EU External Relations: Exclusive Competence Revisited

This Article will focus on the question of exclusive competence in the field of EU external relations, especially in the light of recent developments. After a brief discussion on the origins and development of exclusive competence, a distinction will be made between common commercial policy, which has traditionally been the most important area of an explicit “a priori” exclusive competence, and what is often called an implicit exclusive competence, which, as it is today based on some general criteria enshrined in TFEU Article 3(2), may be called “supervening” exclusive competence. With regard to both categories, the main focus will be on recent developments, notably the impact of the Treaty of Lisbon, which introduced the TFEU and its Articles 2 and 3, as well as the case law of the European Court of Justice (“ECJ” or the “Court”) following the entry into force of the Treaty of Lisbon, on December 1, 2009

UVMag: stellar formation, evolution, structure and environment with space UV and visible spectropolarimetry

Important insights into the formation, structure, evolution and environment of all types of stars can be obtained through the measurement of their winds and possible magnetospheres. However, this has hardly been done up to now mainly because of the lack of UV instrumentation available for long periods of time. To reach this aim, we have designed UVMag, an M-size space mission equipped with a high-resolution spectropolarimeter working in the UV and visible spectral range. The UV domain is crucial in stellar physics as it is very rich in atomic and molecular lines and contains most of the flux of hot stars. Moreover, covering the UV and visible spectral domains at the same time will allow us to study the star and its environment simultaneously. Adding polarimetric power to the spectrograph will multiply tenfold the capabilities of extracting information on stellar magnetospheres, winds, disks, and magnetic fields. Examples of science objectives that can be reached with UVMag are presented for pre-main sequence, main sequence and evolved stars. They will cast new light onto stellar physics by addressing many exciting and important questions. UVMag is currently undergoing a Research and Technology study and will be proposed at the forthcoming ESA call for M-size missions. This spectropolarimeter could also be installed on a large UV and visible observatory (e.g. NASA's LUVOIR project) within a suite of instruments.Comment: Accepted in ApSS's special volume on UV astronom

Statistical methodology for constructing gestational age-related charts using cross-sectional and longitudinal data: The INTERGROWTH-21st project as a case study.

Most studies aiming to construct reference or standard charts use a cross-sectional design, collecting one measurement per participant. Reference or standard charts can also be constructed using a longitudinal design, collecting multiple measurements per participant. The choice of appropriate statistical methodology is important as inaccurate centiles resulting from inferior methods can lead to incorrect judgements about fetal or newborn size, resulting in suboptimal clinical care. Reference or standard centiles should ideally provide the best fit to the data, change smoothly with age (eg, gestational age), use as simple a statistical model as possible without compromising model fit, and allow the computation of Z-scores from centiles to simplify assessment of individuals and enable comparison with different populations. Significance testing and goodness-of-fit statistics are usually used to discriminate between models. However, these methods tend not to be useful when examining large data sets as very small differences are statistically significant even if the models are indistinguishable on actual centile plots. Choosing the best model from amongst many is therefore not trivial. Model choice should not be based on statistical considerations (or tests) alone as sometimes the best model may not necessarily offer the best fit to the raw data across gestational age. In this paper, we describe the most commonly applied methodologies available for the construction of age-specific reference or standard centiles for cross-sectional and longitudinal data: Fractional polynomial regression, LMS, LMST, LMSP, and multilevel regression methods. For illustration, we used data from the INTERGROWTH-21st Project, ie, newborn weight (cross-sectional) and fetal head circumference (longitudinal) data as examples

Design and other methodological considerations for the construction of human fetal and neonatal size and growth charts.

This paper discusses the features of study design and methodological considerations for constructing reference centile charts for attained size, growth, and velocity charts with a focus on human growth charts used during pregnancy. Recent systematic reviews of pregnancy dating, fetal size, and newborn size charts showed that many studies aimed at constructing charts are still conducted poorly. Important design features such as inclusion and exclusion criteria, ultrasound quality control measures, sample size determination, anthropometric evaluation, gestational age estimation, assessment of outliers, and chart presentation are seldom well addressed, considered, or reported. Many of these charts are in clinical use today and directly affect the identification of at-risk newborns that require treatment and nutritional strategies. This paper therefore reiterates some of the concepts previously identified as important for growth studies, focusing on considerations and concepts related to study design, sample size, and methodological considerations with an aim of obtaining valid reference or standard centile charts. We discuss some of the key issues and provide more details and practical examples based on our experiences from the INTERGROWTH-21st Project. We discuss the statistical methodology and analyses for cross-sectional studies and longitudinal studies in a separate article in this issue

Microwave observations of spinning dust emission in NGC6946

We report new cm-wave measurements at five frequencies between 15 and 18GHz of the continuum emission from the reportedly anomalous "region 4" of the nearby galaxy NGC6946. We find that the emission in this frequency range is significantly in excess of that measured at 8.5GHz, but has a spectrum from 15-18GHz consistent with optically thin free-free emission from a compact HII region. In combination with previously published data we fit four emission models containing different continuum components using the Bayesian spectrum analysis package radiospec. These fits show that, in combination with data at other frequencies, a model with a spinning dust component is slightly preferred to those that possess better-established emission mechanisms.Comment: submitted MNRA

Gamma-ray signatures of cosmic ray acceleration, propagation, and confinement in the era of CTA

Galactic cosmic rays are commonly believed to be accelerated at supernova remnants via diffusive shock acceleration. Despite the popularity of this idea, a conclusive proof for its validity is still missing. Gamma-ray astronomy provides us with a powerful tool to tackle this problem, because gamma rays are produced during cosmic ray interactions with the ambient gas. The detection of gamma rays from several supernova remnants is encouraging, but still does not constitute a proof of the scenario, the main problem being the difficulty in disentangling the hadronic and leptonic contributions to the emission. Once released by their sources, cosmic rays diffuse in the interstellar medium, and finally escape from the Galaxy. The diffuse gamma-ray emission from the Galactic disk, as well as the gamma-ray emission detected from a few galaxies is largely due to the interactions of cosmic rays in the interstellar medium. On much larger scales, cosmic rays are also expected to permeate the intracluster medium, since they can be confined and accumulated within clusters of galaxies for cosmological times. Thus, the detection of gamma rays from clusters of galaxies, or even upper limits on their emission, will allow us to constrain the cosmic ray output of the sources they contain, such as normal galaxies, AGNs, and cosmological shocks. In this paper, we describe the impact that the Cherenkov Telescope Array, a future ground-based facility for very-high energy gamma-ray astronomy, is expected to have in this field of research.Comment: accepted to Astroparticle Physics, special issue on Physics with the Cherenkov Telescope Arra

Comparative Survival Analysis of Immunomodulatory Therapy for Coronavirus Disease 2019 Cytokine Storm.

BACKGROUND:Cytokine storm is a marker of coronavirus disease 2019 (COVID-19) illness severity and increased mortality. Immunomodulatory treatments have been repurposed to improve mortality outcomes. RESEARCH QUESTION:Do immunomodulatory therapies improve survival in patients with COVID-19 cytokine storm (CCS)? STUDY DESIGN AND METHODS:We conducted a retrospective analysis of electronic health records across the Northwell Health system. COVID-19 patients hospitalized between March 1, 2020, and April 24, 2020, were included. CCS was defined by inflammatory markers: ferritin, \u3e 700 ng/mL; C-reactive protein (CRP), \u3e 30 mg/dL; or lactate dehydrogenase (LDH), \u3e 300 U/L. Patients were subdivided into six groups: no immunomodulatory treatment (standard of care) and five groups that received either corticosteroids, anti-IL-6 antibody (tocilizumab), or anti-IL-1 therapy (anakinra) alone or in combination with corticosteroids. The primary outcome was hospital mortality. RESULTS:Five thousand seven hundred seventy-six patients met the inclusion criteria. The most common comorbidities were hypertension (44%-59%), diabetes (32%-46%), and cardiovascular disease (5%-14%). Patients most frequently met criteria with high LDH (76.2%) alone or in combination, followed by ferritin (63.2%) and CRP (8.4%). More than 80% of patients showed an elevated D-dimer. Patients treated with corticosteroids and tocilizumab combination showed lower mortality compared with patients receiving standard-of-care (SoC) treatment (hazard ratio [HR], 0.44; 95% CI, 0.35-0.55; P \u3c .0001) and with patients treated with corticosteroids alone (HR, 0.66; 95% CI, 0.53-0.83; P = .004) or in combination with anakinra (HR, 0.64; 95% CI, 0.50-0.81; P = .003). Corticosteroids when administered alone (HR, 0.66; 95% CI, 0.57-0.76; P \u3c .0001) or in combination with tocilizumab (HR, 0.43; 95% CI, 0.35-0.55; P \u3c .0001) or anakinra (HR, 0.68; 95% CI, 0.57-0.81; P \u3c .0001) improved hospital survival compared with SoC treatment. INTERPRETATION:The combination of corticosteroids with tocilizumab showed superior survival outcome when compared with SoC treatment and treatment with corticosteroids alone or in combination with anakinra. Furthermore, corticosteroid use either alone or in combination with tocilizumab or anakinra was associated with reduced hospital mortality for patients with CCS compared with patients receiving SoC treatment

Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study

Background: Human genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress. Methods: We did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria. Findings: Between June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell trait (odds ratio [OR] 0·15, 95% CI 0·11–0·20; p=2·61 × 10−58), blood group O (0·74, 0·66–0·82; p=6·26 × 10−8), and –α3·7-thalassaemia (0·83, 0·76–0·90; p=2·06 × 10−6). We also found strong associations between overall risk of severe malaria and polymorphisms in both ATP2B4 (OR 0·76, 95% CI 0·63–0·92; p=0·001) and FREM3 (0·64, 0·53–0·79; p=3·18 × 10−14). The association with FREM3 could be accounted for by linkage disequilibrium with a complex structural mutation within the glycophorin gene region (comprising GYPA, GYPB, and GYPE) that encodes for the rare Dantu blood group antigen. Heterozygosity for Dantu was associated with risk for severe malaria (OR 0·57, 95% CI 0·49–0·68; p=3·22 × 10−11), as was homozygosity (0·26, 0·11–0·62; p=0·002). Interpretation: Both ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health. Funding: Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative

Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations.

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10-5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10-8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size

Binaries with the eyes of CTA

The binary systems that have been detected in gamma rays have proven very useful to study high-energy processes, in particular particle acceleration, emission and radiation reprocessing, and the dynamics of the underlying magnetized flows. Binary systems, either detected or potential gamma-ray emitters, can be grouped in different subclasses depending on the nature of the binary components or the origin of the particle acceleration: the interaction of the winds of either a pulsar and a massive star or two massive stars; accretion onto a compact object and jet formation; and interaction of a relativistic outflow with the external medium. We evaluate the potentialities of an instrument like the Cherenkov telescope array (CTA) to study the non-thermal physics of gamma-ray binaries, which requires the observation of high-energy phenomena at different time and spatial scales. We analyze the capability of CTA, under different configurations, to probe the spectral, temporal and spatial behavior of gamma-ray binaries in the context of the known or expected physics of these sources. CTA will be able to probe with high spectral, temporal and spatial resolution the physical processes behind the gamma-ray emission in binaries, significantly increasing as well the number of known sources. This will allow the derivation of information on the particle acceleration and emission sites qualitatively better than what is currently available.Comment: 23 pages, 13 figures, accepted for publication in Astroparticle Physics, special issue on Physics with the Cherenkov Telescope Arra