention, and protein intake increased compared to the control period [-388 calories (-674 to -102), p = 0.008, and +15 g (0.4-30), p = 0.044]. Body fat percentage did not change significantly. Conclusion: A 12-week lifestyle intervention improved parent-reported fatigue symptoms in the children, further decreased child-reported fears, and increased caloric and protein intake.

Effects of enzyme replacement therapy on cardiac function in classic infantile Pompe disease.

OBJECTIVE: Patients with classic infantile Pompe disease are born with a hypertrophic cardiomyopathy, which resolves after treatment with Enzyme replacement therapy (ERT). We aimed to assess potential deterioration of cardiac function over time using myocardial deformation analysis. METHODS: Twenty-seven patients treated with ERT were included. Cardiac function was assessed at regular time intervals (before and after start with ERT) using conventional echocardiography and myocardial deformation analysis. Separate linear mixed effect models were used to asses temporal changes within the first year and the long-term follow-up period. Echocardiograms of 103 healthy children served as controls. RESULTS: A total of 192 echocardiograms were analyzed. Median follow-up was 9.9 years (IQR: 7.5-16.3). Mean LVMI before start of ERT was increased 292.3 g/m2 (95% CI: 202.8-381.8, mean Z-score + 7.6) and normalized after 1 year of ERT 87.3 g/m2 (CI: 67.5-107.1, mean Z-score + 0.8, p < 0.001). Mean shortening fraction was within normal limits before start of ERT, up to 22 years of follow-up. Cardiac function measured by RV/LV longitudinal, and circumferential strain was diminished before start of ERT, but normalized (<-16%) within 1 year after start of ERT, and all remained within normal limits during follow-up. Only LV circumferential strain gradually worsened in Pompe patients (+0.24%/year) during follow-up compared to controls. LV longitudinal strain was diminished in Pompe patients, but did not change significantly over time compared to controls. CONCLUSION: Cardiac function, measured using myocardial deformation analysis, normalizes after start of ERT, and seems to remain stable over a median follow-up period of 9.9 years.

Glasshouse vs field experiments: do they yield ecologically similar results for assessing N impacts on peat mosses?

• Peat bogs have accumulated more atmospheric carbon (C) than any other terrestrial ecosystem today. Most of this C is associated with peat moss (Sphagnum) litter. Atmospheric nitrogen (N) deposition can decrease Sphagnum production, compromising the C sequestration capacity of peat bogs. The mechanisms underlying the reduced production are uncertain, necessitating multifactorial experiments. • We investigated whether glasshouse experiments are reliable proxies for field experiments for assessing interactions between N deposition and environment as controls on Sphagnum N concentration and production. We performed a meta-analysis over 115 glasshouse experiments and 107 field experiments. • We found that glasshouse and field experiments gave similar qualitative and quantitative estimates of changes in Sphagnum N concentration in response to N application. However, glasshouse-based estimates of changes in production--even qualitative assessments-- diverged from field experiments owing to a stronger N effect on production response in absence of vascular plants in the glasshouse, and a weaker N effect on production response in presence of vascular plants compared to field experiments. • Thus, although we need glasshouse experiments to study how interacting environmental factors affect the response of Sphagnum to increased N deposition, we need field experiments to properly quantify these effects.

Salivary immune markers are not associated with self-reported childhood maltreatment or psychopathology in adults.

BACKGROUND: Psychological stress has repeatedly been found to be associated with pro-inflammatory markers in blood, and neuro-inflammation may play a role in the development of psychopathology after early life stress. Salivary immune testing is a novel method to non-invasively assess immune functioning. We examined a large range of salivary immune markers in relation to self-reported childhood maltreatment and psychopathology in an adult sample. METHODS: Participants (N = 118, 51% female, mean age = 46.6 yrs, range 22-64) were drawn from a cross-sectional three-generation study, and supplied 2 ml of saliva via passive drool. They reported on childhood maltreatment experiences and on psychopathological symptoms in the last 6 months. Hair cortisol was additionally assessed in a subsample (n = 68). Levels of IL1ß, IL6, IL8, IFNγ, TNFα, tIgE, sIgA, FLCƛ, and FLCƙ were assessed. RESULTS: Linear mixed model analyses showed that several salivary immune markers were associated with age (sIgA and IgE), BMI (sIgA, IL1ß, and IL6), sex (FLCs and IgE), and bad health (IL6, IL8, TNFα). No associations with (anti-inflammatory) medication use or oral health problems were found. Notably, no associations between the immune markers and self-reported childhood maltreatment, psychopathology, or hair cortisol were found. CONCLUSIONS: Salivary immune measures were found to be sensitive to individual differences in age, sex, health and BMI. However. in the current sample there was no indication of inflammation in relation to chronic psychological stress. Larger studies, including participants with higher stress levels, are needed to further examine associations between salivary immune markers and psychological stress.