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Recent work on bullying perpetration includes the hypothesis that bullying carries an evolutionary advantage for perpetrators in terms of health and reproductive success. We tested this hypothesis in the National Child Development Study (n = 4998 male, n = 4831 female), British Cohort Study 1970 (n = 4261 male, n = 4432 female), and TRacking Adolescents’ Individual Lives Survey (n = 486 male, n = 521 female), where bullying was assessed in adolescence (NCDS, BCS70: age 16, TRAILS: age 14) and outcomes in adulthood. Partial support for the evolutionary hypothesis was found as bullies had more children in NCDS and engaged in sexual intercourse earlier in TRAILS. In contrast, bullies reported worse health in NCDS and BCS70.

It is plausible that peer aggression—like general forms of aggression—is transmitted from one generation to the next. As such, parental behavior in childhood and adolescence may be associated with offspring aggressive behavior against peers. This study used 1970 British Cohort Study data to test intergenerational transmission of peer aggression. The baseline sample consisted of 13,135 participants. At the first assessment that was used in this study, participants were on average 4.95 years old (SD = 0.79; 48.20% female). At the last assessment, participants were on average 33.88 years old (SD = 0.36; 52.1% female). Models were computed for early and middle childhood, and adolescence. Significant associations between parents’ and offspring peer aggression were found in most models – especially when correlating aggression in similar developmental periods for parents and children. Other transmission mechanisms such as genetic transmission may be relevant and should be taken into account in future studies.

Purpose: A prostate-specific membrane antigen (PSMA) thyroid incidentaloma (PTI) is an unexpected, PSMA-avid thyroid lesion, newly detected during the investigation of an unrelated condition using PSMA PET/CT. The aim of this study is to examine the incidence and clinical significance of PTI and the associated management strategies since the implementation of the PSMA PET/CT scan. Methods: This study involves a retrospective cohort study of 61 PTI cases depicted on PSMA PET/CT scans performed between January 2016 and July 2021, almost exclusively for (re)staging prostate cancer. The medical records of the included cases were retrospectively reviewed and data of the PSMA PET/CT scans, primary malignancy, thyroid diagnostics, treatment, and follow-up were collected. Results: PTI was reported in 1.1% of the patients who underwent oncologic PSMA PET/CT scans included in this study. Two PTI cases had a histologically proven thyroid cancer: one a benign thyroid lesion and one a metastasis of a renal cell carcinoma. In none of the cases in whom any form of further thyroid workup was withheld, the PTI became clinically relevant during follow-up (median 1.8 years (1.1–3.3)). Six patients (10%) died due to their primary cancer. Conclusion: The incidence of thyroid incidentalomas on PSMA PET/CT was low (1.1%) in this large, two-center experience. Less than half of the PTI cases were analyzed and the risk of malignancy, despite being low, was not negligible. The clinical outcome was good using a standard diagnostic workup for PTI, while the prognosis of the patient was determined by the primary malignancy. The consideration to analyze and treat PTI cases should be part of the shared decision-making in cancer patients.

The aim of this exploratory study was to evaluate diaphragmatic function across various neuromuscular diseases using spirometry-controlled MRI. We measured motion of the diaphragm relative to that of the thoracic wall (cranial-caudal ratio vs. anterior posterior ratio; CC-AP ratio), and changes in the diaphragmatic curvature (diaphragm height and area ratio) during inspiration in 12 adults with a neuromuscular disease having signs of respiratory muscle weakness, 18 healthy controls, and 35 adult Pompe patients – a group with prominent diaphragmatic weakness. CC-AP ratio was lower in patients with myopathies (n=7, 1.25±0.30) and motor neuron diseases (n=5, 1.30±0.10) than in healthy controls (1.37±0.14; p=0.001 and p=0.008), but not as abnormal as in Pompe patients (1.12±0.18; p=0.011 and p=0.024). The mean diaphragm height ratio was 1.17±0.33 in patients with myopathies, pointing at an insufficient diaphragmatic contraction. This was also seen in patients with Pompe disease (1.28±0.36), but not in healthy controls (0.82±0.33) or patients with motor neuron disease (0.82±0.24). We conclude that spirometry-controlled MRI enables us to investigate respiratory dysfunction across neuromuscular diseases, suggesting that the diaphragm is affected in a different way in myopathies and motor neuron diseases. Whether MRI can also be used to evaluate progression of diaphragmatic dysfunction requires additional studies.

Background: Asthma exacerbations are frequently induced by respiratory tract infections (RTIs). Bacterial lysates have been described to possess immune-modulatory effects and reduce RTIs as well as asthma symptoms in children. However, whether bacterial lysates have similar effects in adult asthma patients is unknown. Aims: To reduce asthma exacerbations by add-on bacterial lysate therapy in adults with severe asthma and to characterize the clinical and immune-modulatory effects of this treatment. Methods: Asthma patients (GINA 4) with ≥2 annual exacerbations in the previous year were included. The intervention regimen consisted of OM-85/placebo for 10 consecutive days per month for 6 months during two winter seasons. Primary end-point was the number of severe asthma exacerbations within 18 months. The study was approved by the national and local ethical review board and registered in the Dutch Trial Registry (NL5752). All participants provided written informed consent. Results: Seventy-five participants were included (38 OM-85; 37 placebo). Exacerbation frequencies were not different between the groups after 18 months (incidence rate ratio 1.07, 95%CI [0.68–1.69], p = 0.77). With the use of OM-85, FEV1% increased by 3.81% (p = 0.04) compared with placebo. Nasopharyngeal swabs taken during RTIs detected a virus less frequently in patients using OM-85 compared to placebo (30.5% vs. 48.0%, p = 0.02). In subjects with type 2 inflammation adherent to the protocol (22 OM-85; 20 placebo), a non-statistically significant decrease in exacerbations in the OM-85 group was observed (IRR = 0.71, 95%CI [0.39–1.26], p = 0.25). Immune-modulatory effects included an increase in several plasma cytokines in the OM-85 group, especially IL-10 and interferons. Peripheral blood T- and B cell subtyping, including regulatory T cells, did not show differences between the groups. Conclusion: Although OM-85 may have immune-modulatory effects, it did not reduce asthma exacerbations in this heterogeneous severe adult asthma group. Post hoc analysis showed a potential clinical benefit in patients with type 2 inflammation.

Background & objectives Pain can be significantly lessened by sex/orgasm, likely due to the release of endorphins during sex, considered potent analgesics. The evidence suggests that endorphins are also present during sexual arousal (that is, prior to sex/orgasm). It follows then that pain can be modulated during sexual arousal, independent of sex/orgasm, too. Accordingly, sexual arousal induced by erotic slides has been demonstrated to lessen pain in men, but not in women. One explanation could be that for women, the erotic slides were not potent enough to elicit a lasting primed state of sexual arousal by the time pain was induced. Thus, the current study aims to optimize the means of inducing a potent state of sexual arousal and subsequently examine the potentially analgesic influence of sexual arousal on pain in women. As a subsidiary aim, the study also assesses whether the anticipated analgesic effect of sexual arousal would be stronger than that of distraction or generalized (non-sexual) arousal. Methods Female participants (N = 151) were randomly distributed across four conditions: sexual arousal, generalized arousal, distraction, neutral. Mild pain was induced using a cold pressor while participants were concurrently exposed to film stimuli (pornographic, exciting, distracting, neutral) to induce the targeted emotional states. A visual analogue scale was utilized to measure the subjective level of pain perceived by the participants. Results Sexual arousal did not reduce subjective pain. Generalized arousal and distraction did not result in stronger analgesic effects than the neutral condition. Conclusion The present findings do not support the hypothesis that sexual arousal alone modulates subjective pain in women. This might be due to the possibility that genital stimulation and/or orgasm are key in pain reduction, or, that feelings of disgust may inadvertently have been induced by the pornographic stimulus and interfered with sexual arousal in influencing pain.

Objective: To advance the prediction of the neurocognitive development in MPS II patients by jointly analyzing MRI and neurocognitive data in mucopolysaccharidosis (MPS) II patients. Methods: Cognitive ability scores (CAS) were obtained by neuropsychological testing. Cerebral MRIs were quantified using a disease-specific protocol. MRI sumscores were calculated for atrophy, white-matter abnormalities (WMA) and Virchow-Robin spaces (VRS). To distinguish between atrophy and hydrocephalus the Evans' index and the callosal angle (CA) were measured. A random effects repeated measurement model was used to correlate CAS with the three MRI sumscores. Results: MRI (n = 47) and CAS scores (n = 78) of 19 male patients were analyzed. Ten patients were classified as neuronopathic and nine as non-neuronopathic. Neuronopathic patients had normal cognitive development until age 3 years. Mental age plateaued between ages 3 and 6, and subsequently declined with loss of skills at a maximum developmental age of 4 years. MRIs of neuronopathic patients showed abnormal atrophy sumscores before CAS dropped below the threshold for intellectual disability (

Background There is an ongoing debate on whether fructose plays a role in the development of nonalcoholic fatty liver disease. Objectives The aim of this study was to investigate the effects of fructose restriction on intrahepatic lipid (IHL) content in a double-blind randomized controlled trial using an isocaloric comparator. Methods Between March 2017 and October 2019, 44 adult overweight individuals with a fatty liver index ≥ 60 consumed a 6-wk fructose-restricted diet (

Pompe disease is a rare inherited metabolic and neuromuscular disorder, presenting as a spectrum, with the classic infantile form on one end and the more slowly progressive non-classic form on the other end. While being a hallmark in classic infantile Pompe disease, cardiac involvement in non-classic Pompe disease seems rare. Vascular abnormalities, such as aneurysms and arterial dolichoectasia, likely caused by glycogen accumulation in arterial walls, have been reported in non-classic Pompe patients. With this first systematic review on cardiovascular disease in non-classic Pompe disease, we aim to gain insight in the prevalence and etiology of cardiovascular disease in these patients. Forty-eight studies (eight case-control studies, 15 cohort studies and 25 case reports/series) were included. Fourteen studies reported cardiac findings, 25 studies described vascular findings, and nine studies reported both cardiac and vascular findings. Severe cardiac involvement in non-classic Pompe disease patients has rarely been reported, particularly in adult-onset patients carrying the common IVS1 mutation. There are indications that intracranial dolichoectasia and aneurysms are more prevalent in non-classic Pompe patients compared to the general population. To further investigate the prevalence of cardiovascular disease in non-classic Pompe patients, larger case-control studies that also study established cardiovascular risk factors should be conducted.

Robbert JJ Gobbens,1– 3 Tjeerd van der Ploeg4 1Faculty of Health, Sports and Social Work, Inholland University of Applied Sciences, Amsterdam, the Netherlands; 2Zonnehuisgroep Amstelland, Amstelveen, the Netherlands; 3Department of Primary and Interdisciplinary Care, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; 4Faculty of Engineering, Design and Computer Technology, Inholland University of Applied Sciences, Alkmaar, the NetherlandsCorrespondence: Robbert JJ GobbensFaculty of Health, Sports and Social Work, Inholland University of Applied Sciences, De Boelelaan 1109, Amsterdam 1081 HV, the NetherlandsTel +31 6 21115578Email robbert.gobbens@inholland.nlObjective: To predict mortality by disability in a sample of 479 Dutch community-dwelling people aged 75 years or older.Methods: A longitudinal study was carried out using a follow-up of seven years. The Groningen Activity Restriction Scale (GARS), a self-reported questionnaire with good psychometric properties, was used for data collection about total disability, disability in activities in daily living (ADL) and disability in instrumental activities in daily living (IADL). The mortality dates were provided by the municipality of Roosendaal (a city in the Netherlands). For analyses of survival, we used Kaplan–Meier analyses and Cox regression analyses to calculate hazard ratios (HR) with 95% confidence intervals (CI).Results: All three disability variables (total, ADL and IADL) predicted mortality, unadjusted and adjusted for age and gender. The unadjusted HRs for total, ADL and IADL disability were 1.054 (95%-CI: [1.039;1.069]), 1.091 (95%-CI: [1.062;1.121]) and 1.106 (95%-CI: [1.077;1.135]) with p-values < 0.001, respectively. The AUCs were < 0.7, ranging from 0.630 (ADL) to 0.668 (IADL). Multivariate analyses including all 18 disability items revealed that only “Do the shopping” predicted mortality. In addition, multivariate analyses focusing on 11 ADL items and 7 IADL items separately showed that only the ADL item “Get around in the house” and the IADL item “Do the shopping” significantly predicted mortality.Conclusion: Disability predicted mortality in a seven years follow-up among Dutch community-dwelling older people. It is important that healthcare professionals are aware of disability at early stages, so they can intervene swiftly, efficiently and effectively, to maintain or enhance the quality of life of older people.Keywords: disability, mortality, community-dwelling older people, activities of daily living

Objective: Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency at birth due to disorders of the thyroid gland (thyroidal CH, CH-T), or the hypothalamus or pituitary (central CH, CH-C). The Dutch Newborn Screening (NBS) strategy is primarily based on determination of thyroxine (T4) concentrations in dried blood spots followed, if necessary, by thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) measurement enabling detection of both CH-T and CH-C. A calculated T4/TBG ratio serves as an indirect measure for free T4. A T4/TBG ratio ≤ 17 in a second heel puncture is suggestive of CH-C. Design and methods: In the present study, we evaluated 11 years of Dutch CH NBS using a database of referred cases by assessing the contribution of each criterion in the unique stepwise T4-TSH-TBG NBS algorithm. Results: Between 2007 and the end of 2017, 1 963 465 newborns were screened in the Netherlands. Use of the stepwise algorithm led to 3044 referrals and the identification of 612 CH cases, consisting of 496 CH-T, 86 CH-C, and 30 CH of unknown origin diagnoses. We detected 62.8% of CH-C cases by the T4/TBG ratio in the second heel puncture. The positive predictive value (PPV) of the stepwise T4-TSH-TBG NBS algorithm was 21.0%. Conclusion: This evaluation shows that the Dutch stepwise T4-TSH-TBG NBS algorithm with a calculated T4/TBG ratio is of great value for the detection of both CH-T and CH-C in the Netherlands, at the cost of a lower PPV compared to TSH-based NBS strategies.

Evidence for effectiveness of newborn screening (NBS) for propionic acidemia (PA) and isolated methylmalonic acidemia (MMA) is scarce. Prior to implementation in the Netherlands, we aim to estimate the expected health gain of NBS for PA and MMA. In this national retrospective cohort study, the clinical course of 76/83 Dutch PA and MMA patients, diagnosed between January 1979 and July 2019, was evaluated. Five clinical outcome parameters were defined: adverse outcome of the first symptomatic phase, frequency of acute metabolic decompensations (AMD), cognitive function, mitochondrial complications, and treatment‐related complications. Outcomes of patients identified by family testing were compared with the outcomes of their index siblings. An adverse outcome due to the first symptomatic phase was recorded in 46% of the clinically diagnosed patients. Outcome of the first symptomatic phase was similar in 5/9 sibling pairs and better in 4/9 pairs. Based on the day of diagnosis of the clinically diagnosed patients and sibling pair analysis, a preliminary estimated reduction of adverse outcome due to the first symptomatic phase from 46% to 36%‐38% was calculated. Among the sibling pairs, AMD frequency, cognitive function, mitochondrial, and treatment‐related complications were comparable. These results suggest that the health gain of NBS for PA and MMA in overall outcome may be limited, as only a modest decrease of adverse outcomes due to the first symptomatic phase is expected. With current clinical practice, no reduced AMD frequency, improved cognitive function, or reduced frequency of mitochondrial or treatment‐related complications can be expected.

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p values

Background Increased physical activity (PA), reduced time spent sedentary (SED), healthier diet and reduced body weight may all have a positive impact on cardiometabolic risk. The relative importance of change in each of these variables on cardiometabolic risk, however, is unclear. We therefore sought to investigate the relative contributions of changes in PA, SED, diet and body weight on cardiometabolic risk. Methods This is a secondary analysis of data collected from the EuroFIT randomised controlled trial, which was a 12-week group-based lifestyle intervention for overweight middle-aged men delivered by coaches in football club stadia aiming to improve PA, SED, diet, and body weight. PA and SED were assessed by accelerometry, diet using the Dietary Instrument for Nutrition Education (DINE). An overall cardiometabolic risk score was derived from combining z-scores for glucose, HbA1c, insulin, lipids and blood pressure. In total, 707 men (from the overall cohort of 1113) with complete data for these variables at baseline and 12-month follow-up were included in the multivariable linear regression analyses. Results In multivariable analyses, change in number of steps (explaining 5.1% of R2) and dietary factors (less alcohol, fatty and sugary food, and more fruit and vegetables) (together explaining 4.5% of R2), but not changes in standing time or SED, were significantly associated with change in body weight. Changes in number of steps (R2 = 1.7%), fatty food score (R2 = 2.4%), and sugary food score (R2 = 0.4%) were significantly associated with change in cardiometabolic risk score in univariable models. However, in multivariable models which included changes in weight as well as changes in steps and dietary variables, change in weight explained a substantially larger proportion of the change in cardiometabolic risk score, explaining 14.1% of R2 (out of an overall model R2 of 19.0%). When baseline (as well as change) values were also included in the model, 38.8% of R2 for change in cardiometabolic risk score was explained overall, with 14.1% of R2 still explained by change in weight. Conclusion Change in body weight, together with baseline cardiometabolic risk explained most of the change in cardiometabolic risk. Thus, the benefits of increasing physical activity and improving diet on cardiometabolic risk appear to act largely via an effect on changes in body weight. Trial registration International Standard Randomised Controlled Trials, ISRCTN-81935608. Registered 06052015. https://www.isrctn.com/ISRCTN81935608?q=&filters=recruitmentCountry:Portugal&sort=&offset=7&totalResults=92&page=1&pageSize=10&searchType=basic-search

Background: Systemic mastocytosis is a hematological disease in which aberrant mast cells accumulate because of gain-of-function mutations in the KIT receptor. Group 2 innate lymphoid cells (ILC2s) are effector cells of type 2 immune responses that also express KIT and colocalize with mast cells at barrier tissue sites. In mouse models, mast cell-ILC2 crosstalk can drive local inflammation. However, a possible role for ILC2s in the pathophysiology of mastocytosis remains unexplored. Objective: We sought to characterize circulating ILC2s in a clinically diverse cohort of patients with mastocytosis. Methods: We included 21 adults with systemic mastocytosis and 18 healthy controls. Peripheral blood ILC2 abundance and phenotype were analyzed by flow cytometry and correlated to clinical characteristics, including the presence of the D816V KIT mutation. Results: ILC2 levels were significantly higher in D816V+ patients with mastocytosis compared with D816V− patients or healthy controls. We observed increased proportions of KIT+ ILC2s among patients with mastocytosis, regardless of D816V status. Patients with skin involvement and itch showed the highest levels of ILC2s, which was independent from atopy or serum tryptase levels. Allele-specific quantitative PCR showed that the vast majority of ILC2s did not carry the D816V mutation. Conclusions: Our findings suggest a role for ILC2s and pathogenic ILC2-mast cell crosstalk in mastocytosis. We hypothesize that a high cutaneous D816V+ mast cell burden alters the skin microenvironment to induce chronic local ILC2 activation and their dissemination into the circulation. Activated ILC2s could contribute to skin symptoms by producing inflammatory mediators and by further augmenting mast cell mediator release.

PURPOSE: We studied microRNAs as potential biomarkers for Pompe disease. METHODS: We analyzed microRNA expression by small RNA-seq in tissues from the disease murine model at two different ages (3 and 9 months), and in plasma from Pompe patients. RESULTS: In the mouse model we found 211 microRNAs that were differentially expressed in gastrocnemii and 66 in heart, with a different pattern of expression at different ages. In a preliminary analysis in plasma from six patients 55 microRNAs were differentially expressed. Sixteen of these microRNAs were common to those dysregulated in mouse tissues. These microRNAs are known to modulate the expression of genes involved in relevant pathways for Pompe disease pathophysiology (autophagy, muscle regeneration, muscle atrophy). One of these microRNAs, miR-133a, was selected for further quantitative real-time polymerase chain reaction analysis in plasma samples from 52 patients, obtained from seven Italian and Dutch biobanks. miR-133a levels were significantly higher in Pompe disease patients than in controls and correlated with phenotype severity, with higher levels in infantile compared with late-onset patients. In three infantile patients miR-133a decreased after start of enzyme replacement therapy and evidence of clinical improvement. CONCLUSION: Circulating microRNAs may represent additional biomarkers of Pompe disease severity and of response to therapy.

Objective To examine respiratory muscle function among late-onset Pompe disease (LOPD) patients in the Pompe Registry (NCT00231400/Sanofi Genzyme) during enzyme replacement therapy (ERT) with alglucosidase alfa by assessing the longitudinal course of forced vital capacity (FVC), prognostic factors for FVC, and impact of time from diagnosis to ERT initiation. Methods Longitudinal FVC data from LOPD (symptom onset > 12 months or ≤ 12 months without cardiomyopathy) patients were analyzed. Patients had to have baseline FVC (percent predicted upright) assessments at ERT start and ≥ 2 valid post-baseline assessments. Longitudinal analyses used linear mixed-regression models. Results Among 396 eligible patients, median baseline FVC was 66.9% (range 9.3–126.0). FVC remained stable during the 5-year follow-up (slope = − 0.17%, p = 0.21). Baseline FVC was lower among various subgroups, including patients who were male; older at ERT initiation; had a longer duration from symptom onset to ERT initiation; and had more advanced disease at baseline (based on respiratory support use, inability to ambulate, ambulation device use). Age at symptom onset was not associated with baseline degree of respiratory dysfunction. Differences between subgroups observed at baseline remained during follow-up. Shorter time from diagnosis to ERT initiation was associated with higher FVC after 5 years in all patients and the above subgroups using a cut-off of 1.7 years. Conclusion FVC stability over 5 years suggests that respiratory function is preserved during long-term ERT in real-world settings. Early initiation of alglucosidase alfa was associated with preservation of FVC in LOPD patients with better respiratory function at the time of treatment initiation.

Enzyme replacement therapy for Pompe disease received market authorization in 2006. To implement this costly treatment in the Netherlands in the most sensible way, a multidisciplinary expert committee was installed. We evaluated decision making in adult patients in relation to the European POmpe Consortium stop criteria. Of 125 adult Pompe patients, 111 started treatment; subsequently treatment stopped in 24 patients (21%). In 10 patients, treatment was discontinued for medical or personal reasons, as defined in the six stop criteria (median treatment duration: 2.1 years, range: 0.3-14.6 years). Three of these patients continued follow-up (follow-up: 1.3-8.0 years), these patients did not display a more rapid decline after discontinuation. In 14 of 24 patients, therapy ended at time of death. In 10 patients death was related to Pompe disease (median treatment duration: 7.2 years, range: 0.4-10.3 years). All 10 patients were severely affected at start of treatment, treatment had elicited positive effects in eight. The European POmpe Consortium guidelines worked well in decision making on stopping treatment. However, (re)evaluation of the rationale for continuation of treatment in advanced disease stage is not addressed. We suggest to add this to the treatment evaluation and to handle treatment decisions in a multidisciplinary expert team. (C) 2019 The Author(s). Published by Elsevier B.V.

Background The dietary management of methylmalonic acidaemia (MMA) is a low-protein diet providing sufficient energy to avoid catabolism and to limit production of methylmalonic acid. The goal is to achieve normal growth, good nutritional status and the maintenance of metabolic stability. Aim To describe the dietary management of patients with MMA across Europe. Methods A cross-sectional questionnaire was sent to European colleagues managing inherited metabolic disorders (IMDs) (n=53) with 27 questions about the nutritional management of organic acidaemias. Data were analysed by different age ranges (0–6 months; 7–12 months; 1–10 years; 11–16 years; >16 years). Results Questionnaires were returned from 53 centres. Twenty-five centres cared for 80 patients with MMA vitamin B12 responsive (MMAB12r) and 43 centres managed 215 patients with MMA vitamin B12 non-responsive (MMAB12nr). For MMAB12r patients, 44% of centres (n=11/25) prescribed natural protein below the World Health Organization/Food and Agriculture Organization/United Nations University (WHO/FAO/UNU) 2007 safe levels of protein intake in at least one age range. Precursor-free amino acids (PFAA) were prescribed by 40% of centres (10/25) caring for 36% (29/80) of all the patients. For MMAB12nr patients, 72% of centres (n=31/43) prescribed natural protein below the safe levels of protein intake (WHO/FAO/UNU 2007) in at least one age range. PFAA were prescribed by 77% of centres (n=33/43) managing 81% (n=174/215) of patients. In MMAB12nr patients, 90 (42%) required tube feeding: 25 via a nasogastric tube and 65 via a gastrostomy. Conclusions A high percentage of centres used PFAA in MMA patients together with a protein prescription that provided less than the safe levels of natural protein intake. However, there was inconsistent practices across Europe. Long-term efficacy studies are needed to study patient outcome when using PFAA with different severities of natural protein restrictions in patients with MMA to guide future practice.

Objectives:One-on-one structured Montessori-based activities conducted with people with dementia can improve agitation and enhance engagement. These activities may however not always be implemented by nursing home staff. Family members may present an untapped resource for enabling these activities. This study aimed to evaluate the impact of the Montessori activities implemented by family members on visitation experiences with people who have dementia.Design:Cluster-randomized crossover design.Setting:General and psychogeriatric nursing homes in the state of Victoria, Australia.Participants:Forty participants (20 residents and 20 carers) were recruited.Intervention:During visits, family members interacted with their relative either through engaging in Montessori-based activities or reading a newspaper (the control condition) for four 30-minute sessions over 2 weeks.Measurements:Residents’ predominant affect and engagement were rated for each 30-second interval using the Philadelphia Geriatric Center Affect Rating Scale and the Menorah Park Engagement Scale. The Pearlin Mastery Scale was used to rate carers satisfaction with visits. The 15-item Mutuality Scale measured the carers quality of their relationship with the resident. Carers’ mood and overall quality of life were measured using the Center for Epidemiological Studies Depression Scale and Carer-QoL questionnaires, respectively.Results:Linear regressions within the generalized estimating equations approach assessed residents’ and carers’ outcomes. Relative to the control condition, the Montessori condition resulted in more positive engagement (b = 13.0, 95%CI 6.3–19.7, p < 0.001) and affect (b = 0.4, 95%CI 0.2–0.6, p < 0.001) for the residents and higher satisfaction with visits for carers (b = 1.7, 95%CI 0.45–3.00, p = 0.008). No correction was applied to p-values for multiple comparisons.Conclusion:This study strengthens the evidence base for the use of the Montessori programs in increasing well-being in nursing home residents. The findings also provide evidence that family members are an additional valuable resource in implementing structured activities such as the Montessori program with residents.

Collaboration from previous work institution. Free PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30737479/ Analyses in our diagnostic DNA laboratory include genes involved in autosomal recessive (AR) lysosomal storage disorders such as glycogenosis type II (Pompe disease) and mucopolysaccharidosis type I (MPSI, Hurler disease). We encountered 4 cases with apparent homozygosity for a disease-causing sequence variant that could be traced to one parent only. In addition, in a young child with cardiomyopathy, in the absence of other symptoms, a diagnosis of Pompe disease was considered. Remarkably, he presented with different enzymatic and genotypic features between leukocytes and skin fibroblasts. All cases were examined with microsatellite markers and SNP genotyping arrays. We identified one case of total uniparental disomy (UPD) of chromosome 17 leading to Pompe disease and three cases of segmental uniparental isodisomy (UPiD) causing Hurler-(4p) or Pompe disease (17q). One Pompe patient with unusual combinations of features was shown to have a mosaic segmental UPiD of chromosome 17q. The chromosome 17 UPD cases amount to 11% of our diagnostic cohort of homozygous Pompe patients (plus one case of pseudoheterozygosity) where segregation analysis was possible. We conclude that inclusion of parental DNA is mandatory for reliable DNA diagnostics. Mild or unusual phenotypes of AR diseases should alert physicians to the possibility of mosaic segmental UPiD. SNP genotyping arrays are used in diagnostic workup of patients with developmental delay. Our results show that even small Regions of Homozygosity that include telomeric areas are worth reporting, regardless of the imprinting status of the chromosome, as they might indicate segmental UPiD. info:eu-repo/semantics/publishedVersion

Background: There is limited information about the agreement and reliability of clinical shoulder tests. Objectives: To assess the interrater agreement and reliability of clinical shoulder tests in patients with shoulder pain treated in primary care. Methods: Patients with a primary report of shoulder pain underwent a set of 21 clinical shoulder tests twice on the same day, by pairs of independent physical therapists. The outcome parameters were observed and specific interrater agreement for positive and negative scores, and interrater reliability (Cohen’s kappa (κ)). Positive and negative interrater agreement values of ≥0.75 were regarded as sufficient for clinical use. For Cohen’s κ, the following classification was used

Organic acidurias (OAD) and urea-cycle disorders (UCD) are rare inherited disorders affecting amino acid and protein metabolism. As dietary practice varies widely, we assessed their long-term prescribed dietary treatment against published guideline and studied plasma amino acids levels. We analyzed data from the first visit recorded in the European registry and network for intoxication type metabolic diseases (E-IMD, Chafea no. 2010 12 01). In total, 271 methylmalonic aciduria (MMA) and propionic aciduria (PA) and 361 UCD patients were included. Median natural protein prescription was consistent with the recommended daily allowance (RDA), plasma L-valine (57%), and L-isoleucine (55%) levels in MMA and PA lay below reference ranges. Plasma levels were particularly low in patients who received amino acid mixtures (AAMs-OAD) and L-isoleucine:L-leucine:L-valine (BCAA) ratio was 1.0:3.0:3.2. In UCD patients, plasma L-valine, L-isoleucine, and L-leucine levels lay below reference ranges in 18%, 30%, and 31%, respectively. In symptomatic UCD patients who received AAM-UCD, the median natural protein prescription lay below RDA, while their L-valine and L-isoleucine levels and plasma BCAA ratios were comparable to those in patients who did not receive AAM-UCD. Notably, in patients with ornithine transcarbamylase syndrome (OTC-D), carbamylphosphate synthetase 1 syndrome (CPS1-D) and hyperammonemia-hyperornithinemia-homocitrullinemia (HHH) syndrome selective L-citrulline supplementation resulted in higher plasma L-arginine levels than selective L-arginine supplementation. In conclusion, while MMA and PA patients who received AAMs-OAD had very low BCAA levels and disturbed plasma BCAA ratios, AAMs-UCD seemed to help UCD patients obtain normal BCAA levels. In patients with OTC-D, CPS1-D, and HHH syndrome, selective L-citrulline seemed preferable to selective L-arginine supplementation.

Approximately 1·5 billion people worldwide live with a physical, mental, sensory, or intellectual disability, about 80% of which are in low-income and middle-income countries. This Series paper provides a global overview of the prevalence, benefits, and promotion policies for physical activity for people living with disabilities (PLWD). PLWD are 16–62% less likely to meet physical activity guidelines and are at higher risk of serious health problems related to inactivity than people without disabilities. Meta-analyses have shown that physical activity has beneficial effects on cardiovascular fitness (average standardised mean difference [SMD] 0·69 [95% CI 0·31–1·01]), musculoskeletal fitness (0·59 [0·31–0·87]), cardiometabolic risk factors (0·39 [0·04–0·75]), and brain and mental health outcomes (0·47 [0·21–0·73]). These meta-analyses also show that health benefits can be achieved even with less than 150 min of physical activity per week, and suggest that some physical activity is better than none. Meta-analyses of interventions to increase physical activity for PLWD have reported effect sizes ranging from SMD 0·29 (95% CI 0·17–0·41, k=10) to 1·00 (0·46–1·53, k=10). There is increasing awareness among policy makers of the needs of PLWD for full participation in physical activity. Physical activity action plans worldwide must be adequately resourced, monitored, and enforced to truly advance the fundamental rights of PLWD to fully participate in physical activity.

Summary Background Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barre syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barre syndrome with a predicted poor outcome. Methods In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (≥12 years) with Guillain-Barre syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of ≥6) according to the modified Erasmus Guillain-Barre syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7–9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barre syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis. This study is registered with the Netherlands Trial Register, NTR 2224/NL2107. Findings Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barre syndrome disability score at 4 weeks was 1·4 (95% CI 0·6–3·3; p=0·45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13–24 weeks after randomisation). Interpretation Our study does not provide evidence that patients with Guillain-Barre syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barre syndrome. Funding Prinses Beatrix Spierfonds and Sanquin Plasma Products.

To determine the predictive value of quality of life for mortality at the domain and item levels.This longitudinal study was carried out in a sample of 479 Dutch people aged 75 years or older living independently, using a follow-up of 7 years. Participants completed a self-report questionnaire. Quality of life was assessed with the WHOQOL-BREF, including four domains: physical health, psychological, social relationships, and environment. The municipality of Roosendaal (a town in the Netherlands) indicated the dates of death of the individuals.Based on mean, all quality of life domains predicted mortality adjusted for gender, age, marital status, education, and income. The hazard ratios ranged from 0.811 (psychological) to 0.933 (social relationships). The areas under the curve (AUCs) of the four domains were 0.730 (physical health), 0.723 (psychological), 0.693 (social relationships), and 0.700 (environment). In all quality of life domains, at least one item predicted mortality (adjusted).Our study showed that all four quality of life domains belonging to the WHOQOL-BREF predict mortality in a sample of Dutch community-dwelling older people using a follow-up period of 7 years. Two AUCs were above threshold (psychological, physical health). The findings offer health care and welfare professionals evidence for conducting interventions to reduce the risk of premature death.

Group 2 innate lymphoid cells (ILC2s) orchestrate protective type 2 immunity and have been implicated in various immune disorders. In the mouse, circulatory inflammatory ILC2s (iILC2s) were identified as a major source of type 2 cytokines. The human equivalent of the iILC2 subset remains unknown. Here, we identify a human inflammatory ILC2 population that resides in inflamed mucosal tissue and is specifically marked by surface CD45RO expression. CD45RO+ ILC2s are derived from resting CD45RA+ ILC2s upon activation by epithelial alarmins such as IL-33 and TSLP, which is tightly linked to STAT5 activation and up-regulation of the IRF4/BATF transcription factors. Transcriptome analysis reveals marked similarities between human CD45RO+ ILC2s and mouse iILC2s. Frequencies of CD45RO+ inflammatory ILC2 are increased in inflamed mucosal tissue and in the circulation of patients with chronic rhinosinusitis or asthma, correlating with disease severity and resistance to corticosteroid therapy. CD45RA-to-CD45RO ILC2 conversion is suppressed by corticosteroids via induction of differentiation toward an immunomodulatory ILC2 phenotype characterized by low type 2 cytokine and high amphiregulin expression. Once converted, however, CD45RO+ ILC2s are resistant to corticosteroids, which is associated with metabolic reprogramming resulting in the activation of detoxification pathways. Our combined data identify CD45RO+ inflammatory ILC2s as a human analog of mouse iILC2s linked to severe type 2 inflammatory disease and therapy resistance.

Funder: Public Health Agency of Canada, Funder: Government of Norway, BACKGROUND: In July, 2019, the World Health Organization (WHO) commenced work to update the 2010 Global Recommendations on Physical Activity for Health and established a Guideline Development Group (GDG) comprising expert public health scientists and practitioners to inform the drafting of the 2020 Guidelines on Physical Activity and Sedentary Behavior. The overall task of the GDG was to review the scientific evidence and provide expert advice to the WHO on the amount of physical activity and sedentary behavior associated with optimal health in children and adolescents, adults, older adults (> 64 years), and also specifically in pregnant and postpartum women and people living with chronic conditions or disabilities. METHODS: The GDG reviewed the available evidence specific to each sub-population using systematic protocols and in doing so, identified a number of gaps in the existing literature. These proposed research gaps were discussed and verified by expert consensus among the entire GDG. RESULTS: Evidence gaps across population sub-groups included a lack of information on: 1) the precise shape of the dose-response curve between physical activity and/or sedentary behavior and several of the health outcomes studied; 2) the health benefits of light-intensity physical activity and of breaking up sedentary time with light-intensity activity; 3) differences in the health effects of different types and domains of physical activity (leisure-time; occupational; transportation; household; education) and of sedentary behavior (occupational; screen time; television viewing); and 4) the joint association between physical activity and sedentary time with health outcomes across the life course. In addition, we acknowledge the need to conduct more population-based studies in low- and middle-income countries and in people living with disabilities and/or chronic disease, and to identify how various sociodemographic factors (age, sex, race/ethnicity, socioeconomic status) modify the health effects of physical activity, in order to address global health disparities. CONCLUSIONS: Although the 2020 WHO Guidelines for Physical Activity and Sedentary Behavior were informed by the most up-to-date research on the health effects of physical activity and sedentary time, there is still substantial work to be done in advancing the global physical activity agenda.

This study evaluates the effectiveness of the KiVa antibullying program in the Netherlands through a randomized controlled trial of students in grades 3–4 (Dutch grades 5–6). The sample involved 98 schools who volunteered to participate in the research, with 245 classes and 4383 students at the baseline (49% girls; M age = 8.7 years), who participated in five measurement waves, collected in three consecutive school years. After the baseline, two-thirds of the schools were assigned to the intervention condition (KiVa or KiVa+, the latter included an additional intervention component of network feedback to teachers) and one-third to the control condition (waiting list, care as usual) with a stratified randomization procedure. The effects of the intervention on self-reported victimization and bullying were tested using cross-classified ordered multinomial models and binomial logistic regression models. These longitudinal models showed that self-reported victimization and bullying reduced more strongly in KiVa-schools compared with control schools, with stronger effects after two school years than after one school year of implementation. The results showed that for students in control schools, the odds of being a victim were 1.29–1.63 higher, and the odds of being a bully were 1.19–1.66 higher than for KiVa students. No significant differences between KiVa and KiVa+ emerged. Overall, the findings provide evidence of the effectiveness of the KiVa program in the Netherlands. Electronic supplementary material The online version of this article (10.1007/s11121-020-01116-4) contains supplementary material, which is available to authorized users.

Understanding the sources of the large individual differences in sedentary behavior is of great importance as this behavior is associated with pre-mature mortality and non-communicable diseases. Here, we report on the contribution of genetic and environmental factors to the variation in objectively assessed (accelerometer) sedentary behavior and self-reported sitting and their shared genetic basis. In addition, the overlap of the genetic risk factors influencing sedentary time and moderate-to-vigorous physical activity (MVPA) was estimated. A sample of 800 individuals (twins and their siblings) was equipped with an Actigraph accelerometer for 7 days and reported on their sitting time and time spent on MVPA on those days using the IPAQ-SF. Genetic factors explained 56% (CI: 44%, 65%) of the individual differences in objective sedentary behavior (Actigraph) and 26% (CI: 0%, 51%) of the individual differences in self-reported sedentary behavior (IPAQ-SF). A modest correlation (0.33) was found between these measures, which was for 45% accounted for by genetic influences. The genetic correlation was 0.49 reflecting a partly overlapping set of genes that influenced both measurements. A modest correlation (−0.27) between Actigraph-derived sedentary time and MVPA was found, which was 13% accounted for by genetic effects. The genetic correlation was −0.31, indicating that there are overlapping genetic variants that increase sedentary time and decrease MVPA or vice versa. To conclude, more than half of the individual differences in objective sedentary time could be attributed to genetic differences, while for self-reported sitting this was much lower. In addition, using objective measurements, this study confirms that sedentary time is not simply the inverse of MVPA. Future studies are needed to understand the pathways translating genomic variation into variation in these behaviors and how this knowledge might feed into the development of health promotion interventions.

ObjectiveSit-stand workstations have been shown to be effective in reducing sitting time in office workers. The aim of this study was to explore reasons for use and non-use of sit-stand workstations and strategies to decrease sitting and increase physical activity in the workplace from perspectives of users and non-users, as well as from managers and ergo-coaches.MethodsSix group interviews with employees who have had access to sit-stand workstations for several years were conducted in a large semi-governmental organisation in the Netherlands. Verbatim transcripts were analysed using thematic analysis. Open coding was conducted by three researchers and codes and themes were discussed within the research team.ResultsThematic analysis resulted in two major themes: 1) Reasons for use and non-use and 2) Strategies to increase standing and physical activity in the workplace. Shared and distinct reasons for use and non-use were identified between users and non-users of the sit-stand workstations. The most important reasons for use indicated by users were that they had experiencing immediate benefits, including staying alert and increasing focus; these benefits were not acknowledged by non-users. Non-users indicated that sitting was comfortable for them and that they were therefore not motivated to use the standing option. Strategies to increase the use of the standing option included an introductory phase to become familiar with working while standing and to experience the immediate benefits that come from using the standing option. Furthermore, providing reminders to use the standing option was suggested as a strategy to increase and sustain the use of sit-stand workstations. Increased use may lead to a change in the sitting culture within the organisation, as more employees would adopt active movement behaviours.ConclusionImmediate benefits of the use of the standing option-only mentioned by the users-was the most distinct reason to use sit-stand workstations. Future research should explore how to motivate potential users to adhere to an introductory phase in order to experience these immediate benefits, whether it is linked to the use of sit-stand workstations or other interventions to reduce sitting time.

This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t1/2z∼1.0 h). AUC was 5-6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development. ispartof: NEUROMUSCULAR DISORDERS vol:29 issue:3 pages:167-186 ispartof: location:England status: published

Sit&ndash, stand workstations have shown to reduce sitting time in office workers on a group level. However, movement behaviour patterns might differ between subgroups of workers. Therefore, the objective of this study was to examine sitting, standing and stepping outcomes between habitual users and non-users of sit&ndash, stand workstations. From an international office population based in the Netherlands, 24 users and 25 non-users of sit&ndash, stand workstations were included (all had long-term access to these workstations). Using the ActivPAL, sitting, standing and stepping were objectively measured during and outside working hours. Differences in outcomes between users and non-users were analysed using linear regression. During working hours, users sat less (&minus, 1.64, 95% IC= &minus, 2.27&ndash, &minus, 1.01 hour/8 hour workday) and stood more (1.51, 95% IC= 0.92&ndash, 2.10 hour/8 hour workday) than non-users. Attenuated but similar differences were also found for total sitting time over the whole week. Furthermore, time in static standing bouts was relatively high for users during working hours (median= 0.56, IQR = 0.19&minus, 1.08 hour/8 hour workday). During non-working hours on workdays and during non-working days, no differences were found between users and non-users. During working hours, habitual users of their sit&ndash, stand workstation sat substantially less and stood proportionally more than non-users. No differences were observed outside working hours, leading to attenuated but similar differences in total sitting and standing time between users and non-users for total days. This indicated that the users of sit&ndash, stand workstations reduced their sitting time at work, but this seemed not to be accompanied by major carry-over or compensatory effects outside working hours.

Objective Prolonged sitting, which is highly prevalent in office workers, has been associated with several health risks. The aim of this study was to evaluate the Dynamic Work intervention by determining its effect on total sitting time at the 8-month follow-up in comparison to the control. Methods This two-arm pragmatic cluster randomised controlled trial included 244 office workers from 14 different departments of a large, Dutch insurance company. The Dynamic Work intervention was a real-life, worksite intervention that included environmental components (i.e. sit-stand workstations), organisational components (i.e. group sessions), and individual components (e.g. activity/sitting trackers). Outcomes were assessed at baseline, 4-month follow-up, and 8-month follow-up. The primary outcome was total sitting time per day, objectively assessed using the activPAL activity monitor at 8-month follow-up. Secondary outcomes included other total and occupational movement behaviour outcomes, health-related outcomes, and work-related outcomes. Data analyses were performed using linear and logistic mixed models. Results Total sitting time did not differ between the intervention and control group at the 8-month follow-up. Secondary outcomes also showed no difference between the intervention and control group at either the 4-month or at 8-month follow-up, with the exception of number of occupational steps, which showed a statistically significant effect at 4-month follow-up (but not at 8-month follow-up) of 913 (95% CI = 381–1445) steps/8-h working day. Conclusions This study evaluated the effectiveness of a real-life worksite intervention to reduce sitting time and showed little to no effect. This may be due to the relatively low intensity of the intervention, i.e. that it only involved the replacement of 25% of sitting workstations with sit-stand workstations. Future research should focus on the evaluation of more intensive real-life worksite interventions that are still feasible for implementation in daily practice. Clinicaltrials.gov, registration number NCT03115645 .

Funder: Ministero delle Politiche Agricole Alimentari e Forestali; doi: http://dx.doi.org/10.13039/501100005401, Funder: ZonMw; doi: http://dx.doi.org/10.13039/501100001826, Funder: The Research Council of Norway, Division for Society and Health., Background: Levels of physical activity and variation in physical activity and sedentary time by place and person in European children and adolescents are largely unknown. The objective of the study was to assess the variations in objectively measured physical activity and sedentary time in children and adolescents across Europe. Methods: Six databases were systematically searched to identify pan-European and national data sets on physical activity and sedentary time assessed by the same accelerometer in children (2 to 9.9 years) and adolescents (≥10 to 18 years). We harmonized individual-level data by reprocessing hip-worn raw accelerometer data files from 30 different studies conducted between 1997 and 2014, representing 47,497 individuals (2–18 years) from 18 different European countries. Results: Overall, a maximum of 29% (95% CI: 25, 33) of children and 29% (95% CI: 25, 32) of adolescents were categorized as sufficiently physically active. We observed substantial country- and region-specific differences in physical activity and sedentary time, with lower physical activity levels and prevalence estimates in Southern European countries. Boys were more active and less sedentary in all age-categories. The onset of age-related lowering or leveling-off of physical activity and increase in sedentary time seems to become apparent at around 6 to 7 years of age. Conclusions: Two third of European children and adolescents are not sufficiently active. Our findings suggest substantial gender-, country- and region-specific differences in physical activity. These results should encourage policymakers, governments, and local and national stakeholders to take action to facilitate an increase in the physical activity levels of young people across Europe.

Objectives Increasing physical activity reduces the risk of chronic illness including Type 2 diabetes, cardiovascular disease and certain types of cancer. Lifestyle interventions can increase physical activity but few successfully engage men. This study aims to investigate the 5 year cost-effectiveness of EuroFIT, a program to improve physical activity tailored specifically for male football (soccer) fans compared to a no intervention comparison group. Methods We developed a Markov cohort model in which the impact of improving physical activity on five chronic health conditions (colorectal cancer, Type 2 diabetes, coronary heart disease, stroke and depression) and mortality was modelled. We estimated costs from a societal perspective and expressed benefits as quality adjusted life years (QALYs). We obtained data from a 4-country (England, Netherlands, Portugal and Norway) pragmatic randomised controlled trial evaluating EuroFIT, epidemiological and cohort studies, and meta-analyses. We performed deterministic and probabilistic sensitivity analyses to assess the impact of uncertainty in the model’s parameter values on the cost-effectiveness results. We used Monte Carlo simulations to estimate uncertainty and presented this using cost-effectiveness acceptability curves (CEACs). We tested the robustness of the base case analysis using five scenario analyses. Results Average costs over 5 years per person receiving EuroFIT were €14,663 and per person receiving no intervention €14,598. Mean QALYs over 5 years were 4.05 per person for EuroFIT and 4.04 for no intervention. Thus, the average incremental cost per person receiving EuroFIT was €65 compared to no intervention, while the average QALY gain was 0.01. This resulted in an ICER of €5206 per QALY gained. CEACs show that the probability of EuroFIT being cost-effective compared to no intervention is 0.53, 0.56 and 0.58 at thresholds of €10,000, €22,000 and €34,000 per QALY gained, respectively. When using a time horizon of 10 years, the results suggest that EuroFIT is more effective and less expensive compared to (i.e. dominant over) no intervention with a probability of cost-effectiveness of 0.63 at a threshold of €22,000 per QALY gained. Conclusions We conclude the EuroFIT intervention is not cost-effective compared to no intervention over a period of 5 years from a societal perspective, but is more effective and less expensive (i.e. dominant) after 10 years. We thus suggest that EuroFIT can potentially improve public health in a cost-effective manner in the long term.

Background Digitally enabled rehabilitation may lead to better outcomes but has not been tested in large pragmatic trials. We aimed to evaluate a tailored prescription of affordable digital devices in addition to usual care for people with mobility limitations admitted to aged care and neurological rehabilitation. Methods and findings We conducted a pragmatic, outcome-assessor-blinded, parallel-group randomised trial in 3 Australian hospitals in Sydney and Adelaide recruiting adults 18 to 101 years old with mobility limitations undertaking aged care and neurological inpatient rehabilitation. Both the intervention and control groups received usual multidisciplinary inpatient and post-hospital rehabilitation care as determined by the treating rehabilitation clinicians. In addition to usual care, the intervention group used devices to target mobility and physical activity problems, individually prescribed by a physiotherapist according to an intervention protocol, including virtual reality video games, activity monitors, and handheld computer devices for 6 months in hospital and at home. Co-primary outcomes were mobility (performance-based Short Physical Performance Battery [SPPB]; continuous version; range 0 to 3; higher score indicates better mobility) and upright time as a proxy measure of physical activity (proportion of the day upright measured with activPAL) at 6 months. The dataset was analysed using intention-to-treat principles. The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000936628). Between 22 September 2014 and 10 November 2016, 300 patients (mean age 74 years, SD 14; 50% female; 54% neurological condition causing activity limitation) were randomly assigned to intervention (n = 149) or control (n = 151) using a secure online database (REDCap) to achieve allocation concealment. Six-month assessments were completed by 258 participants (129 intervention, 129 control). Intervention participants received on average 12 (SD 11) supervised inpatient sessions using 4 (SD 1) different devices and 15 (SD 5) physiotherapy contacts supporting device use after hospital discharge. Changes in mobility scores were higher in the intervention group compared to the control group from baseline (SPPB [continuous, 0–3] mean [SD]: intervention group, 1.5 [0.7]; control group, 1.5 [0.8]) to 6 months (SPPB [continuous, 0–3] mean [SD]: intervention group, 2.3 [0.6]; control group, 2.1 [0.8]; mean between-group difference 0.2 points, 95% CI 0.1 to 0.3; p = 0.006). However, there was no evidence of a difference between groups for upright time at 6 months (mean [SD] proportion of the day spent upright at 6 months: intervention group, 18.2 [9.8]; control group, 18.4 [10.2]; mean between-group difference −0.2, 95% CI −2.7 to 2.3; p = 0.87). Scores were higher in the intervention group compared to the control group across most secondary mobility outcomes, but there was no evidence of a difference between groups for most other secondary outcomes including self-reported balance confidence and quality of life. No adverse events were reported in the intervention group. Thirteen participants died while in the trial (intervention group: 9; control group: 4) due to unrelated causes, and there was no evidence of a difference between groups in fall rates (unadjusted incidence rate ratio 1.19, 95% CI 0.78 to 1.83; p = 0.43). Study limitations include 15%–19% loss to follow-up at 6 months on the co-primary outcomes, as anticipated; the number of secondary outcome measures in our trial, which may increase the risk of a type I error; and potential low statistical power to demonstrate significant between-group differences on important secondary patient-reported outcomes. Conclusions In this study, we observed improved mobility in people with a wide range of health conditions making use of digitally enabled rehabilitation, whereas time spent upright was not impacted. Trial registration The trial was prospectively registered with the Australian New Zealand Clinical Trials Register; ACTRN12614000936628

Round window membrane (RWM) application of ouabain is known to selectively destroy type I spiral ganglion cells (SGCs) in cochleas of several rodent species, while leaving hair cells intact. This protocol has been used in rats and Mongolian gerbils, but observations in the guinea pig are conflicting. This is why we reinvestigated the effect of ouabain on the guinea pig cochlea. Ouabain solutions of different concentrations were placed, in a piece of gelfoam, upon the RWM of the right cochleas. Auditory function was assessed using acoustically evoked auditory brainstem responses (aABR). Finally, cochleas were fixed and processed for histological examination. Due to variability within treatment groups, histological data was pooled and three categories based upon general histological observations were defined: cochleas without outer hair cell (OHC) and SGC loss (Category 1), cochleas with OHC loss only (Category 2), and cochleas with OHC and SGC loss (Category 3). Animals treated with 1 mM or 10 mM ouabain showed shifts in hearing thresholds, corresponding with varying histological changes in their cochleas. Most cochleas exhibited complete outer hair cell loss in the basal and middle turns, while some had no changes, together with either moderate or near-complete loss of SGCs. Neither loss of inner hair cells nor histological changes of the stria vascularis were observed in any of the animals. Cochleas in Category 1 had normal aABRs and morphology. On average, in Category 2 OHC loss was 46.0±5.7%, SGC loss was below threshold, ABR threshold shift was 44.9±2.7 dB, and ABR wave II amplitude was decreased by 17.1±3.8 dB. In Category 3 OHC loss was 68.3±6.9%, SGC loss was 49.4±4.3%, ABR threshold shift was 39.0±2.4 dB, and ABR amplitude was decreased by 15.8±1.6 dB. Our results show that ouabain does not solely destroy type I SGCs in the guinea pig cochlea.

Context The hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), orMC4R genes, have been shown to cause early-onset severe obesity. Methods Through a comprehensive epidemiological analysis of known and predicted LoF variants in thePOMC, PCSK1, andLEPR genes, we sought to estimate the number of US individuals with biallelic MC4R pathway LoF variants. Results We predict ~650α-melanocyte-stimulating hormone (MSH)/POMC, 8500PCSK1, and 3600LEPR homozygous and compound heterozygous individuals in the United States, cumulatively enumerating >12,800 MC4R pathway–deficient obese patients. Few of these variants have been genetically diagnosed to date. These estimates increase when we include a small subset of less rare variants:β-MSH/POMC,PCSK1 N221D, and aPCSK1 LoF variant (T640A). To further define the MC4R pathway and its potential impact on obesity, we tested associations between body mass index (BMI) and LoF mutation burden in thePOMC, PCSK1, andLEPR genes in various populations. We show that the cumulative allele burden in individuals with two or more LoF alleles in one or more genes in the MC4R pathway are predisposed to a higher BMI than noncarriers or heterozygous LoF carriers with a defect in only one gene. Conclusions Our analysis represents a genetically rationalized study of the hypothalamic MC4R pathway aimed at genetic patient stratification to determine which obese subpopulations should be studied to elucidate MC4R agonist (e.g., setmelanotide) treatment responsiveness., This is a genetic epidemiology study of melanocortin 4 receptor (MC4R) pathway dysfunction in obesity aimed at genetic patient stratification for clinical study of MC4R agonist treatment responsiveness.

AIM: To assess gender differences in ankylosing spondylitis (AS) patients in relation to tumor necrosis factor alpha inhibitor (TNFi) drug survival and occurrence of adverse events in daily practice in a large peripheral hospital.METHOD: Retrospective data were collected from AS patients treated with etanercept, infliximab and adalimumab between January 2004 and January 2014. Kaplan-Meier survival curves were conducted to describe the drug survival and occurrence of adverse events in time.RESULTS: Overall, 122 AS patients (60.7% male) were included over a 10-year time period, with a mean treatment period of 51 months (1-127 months). In total, 21 (17.2%) patients stopped the TNFi, mainly due to inefficacy (52.4%). Female patients showed a significant shorter treatment period compared to males (33.4 vs. 44.9 months). In addition, female patients switched more between TNFi compared to males (26.9% vs. 16.3%) and had a significantly higher risk at developing infections compared to male patients (26% vs.19%).CONCLUSION: Females stayed on the same TNFi for a significantly shorter period compared to males (33.4 vs. 44.9 months) and the most important reason to stop or switch the drug was inefficacy. Moreover, females seemed to be more prone to infections during TNFi treatment than males.

Purpose. Pedometers, which enable self-monitoring of step counts, are effective in facilitating increases in physical activity. Similar devices which provide real-time feedback on sedentary (sitting) behavior are limited. This study aimed to develop and validate a novel device – the SitFIT – which could accurately measure and provide feedback on sedentary behavior and physical activity. Methods. The SitFIT is a tri-axial accelerometer, developed by PAL Technologies, which is worn in the front trouser pocket. This enables tracking of thigh inclination and therefore differentiation between sitting and upright postures, as well as tracking of step count. It has a display to provide user feedback. To determine the validity of the SitFIT for measuring sedentary behavior and step counts, 21 men, aged 30-65 years, with body mass index 26.6±3.9 kg.m-2 wore a SitFIT in a front trouser pocket and an activPAL accelerometer attached to their thigh for up to seven days. Outputs from the SitFIT were compared with the activPAL, which was assumed to provide gold-standard measurements of sitting and step counts. Results. Mean step counts were ~4% lower with the SitFIT than activPAL, with correlation between the two methods being very high (r=0.98) and no obvious bias from the line of equality (regression line: y=1.0035x+418.35). Mean sedentary time was ~5% higher with the SitFIT than activPAL, correlation between methods was high (r=0.84) and the equation of the regression line was close to the line of equality (y=0.8728x+38.445). Conclusions. The SitFIT has excellent validity for measurement of free-living step counts and sedentary time and therefore addresses a clear need for a device that can be used as a tool to provide feedback on sedentary behavior to facilitate behavior change. Keywords: sedentary; sitting; objective measurement; validation;behavior change

Objectives Pompe disease is a progressive metabolic myopathy for which enzyme replacement therapy (ERT) was approved in 2006. While various publications have examined the effects of ERT in classic-infantile patients and in adults, little has been published on ERT in children with non-classic presentations. Study design This prospective study was conducted from June 1999 to May 2015. Seventeen patients from various countries participated. Outcome measures comprised muscle function (6-minute walk test, quick motor-function test (QMFT)), muscle strength (hand-held dynamometry; manual muscle testing), and lung function (FVC sitting and supine). For each outcome measure, we used linear mixed-effects models to calculate the difference at group level between the start of therapy and 7 years of ERT. Patients’ individual responses over time were also evaluated. Results Eleven males and six females started ERT at ages between 1.1 and 16.4 years (median 11.9 years); 82% of them carried the common c.-32-13T > G GAA gene variant on one allele. At group level, distance walked increased by 7.4 percentage points (p

Background The loss of the ability to walk is among the most prominent signs of Pompe disease. The associations with muscle strength have not been described. Objective The objective of this study was to estimate the associations of walking performance with muscle strength in 4 specific lower extremity muscle groups along with other factors in adult patients with Pompe disease. Design This was a single-center, cross-sectional study. Methods Muscle strength (hand-held dynamometry of hip flexion and abduction and knee extension and flexion) and walking performance (unable to walk, able with aids, walking without aids but with a waddling gait, or walking without aids and with a normal gait) were assessed in 107 patients at their first visit. Relationships between walking performance and muscle strength were studied through multivariate analyses and regression modeling. Age, sex, body mass index (BMI), disease duration, and use of ventilator support were taken into account as potential confounders. The results were transformed into a nomogram to allow the probability of a patient having a certain level of walking performance to be calculated based on the values of the independent variables. Results Walking performance declined significantly with decreasing muscle strength of hip flexion and abduction and knee extension and flexion. The final selected model, including strength of the hip abductor and knee extensor, BMI, age, sex, and use of ventilation, predicted 66% of the cases accurately. Limitations These results are based on cross-sectional data and do not predict future changes. Conclusions In adult people with Pompe disease, walking performance can be explained by muscle strength, BMI, age, sex, and ventilation use. The proposed model gives insight into how an individual is expected to walk based on his or her risk factors and serves as a starting point to unraveling factors associated with walking performance and ultimately to developing a prognostic model.

Pompe disease is a rare metabolic disorder caused by a deficiency of the lysosomal enzyme acid α-glucosidase. Glycogen accumulation damages skeletal, cardiac, and smooth muscles, causing a progressive and debilitating muscle weakness and cardiomyopathy. As life expectancy has much improved since the introduction of enzyme replacement therapy an increasing number of patients are referred for surgical procedures. Due to the potential cardiopulmonary complications, these patients form a high-risk group for the anesthesiologist.In this study, we investigated the incidence of perioperative complications in children with Pompe disease treated in our hospital since the introduction of enzyme replacement therapy.Anesthetic and perioperative data of children with Pompe disease treated between 1999 and 2015 in the Erasmus MC-Sophia Children's Hospital, University Medical Centre, Rotterdam, The Netherlands, were collected, retrospectively.Of the 65 children with Pompe disease, 34 patients underwent in total 77, mostly low-risk, surgical procedures. Twenty-one children had the classic infantile form and 13 had a nonclassic presentation of Pompe disease. In 13 (16.8%) procedures, 1 or more perioperative complications occurred. Perioperative desaturation was the main complication (12.9%), followed by arrhythmia (3.8%) and heart failure requiring diuretic treatment (2.6%). One child died 2 days postoperatively, but this was considered unrelated to the procedure.Despite the potentially high anesthetic risk for children with Pompe disease under enzyme replacement therapy, the incidence of perioperative complications in our study was relatively low. Our data suggest that with proper precautionary measures and a critical choice of timing of the operation, general anesthesia in children with Pompe disease could be relatively safe nowadays.

BACKGROUND: The aging work force makes sustainable employability (SE) of workers a priority. However, it is unknown to what extent employees use implemented SE measures.OBJECTIVE: To determine the utilization of 1) SE measures offered by employers, 2) employee SE strategies, and 3) to identify barriers and facilitators of SE strategies.METHODS: Survey data were collected among 731 blue collar and 879 white collar workers to determine the utilization of employer SE measures. Focus groups were held with 16 blue collar and 17 white collar workers to identify employee SE strategies and their barriers and facilitators.RESULTS: Utilization of employer SE measures was highest for personal development measures. Strategies applied by blue collar workers included using equipment, suggesting improvements of their working conditions, and seeking promotion to a less physically demanding job. White collar workers named engaging in leisure time physical activity and seeking an adequate work-life balance. Implementation of these strategies was influenced by employee awareness and self-efficacy, the accessibility and costs and benefits of the strategy, management support and company culture.CONCLUSION: Usage of employer SE measures was generally low and recommendations are given for both blue and white collar workers to improve SE strategies.

Netta Van’t Leven,1 Jacomine de Lange,1 Eva S van der Ploeg,2 Anne Margriet Pot3,4 1Research Centre Innovations in Care, Rotterdam University of Applied Sciences, Rotterdam, the Netherlands; 2Department of Public Health & Primary Care, Leiden University Medical Center, Leiden, the Netherlands; 3Department of Clinical Psychology, Vrije Universiteit, Amsterdam, the Netherlands; 4Amsterdam Public Health Research Institute, Amsterdam, the Netherlands Background: People living with dementia (PWD) and their informal caregivers often report difficulties in maintaining their usual activities. Several dyadic, psychosocial, activating interventions were developed to create insight into how to cope with limitations in a practical way and to increase skills for maintaining personal activities. Effects of these interventions varied so far. More knowledge on the working mechanisms of activating interventions might help to increase their impact. This study will provide more insights into the working mechanisms of three dyadic, psychosocial, activating interventions as the participating PWD, caregivers, and coaches perceived them during the interventions. Participants and methods: We used a qualitative design with semi-structured interviews of 34 dyads that included 27 PWD, 34 caregivers, and 19 coaches. The data were analyzed with the constant comparative method. Results: Many PWD and caregivers found capacity-building approaches beneficial. We identified “empowerment” as the core theme. Three working mechanisms explained why the interventions were perceived as having a beneficial impact: 1) enabling activities without providing false hope; 2) exploring the most important personal activity needs of the PWD and caregivers; and 3) a solution-focused approach to adapt, test, and practice activities. An individualized approach contributed to positive change. Conclusion: For the overarching working mechanism empowerment, expertise in the field of dementia and psychological skills of coaches seem to be important. Assessing the needs, capacities, and limitations of both the PWD and the caregivers to take part in activities seems to be key, as well as the communication about it and the skills to teach a solution-focused approach. Studies on the impact of psychosocial and activating interventions might benefit from considering outcome measures directed at empowerment, along with aspects such as hope and belief in one’s own capacities versus traditional outcome measures as mood, burden, or quality of life. Keywords: occupational therapy, exercise, pleasant events, psychosocial interventions, working mechanisms, components