PM2.5 source allocation in European cities: A SHERPA modelling study

Many European cities suffer from poor air quality and still exceed the European standards prescribed by the Air Quality Directive, and the guidelines recommended by the World Health Organization (WHO). This is especially the case for PM2.5, focus of this work. While international, national and local level actions to reduce air pollution have undoubtedly resulted in an overall improvement of the air quality over the years, there are still problems, which are localised in specific regions and many cities. A key issue is to determine at which scale to act in order to abate these remaining air pollution problems most effectively. Central to this, for cities, is a quantitative assessment of the different origins of air pollution (urban, regional, national and transboundary) to support the design of efficient, effective air quality plans, which are a legal obligation for countries and regions whenever exceedances occur. The “Screening for High Emission Reduction Potentials for Air quality” tool (SHERPA) is used in this work to quantify the origins of air pollution in cities and regions, both from a spatial (urban, country…) and sectoral (transport, residential, agriculture…) perspectives. For PM2.5 we conclude that (1) for many cities, local actions at the city scale are an effective means of improving air quality in that city; (2) the target sectors and scales to abate air pollution are city specific, even for cities that are located in the same country. Consequently, it is important to take into account these city-specific circumstances when designing air quality plans and (3) for many cities, sectoral measures addressing agriculture at country or EU scale would have a clear benefit on urban air quality

Enantiomer specific pharmacokinetics of ibuprofen in preterm neonates with patent ductus arteriosus

Aims: Racemic ibuprofen is widely used for the treatment of preterm neonates with patent ductus arteriosus. Currently used bodyweight-based dosing guidelines are based on total ibuprofen, while only the S-enantiomer of ibuprofen is pharmacologically active. We aimed to optimize ibuprofen dosing for preterm neonates of different ages based on an enantiomer-specific population pharmacokinetic model. Methods: We prospectively collected 210 plasma samples of 67 preterm neonates treated with ibuprofen for patent ductus arteriosus (median gestational age [GA] 26 [range 24–30] weeks, median body weight 0.83 [0.45–1.59] kg, median postnatal age [PNA] 3 [1–12] days), and developed a population pharmacokinetic model for S- and R-ibuprofen. Results: We found that S-ibuprofen clearance (CLS, 3.98 mL/h [relative standard error {RSE} 8%]) increases with PNA and GA, with exponents of 2.25 (RSE 6%) and 5.81 (RSE 15%), respectively. Additionally, a 3.11-fold higher CLS was estimated for preterm neonates born small for GA (RSE 34%). Clearance of R-ibuprofen was found to be high compared to CLS (18 mL/h [RSE 24%]), resulting in a low contribution of R-ibuprofen to total ibuprofen exposure. Current body weight was identified as covariate on both volume of distribution of S-ibuprofen and R-ibuprofen. Conclusion: S-ibuprofen clearance shows important maturation, especially with PNA, resulting in an up to 3-fold increase in CLS during a 3-day treatment regimen. This rapid increase in clearance needs to be incorporated in dosing guidelines by adjusting the dose for every day after birth to achieve equal ibuprofen exposure

Learning from Conect4children: A Collaborative Approach towards Standardization of Disease-Specific Paediatric Research Data

The conect4children (c4c) initiative was established to facilitate the development of new drugs and other therapies for paediatric patients. It is widely recognized that there are not enough medicines tested in all relevant ages of the paediatric population. To overcome this, it is imperative that clinical data from different sources are interoperable and can be pooled for larger post-hoc studies. c4c has collaborated with the Clinical Data Interchange Standards Consortium (CDISC) to develop the cross-cutting data resources that build on existing CDISC standards, in an effort to standardize paediatric data. The natural next step was an extension to disease-specific data items. c4c brought together several existing initiatives and resources relevant to disease-specific data and to analyse their use for standardizing disease-specific data in clinical trials. Several case studies that combined disease-specific data from multiple trials have demonstrated the need for disease-specific data standardization. We identified three relevant initiatives. These include European Reference Networks, European Joint Programme on Rare Diseases, and Pistoia Alliance. Other resources reviewed were: National Cancer Institute Enterprise Vocabulary Services, CDISC standards, pharmaceutical company-specific data dictionaries, Human Phenotype Ontology, Phenopackets, Unified Registry for Inherited Metabolic Disorders, Orphacodes, Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP) and Observational Medical Outcomes Partnership. The collaborative partners associated with these resources were also reviewed briefly. A plan of action focussed on collaboration was generated for standardizing disease-specific paediatric clinical trial data. A paediatric data standards multistakeholder and multi-project user group was established to guide the remaining actions– FAIRification of metadata, a Phenopackets pilot with RDCA-DAP, applying Orphacodes to case report forms of clinical trials, introducing CDISC standards into European Reference Networks, testing of the CDISC Pediatric User Guide using data from the mentioned resources and organization of further workshops and educational materials

The bioavailability and maturing clearance of doxapram in preterm infants

Background Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the pharmacokinetics of doxapram and keto-doxapram in preterm infants. Methods Data (302 samples) from 75 neonates were included with a median (range) gestational age (GA) 25.9 (23.9-29.4) weeks, bodyweight 0.95 (0.48-1.61) kg, and postnatal age (PNA) 17 (1-52) days at the start of continuous treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling (NONMEM (R)). Results A two-compartment model best described the pharmacokinetics of doxapram and keto-doxapram. PNA and GA affected the formation clearance of keto-doxapram (CLFORMATION KETO-DOXAPRAM) and clearance of doxapram via other routes (CLDOXAPRAM OTHER ROUTES). For a median individual of 0.95 kg, GA 25.6 weeks, and PNA 29 days, CL(FORMATION KETO-DOXAPRAM)was 0.115 L/h (relative standard error (RSE) 12%) and CL(DOXAPRAM OTHER ROUTES)was 0.645 L/h (RSE 9%). Oral bioavailability was estimated at 74% (RSE 10%). Conclusions Dosing of doxapram only based on bodyweight results in the highest exposure in preterm infants with the lowest PNA and GA. Therefore, dosing may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. For switching to oral therapy, a 33% dose increase is required to maintain exposure. ImpactCurrent dosing regimens of doxapram in preterm infants only based on bodyweight result in the highest exposure in infants with the lowest PNA and GA. Dosing of doxapram may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. Describing the pharmacokinetics of doxapram and its active metabolite keto-doxapram following intravenous and gastroenteral administration enables to include drug exposure to the evaluation of treatment of AOP. The oral bioavailability of doxapram in preterm neonates is 74%, requiring a 33% higher dose via oral than intravenous administration to maintain exposure.Pharmacolog

A failed attempt to conduct an individual patient data meta-analysis

A study-level meta-analysis has shown that proton magnetic resonance spectroscopy is a promising prognostic marker in neonatal hypoxic-ischemic encephalopathy. An individual patient data meta-analysis could yield a prognostic tool with improved accuracy enabling well-founded clinical decisions. Our request to share patient data remained unanswered by five out of 18 research groups. Another four declined collaboration for various reasons, including own reanalysis of the data, and lack of parental consent. With less than 40% of the individual patient data available, we refrained from pursuing the proposed study. As future patients may benefit from it, policies mandating data sharing should be introduced

Impact of maritime transport emissions on coastal air quality in Europe

Shipping emissions are currently increasing and will most likely continue to do so in the future due to the increase of global-scale trade. Ship emissions have the potential to contribute to air quality degradation in coastal areas, in addition to contributing to global air pollution. With the aim to quantify the impacts of shipping emissions on urban air quality in coastal areas in Europe, an in depth literature review was carried out focussing on particulate matter and gaseous pollutants but also reviewing the main chemical tracers of shipping emissions, the particle size distribution of ship-derived particulates and their contributions to population exposure and atmospheric deposition. Mitigation strategies were also addressed. In European coastal areas, shipping emissions contribute with 1-7% of ambient air PM10 levels, 1-14% of PM2.5, and at least 11% of PM1. Contributions from shipping to ambient NO2 levels range between 7 and 24%, with the highest values being recorded in the Netherlands and Denmark. Impacts from shipping emissions on SO2 concentrations were reported for Sweden and Spain. Shipping emissions impact not only the levels and composition of particulate and gaseous pollutants, but may also enhance new particle formation processes in urban areas. © 2014 The Authors

Antenatal steroids and neonatal outcome after chorioamnionitis: A meta-analysis

Background: There is debate concerning the safety and efficacy of antenatal steroids in preterm labour with suspected intrauterine infection (chorioamnionitis). Objectives We performed a systematic literature review and meta-analysis aimed at evaluating the efficacy and safety of antenatal steroids in clinical and histological chorioamnionitis. Search strategy MEDLINE, EMBASE, BioMed Central and the Cochrane databases were searched using the terms 'chorioamnionitis OR intrauterine infection' and '*steroids OR *corticoids'. Selection criteria Studies that reported selected neonatal outcome measures in preterm infants with clinical or histological chorio-amnionitis, according to antenatal steroid exposure, were eligible. Data collection and analysis Study selection, data extraction and data analysis were performed by two independent investigators. The meta-analysis techniques used included: Mantel-Haenszel analysis; an assessment of study heterogeneity using the Q statistic; and Egger's regression test and funnel plots, to assess publication bias. Main results Seven observational studies were included. In histological chorioamnionitis (five studies), antenatal steroids were associated with reduced mortality (OR = 0.45; 95% CI = 0.30-0.68; P = 0.0001), respiratory distress syndrome (OR = 0.53; 95% CI = 0.40-0.71; P < 0.0001), patent ductus arteriosus (OR = 0.56; 95% CI = 0.37-0.85; P = 0.007), intraventricular haemorrhage (IVH; OR = 0.35; 95% CI = 0.18-0.66; P = 0.001) and severe IVH (OR = 0.39; 95% CI = 0.19-0.82; P = 0.01). In clinical chorioamnionitis (four studies), antenatal steroids were associated with reduced severe IVH (OR = 0.29; 95% CI = 0.10-0.89; P = 0.03) and periventricular leucomalacia (OR = 0.35; 95% CI = 0.14-0.85; P = 0.02). Conclusions Antenatal steroids may be safe and reduce adverse neonatal outcome after preterm birth associated with chorioamnionitis. There is a need for randomised clinical trials to address this issue

Chorioamnionitis appears not to be a Risk Factor for Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-Analysis

The contribution of chorioamnionitis (CA) to mortality and morbidity in preterm infants is difficult to assess because observational studies frequently present significant differences in baseline characteristics of the infants exposed or non-exposed to CA. In an attempt to perform a thorough assessment of the possible association between CA and patent ductus arteriosus (PDA) in preterm infants, we conducted a meta-analysis in which adjusted odds ratios (ORs) were pooled and we analyzed the effects of potential confounders, such as gestational age (GA) or birth weight (BW). We identified 45 relevant studies (27186 patients, 7742 CA cases). Random effects meta-analysis of crude ORs showed a significant positive association between CA and PDA (OR 1.352, 95% CI 1.172 to 1.560). Adjusted ORs were reported in 11 studies (19577 infants). Meta-analysis of these studies showed a significant negative association between CA and PDA (OR 0.802, 95% CI 0.751 to 0.959). Meta-regression showed that the differences in GA or BW between the CA-exposed and non-exposed groups were significantly correlated with the effect size of the association between PDA and CA. In conclusion, our study confirms that confounders need to be taken into account when assessing the association between CA and clinical outcomes in preterm infants