Blocking T cell co-stimulation in primary Sjögren's syndrome:rationale, clinical efficacy and modulation of peripheral and salivary gland biomarkers

There is accumulating evidence that patients with primary Sjögren's syndrome (pSS) display aberrant CD4+ T cell responses, both in the peripheral compartment and in the inflamed salivary glands. CD4+ T cell abnormalities are also critically associated with B cell hyper activation, one of the hallmarks of disease, which is linked with disease severity and evolution to lymphoma. T cell activation and the cross-talk between T and B cells are tightly regulated by the balance between co-stimulatory pathways, such as the interactions between CD80/CD86:CD28, CD40:CD40L and ICOS:ICOSL, and co-inhibitory signals, including the immunoregulatory CTLA-4 protein. Evidence from patients with pSS as well as data from animal models of the disease suggests that these pathways play a critical role in pSS pathogenesis and their targeting could be exploited for therapeutic purposes. In this review, we first summarise the evidence implicating aberrant T cell co-stimulation and co-inhibition in driving the disease before focusing on the results of recent randomised controlled trials (RCTs) with compounds able to block T cell co-stimulation and enhance T cell co-inhibition. Despite a clear biological effect on downstream B cell activation has been observed in patients treated with CTLA-4-Ig (abatacept) and with monoclonal antibodies targeting CD40 and ICOSL, the clinical efficacy of this approach has so far yielded mixed results; while the anti-CD40 monoclonal antibody iscalimab showed significant improvement in systemic disease activity compared to placebo, two large RCTs with abatacept and a phase IIa RCT with an anti-ICOSL monoclonal antibody (prezalumab) failed to reach their primary endpoints. Although the discrepancies between biological and clinical efficacy of targeting T cell co-stimulation on pSS remain unresolved, several factors including drug bioavailability and receptor occupancy, patient stratification based on T-cell related biomarkers and the choice of study outcome are likely to play an important role and form the basis for further work towards the quest for a disease-modifying biologic therapy in pSS

Blocking T cell co-stimulation in primary Sjögren's syndrome:rationale, clinical efficacy and modulation of peripheral and salivary gland biomarkers

There is accumulating evidence that patients with primary Sjögren's syndrome (pSS) display aberrant CD4+ T cell responses, both in the peripheral compartment and in the inflamed salivary glands. CD4+ T cell abnormalities are also critically associated with B cell hyper activation, one of the hallmarks of disease, which is linked with disease severity and evolution to lymphoma. T cell activation and the cross-talk between T and B cells are tightly regulated by the balance between co-stimulatory pathways, such as the interactions between CD80/CD86:CD28, CD40:CD40L and ICOS:ICOSL, and co-inhibitory signals, including the immunoregulatory CTLA-4 protein. Evidence from patients with pSS as well as data from animal models of the disease suggests that these pathways play a critical role in pSS pathogenesis and their targeting could be exploited for therapeutic purposes. In this review, we first summarise the evidence implicating aberrant T cell co-stimulation and co-inhibition in driving the disease before focusing on the results of recent randomised controlled trials (RCTs) with compounds able to block T cell co-stimulation and enhance T cell co-inhibition. Despite a clear biological effect on downstream B cell activation has been observed in patients treated with CTLA-4-Ig (abatacept) and with monoclonal antibodies targeting CD40 and ICOSL, the clinical efficacy of this approach has so far yielded mixed results; while the anti-CD40 monoclonal antibody iscalimab showed significant improvement in systemic disease activity compared to placebo, two large RCTs with abatacept and a phase IIa RCT with an anti-ICOSL monoclonal antibody (prezalumab) failed to reach their primary endpoints. Although the discrepancies between biological and clinical efficacy of targeting T cell co-stimulation on pSS remain unresolved, several factors including drug bioavailability and receptor occupancy, patient stratification based on T-cell related biomarkers and the choice of study outcome are likely to play an important role and form the basis for further work towards the quest for a disease-modifying biologic therapy in pSS

The Herschel Virgo Cluster Survey XVI: a cluster inventory

Herschel FIR observations are used to construct Virgo cluster galaxy luminosity functions and to show that the cluster lacks the very bright and the numerous faint sources detected in field galaxy surveys. The far-infrared SEDs are fitted to obtain dust masses and temperatures and the dust mass function. The cluster is over dense in dust by about a factor of 100 compared to the field. The same emissivity (beta) temperature relation applies for different galaxies as that found for different regions of M31. We use optical and HI data to show that Virgo is over dense in stars and atomic gas by about a factor of 100 and 20 respectively. Metallicity values are used to measure the mass of metals in the gas phase. The mean metallicity is about 0.7 solar and 50% of the metals are in the dust. For the cluster as a whole the mass density of stars in galaxies is 8 times that of the gas and the gas mass density is 130 times that of the metals. We use our data to consider the chemical evolution of the individual galaxies, inferring that the measured variations in effective yield are due to galaxies having different ages, being affected to varying degrees by gas loss. Four galaxy scaling relations are considered: mass-metallicity, mass-velocity, mass-star formation rate and mass-radius - we suggest that initial galaxy mass is the prime driver of a galaxy's ultimate destiny. Finally, we use X-ray observations and galaxy dynamics to assess the dark and baryonic matter content compared to the cosmological model

HERschel Observations of Edge-on Spirals (HEROES). II: Tilted-ring modelling of the atomic gas disks

Context. Edge-on galaxies can offer important insights in galaxy evolution as they are the only systems where the distribution of the different components can be studied both radially and vertically. The HEROES project was designed to investigate the interplay between the gas, dust, stars and dark matter (DM) in a sample of 7 massive edge-on spiral galaxies. Aims. In this second HEROES paper we present an analysis of the atomic gas content of 6 out of 7 galaxies in our sample. The remaining galaxy was recently analysed according to the same strategy. The primary aim of this work is to constrain the surface density distribution, the rotation curve and the geometry of the gas disks in a homogeneous way. In addition we identify peculiar features and signs of recent interactions. Methods. We construct detailed tilted-ring models of the atomic gas disks based on new GMRT 21-cm observations of NGC 973 and UGC 4277 and re-reduced archival HI data of NGC 5907, NGC 5529, IC 2531 and NGC 4217. Potential degeneracies between different models are resolved by requiring a good agreement with the data in various representations of the data cubes. Results. From our modelling we find that all but one galaxy are warped along the major axis. In addition, we identify warps along the line of sight in three galaxies. A flaring gas layer is required to reproduce the data only for one galaxy, but (moderate) flares cannot be ruled for the other galaxies either. A coplanar ring-like structure is detected outside the main disk of NGC 4217, which we suggest could be the remnant of a recent minor merger event. We also find evidence for a radial inflow of 15 +- 5 km/s in the disk of NGC 5529, which might be related to the ongoing interaction with two nearby companions. (Abridged)Comment: 39 pages, 38 figures, Accepted for publication in Astronomy & Astrophysic

HERschel Observations of Edge-on Spirals (HEROES). I: Far-infrared morphology and dust mass determination

Context. Edge-on spiral galaxies with prominent dust lanes provide us with an excellent opportunity to study the distribution and properties of the dust within them. The HEROES project was set up to observe a sample of seven large edge-on galaxies across various wavelengths for this investigation. Aims. Within this first paper, we present the Herschel observations and perform a qualitative and quantitative analysis on them, and we derive some global properties of the far infrared and submillimetre emission. Methods. We determine horizontal and vertical profiles from the Herschel observations of the galaxies in the sample and describe the morphology. Modified black-body fits to the global fluxes, measured using aperture photometry, result in dust temperatures and dust masses. The latter values are compared to those that are derived from radiative transfer models taken from the literature. Results. On the whole, our Herschel flux measurements agree well with archival values. We find that the exponential horizontal dust distribution model often used in the literature generally provides a good description of the observed horizontal profiles. Three out of the seven galaxies show signatures of extended vertical emission at 100 and 160 {\mu}m at the 5{\sigma} level, but in two of these it is probably due to deviations from an exactly edge-on orientation. Only for NGC 4013, a galaxy in which vertically extended dust has already been detected in optical images, we can detect vertically extended dust, and the derived scaleheight agrees with the value estimated through radiative transfer modelling. Our analysis hints at a correlation between the dust scaleheight and its degree of clumpiness, which we infer from the difference between the dust masses as calculated from modelling of optical data and from fitting the spectral energy distribution of Herschel datapoints.Comment: 21 pages, 12 figures. Accepted for publication in Astronomy & Astrophysic

A research agenda on patient safety in primary care. Recommendations by the LINNEAUS collaboration on patient safety in primary care

This is the final version of the article. Available from Taylor & Francis via the DOI in this record.BACKGROUND: Healthcare can cause avoidable serious harm to patients. Primary care is not an exception, and the relative lack of research in this area lends urgency to a better understanding of patient safety, the future research agenda and the development of primary care oriented safety programmes. OBJECTIVE: To outline a research agenda for patient safety improvement in primary care in Europe and beyond. METHODS: The LINNEAUS collaboration partners analysed existing research on epidemiology and classification of errors, diagnostic and medication errors, safety culture, and learning for and improving patient safety. We discussed ideas for future research in several meetings, workshops and congresses with LINNEAUS collaboration partners, practising GPs, researchers in this field, and policy makers. RESULTS: This paper summarizes and integrates the outcomes of the LINNEAUS collaboration on patient safety in primary care. It proposes a research agenda on improvement strategies for patient safety in primary care. In addition, it provides background information to help to connect research in this field with practicing GPs and other healthcare workers in primary care. CONCLUSION: Future research studies should target specific primary care domains, using prospective methods and innovative methods such as patient involvement.The research leading to these results has received funding from the European Community’s Seventh Framework Programme FP7/2008–2012 under grant agreement no. 223424

A resolved analysis of cold dust and gas in the nearby edge-on spiral NGC 891

We investigate the connection between dust and gas in the nearby edge-on spiral galaxy NGC 891. High resolution Herschel PACS and SPIRE 70, 100, 160, 250, 350, and 500 $\mu$m images are combined with JCMT SCUBA 850 $\mu$m observations to trace the far-infrared/submillimetre spectral energy distribution (SED). Maps of the HI 21 cm line and CO(J=3-2) emission trace the atomic and molecular hydrogen gas, respectively. We fit one-component modified blackbody models to the integrated SED, finding a global dust mass of 8.5$\times$10$^{7}$ M$_{\odot}$ and an average temperature of 23$\pm$2 K. We also fit the pixel-by-pixel SEDs to produce maps of the dust mass and temperature. The dust mass distribution correlates with the total stellar population as traced by the 3.6 $\mu$m emission. The derived dust temperature, which ranges from approximately 17 to 24 K, is found to correlate with the 24 $\mu$m emission. Allowing the dust emissivity index to vary, we find an average value of $\beta$ = 1.9$\pm$0.3. We confirm an inverse relation between the dust emissivity spectral index and dust temperature, but do not observe any variation of this relationship with vertical height from the mid-plane of the disk. A comparison of the dust properties with the gaseous components of the ISM reveals strong spatial correlations between the surface mass densities of dust and the molecular hydrogen and total gas surface densities. Observed asymmetries in the dust temperature, and the H$_{2}$-to-dust and total gas-to-dust ratios hint that an enhancement in the star formation rate may be the result of larger quantities of molecular gas available to fuel star formation in the NE compared to the SW. Whilst the asymmetry likely arises from dust obscuration due to the geometry of the line-of-sight projection of the spiral arms, we cannot exclude an enhancement in the star formation rate in the NE side of the disk.Comment: Accepted for publication in A&A. 21 pages, including 13 figures and 4 table

The dust energy balance in the edge-on spiral galaxy NGC 4565

We combine new dust continuum observations of the edge-on spiral galaxy NGC 4565 in all Herschel/SPIRE (250, 350, 500 micron) wavebands, obtained as part of the Herschel Reference Survey, and a large set of ancillary data (Spitzer, SDSS, GALEX) to analyze its dust energy balance. We fit a radiative transfer model for the stars and dust to the optical maps with the fitting algorithm FitSKIRT. To account for the observed UV and mid-infrared emission, this initial model was supplemented with both obscured and unobscured star-forming regions. Even though these star-forming complexes provide an additional heating source for the dust, the far-infrared/submillimeter emission long wards of 100 micron is underestimated by a factor of 3-4. This inconsistency in the dust energy budget of NGC 4565 suggests that a sizable fraction (two-thirds) of the total dust reservoir (Mdust ~ 2.9e+8 Msun) consists of a clumpy distribution with no associated young stellar sources. The distribution of those dense dust clouds would be in such a way that they remain unresolved in current far-infrared/submillimeter observations and hardly comtribute to the attenuation at optical wavelengths. More than two-thirds of the dust heating in NGC 4565 is powered by the old stellar population, with localized embedded sources supplying the remaining dust heating in NGC 4565. The results from this detailed dust energy balance study in NGC 4565 is consistent with that of similar analyses of other edge-on spirals.Comment: 16 pages, 7 figures, accepted for publication in MNRA