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This article focuses on understanding professionalism and the need to teach students about it, and includes a case study from the Claude Littner Business School (CLBS) at the University of West London. Teaching professional skills to students is of paramount importance as it has a direct impact on their career success. However, embedding it within curricula and making it part of the students’ mindset is not so straightforward, as the concept of professionalism may often be affected by public perception. CLBS has employed a variety of pedagogical models and business approaches in doing this, such as horizontal and vertical integration through a spiral curriculum, experiential and reflective learning techniques, and has established HR practices such as onboarding and appraisal meetings, resulting in high submission rates and positive student feedback.

Ice giants are the only unexplored class of planet in our Solar System. Much that we currently know about these systems challenges our understanding of how planets, rings, satellites, and magnetospheres form and evolve. We assert that an ice giant Flagship mission with an atmospheric probe should be a priority for the decade 2023-2032.

Icy satellites represent compelling astrobiological targets, but their rocky interiors must be better characterized. Fundamental research programs and thematic workshops promoting ocean world interdisciplinarity are key. Future missions to icy satellites should explicitly include objectives to characterize interfaces between rock and water or high-pressure ices., 7 pages, 2 figures, prepared for the NASEM Planetary Science and Astrobiology Decadal Survey 2023-2032

We advocate for establishing key scientific priorities for the future of Mercury exploration, including the development of specific science goals for a landed mission. We support the Mercury science community in fostering closer collaboration with ongoing and planned exoplanet investigations. The continued exploration of Mercury should be conceived as a multi-mission, multi-generational effort, and that the landed exploration of Mercury be a high scientific priority in the coming decade., 8 pages, 6 figures, white paper prepared for the NASEM Planetary Science and Astrobiology Decadal Survey 2023-2032

Mercury's geological history has been dominated by global contraction caused by secular cooling of the planet's interior. This cooling has had a profound effect on the expression of the planet's volcanism and tectonism, and the expressions of these two surface evolutionary processes are deeply intertwined. Here, we use case studies from the Hokusai quadrangle of Mercury to gain insight into the interplay between Mercury's volcanism and tectonism, which we review throughout this paper. We perform the first crater size–frequency analysis of the southernmost extent of Borealis Planitia, Mercury's largest expanse of volcanic plains, and find that it formed ~3.8–3.7 Ga. We discuss the importance of “intermediate plains”, a widespread unit in the Hokusai quadrangle, as the manifestation of relatively low-volume effusions with an uncertain stratigraphic relationship with Borealis Planitia. Finally, we detail the formation of the Suge Facula pitted ground during the geological history of Rachmaninoff crater, and hypothesise that such textures probably formed more widely on Mercury but have often either been buried by thick lava flows or otherwise obscured. Unanswered questions in this work can be used to drive the next phase of Mercury exploration and research with the arrival of the BepiColombo mission.

Additional file 1: Figure S1. Sequential Multi-gating strategy: to identify hemopoietic progenitor cells (HPC: CD45+CD34+) and Eosinophil-lineage committed progenitors (EoP; CD45+CD34+CD125+) in blood using FlowJo software on a LSRII. FlowJo plots of specific antibody and isotype control antibody for IL-17RA and IL-17RB on (A) HPC and (B) EoP with a 98% confidence limit. Absolute cell numbers were calculated by multiplying the % positive quadrant static (upper right quadrant) with the absolute progenitor cell count and expressed per million white blood cells.

Additional file 2: Figure S2. Histological analysis of lungs. Hematoxylin-eosin staining of the C57BL/6 in wild type and IL-25 KO mouse models that were sensitized and challenged with OVA or PBS (control).

Proportion of patients with baseline reliever use â Ľ1 and >2 occasions/day who achieved mean reliever use thresholds of

Oversight Authorities for SYGMA1 and SYGMA2. (DOCX 20 kb)

SPIRIT Checklist for SYGMA1 and SYGMA2. (DOCX 52 kb)

Summary of demographic characteristics and treatment exposure by treatment group (DOCX 41 kb)

Summary of demographic characteristics and treatment exposure by treatment group (DOCX 41 kb)

Crater size–frequency analyses have shown that the largest volcanic plains deposits on Mercury were emplaced around 3.7 Ga, as determined with recent model production function chronologies for impact crater formation on that planet. To test the hypothesis that all major smooth plains on Mercury were emplaced by about that time, we determined crater size–frequency distributions for the nine next‐largest deposits, which we interpret also as volcanic. Our crater density measurements are consistent with those of the largest areas of smooth plains on the planet. Model ages based on recent crater production rate estimates for Mercury imply that the main phase of plains volcanism on Mercury had ended by ~3.5 Ga, with only small‐scale volcanism enduring beyond that time. Cessation of widespread effusive volcanism is attributable to interior cooling and contraction of the innermost planet.

Lobate scarps, landforms interpreted as the surface manifestation of thrust faults, are widely distributed across Mercury and preserve a record of its history of crustal deformation. Their formation is primarily attributed to the accommodation of horizontal shortening of Mercury's lithosphere in response to cooling and contraction of the planet's interior. Analyses of images acquired by the Mariner 10 and MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft during flybys of Mercury showed that thrust faults were active at least as far back in time as near the end of emplacement of the largest expanses of smooth plains. However, the full temporal extent of thrust fault activity on Mercury, particularly the duration of this activity following smooth plains emplacement, remained poorly constrained. Orbital images from the MESSENGER spacecraft reveal previously unrecognized stratigraphic relations between lobate scarps and impact craters of differing ages and degradation states. Analysis of these stratigraphic relations indicates that contraction has been a widespread and long‐lived process on the surface of Mercury. Thrust fault activity had initiated by a time near the end of the late heavy bombardment of the inner solar system and continued through much or all of Mercury's subsequent history. Such deformation likely resulted from the continuing secular cooling of Mercury's interior.

Orbital images acquired by the Mercury, Surface, Space Environment, Geochemistry, and Ranging (MESSENGER) spacecraft reveal a distinctive low-reflectance material on the surface of Mercury. Such material occurs in small, isolated, and thin surficial units. We term these features “dark spots.” Dark spots have the lowest average reflectance yet documented on the planet. In every case observed at sufficiently high resolution, dark spots feature hollows at their centers. Not all hollows, however, are surrounded by a dark spot. Dark spots have been found on low-reflectance smooth plains, intercrater plains, heavily cratered terrain, and impact craters at almost all longitudes on Mercury, but they have not been documented on high-reflectance smooth plains material. Dark spots are one of the youngest endogenic features on Mercury, and some postdate craters with distinctive rays. Sulfides may be the phase responsible for the low albedo of dark spot material. We propose that dark spots form during the initial stages of hollow formation, perhaps in a manner similar to intense outgassing events that feature exit velocities in excess of 100 m/s. Such outgassing could contemporaneously produce a depression that constitutes an embryonic hollow. Under this scenario, dark spot material is subsequently removed or modified by regolith gardening or other surface processes on time scales shorter than the lifetime of the central hollow.

In contrast to other terrestrial planets, Mercury does not possess a great variety of volcanic features, its history of volcanism instead largely manifest by expansive smooth plains. However, a set of landforms at high northern latitudes on Mercury resembles surface flow features documented on Earth, the Moon, Mars, and Venus. The most striking of such landforms are broad channels that host streamlined islands and that cut through the surrounding intercrater plains. Together with narrower, more sinuous channels, coalesced depressions, evidence for local flooding of intercrater plains by lavas, and a first-order analysis of lava flow rates, the broad channels define an assemblage of flow features formed by the overland flow of, and erosion by, voluminous, high-temperature, low-viscosity lavas. This interpretation is consistent with compositional data suggesting that substantial portions of Mercury's crust are composed of magnesian, iron-poor lithologies. Moreover, the proximity of this partially flooded assemblage to extensive volcanic plains raises the possibility that the formation of these flow features may preface total inundation of an area by lavas emplaced in a flood mode and that they escaped complete burial only due to a waning magmatic supply. Finally, that these broad channels on Mercury are volcanic in nature yet resemble outflow channels on Mars, which are commonly attributed to catastrophic water floods, implies that aqueous activity is not a prerequisite for the formation of such distinctive landforms on any planetary body.

The Rachmaninoff, Raditladi, and Mozart peak-ring impact basins on Mercury display a distinctive pattern of tectonic features consisting of a central zone that is either devoid of tectonic landforms or contains small ridges, a medial annulus of prominent and predominantly circumferentially oriented graben, and a distal zone displaying graben that occur in a mix of orientations and that are less evident toward the peak ring. Here we use finite element models to explore three candidate scenarios for the formation of these tectonic features: (1) thermal contraction of the interior smooth plains, (2) isostatic uplift of the basin floor, and (3) subsidence following volcanic loading. Our results suggest that only thermal contraction can account for the observed pattern of graben, whereas some combination of subsidence and global contraction is the most likely explanation for the central ridges in Rachmaninoff and Mozart. Thermal contraction models, however, predict the formation of graben in the centermost region of each basin, where no graben are observed. We hypothesize that graben in this region were buried by a thin, late-stage flow of plains material, and images of partially filled graben provide evidence of such late-stage plains emplacement. These results suggest that the smooth plains units in these three basins are volcanic in origin. The thermal contraction models also imply a cooling unit ~1 km thick near the basin center, further supporting the view that plains-forming lavas on Mercury were often of sufficiently high volume and low viscosity to pool to substantial thicknesses within basins and craters.

Volcanic plains identified on Mercury are morphologically similar to lunar mare plains but lack constructional and erosional features that are prevalent on other terrestrial planetary bodies. We analyzed images acquired by the MESSENGER spacecraft to identify features on Mercury that may have formed by lava erosion. We used analytical models to estimate eruption flux, erosion rate, and eruption duration to characterize the formation of candidate erosional features, and we compared results with analyses of similar features observed on Earth, the Moon, and Mars. Results suggest that lava erupting at high effusion rates similar to those required to form the Teepee Butte Member of the Columbia River flood basalts (0.1-1.2 × 106 m3 s-1) would have been necessary to form wide valleys (>15 km wide) observed in Mercury's northern hemisphere, first by mechanical erosion to remove an upper regolith layer, then by thermal erosion once a lower rigid layer was encountered. Alternatively, results suggest that lava erupting at lower effusion rates similar to those predicted to have formed Rima Prinz on the Moon (4400 m3 s-1) would have been required to form, via thermal erosion, narrower channels (

The X-Ray Spectrometer (XRS) on the MESSENGER spacecraft measures elemental abundances on the surface of Mercury by detecting fluorescent X-ray emissions induced on the planet's surface by the incident solar X-ray flux. The XRS began orbital observations on 23 March 2011 and has observed X-ray fluorescence (XRF) from the surface of the planet whenever a sunlit portion of Mercury has been within the XRS field of view. Solar flares are generally required to provide sufficient signal to detect elements that fluoresce at energies above ∼2 keV, but XRF up to the calcium line (3.69 keV) has been detected from Mercury's surface at times when the XRS field of view included only unlit portions of the planet. Many such events have been detected and are identified as electron-induced X-ray emission produced by the interaction of ∼1-10 keV electrons with Mercury's surface. Electrons in this energy range were detected by the XRS during the three Mercury flybys and have also been observed regularly in orbit about Mercury. Knowledge of the energy spectrum of the electrons precipitating at the planet's surface makes it possible to infer surface composition from the measured fluorescent spectra, providing additional measurement opportunities for the XRS. Abundance results for Mg, Al, and Si are in good agreement with those derived from solar-induced XRF data, providing independent validation of the analysis methodologies. Derived S and Ca abundances are somewhat higher than derived from the solar-induced fluorescence data, possibly reflecting incomplete knowledge of the energy spectra of electrons impacting the planet.

We present the analysis of 205 spatially resolved measurements of the surface composition of Mercury from MESSENGER's X-Ray Spectrometer. The surface footprints of these measurements are categorized according to geological terrain. Northern smooth plains deposits and the plains interior to the Caloris basin differ compositionally from older terrain on Mercury. The older terrain generally has higher Mg/Si, S/Si, and Ca/Si ratios, and a lower Al/Si ratio than the smooth plains. Mercury's surface mineralogy is likely dominated by high-Mg mafic minerals (e.g., enstatite), plagioclase feldspar, and lesser amounts of Ca, Mg, and/or Fe sulfides (e.g., oldhamite). The compositional difference between the volcanic smooth plains and the older terrain reflects different abundances of these minerals and points to the crystallization of the smooth plains from a more chemically evolved magma source. High-degree partial melts of enstatite chondrite material provide a generally good compositional and mineralogical match for much of the surface of Mercury. An exception is Fe, for which the low surface abundance on Mercury is still higher than that of melts from enstatite chondrites and may indicate an exogenous contribution from meteoroid impacts.

Images of Mercury's northern volcanic plains taken by the MESSENGER spacecraft reveal a large number of buried impact craters and basins discernible by wrinkle-ridge rings that overlie their rims. Many of these "ghost" craters and basins contain interior graben of diverse widths and orientations. Here we use finite element models to test a variety of mechanisms for the formation of these graben and ridges. Results show that graben are best explained by cooling of large thicknesses of flood lavas within the craters and basins; conservation of surface area during cooling induces the required extensional stress state. In contrast, the development of wrinkle-ridge rings is best explained as the result of cooling and contraction of Mercury's interior, during which a reduction in Mercury's surface area led to a compressional state of stress. The critical factor in determining where large graben form is the thickness of the youngest cooling unit, the topmost sequence of lavas that cooled coevally. A thicker cooling unit leads to a deeper initiation of normal faulting (wider graben floors). Consistent with observations, the widest graben are predicted to occur where pooled lavas were thickest, and no graben are predicted within generally thinner plains outside of major craters. Observed concentrically oriented graben can be explained by variations in the thickness of the youngest cooling unit. In contrast, none of the basin uplift mechanisms considered, including isostatic response to crater topography, inward flow of the lower crust, or exterior loading by volcanic plains, can account for concentrically oriented graben.

Since its insertion into orbit about Mercury in March 2011, the MESSENGER spacecraft has imaged most previously unseen regions of the planet in unprecedented detail, revealing extensive regions of contiguous smooth plains at high northern latitudes and surrounding the Caloris basin. These smooth plains, thought to be emplaced by flood volcanism, are populated with several hundred ghost craters and basins, nearly to completely buried impact features having rims for which the surface expressions are now primarily rings of deformational landforms. Associated with some ghost craters are interior groups of graben displaying mostly polygonal patterns. The origin of these graben is not yet fully understood, but comparison with numerical models suggests that the majority of such features are the result of stresses from local thermal contraction. In this paper, we highlight a previously unreported category of ghost craters, quantify extensional strains across graben-bearing ghost craters, and make use of graben geometries to gain insights into the subsurface geology of smooth plains areas. In particular, the style and mechanisms of graben development imply that flooding of impact craters and basins led to substantial pooling of lavas, to thicknesses of ∼1.5 km. In addition, surface strains derived from groups of graben are generally in agreement with theoretically and numerically derived strains for thermal contraction.

The volcanic plains that fill the Caloris basin, the largest recognized impact basin on Mercury, are deformed by many graben and wrinkle ridges, among which the multitude of radial graben of Pantheon Fossae allow us to resolve variations in the depth extent of associated faulting. Displacement profiles and displacement-to-length scaling both indicate that faults near the basin center are confined to a ~ 4-km-thick mechanical layer, whereas faults far from the center penetrate more deeply. The fault scaling also indicates that the graben formed in mechanically strong material, which we identify with dry basalt-like plains. These plains were also affected by changes in long-wavelength topography, including undulations with wavelengths of up to 1300 km and amplitudes of 2.5 to 3 km. Geographic correlation of the depth extent of faulting with topographic variations allows a first-order interpretation of the subsurface structure and mechanical stratigraphy in the basin. Further, crosscutting and superposition relationships among plains, faults, craters, and topography indicate that development of long-wavelength topographic variations followed plains emplacement, faulting, and much of the cratering within the Caloris basin. As several examples of these topographic undulations are also found outside the basin, our results on the scale, structural style, and relative timing of the topographic changes have regional applicability and may be the surface expression of global-scale interior processes on Mercury.

Background: Pharmacovigilance studies in hospice/palliative care provide extra information to improve medication safety. Combination controlled release oxycodone-naloxone offers an alternative opioid with less risk of opioid-induced constipation.Objective: To examine why palliative care clinicians chose to cease oxycodone-naloxone and to explore immediate and short-term benefits and harms of this medication change.Design: A consecutive cohort study.Setting: 112 adults from 13 palliative care centers.Measurements: Reasons for ceasing medication and the harms and benefits that followed this 24 and 72 hours later. Symptom burdens were summarised by the National Cancer Institute Common Terminology Criteria for Adverse Events Toxicity Gradings. Results: Combination medication was most commonly ceased because of poor pain control or impaired hepatic function. The last median oral morphine equivalent oxycodone dose before the switch was 45 mg (range 7.5–240 mg) with 76 switched to an alternative long-acting opioid (initial median oral morphine equivalent dose being 45 mg [range 5–210 mg]). Subgroup analysis of those switched because of clinicians' concerns about hepatic dysfunction demonstrated this group were receiving significantly lower opioid doses pre-cessation compared to those switched because of other reasons( p = 0.007). Regardless of why the medication was changed, improvements in pain and constipation scores were seen, the latter associated with an attendant increase in laxatives.Conclusions: This preliminary work suggests that despite theoretical concerns regarding the effect of the naloxone on opioid doses, most people were switched safely to very similar opioid doses with attendant improvements in pain control. Refereed/Peer-reviewed

The present paper addresses severe asthma which is limited to 5-10% of the overall population of asthmatics. However, it accounts for 50% or more of socials costs of the disease, as it is responsible for hospitalizations and Emergency Department accesses as well as expensive treatments.The recent identification of different endotypes of asthma, based on the inflammatory pattern, has led to the development of tailored treatments that target different inflammatory mediators. These are major achievements in the perspective of Precision Medicine: a leading approach to the modern treatment strategy.Omalizumab, an anti-IgE antibody, has been the only biologic treatment available on the market for severe asthma during the last decade. It prevents the linkage of the IgE and the receptors, thereby inhibiting mast cell degranulation. In clinical practice omalizumab significantly reduced the asthma exacerbations as well as the concomitant use of oral glucocorticoids.In the “Th2-high asthma” phenotype, the hallmarks are increased levels of eosinophils and other markers (such as periostin). Because anti-IL-5 in this condition plays a crucial role in driving eosinophil inflammation, this cytokine or its receptors on the eosinophil surface has been studied as a potential target for therapy.Two different anti-IL-5 humanized monoclonal antibodies, mepolizumab and reslizumab, have been proven effective in this phenotype of asthma (recently they both came on the market in the United States), as well as an anti-IL-5 receptor alpha (IL5Rα), benralizumab.Other monoclonal antibodies, targeting different cytokines (IL-13, IL-4, IL-17 and TSLP) are still under evaluation, though the preliminary results are encouraging.Finally, AIT, Allergen Immunotherapy, a prototype of Precision Medicine, is considered, also in light of the recent evidences of Sublingual Immunotherapy (SLIT) tablet efficacy and safety in mite allergic asthma patients.Given the high costs of these therapies, however, there is an urgent need to identify biomarkers that can predict the clinical responders. Keywords: Severe asthma, Phenotypes, Biological therapeutics, Eosinophils

Asthma is an inflammatory disorder of the airways, and there has been growing insight into the cellular and molecular mechanisms underlying the inflammatory basis of this disease. Research into the inflammatory mechanisms of asthma has progressively shifted focus from downstream effectors, such as mast cells and eosinophils, up to Th2 lymphocytes and their proallergic cytokines. Even more upstream in the allergic cascade are dendritic cells (DCs), potent APCs that orchestrate immune responses. Evidence supporting a role of DCs in regulating airway allergic inflammation is derived mainly from animal studies. In animal models of asthma, myeloid DCs (mDCs) induce and maintain airway inflammation, while plasmacytoid DCs (pDCs) mediate tolerance and lung homeostasis. It remains uncertain, however, whether this concept of pro-allergic mDCs and anti-allergic pDCs translates from animal to human models. The overall objective of this thesis was to investigate the biology of DC subsets in allergen-induced asthma in asthmatic subjects. Initially, we demonstrate that both mDCs and pDCs increase in the airways of subjects with mild asthma after allergen inhalation. Next, we describe a distinct subpopulation of mDCs, called mDC2s, and demonstrate their association with allergy and asthma severity. Expanding on these findings, we show that mDC2s increase in the airways of mild asthmatics after allergen challenge. Lastly, we explore the potential of pharmacological therapies, anti-OX40L MAb and anti-TSLP MAb, to affect DCs in subjects with mild asthma, and demonstrate no effect of either drug on circulating DC subsets. The studies presented here provide evidence for multiple DC subtypes being involved in the regulation of allergen-induced inflammatory responses, and support continued investigations into the biology of different DC subsets in allergen-induced asthma. Doctor of Philosophy (Medical Science)

Exercise has long been recognized to be an important natural stimulus causing bronchoconstriction in most patients with symptomatic asthma, particularly in children and young adults. In the laboratory, bronchoconstriction caused by exercise is documented by examining a reduction in airway calibre after exercise which is measured as a fall in the forced expired volume in one second (FEV₁). Exercise bronchoconstriction is generally short lived, wearing off within 60 minutes. More than 50% of asthmatic subjects, experience progressively less and less airway narrowing with repeated exercise challenges on the same day. This progressive decrease in exercise bronchoconstriction is considered to be a potentially important airway inhibitory protective effect and is termed exercise refractoriness. O'Byrne and Jones (O'Byrne and Jones, 1986), first demonstrated the likely involvement of inhibitory prostaglandins in exercise refractoriness, when they demonstrated that indomethacin inhibited the effect in asthmatic subjects. The precise mechanism underlying exercise bronchoconstriction is unclear. However, the initiating stimulus may involve either alterations in osmolarity of the epithelial-lining fluid or changes in airway temperature resulting from the inhalation of inadequately conditioned air during exercise or both. These changes cause the release of bronchoconstrictor mediators and the development of bronchoconstriction. The work described in this thesis was undertaken to establish the role of leukotriene (LT) D₄ in the pathogenesis of exercise bronchoconstriction and of histamine-, and LTD₄ induced, inhibitory prostaglandin release in causing exercise refractoriness. The body of research described in this thesis details new findings in relation to LTD₄ and exercise responses in asthmatic subjects. It shows that tachyphylaxis, a potential airway protective mechanism, occurs to repeated challenges with LTD₄ inhalations in asthmatic subjects and that flurbiprofen, a cyclooxygenase inhibitor, blocks this effect implicating inhibitory prostaglandin release in the mechanism. Using a specific LTD₄ receptor antagonist, it shows for the first time, that LTD₄, an important mediator in asthma, is involved in exercise bronchoconstriction in asthmatic subjects. In addition, it demonstrates also that complete cross refractoriness/tachyphylaxis occurs following exercise and LTD₄ stimulation an effect which is also inhibited by flurbiprofen. However, complete cross refractoriness/tachyphylaxis does not occur following exercise and histamine. The conclusion from the work in this thesis is that LTD₄, rather than histamine, plays the more important role in exercise bronchoconstriction and that LTD₄ induced inhibitory prostaglandin release is the cause of exercise refractoriness in asthmatic subjects. Doctor of Philosophy (PhD)