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Severe asthma in children carries an unacceptable treatment burden, yet its rarity means clinical experience in treating it is limited, even among specialists. Practical guidance is needed to support clinical decision-making to optimize treatment for children with this condition. This modified Delphi convened 16 paediatric pulmonologists and allergologists from northern Europe, all experienced in treating children with severe asthma. Informed by interviews with stakeholders involved in the care of children with severe asthma (including paediatricians, nurses and carers), and an analysis of European guidelines, the experts built a consensus focused on the gaps in existing guidance. Explored were considerations for optimizing care for patients needing biologic treatment, and for selecting home or hospital delivery of biologics. This consensus is aimed at clinicians in specialist centres, as well as general paediatricians, paediatric allergologists and paediatric pulmonologists who refer children with the most severe asthma to specialist care. Consensus is based on expert opinion and is intended for use alongside published guidelines. Our discussions revealed three key facets to optimizing care. Firstly, early asthma detection in children presenting with wheezing and/or dyspnoea is vital, with a low threshold for referral from primary to specialist care. Secondly, children who may need biologics should be referred to and managed by specialist paediatric asthma centres; we define principles for the specialist team members, tests, and expertise necessary at such centres, as well as guidance on when homecare biologics delivery is and is not appropriate. Thirdly, shared decision-making is essential at all stages of the patient’s journey: clear, concise treatment plans are vital for patient/carer self-management, and structured processes for transition from paediatric to adult services are valuable. The experts identified the potential for specialist paediatric asthma nu

Item does not contain fulltext, PURPOSE OF REVIEW: We highlight the recent advances in home monitoring of patients with asthma, and show that these advances converge towards the implementation of digital twin systems. RECENT FINDINGS: Connected devices for asthma are increasingly numerous, reliable and effective: new electronic monitoring devices extend to nebulizers and spacers, are able to assess the quality of the inhalation technique, and to identify asthma attack triggers when they include a geolocation function; environmental data can be acquired from databases and refined by wearable air quality sensors; smartwatches are better validated. Connected devices are increasingly integrated into global monitoring systems. At the same time, machine learning techniques open up the possibility of using the large amount of data collected to obtain a holistic assessment of asthma patients, and social robots and virtual assistants can help patients in the daily management of their asthma. SUMMARY: Advances in the internet of things, machine learning techniques and digital patient support tools for asthma are paving the way for a new era of research on digital twins in asthma.

A key test of the isotropy of the Universe on large scales consists in comparing the dipole in the Cosmic Microwave Background (CMB) temperature with the dipole in the distribution of sources at low redshift. Current analyses find a dipole in the number counts of quasars and radio sources that is 2-5 times larger than expected from the CMB, leading to a tension reaching 5$\sigma$. In this paper, we derive a consistent framework to measure the dipole independently from gravitational wave (GW) detections. We exploit the fact that the observer velocity does not only change the distribution of events in the sky, but also the luminosity distance and redshifted chirp mass, that can be extracted from the GW waveform. We show that the estimator with higher signal-to-noise ratio is the dipole in the chirp mass measured from a population of binary neutron stars. Combining all estimators (accounting for their covariance) improves the detectability of the dipole by 30-50 percent compared to number counting of binary black holes alone. We find that a few $10^6$ events are necessary to detect a dipole consistent with the CMB one, whereas if the dipole is as large as predicted by radio sources, it will already be detectable with $10^5$ events, which would correspond to a single year of observation with next generation GW detectors. GW sources provide therefore a robust and independent way of testing the isotropy of the Universe., Comment: 17 pages, 11 figures, accepted for publication in MNRAS; minor revision compared to Version 1

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Contains fulltext : 287923.pdf (Publisher’s version ) (Open Access)

The Paediatric Assembly of the European Respiratory Society (ERS) maintained its high profile at the 2015 ERS International Congress in Amsterdam. There were symposia on preschool wheeze, respiratory sounds and cystic fibrosis; an educational skills workshop on paediatric respiratory resuscitation; a hot topic session on risk factors and early origins of respiratory diseases; a meet the expert session on paediatric lung function test reference values; and the annual paediatric grand round. In this report the Chairs of the Paediatric Assembly's Groups highlight the key messages from the abstracts presented at the Congress.

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Contains fulltext : 96409.pdf (publisher's version ) (Open Access), OBJECTIVE: In type 2 diabetes mellitus (T2DM), oxidative stress gives rise to endothelial dysfunction. Bilirubin, a powerful endogenous antioxidant, significantly attenuates endothelial dysfunction in preclinical experiments. The Gilbert syndrome is accompanied by a mild and lifelong hyperbilirubinemia and associated with only one third of the usual cardiovascular mortality risk. The hyperbilirubinemia caused by atazanavir treatment closely resembles the Gilbert syndrome. We thus hypothesized that treatment with atazanavir would ameliorate oxidative stress and vascular inflammation and improve endothelial function in T2DM. METHODS AND RESULTS: In a double-blind, placebo-controlled crossover design, we induced a moderate hyperbilirubinemia by a 3-day atazanavir treatment in 16 subjects experiencing T2DM. On the fourth day, endothelial function was assessed by venous occlusion plethysmography. Endothelium-dependent and endothelium-independent vasodilation were assessed by intraarterial infusion of acetylcholine and nitroglycerin, respectively. Atazanavir treatment induced an increase in average bilirubin levels from 7 mumol/L (0.4 mg/dL) to 64 mumol/L (3.8 mg/dL). A significant improvement in plasma antioxidant capacity (P<0.001) and endothelium-dependent vasodilation (P=0.036) and a decrease in plasma von Willebrand factor (P=0.052) were observed. CONCLUSIONS: Experimental hyperbilirubinemia is associated with a significant improvement of endothelial function in T2DM.

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Contains fulltext : 96409.pdf (publisher's version ) (Open Access), OBJECTIVE: In type 2 diabetes mellitus (T2DM), oxidative stress gives rise to endothelial dysfunction. Bilirubin, a powerful endogenous antioxidant, significantly attenuates endothelial dysfunction in preclinical experiments. The Gilbert syndrome is accompanied by a mild and lifelong hyperbilirubinemia and associated with only one third of the usual cardiovascular mortality risk. The hyperbilirubinemia caused by atazanavir treatment closely resembles the Gilbert syndrome. We thus hypothesized that treatment with atazanavir would ameliorate oxidative stress and vascular inflammation and improve endothelial function in T2DM. METHODS AND RESULTS: In a double-blind, placebo-controlled crossover design, we induced a moderate hyperbilirubinemia by a 3-day atazanavir treatment in 16 subjects experiencing T2DM. On the fourth day, endothelial function was assessed by venous occlusion plethysmography. Endothelium-dependent and endothelium-independent vasodilation were assessed by intraarterial infusion of acetylcholine and nitroglycerin, respectively. Atazanavir treatment induced an increase in average bilirubin levels from 7 mumol/L (0.4 mg/dL) to 64 mumol/L (3.8 mg/dL). A significant improvement in plasma antioxidant capacity (P<0.001) and endothelium-dependent vasodilation (P=0.036) and a decrease in plasma von Willebrand factor (P=0.052) were observed. CONCLUSIONS: Experimental hyperbilirubinemia is associated with a significant improvement of endothelial function in T2DM.

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Contains fulltext : 96409.pdf (publisher's version ) (Open Access), OBJECTIVE: In type 2 diabetes mellitus (T2DM), oxidative stress gives rise to endothelial dysfunction. Bilirubin, a powerful endogenous antioxidant, significantly attenuates endothelial dysfunction in preclinical experiments. The Gilbert syndrome is accompanied by a mild and lifelong hyperbilirubinemia and associated with only one third of the usual cardiovascular mortality risk. The hyperbilirubinemia caused by atazanavir treatment closely resembles the Gilbert syndrome. We thus hypothesized that treatment with atazanavir would ameliorate oxidative stress and vascular inflammation and improve endothelial function in T2DM. METHODS AND RESULTS: In a double-blind, placebo-controlled crossover design, we induced a moderate hyperbilirubinemia by a 3-day atazanavir treatment in 16 subjects experiencing T2DM. On the fourth day, endothelial function was assessed by venous occlusion plethysmography. Endothelium-dependent and endothelium-independent vasodilation were assessed by intraarterial infusion of acetylcholine and nitroglycerin, respectively. Atazanavir treatment induced an increase in average bilirubin levels from 7 mumol/L (0.4 mg/dL) to 64 mumol/L (3.8 mg/dL). A significant improvement in plasma antioxidant capacity (P<0.001) and endothelium-dependent vasodilation (P=0.036) and a decrease in plasma von Willebrand factor (P=0.052) were observed. CONCLUSIONS: Experimental hyperbilirubinemia is associated with a significant improvement of endothelial function in T2DM.

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Dat de Tridentijnse Mis in 1971 voorgoed zou verdwijnen, was voor velen aanleiding om bij paus Paulus VI te protesteren. Zelfs zijn eigen trouwe kardinalen, zoals Alfredo Ottaviani en Antonio Bacci, kropen in de pen en schreven, ondanks zijn onfeilbaarheid, een open brief aan de heilige vader. Maar zij waren niet de enigen. Het protest werd niet alleen vanwege de theologische of liturgische waarde van de Mis gevoerd. In Engeland verzamelde de culturele elite zich, om voor het behoud van de oude Tridentijnse Mis te pleiten. Het is inmiddels duidelijk waarom nu juist in Engeland werd gepleit voor het behoud van de Tridentijnse Mis. Allereerst is er de bijzondere waarde die de Latijnse Mis had voor de Engelsen, en dan met name de Tridentijnse variant, die zou worden afgeschaft. Nadat door de Reformatie de Mis was verboden, waren meerdere Engelse priesters en leken de marteldood gestorven. In 1970, kort voordat de petitie werd uitgevaardigd, werden veertig van deze martelaren door paus Paulus heilig verklaard. Zij waren gestorven om de Latijnse Mis te behouden, en door de afschaffing van de Tridentijnse Mis zou hun levenswerk en erfenis worden vernietigd. Een tweede reden voor de bijzondere band met de Tridentijnse Mis heeft eveneens te maken met de uitzonderlijke geschiedenis van de Rooms-katholieke Kerk in Engeland. Een langdurig en moeizaam proces van emancipatie werd voltooid, toen kardinaal Nicholas Wiseman de Tridentijnse Mis in Engeland invoerde. Een andere reden voor het opkomen van een protestbeweging in Engeland ligt in het daar ontstane debat over de waarde van geschiedenis in de samenleving, het door mij benoemde proto-erfgoeddebat. Doordat sinds de jaren vijftig een hausse aan bouwwerken en voorwerpen voor vernietiging waren behouden, vanwege hun erfgoedwaarde, kwam een reactie op gang die zich deels afkeerde en deels de idealen van deze Preservation Mania toe-eigende. In de petitie wierpen de ondertekenaars zich op voor het behoud van een immaterieel erfgo

Dat de Tridentijnse Mis in 1971 voorgoed zou verdwijnen, was voor velen aanleiding om bij paus Paulus VI te protesteren. Zelfs zijn eigen trouwe kardinalen, zoals Alfredo Ottaviani en Antonio Bacci, kropen in de pen en schreven, ondanks zijn onfeilbaarheid, een open brief aan de heilige vader. Maar zij waren niet de enigen. Het protest werd niet alleen vanwege de theologische of liturgische waarde van de Mis gevoerd. In Engeland verzamelde de culturele elite zich, om voor het behoud van de oude Tridentijnse Mis te pleiten. Het is inmiddels duidelijk waarom nu juist in Engeland werd gepleit voor het behoud van de Tridentijnse Mis. Allereerst is er de bijzondere waarde die de Latijnse Mis had voor de Engelsen, en dan met name de Tridentijnse variant, die zou worden afgeschaft. Nadat door de Reformatie de Mis was verboden, waren meerdere Engelse priesters en leken de marteldood gestorven. In 1970, kort voordat de petitie werd uitgevaardigd, werden veertig van deze martelaren door paus Paulus heilig verklaard. Zij waren gestorven om de Latijnse Mis te behouden, en door de afschaffing van de Tridentijnse Mis zou hun levenswerk en erfenis worden vernietigd. Een tweede reden voor de bijzondere band met de Tridentijnse Mis heeft eveneens te maken met de uitzonderlijke geschiedenis van de Rooms-katholieke Kerk in Engeland. Een langdurig en moeizaam proces van emancipatie werd voltooid, toen kardinaal Nicholas Wiseman de Tridentijnse Mis in Engeland invoerde. Een andere reden voor het opkomen van een protestbeweging in Engeland ligt in het daar ontstane debat over de waarde van geschiedenis in de samenleving, het door mij benoemde proto-erfgoeddebat. Doordat sinds de jaren vijftig een hausse aan bouwwerken en voorwerpen voor vernietiging waren behouden, vanwege hun erfgoedwaarde, kwam een reactie op gang die zich deels afkeerde en deels de idealen van deze Preservation Mania toe-eigende. In de petitie wierpen de ondertekenaars zich op voor het behoud van een immaterieel erfgo

This European Respiratory Society task force has reviewed the evidence for paediatric medicines in respiratory disease occurring in adults and children. We describe off-licence use, research priorities and ongoing studies. Off-licence and off-label prescribing in children is widespread and potentially harmful. Research areas in asthma include novel formulations and regimens, and individualised prescribing. In cystic fibrosis, future studies will focus on screened infants and robust outcome measures are needed. Other areas include new enzyme and antibiotic formulations and the basic defect. Research into pneumonia should include evaluation of new antibacterials and regimens, rapid diagnostic tests and, in pleural infection, antibiotic penetration, fibrinolytics and surveillance. In uncommon conditions, such as primary ciliary dyskinesia, congenital pulmonary abnormalities or neuromuscular disorders, drugs indicated for other conditions (e.g. dornase alfa) are commonly used and trials are needed. In neuromuscular disorders, the beta-agonists may enhance muscle strength and are in need of evaluation. Studies of antibiotic prophylaxis, immunoglobulin and antifungal drugs are needed in immune deficiency. We hope that this summary of the evidence for respiratory medicines in children, highlighting gaps and research priorities, will be useful for the pharmaceutical industry, the paediatric committee of the European Medicines Agency, academic investigators and the lay public.

This European Respiratory Society task force has reviewed the evidence for paediatric medicines in respiratory disease occurring in adults and children. We describe off-licence use, research priorities and ongoing studies. Off-licence and off-label prescribing in children is widespread and potentially harmful. Research areas in asthma include novel formulations and regimens, and individualised prescribing. In cystic fibrosis, future studies will focus on screened infants and robust outcome measures are needed. Other areas include new enzyme and antibiotic formulations and the basic defect. Research into pneumonia should include evaluation of new antibacterials and regimens, rapid diagnostic tests and, in pleural infection, antibiotic penetration, fibrinolytics and surveillance. In uncommon conditions, such as primary ciliary dyskinesia, congenital pulmonary abnormalities or neuromuscular disorders, drugs indicated for other conditions (e.g. dornase alfa) are commonly used and trials are needed. In neuromuscular disorders, the beta-agonists may enhance muscle strength and are in need of evaluation. Studies of antibiotic prophylaxis, immunoglobulin and antifungal drugs are needed in immune deficiency. We hope that this summary of the evidence for respiratory medicines in children, highlighting gaps and research priorities, will be useful for the pharmaceutical industry, the paediatric committee of the European Medicines Agency, academic investigators and the lay public.

In deze studie wordt onderzocht hoe de bevrijding van de stad Tilburg tussen 24 en 27 oktober 1944 tot stand is gekomen, en in hoeverre de Koninklijke Nederlandse Brigade "Prinses Irene" een hoofdrol heeft vervuld in de bevrijding van de stad. Er wordt onderzocht of de stad Tilburg van enige strategische betekenis was voor de Geallieerde troepen, in hoeverre de Geallieerde troepen bij hun krijgsverrichtingen in en om de stad hinder ondervonden, en of de rol van de Brigade als bevrijder een feit is of een naoorlogse veteranenmythe. Bovendien wordt het standaardwerk Vom Kriege van Carl von Clausewitz gebruikt om het geheel theoretisch te onderbouwen.

In deze studie wordt onderzocht hoe de bevrijding van de stad Tilburg tussen 24 en 27 oktober 1944 tot stand is gekomen, en in hoeverre de Koninklijke Nederlandse Brigade "Prinses Irene" een hoofdrol heeft vervuld in de bevrijding van de stad. Er wordt onderzocht of de stad Tilburg van enige strategische betekenis was voor de Geallieerde troepen, in hoeverre de Geallieerde troepen bij hun krijgsverrichtingen in en om de stad hinder ondervonden, en of de rol van de Brigade als bevrijder een feit is of een naoorlogse veteranenmythe. Bovendien wordt het standaardwerk Vom Kriege van Carl von Clausewitz gebruikt om het geheel theoretisch te onderbouwen.

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