Systemic phenotype related to primary Sjögren's syndrome in 279 patients carrying isolated anti-La/SSB antibodies

Objective. To evaluate the systemic phenotype associated with the presence of isolated anti-La/SSB antibodies in a large international registry of patients with primary Sjögren's syndrome (pSS) fulfilling the 2002 classification criteria. Methods. The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. Baseline clinical information from leading centres on clinical research in SS of the 5 continents was collected. Combination patterns of anti-Ro/SSA-La/SSB antibodies at the time of diagnosis defined the following four immu-nological phenotypes: Double positive (combined Ro/SSA and La/SSB,) isolated anti-Ro/SSA, isolated anti-La/ SSB, and immunonegative. Results. The cohort included 12,084 patients (11,293 females, mean 52.4 years) with recorded ESSDAI scores available. Among them, 279 (2.3%) had isolated anti-La/SSB antibodies. The mean total ESSDAI score at diagnosis of patients with pSS carrying isolated anti-La/SSB was 6.0, and 80.4% of patients had systemic activity (global ESSDAI score ≥ 1) at diagnosis. The domains with the highest frequency of active patients were the biological (42.8%), glandular (36.8%) and articular (31.2%) domains. Patients with isolated anti-La/ SSB showed a higher frequency of active patients in all ESSDAI domains but two (articular and peripheral nerve) in com-parison with immune-negative patients, and even a higher absolute frequency in six clinical ESSDAI domains in comparison with patients with isolated anti-Ro/ SSA. In addition, patients with isolated anti-La/SSB showed a higher frequency of active patients in two ESSDAI domains (pulmonary and glandular) with respect to the most active immunological subset (double-positive antibodies). Meanwhile, systemic activity detected in patients with isolated anti-La/SSB was overwhelmingly low. Even in ESSDAI domains where patients with isolated anti-La/SSB had the highest frequencies of systemic activity (lymphadenopathy and muscular), the percentage of patients with moderate or high activity was lower in comparison with the combined Ro/SSA and La/SSB group. Conclusion. Patients carrying isolated La/SSB antibodies represent a very small subset of patients with a systemic SS phenotype characterised by a significant frequency of active patients in most clinical ESSDAI domains but with a relative low frequency of the highest severe organ-specific involvements. Primary SS still remains the best clinical diagnosis for this subset of patients

Characterization and outcomes of 414 patients with primary SS who developed haematological malignancies

Objective: To characterize 414 patients with primary SS who developed haematological malignancies and to analyse how the main SS- and lymphoma-related features can modify the presentation patterns and outcomes. Methods: By January 2021, the Big Data Sjögren Project Consortium database included 11 966 patients fulfilling the 2002/2016 classification criteria. Haematological malignancies diagnosed according to the World Health Organization (WHO) classification were retrospectively identified. Results: There were 414 patients (355 women, mean age 57 years) with haematological malignancies (in 43, malignancy preceded at least one year the SS diagnosis). A total of 376 (91%) patients had mature B-cell malignancy, nearly half had extranodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT lymphoma) (n = 197), followed by diffuse large B-cell lymphoma (DLBCL) (n = 67), nodal MZL lymphoma (n = 29), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (n = 19) and follicular lymphoma (FL) (n = 17). Rates of complete response, relapses and death were 80%, 34% and 13%, respectively, with a 5-year survival rate of 86.5% after a mean follow-up of 8 years. There were significant differences in age at diagnosis (younger in MALT, older in CLL/SLL), predominant clinical presentation (glandular enlargement in MALT lymphoma, peripheral lymphadenopathy in nodal MZL and FL, constitutional symptoms in DLBCL, incidental diagnosis in CLL/SLL), therapeutic response (higher in MALT lymphoma, lower in DLBCL) and survival (better in MALT, nodal MZL and FL, worse in DLBCL). Conclusion: In the largest reported study of haematological malignancies complicating primary SS, we confirm the overwhelming predominance of B-cell lymphomas, especially MALT, with the salivary glands being the primary site of involvement. This highly-specific histopathological scenario is linked with the overall good prognosis with a 5-year survival rate of nearly 90%

H.E.S.S. observations of the 2021 periastron passage of PSR B1259-63/LS 2883

PSR B1259-63 is a gamma-ray binary system that hosts a pulsar in an eccentric orbit, with a 3.4 year period, around an O9.5Ve star. At orbital phases close to periastron passages, the system radiates bright and variable non-thermal emission. We report on an extensive VHE observation campaign conducted with the High Energy Stereoscopic System, comprised of ~100 hours of data taken from $t_p-24$ days to $t_p+127$ days around the system's 2021 periastron passage. We also present the timing and spectral analyses of the source. The VHE light curve in 2021 is consistent with the stacked light curve of all previous observations. Within the light curve, we report a VHE maximum at times coincident with the third X-ray peak first detected in the 2021 X-ray light curve. In the light curve -- although sparsely sampled in this time period -- we see no VHE enhancement during the second disc crossing. In addition, we see no correspondence to the 2021 GeV flare in the VHE light curve. The VHE spectrum obtained from the analysis of the 2021 dataset is best described by a power law of spectral index $\Gamma = 2.65 \pm 0.04_{\text{stat}}$ $\pm 0.04_{\text{sys}}$, a value consistent with the previous H.E.S.S. observations of the source. We report spectral variability with a difference of $\Delta \Gamma = 0.56 ~\pm~ 0.18_{\text{stat}}$ $~\pm~0.10_{\text{sys}}$ at 95% c.l., between sub-periods of the 2021 dataset. We also find a linear correlation between contemporaneous flux values of X-ray and TeV datasets, detected mainly after $t_p+25$ days, suggesting a change in the available energy for non-thermal radiation processes. We detect no significant correlation between GeV and TeV flux points, within the uncertainties of the measurements, from $\sim t_p-23$ days to $\sim t_p+126$ days. This suggests that the GeV and TeV emission originate from different electron populations.Comment: accepted to A&

Salivary Gland Disorders and Diseases

Saliva plays an important role in maintaining healthy oral mucosa and teeth as well as oral function by continually covering and lubricating the oral tissues. Salivary gland dysfunction designates decreased saliva flow rate (salivary gland hypofunction), increased saliva flow rate (sialorrhea or hypersalivation), and changed saliva composition. Xerostomia (the subjective feeling of oral dryness) is often associated with salivary gland hypofunction and may severely affect nutritional intake, social interaction and quality of life. Local or systemic disorders and diseases are common causes of compromised saliva secretion. Some of these are related to gland pathology or to the pathophysiological conditions of the host, whereas others affect the gland innervation or are an iatrogenic result of treatment of a disease (e.g., radiation therapy for head and neck cancer, side effects of medications). In general, many patients suffering from diseases that influence salivary gland function also undergo treatments that may impair saliva secretion and/or induce xerostomia as an adverse effect. Consequently, it can be difficult to distinguish what can be attributed to the disease per se or what can be induced by treatment (e.g., medication intake). Thus, a thorough diagnostic workup and early diagnosis of salivary gland dysfunction are crucial to provide appropriate evidence-based treatment of salivary gland dysfunction to prevent oral sequelae and to initiate individualized alleviating management strategies of xerostomia.</p

Prospects for γ-ray observations of the Perseus galaxy cluster with the Cherenkov Telescope Array

Galaxy clusters are expected to be both dark matter (DM) reservoirs and storage rooms for the cosmic-ray protons (CRp) that accumulate along the cluster’s formation history. Accordingly, they are excellent targets to search for signals of DM annihilation and decay at γ-ray energies and are predicted to be sources of large-scale γ-ray emission due to hadronic interactions in the intracluster medium (ICM). In this paper, we estimate the sensitivity of the Cherenkov Telescope Array (CTA) to detect diffuse γ-ray emission from the Perseus galaxy cluster. We first perform a detailed spatial and spectral modelling of the expected signal for both the DM and the CRp components. For each case, we compute the expected CTA sensitivity accounting for the CTA instrument response functions. The CTA observing strategy of the Perseus cluster is also discussed. In the absence of a diffuse signal (non-detection), CTA should constrain the CRp to thermal energy ratio X500 within the characteristic radius R500 down to about X500 &lt; 3 × 10−3, for a spatial CRp distribution that follows the thermal gas and a CRp spectral index αCRp = 2.3. Under the optimistic assumption of a pure hadronic origin of the Perseus radio mini-halo and depending on the assumed magnetic field profile, CTA should measure αCRp down to about ∆αCRp ≃ 0.1 and the CRp spatial distribution with 10% precision, respectively. Regarding DM, CTA should improve the current ground-based γ-ray DM limits from clusters observations on the velocity-averaged annihilation cross-section by a factor of up to ∼ 5, depending on the modelling of DM halo substructure. In the case of decay of DM particles, CTA will explore a new region of the parameter space, reaching models with τχ &gt; 1027 s for DM masses above 1 TeV. These constraints will provide unprecedented sensitivity to the physics of both CRp acceleration and transport at cluster scale and to TeV DM particle models, especially in the decay scenario

Joint searches by FACT, H.E.S.S., MAGIC and VERITAS for VHE gamma-ray emission associated with neutrinos detected by IceCube

The sources of the astrophysical flux of high-energy neutrinos detected by IceCube are still largely unknown, but searches for temporal and spatial correlation between neutrinos and electromagnetic radiation are a promising approach in this endeavor. All major imaging atmospheric Cherenkov telescopes (IACTs) - FACT, H.E.S.S., MAGIC, and VERITAS - operate an active follow-up program of target-of-opportunity observations of neutrino alerts issued by IceCube. These programs use several complementary neutrino alert streams. A publicly distributed alert stream is formed by individual high-energy neutrino candidate events of potentially astrophysical origin, such as IceCube-170922A (which could be linked to the flaring blazar TXS 0506+056). A privately distributed alert stream is formed by clusters of neutrino events in time and space around either pre-selected gamma-ray sources or anywhere in the sky. Here, we present joint searches for multi-wavelength emission associated with a set of IceCube alerts, both private and public, received through mid-January 2021. We will give an overview of the programs of the participating IACTs. We will showcase the various follow-up and data analysis strategies employed in response to the different alert types and various possible counterpart scenarios. Finally, we will present results from a combined analysis of the VHE gamma-ray observations obtained across all involved instruments, as well as relevant multi-wavelength data

Recommendations for early referral of individuals with suspected polymyalgia rheumatica: an initiative from the international giant cell arteritis and polymyalgia rheumatica study group

Objective To develop international consensus-based recommendations for early referral of individuals with suspected polymyalgia rheumatica (PMR). Methods A task force including 29 rheumatologists/internists, 4 general practitioners, 4 patients and a healthcare professional emerged from the international giant cell arteritis and PMR study group. The task force supplied clinical questions, subsequently transformed into Population, Intervention, Comparator, Outcome format. A systematic literature review was conducted followed by online meetings to formulate and vote on final recommendations. Levels of evidence (LOE) (1–5 scale) and agreement (LOA) (0–10 scale) were evaluated. Results Two overarching principles and five recommendations were developed. LOE was 4–5 and LOA ranged between 8.5 and 9.7. The recommendations suggest that (1) each individual with suspected or recently diagnosed PMR should be considered for specialist evaluation, (2) before referring an individual with suspected PMR to specialist care, a thorough history and clinical examination should be performed and preferably complemented with urgent basic laboratory investigations, (3) individuals with suspected PMR with severe symptoms should be referred for specialist evaluation using rapid access strategies, (4) in individuals with suspected PMR who are referred via rapid access, the commencement of glucocorticoid therapy should be deferred until after specialist evaluation and (5) individuals diagnosed with PMR in specialist care with a good initial response to glucocorticoids and a low risk of glucocorticoid related adverse events can be managed in primary care. Conclusions These are the first international recommendations for referral of individuals with suspected PMR, which complement the European Alliance of Associations for Rheumatology/American College of Rheumatology management guidelines for established PMR

Prospects for γ-ray observations of the Perseus galaxy cluster with the Cherenkov Telescope Array

Galaxy clusters are expected to be dark matter (DM) reservoirs and storage rooms for the cosmic-ray protons (CRp) that accumulate along the cluster's formation history. Accordingly, they are excellent targets to search for signals of DM annihilation and decay at gamma-ray energies and are predicted to be sources of large-scale gamma-ray emission due to hadronic interactions in the intracluster medium. We estimate the sensitivity of the Cherenkov Telescope Array (CTA) to detect diffuse gamma-ray emission from the Perseus galaxy cluster. We perform a detailed spatial and spectral modelling of the expected signal for the DM and the CRp components. For each, we compute the expected CTA sensitivity. The observing strategy of Perseus is also discussed. In the absence of a diffuse signal (non-detection), CTA should constrain the CRp to thermal energy ratio within the radius $R_{500}$ down to about X_{500}<3\times 10^{-3}, for a spatial CRp distribution that follows the thermal gas and a CRp spectral index $α_{\rm CRp}=2.3$. Under the optimistic assumption of a pure hadronic origin of the Perseus radio mini-halo and depending on the assumed magnetic field profile, CTA should measure $α_{\rm CRp}$ down to about $Δα_{\rm CRp}\simeq 0.1$ and the CRp spatial distribution with 10% precision. Regarding DM, CTA should improve the current ground-based gamma-ray DM limits from clusters observations on the velocity-averaged annihilation cross-section by a factor of up to $\sim 5$, depending on the modelling of DM halo substructure. In the case of decay of DM particles, CTA will explore a new region of the parameter space, reaching models with τ_χ>10^{27}s for DM masses above 1 TeV. These constraints will provide unprecedented sensitivity to the physics of both CRp acceleration and transport at cluster scale and to TeV DM particle models, especially in the decay scenario

Dark matter line searches with the Cherenkov Telescope Array

Monochromatic gamma-ray signals constitute a potential smoking gun signature for annihilating or decaying dark matter particles that could relatively easily be distinguished from astrophysical or instrumental backgrounds. We provide an updated assessment of the sensitivity of the Cherenkov Telescope Array (CTA) to such signals, based on observations of the Galactic centre region as well as of selected dwarf spheroidal galaxies. We find that current limits and detection prospects for dark matter masses above 300 GeV will be significantly improved, by up to an order of magnitude in the multi-TeV range. This demonstrates that CTA will set a new standard for gamma-ray astronomy also in this respect, as the world's largest and most sensitive high-energy gamma-ray observatory, in particular due to its exquisite energy resolution at TeV energies and the adopted observational strategy focussing on regions with large dark matter densities. Throughout our analysis, we use up-to-date instrument response functions, and we thoroughly model the effect of instrumental systematic uncertainties in our statistical treatment. We further present results for other potential signatures with sharp spectral features, e.g. box-shaped spectra, that would likewise very clearly point to a particle dark matter origin

Broadband multi-wavelength properties of M87 during the 2018 EHT campaign including a very high energy flaring episode

Context. The nearby elliptical galaxy M87 contains one of only two supermassive black holes whose emission surrounding the event horizon has been imaged by the Event Horizon Telescope (EHT). In 2018, more than two dozen multi-wavelength (MWL) facilities (from radio to γ-ray energies) took part in the second M87 EHT campaign. Aims. The goal of this extensive MWL campaign was to better understand the physics of the accreting black hole M87*, the relationship between the inflow and inner jets, and the high-energy particle acceleration. Understanding the complex astrophysics is also a necessary first step towards performing further tests of general relativity. Methods. The MWL campaign took place in April 2018, overlapping with the EHT M87* observations. We present a new, contemporaneous spectral energy distribution (SED) ranging from radio to very high-energy (VHE) γ-rays as well as details of the individual observations and light curves. We also conducted phenomenological modelling to investigate the basic source properties. Results. We present the first VHE γ-ray flare from M87 detected since 2010. The flux above 350 GeV more than doubled within a period of ≈36 hours. We find that the X-ray flux is enhanced by about a factor of two compared to 2017, while the radio and millimetre core fluxes are consistent between 2017 and 2018. We detect evidence for a monotonically increasing jet position angle that corresponds to variations in the bright spot of the EHT image. Conclusions. Our results show the value of continued MWL monitoring together with precision imaging for addressing the origins of high-energy particle acceleration. While we cannot currently pinpoint the precise location where such acceleration takes place, the new VHE γ-ray flare already presents a challenge to simple one-zone leptonic emission model approaches, and it emphasises the need for combined image and spectral modelling