Cardiopulmonary exercise testing in a combined screening approach to individuate pulmonary arterial hypertension in systemic sclerosis

Objectives The DETECT algorithm has been developed to identify SSc patients at risk for pulmonary arterial hypertension (PAH) yielding high sensitivity but low specificity, and positive predictive value. We tested whether cardiopulmonary exercise testing (CPET) could improve the performance of the DETECT screening strategy. Methods Consecutive SSc patients over a 30-month period were screened with the DETECT algorithm and positive subjects were referred for CPET before the execution of right-heart catheterization. The predictive performance of CPET on top of DETECT was evaluated and internally validated via bootstrap replicates. Results Out of 314 patients, 96 satisfied the DETECT application criteria and 54 were positive. PAH was ascertained in 17 (31.5%) and pre-capillary pulmonary hypertension in 23 (42.6%) patients. Within CPET variables, the slope of the minute ventilation to carbon dioxide production relationship (VE/VCO2 slope) had the best performance to predict PAH at right-heart catheterization [median (interquartile range) of specificity 0.778 (0.714\u20130.846), positive predictive value 0.636 (0.556\u20130.750)]; exploratory analysis on pre-capillary yielded a specificity of 0.714 (0.636\u20130.8) and positive predictive value of 0.714 (0.636\u20130.8). Conclusion In association with the DETECT algorithm, CPET may be considered as a useful tool in the workup of SSc-related pulmonary hypertension. The sequential determination of the VE/VCO2 slope in DETECT-positive subjects may reduce the number of unnecessary invasive procedures without any loss in the capability to capture PAH. This strategy had also a remarkable performance in highlighting the presence of pre-capillary pulmonary hypertension

Modulation of Human Immunodeficiency Virus 1 Replication by Interferon Regulatory Factors

Transcription of the human immunodeficiency virus (HIV)-1 is controlled by the cooperation of virally encoded and host regulatory proteins. The Tat protein is essential for viral replication, however, expression of Tat after virus entry requires HIV-1 promoter activation. A sequence in the 5′ HIV-1 LTR, containing a binding site for transcription factors of the interferon regulatory factors (IRF) family has been suggested to be critical for HIV-1 transcription and replication. Here we show that IRF-1 activates HIV-1 LTR transcription in a dose-dependent fashion and in the absence of Tat. This has biological significance since IRF-1 is produced early upon virus entry, both in cell lines and in primary CD4+ T cells, and before expression of Tat. IRF-1 also cooperates with Tat in amplifying virus gene transcription and replication. This cooperation depends upon a physical interaction that is blocked by overexpression of IRF-8, the natural repressor of IRF-1, and, in turn is released by overexpression of IRF-1. These data suggest a key role of IRF-1 in the early phase of viral replication and/or during viral reactivation from latency, when viral transactivators are absent or present at very low levels, and suggest that the interplay between IRF-1 and IRF-8 may play a key role in virus latency

Limited impact of jet induced feedback in the multi-phase nuclear interstellar medium of 4C12.50

Although the ultraluminous infrared radio galaxy 4C12.50 at z=0.12 is a promising candidate to reveal how radio induced feedback may regulate star formation in galaxies, we find no solid evidence for current or past impact of this mechanism on the evolution of this system, neither by clearing out the dusty central cocoon efficiently, nor by suppressing star formation. We study in detail for the first time the hot (>~1500 K) molecular gas in this object. The potential impact of the radio jet on this gas phase, as well as on the star formation activity, are investigated. 4C12.50 hosts (2.1+/-0.4)x1e4 Msun of hot molecular gas. An unusually high rotational temperature T =3020+/-160 K is inferred. The molecular gas mass obeys a power law temperature distribution d(M(H2))/dT ~ T^-5 from T~300 K and up to ~3000 K. Both results support that shocks (probably induced by the radio jet) contribute to the heating and excitation of the hot molecular gas. A molecular outflow is not detected. The coupling of the outflowing ionized and neutral outflows with the hot molecular gas is poor. We find no evidence for star formation supression. NIR and MIR integral field spectroscopy at very high spatial resolution (for instance, with the JWST) would be of key value to further investigate these issues.Comment: Accepted for publication in A&A,18 pages, 13 figure

Identification of a Shared Microbiomic and Metabolomic Profile in Systemic Autoimmune Diseases

Dysbiosis has been described in systemic autoimmune diseases (SADs), including systemic lupus erythematosus (SLE), Sjögren’s syndrome (SjS), and primary anti-phosholipid syndrome (PAPS), however the biological implications of these associations are often elusive. Stool and plasma samples from 114 subjects, including in SLE (n = 27), SjS (n = 23), PAPs (n = 11) and undifferentiated connective tissue (UCTD, n = 26) patients, and geographically-matched healthy controls (HCs, n = 27), were collected for microbiome (16s rRNA gene sequencing) and metabolome (high-performance liquid chromatography coupled to mass spectrometry) analysis to identify shared characteristics across diseases. Out of 130 identified microbial genera, a subset of 29 bacteria was able to differentiate study groups (area under receiver operating characteristics (AUROC) = 0.730 ± 0.025). A fair classification was obtained with a subset of 41 metabolic peaks out of 254 (AUROC = 0.748 ± 0.021). In both models, HCs were well separated from SADs, while UCTD largely overlapped with the other diseases. In all of the SADs pro-tolerogenic bacteria were reduced, while pathobiont genera were increased. Metabolic alterations included two clusters comprised of: (a) members of the acylcarnitine family, positively correlating with a Prevotella-enriched cluster and negatively correlating with a butyrate-producing bacteria-enriched cluster; and (b) phospholipids, negatively correlating with butyrate-producing bacteria. These findings demonstrate a strong interaction between intestinal microbiota and metabolic function in patients with SADs.This work was supported by EU/EFPIA/Innovative Medicines Initiative Joint Undertaking PRECISESADS grant No. 115565

Physics of ULIRGs with MUSE and ALMA: The PUMA project: I. Properties of the survey and first MUSE data results

Ultraluminous infrared galaxies (ULIRGs) are characterised by extreme starburst (SB) and AGN activity, and are therefore ideal laboratories for studying the outflow phenomena. We have recently started a project called Physics of ULIRGs with MUSE and ALMA (PUMA), which is a survey of 25 nearby (z < 0.165) ULIRGs observed with the integral field spectrograph MUSE and the interferometer ALMA. This sample includes systems with both AGN and SB nuclear activity in the pre- and post-coalescence phases of major mergers. The main goals of the project are to study the prevalence of multi-phase outflows as a function of the galaxy properties, to constrain the driving mechanisms of the outflows (e.g. distinguish between SB and AGN winds), and to identify feedback effects on the host galaxy. In this first paper, we present details on the sample selection, MUSE observations, and derive first data products. MUSE data were analysed to study the dynamical status of each of the 21 ULIRGs observed so far, taking the stellar kinematics and the morphological properties inferred from MUSE narrow-band images into account. We also located the ULIRG nuclei, using near-IR (HST) and mm (ALMA) data, and studied their optical spectra to infer the ionisation state through BPT diagnostics, and outflows in both ionised and neutral gas. We show that the morphological and stellar kinematic classifications are consistent: post-coalescence systems are more likely associated with ordered motions, while interacting (binary) systems are dominated by non-ordered and streaming motions. We also find broad and asymmetric [OIII] and NaID profiles in almost all nuclear spectra, with line widths in the range 300-2000 km/s, possibly associated with AGN- and SB-driven winds. This result reinforces previous findings that indicated that outflows are ubiquitous during the pre- and post-coalescence phases of major mergers.ERC STF

Impact of biliary stents on the diagnostic accuracy of EUS-guided fine-needle biopsy of solid pancreatic head lesions: A multicenter study

There is no clear evidence of a negative impact of biliary stents on the diagnostic yield of EUS-guided fine-needle biopsy (EUS-FNB) for diagnosing pancreatic head lesions. We aimed to evaluate the association between the presence of biliary stents and the diagnostic accuracy of EUS-FNB. Materials and Methods: A multicenter retrospective study including all jaundiced patients secondary to pancreatic head masses was performed. Patients were divided into two groups according to the presence of a biliary stent placed before EUS-FNB. Pathological results were classified according to the Papanicolaou classification and compared against the final diagnosis. Diagnostic measures in the two groups were compared. Multivariate logistic regression analyses including potential factors affecting EUS-FNB accuracy were performed. Results: Overall, 842 patients were included, 495 (58.8%) without and 347 (41.2%) with biliary stent. A plastic or a metal stent was placed in 217 (62.5%) and 130 (37.5%) cases, respectively. Diagnostic sensitivity and accuracy were significantly higher in patients without biliary stent than in those with stent (91.9% and 92.1% vs. 85.9% and 86.4%, P = 0.010 At multivariate analyses, lesion size (odds ratio [OR]: 1.05, 95% confidence interval [CI]: 1.02-1.09, P = 0.01) and presence of biliary stent (OR: 0.51, 95% CI: 0.32-0.89, P = 0.01) were independently associated with diagnostic accuracy. In the subgroup of patients with biliary stent, the type of stent (plastic vs. metal) did not impact EUS-FNB yield, whereas the use of larger bore needles enhanced diagnostic accuracy (OR: 2.29, 95% CI: 1.28-4.12, P = 0.005). Conclusions: In this large retrospective study, an indwelling biliary stent negatively impacted the diagnostic accuracy of EUS-FNB. Preferably, EUS-FNB should precede endoscopic retrograde cholangiopancreatography, especially in the case of small tumors

SARS-CoV-2 variants and their relevant mutational profiles: update summer 2021

: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic caused by it, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been undergoing a genetic diversification leading to the emergence of new variants. Nevertheless, a clear definition of the genetic signatures underlying the circulating variants is still missing. Here, we provide a comprehensive insight into mutational profiles characterizing each SARS-CoV-2 variant, focusing on spike mutations known to modulate viral infectivity and/or antigenicity. We focused on variants and on specific relevant mutations reported by GISAID, Nextstrain, Outbreak.info, Pango, and Stanford database websites that were associated with any clinical/diagnostic impact, according to published manuscripts. Furthermore, 1,223,338 full-length high-quality SARS-CoV-2 genome sequences were retrieved from GISAID and used to accurately define the specific mutational patterns in each variant. Finally, mutations were mapped on the three-dimensional structure of the SARS-CoV-2 spike protein to assess their localization in the different spike domains. Overall, this review sheds light and assists in defining the genetic signatures characterizing the currently circulating variants and their clinical relevance. IMPORTANCE Since the emergence of SARS-CoV-2, several recurrent mutations, particularly in the spike protein, arose during human-to-human transmission or spillover events between humans and animals, generating distinct worrisome variants of concern (VOCs) or of interest (VOIs), designated as such due to their clinical and diagnostic impacts. Characterizing these variants and their related mutations is important in tracking SAR-CoV-2 evolution and understanding the efficacy of vaccines and therapeutics based on monoclonal antibodies, convalescent-phase sera, and direct antivirals. Our study provides a comprehensive survey of the mutational profiles characterizing the important SARS-CoV-2 variants, focusing on spike mutations and highlighting other protein mutations

Deconstructing the narrow-line region of the nearest obscured quasar

We study the physical and kinematic properties of the narrow-line region (NLR) of the nearest obscured quasar MRK 477 (z = 0.037), using optical and near-infrared (NIR) spectroscopy. About 100 emission lines are identified in the optical+NIR spectrum (90 in the optical), including several narrow optical Fe+ lines. To our knowledge, this is the first type 2 active galactic nucleus (AGN) with such a detection. The Fe+ lines can be explained as the natural emission from the NLR photoionized by the AGN. Coronal line emission can only be confirmed in the NIR spectrum. As in many other AGNs, a significant correlation is found between the lines’ full width at half-maximum and the critical density log(ncrit). We propose that it is caused by the outflow. This could be the case in other AGNs. The nuclear jet-induced ionized outflow has been kinematically isolated in many emission lines covering a broad range of ionization potentials and critical densities. It is concentrated within R ∼few×100 pc from the central engine. The outflowing gas is denser (n ≳ 8000 cm−3) than the ambient non-perturbed gas (n ∼ 400–630 cm−3). This could be due to the compression effect of the jet-induced shocks. Alternatively, we propose that the outflow has been triggered by the jet at R ≲ 220 pc (possibly at ≲ 30 pc), and we trace how the impact weakens as it propagates outwards following the radiation-pressure-dominated density gradient. The different kinematic behaviour of [Fe II] λ1.644 μm suggests that its emission is enhanced by shocks induced by the nuclear outflow/jet and is preferentially emitted at a different, less reddened spatial location

MUSE view of Arp220: Kpc-scale multi-phase outflow and evidence for positive feedback

Arp220 is the nearest and prototypical ULIRG, and shows evidence of pc-scale molecular outflows in its nuclear regions and strongly perturbed ionised gas kinematics on kpc scales. It is therefore the ideal system for investigating outflows and feedback phenomena in details. We investigate the feedback effects on the Arp220 ISM, deriving a detailed picture of the atomic gas in terms of physical and kinematic properties, with a spatial resolution never obtained before (0.56", i.e. ~ 210 pc). We use optical IFS observations from VLT/MUSE-AO to obtain spatially resolved stellar and gas kinematics, for both ionised ([N II]6583) and neutral (Na ID5891,96) components; we also derive dust attenuation, electron density, ionisation conditions and hydrogen column density maps to characterise the ISM properties. Arp220 kinematics reveal the presence of a disturbed, kpc-scale disk in the innermost nuclear regions, and highly perturbed, multi-phase (neutral and ionised) gas along the minor-axis of the disk, which we interpret as a galactic-scale outflow emerging from the Arp220 eastern nucleus. This outflow involves velocities up to ~ 1000 km/s at galactocentric distances of ~ 5 kpc, and has a mass rate of ~ 50 Msun/yr, and kinetic and momentum power of ~ 1e43 erg/s and ~ 1e35 dyne, respectively. The inferred energetics do not allow us to distinguish the origin of the outflows, i.e. whether they are AGN-driven or starburst-driven. We also present evidence for enhanced star formation at the edges of - and within - the outflow, with a star formation rate SFR ~ 5 Msun/yr (i.e. ~ 2% of the total SFR). Our findings suggest the presence of powerful winds in Arp220: they might be capable of removing or heating large amounts of gas from the host ("negative feedback"), but could be also responsible for triggering star formation ("positive feedback").STFC ER