Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure

<p>Abstract</p> <p>Background</p> <p>Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder that results in the accumulation of glycosaminoglycans causing progressive multi-organ dysfunction. Its clinical spectrum is very broad and varies from the severe Hurler phenotype (MPS I-H) which is characterized by early and progressive central nervous system (CNS) involvement to the attenuated Scheie phenotype (MPS I-S) with no CNS involvement. Indication, optimal timing, safety and efficacy of the two available treatment options for MPS I, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), are subject to continuing debate. A European consensus procedure was organized to reach consensus about the use of these two treatment strategies.</p> <p>Methods</p> <p>A panel of specialists, including 8 specialists for metabolic disorders and 7 bone marrow transplant physicians, all with acknowledged expertise in MPS I, participated in a modified Delphi process to develop consensus-based statements on MPS I treatment. Fifteen MPS I case histories were used to initiate the discussion and to anchor decisions around either treatment mode. Before and at the meeting all experts gave their opinion on the cases (YES/NO transplantation) and reasons for their decisions were collected. A set of draft statements on MPS I treatment options composed by a planning committee were discussed and revised during the meeting until full consensus.</p> <p>Results</p> <p>Full consensus was reached on several important issues, including the following: 1) The preferred treatment for patients with MPS I-H diagnosed before age 2.5 yrs is HSCT; 2) In individual patients with an intermediate phenotype HSCT may be considered if there is a suitable donor. However, there are no data on efficacy of HSCT in patients with this phenotype; 3) All MPS I patients including those who have not been transplanted or whose graft has failed may benefit significantly from ERT; 4) ERT should be started at diagnosis and may be of value in patients awaiting HSCT.</p> <p>Conclusions</p> <p>This multidisciplinary consensus procedure yielded consensus on the main issues related to therapeutic choices and research for MPS I. This is an important step towards an international, collaborative approach, the only way to obtain useful evidence in rare diseases.</p

Systemic hydrocortisone to prevent bronchopulmonary dysplasia in preterm infants (the SToP-BPD study); a multicenter randomized placebo controlled trial

<p>Abstract</p> <p>Background</p> <p>Randomized controlled trials have shown that treatment of chronically ventilated preterm infants after the first week of life with dexamethasone reduces the incidence of the combined outcome death or bronchopulmonary dysplasia (BPD). However, there are concerns that dexamethasone may increase the risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. So far no randomized controlled trial has investigated its efficacy when administered after the first week of life to ventilated preterm infants.</p> <p>Methods/Design</p> <p>The SToP-BPD trial is a randomized double blind placebo controlled multicenter study including 400 very low birth weight infants (gestational age < 30 weeks and/or birth weight < 1250 grams), who are ventilator dependent at a postnatal age of 7 - 14 days. Hydrocortisone (cumulative dose 72.5 mg/kg) or placebo is administered during a 22 day tapering schedule. Primary outcome measure is the combined outcome mortality or BPD at 36 weeks postmenstrual age. Secondary outcomes are short term effects on the pulmonary condition, adverse effects during hospitalization, and long-term neurodevelopmental sequelae assessed at 2 years corrected gestational age. Analysis will be on an intention to treat basis.</p> <p>Discussion</p> <p>This trial will determine the efficacy and safety of postnatal hydrocortisone administration at a moderately early postnatal onset compared to placebo for the reduction of the combined outcome mortality and BPD at 36 weeks postmenstrual age in ventilator dependent preterm infants.</p> <p>Trial registration number</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2768">NTR2768</a></p

Development of an international standard set of patient-centred outcome measures for overall paediatric health: a consensus process

Objective: To develop an Overall Pediatric Health Standard Set (OPH-SS) of outcome measures that captures what matters to young people and their families and recognising the biopsychosocial aspects of health for all children and adolescents regardless of health condition. Design: A modified Delphi process. Setting: The International Consortium for Health Outcomes Measurement convened an international Working Group (WG) comprised of 23 international experts from 12 countries in the field of paediatrics, family medicine, psychometrics as well as patient advisors. The WG participated in 11 video-conferences, through a modified Delphi process and 9 surveys between March 2018 and January 2020 consensus was reached on a final recommended health outcome standard set. By a literature review conducted in March 2018, 1136 articles were screened for clinician and patient-reported or proxy-reported outcomes. Further, 4315 clinical trials and 12 paediatric health surveys were scanned. Between November 2019 and January 2020, the final standard set was endorsed by a patient validation (n=270

Algorithms for radio interference detection and removal

Tijdens dit onderzoek hebben we gekeken naar de invloed van storing door menselijke apparatuur op radioastronomie. Radiosterrenwachten zoals Westerbork kunnen de hemel met een enorme gevoeligheid en resolutie in kaart brengen. Vaak bestaan zulke sterrenwachten uit een aantal grote schotelantennes. Echter, nieuwe technologische ontwikkelingen hebben ervoor gezorgd dat op lage frequenties vele kleine antennes efficiënt gecombineerd kunnen worden tot een grote schoteltelescoop. LOFAR is een nieuwe, deels-Nederlandse supertelescoop die gebruik maakt van dit principe. Deze telescoop bestaat uit tientallen velden gevuld met vele antennetjes, verspreid over Nederland en omringende landen. Het centrum van LOFAR bevindt zich in de buurt van het Drentse dorp Exloo. Radiotelescopen worden meestal in zeer afgelegen gebieden geplaatst, omdat menselijke apparatuur storing veroorzaakt. Het bouwen van een radiotelescoop op afgelegen locaties is echter niet goedkoop. LOFAR is een nieuwe weg ingeslagen en bevat antennevelden op diverse plaatsen in ons druk bevolkte land. Een belangrijke vraag was daardoor of de storing van menselijke apparatuur niet schadelijk zou zijn voor LOFAR-observaties. In dit proefschrift beantwoorden we deze vraag. We hebben volledig geautomatiseerde technieken ontworpen om storing te verwijderen. Met deze nieuwe technieken weten we de storing op zeer accurate wijze te scheiden van het hemelsignaal. We analyseren de gefilterde data en concluderen dat, na toepassing van deze technieken, we in staat zijn om zeer gevoelige hemelkaarten te maken met LOFAR. Daarmee lijkt het dus een goede keuze geweest te zijn om LOFAR in Nederland te bouwen. This project concerns the effects of interference on radio astronomy caused by human devices. Radio astronomy is a challenging astronomical application and with its help, many surprising details of our Universe have been discovered. Modern radio telescopes can observe the sky with an enormous sensitivity and resolution. To achieve this, observatories are often composed of large dishes. Because of several technological advancements, on low frequenties it has become very efficient to synthesize many small antennas into one large telescope. LOFAR is a new telescope that makes use of this idea. It consists of tens of antenna fields, which are spread over the Netherlands and several neighbouring countries. LOFAR’s centre is near the city of Exloo in the Dutch province of Drenthe. Human devices can interfere with radio astronomical observations. Therefore, telescopes are often build in remote areas with a very low population density. However, building telescopes at remote locations is costly. LOFAR has taken a different approach by building antenna fields all over populated areas of the Netherlands. This has raised concerns about the harmful effects that human hardware could cause. This thesis addresses these concerns. We have designed several automated methods that can filter interference from radio observations. The techniques remove the interference from the data with an unprecendented accuracy. We extensively analyse the resulting data and conclude that after the application of our filters, we can make very sensitive sky maps with LOFAR. Consequently, it appears it was an excellent decision to build LOFAR in the Netherlands.

Neurodevelopment after neonatal hypoglycemia: a systematic review and design of an optimal future study

OBJECTIVE: Our goal was to assess the effect of episodes of neonatal hypoglycemia on subsequent neurodevelopment. METHODS: We searched Medline and Embase for cohort studies on subsequent neurodevelopment after episodes of hypoglycemia in the first week of life. Reference lists of available studies were reviewed, and content experts were contacted for additional studies. Included studies were selected and appraised for methodologic quality by 2 reviewers. Methodologic quality was assessed according to well-accepted criteria for prognostic studies. Eventually, all studies were given an overall quality score: poor, moderate, or high quality. Studies in the latter 2 categories were considered for quantitative data analysis. RESULTS: Eighteen eligible studies were identified. The overall methodologic quality of the included studies was considered poor in 16 studies and high in 2 studies. Pooling of results of the 2 high-quality studies was deemed inappropriate because of major clinical and methodologic heterogeneity. None of the studies provided a valid estimate of the effect of neonatal hypoglycemia on neurodevelopment. Building on the strengths and weaknesses of existing studies, we developed a proposal for an "optimal" future study design. CONCLUSIONS: Recommendations for clinical practice cannot be based on valid scientific evidence in this field. To assess the effect of neonatal hypoglycemia on subsequent neurodevelopment, a well-designed prospective study should be undertaken. We submit a design for a study that may answer the still-open question

Open-label glucocorticoids modulate dexamethasone trial results in preterm infants

CONTEXT: Open-label glucocorticoids (OLGs) were often used in trials that investigated postnatal dexamethasone treatment in ventilated preterm infants. OBJECTIVE: To determine if OLG use modulates the dexamethasone treatment effect on mortality, bronchopulmonary dysplasia (BPD), and neurodevelopmental outcome. METHODS: Electronic databases, abstracts from the Pediatric Academic Societies, and results of manual reference searches were used as data sources. Fifteen randomized controlled trials comparing dexamethasone with placebo in 721 ventilated preterm infants older than 7 days were identified. The interaction between dexamethasone treatment effect and OLG use was assessed by meta-regression analysis and subgroup meta-analysis according to the percentage of OLG use in the placebo group. Trials with a moderately early (7- to 14-day) or delayed (>3-week) treatment onset were analyzed separately. RESULTS: Moderately early, but not delayed, dexamethasone treatment significantly reduced mortality rates in trials with OLG use at <30% in the placebo arm. Meta-regression analysis revealed that this reduction was inversely related to OLG use. Increasing OLG use strengthened the positive effect of dexamethasone on BPD in the moderately early trials but attenuated the effect in the delayed-treatment trials. In trials with <30% OLG use, dexamethasone increased the risk for cerebral palsy in the delayed, but not the moderately early, treatment trials. CONCLUSIONS: When OLG use is taken into account moderately early dexamethasone treatment reduced mortality rates and the combined outcome mortality and BPD without increasing the risk of adverse neurodevelopmental outcome in ventilated preterm infants. A large randomized controlled trial is needed to confirm or refute these finding

An INDEHISCENT-Controlled Auxin Response Specifies the Separation Layer in Early Arabidopsis Fruit

Seed dispersal is an important moment in the life cycle of a plant species. In Arabidopsis thaliana, it is dependent on transcription factor INDEHISCENT (IND)-mediated specification of a separation layer in the dehiscence zone found in the margin between the valves (carpel walls) and the central replum of the developing fruit. It was proposed that IND specifies the separation layer by inducing a local auxin minimum at late stages of fruit development. Here we show that morphological differences between the ind mutant and wild-type fruit already arise at early stages of fruit development, coinciding with strong IND expression in the valve margin. We show that IND-reduced PIN-FORMED3 (PIN3) auxin efflux carrier abundance leads to an increased auxin response in the valve margin during early fruit development, and that the concomitant cell divisions that form the dehiscence zone are lacking in ind mutant fruit. Moreover, IND promoter-driven ectopic expression of the AGC kinases PINOID (PID) and WAG2 induced indehiscence by expelling auxin from the valve margin at stages 14-16 of fruit development through increased PIN3 abundance. Our results show that IND, besides its role at late stages of Arabidopsis fruit development, functions at early stages to facilitate the auxin-triggered cell divisions that form the dehiscence zone

Effects of higher versus lower dexamethasone doses on pulmonary and neurodevelopmental sequelae in preterm infants at risk for chronic lung disease: a meta-analysis

OBJECTIVES: Systemic postnatal dexamethasone treatment reduces the risk of chronic lung disease in preterm infants but also may be associated with increased risk of neurodevelopmental impairment. Because it is not known whether these effects are modulated by the cumulative dexamethasone dose, we systematically reviewed the available randomized evidence on the effects of lower versus higher cumulative dexamethasone doses, in terms of death, pulmonary morbidity, and neurodevelopmental outcomes, in preterm infants. METHODS: Randomized, controlled trials comparing higher- versus lower-dosage dexamethasone regimens in ventilated preterm infants were identified by searching the main electronic databases, references from relevant studies, and abstracts from the Societies for Pediatric Research (from 1990 onward). Eligibility and quality of trials were assessed, and data on study design, patient characteristics, and relevant outcomes were extracted. RESULTS: Six studies that enrolled a total of 209 participants were included; 2 studies contrasted cumulative dexamethasone doses in the higher ranges (>2.7 mg/kg in the higher-dosage regimen) and 4 in the lower ranges ( <or=2.7 mg/kg in the higher-dosage regimen). Meta-analysis revealed no effect of dexamethasone dose on rates of death and neurodevelopmental sequelae in these 2 subgroups. Subgroup analysis of the studies contrasting dexamethasone doses in the higher ranges showed that the higher dose of dexamethasone was more effective in reducing the occurrence of chronic lung disease than was the lower dose. Interpretation of these data was hampered by the small samples of randomly assigned children, heterogeneity of study populations and designs, use of late rescue glucocorticoids, and lack of long-term neurodevelopmental data in some studies. CONCLUSIONS: Recommendations for optimal dexamethasone doses for preterm infants at risk for chronic lung disease cannot be based on current evidence. A well-designed, large, randomized, controlled trial is urgently needed to establish the optimal dexamethasone dosage regime