Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO

Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy

We measure the energy emitted by extensive air showers in the form of radio emission in the frequency range from 30 to 80 MHz. Exploiting the accurate energy scale of the Pierre Auger Observatory, we obtain a radiation energy of 15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV arriving perpendicularly to a geomagnetic field of 0.24 G, scaling quadratically with the cosmic-ray energy. A comparison with predictions from state-of-the-art first-principle calculations shows agreement with our measurement. The radiation energy provides direct access to the calorimetric energy in the electromagnetic cascade of extensive air showers. Comparison with our result thus allows the direct calibration of any cosmic-ray radio detector against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI. Supplemental material in the ancillary file

Recommendations for physical activity and exercise in persons living with Systemic Lupus Erythematosus (SLE): consensus by an international task force

Objective: This international task force aimed to provide healthcare professionals and persons living with systemic lupus erythematosus (SLE) with consensus-based recommendations for physical activity and exercise in SLE. Methods: Based on evidence from a systematic literature review and expert opinion, 3 overarching principles and 15 recommendations were agreed on by Delphi consensus. Results: The overarching principles highlight the importance of shared decision-making and the need to explain the benefits of physical activity to persons living with SLE and other healthcare providers. The 15 specific recommendations state that physical activity is generally recommended for all people with SLE, but in some instances, a medical evaluation may be needed to rule out contraindications. Pertaining to outdoor activity, photoprotection is necessary. Both aerobic and resistance training programmes are recommended, with a gradual increase in frequency and intensity, which should be adapted for each individual, and ideally supervised by qualified professionals. Conclusion: In summary, the consensus reached by the international task force provides a valuable framework for the integration of physical activity and exercise into the management of SLE, offering a tailored evidence-based and eminence-based approach to enhance the well-being of individuals living with this challenging autoimmune condition

Traitements de fond de la polyarthrite rhumatoïde : revue systématique des essais cliniques à partir des 17 bases de données recensées par l’OMS

Médecine. RhumatologieIntroduction : l’arsenal thérapeutique dans la polyarthrite rhumatoïde s’est considérablement développé ces dernières années avec l’arrivée sur le marché dans un premier temps des DMARDs (disease-modifying anti-rheumatic drugs) dits conventionnels (csDMARDs) avec comme chef de file le méthotrexate puis des biothérapies (bDMARDS) fabriquées à partir d’organismes vivants et enfin plus récemment les thérapies ciblées synthétiques (tsDMARDs). Malgré ces récents progrès seuls environs 20% des patients non répondeurs au méthotrexate atteignent une réponse ACR70. Pour ces patients n’atteignant pas la rémission et qui continuent à s’aggraver, une meilleure compréhension de la maladie et la recherche de nouvelles approches thérapeutiques est un enjeu majeur. L’objectif de notre étude était d’analyser l’ensemble des essais cliniques évaluant des traitements de fond (cs-, b- et tsDMARDs) de la polyarthrite rhumatoïde et d’en décrire leur mécanisme d’action ainsi que leur phase de développement clinique. Méthode : nous avons effectué une revue systématique de l’ensemble des molécules faisant l’objet d’un essai clinique dans la polyarthrite rhumatoïde à partir des 17 bases de données internationales référencées par l’OMS. Nous avons exclu les essais ne faisant pas l’objet d’une thérapeutique médicamenteuse, les thérapies cellulaires, les anti inflammatoires non stéroïdiens, les glucocorticoïdes et leurs dérivés, les molécules n’ayant pas d’effet immunomodulateur. Résultats : notre recherche a abouti à 4652 essais cliniques à partir desquels nous avons identifié 243 molécules. Ces molécules sont des csDMARDs (n=22), bDMARDs (n=118) et tsDMARDs (n=103). Parmi elles, 24 sont actuellement commercialisées dans au moins un pays. Les molécules en développement sont principalement des bDMARDs (n=34) et tsDMARDs (n=33). Sept molécules (en dehors de celles déjà commercialisées) ont atteint au moins un essai clinique de phase III. Parmi elles, nous retrouvons un nouvel anti TNF-alpha (ozoralizumab), un inhibiteur direct de l’IL-6 (olokizumab), un inhibiteur de l’IL-17 (sécukinumab) et un inhibiteur de RANKL (dénosumab). Les trois autres molécules évaluées en phase III ciblent des voies physiopathologiques novatrices, l’otilimab, un inhibiteur de GM-CSF évalué actuellement dans deux essais de phase III. Le télitacicept, un inhibiteur de la protéine de fusion TACI qui est un récepteur exprimé par les lymphocytes B. Le piclidenoson un agoniste du récepteur A3 de l’adénosine induisant des effets anti-inflammatoires via l’inhibition de la voie NF-KB. Notre étude a également permis de relever un nombre important de molécules abandonnées (n=150). Parmi les causes d’abandons de molécules, la première est le manque d’efficacité (pour 66 molécules sur 150). Conclusion : la poursuite de la recherche est toujours active avec 243 molécules faisant l’objet d’essais cliniques. L’objectif étant d’explorer de nouvelles voies thérapeutiques et développer de nouveaux médicaments que l’on souhaiterait idéalement : plus efficaces, mieux tolérés et à l’administration moins contraignante afin de favoriser une meilleure observance thérapeutique.Objectives: With the arrival of conventional synthetic (csDMARDs), biological (bDMARDS) and then targeted synthetic (tsDMARDs) disease-modifying anti-rheumatic drugs, the therapeutic arsenal against rheumatoid arthritis (RA) has recently expanded. However, there are still some unmet needs for patients who do not achieve remission and continue to worsen despite treatments. Of note, most randomized controlled trials show that, for methotrexate-inadequate responders, only 20% of patients are ACR70 responders. With our better understanding of RA pathogenesis, finding new treatments is a necessary challenge. The objective of our study was to analyze the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development. Methods: We conducted a systematic review of all drugs in clinical development in RA, in 17 online registries of clinical trials. Results: The search yielded 4652 trials, from which we identified 243 molecules. Those molecules belong to csDMARDs (n=22), bDMARDs (n=118), tsDMARDs (n=103). Twenty-four molecules are already marketed in RA in at least one country: 8 csDMARDs, 10 bDMARDs and 6 tsDMARDs. Molecules under current development are mainly bDMARDs (n=34) and tsDMARDs (n=33). Seven of those have reached phase III. A large number of molecules (150 /243, 61.7%) have been withdrawn. Conclusion: Despite the availability of 24 marketed molecules, the development of new targeted molecules is ongoing with a total of 243 molecules in RA. With 7 molecules currently reaching phase III, we can expect an increase in the armamentarium in the years to come

Käytännön kosteikkosuunnittelu

Maatalouden vesiensuojelua edistetään monin tavoin. Ravinteita ja eroosioainesta sisältäviä valumavesiä pyritään puhdistamaan erilaisissa kosteikoissa. Tämä opas on kirjoitettu avuksi pienimuotoisten kosteikkojen perustamiseen. Oppaassa esitetään käytännönläheisesti kosteikon toteuttamisen eri vaiheet paikan valinnasta suunnitteluun ja rakentamiseen. Vuonna 2010 julkaistun painoksen tiedot on saatettu ajantasalle. Julkaisu on toteutettu osana Tehoa maatalouden vesiensuojeluun (TEHO) -hanketta ja päivitetty TEHO Plus -hankkeen toimesta. Oppaan toivotaan lisäävän kiinnostusta kosteikkojen suunnitteluun ja edelleen niiden rakentamiseen

Erratum: Combined fit of spectrum and composition data as measured by the Pierre Auger Observatory

We present a combined fit of a simple astrophysical model of UHECR sources to both the energy spectrum and mass composition data measured by the Pierre Auger Observatory. The fit has been performed for energies above 5 ⋅ 10(18) eV, i.e. the region of the all-particle spectrum above the so-called ankle feature. The astrophysical model we adopted consists of identical sources uniformly distributed in a comoving volume, where nuclei are accelerated through a rigidity-dependent mechanism. The fit results suggest sources characterized by relatively low maximum injection energies, hard spectra and heavy chemical composition. We also show that uncertainties about physical quantities relevant to UHECR propagation and shower development have a non-negligible impact on the fit results