The Efficacy of Sequential Biologic Agents in Refractory Rheumatoid Arthritis After Failure of Initial DMARD and Anti-Tumor Necrosis Factor Therapy

Introduction/Objective: The efficacy of biologic therapy in the treatment of rheumatoid arthritis (RA) has been well-established but, in practice, a quarter of patients will either not respond to the first biologic agent or will suffer an adverse event requiring a switch to a different drug. While clinical guidelines exist to help guide therapy and previous studies have examined sequential use of anti-TNF agents, there is little data to inform a multiple switch strategy. Our aim was to measure the efficacy of multiple switches of biologic in severe refractory RA. Methods: We enrolled 111 patients whose therapy with one anti-TNF agent had failed in this open-label observational study. These patients were all treated with a second biologic agent and 27 ultimately required treatment with a third. The response to the therapy and disease activity were assessed at 6 and 12 months after each switch. Results: The remission rates at 6 months were lower than previously reported and the initiation of a second biologic agent resulted in significant improvement at 12 months, including DAS remission in 36% of patients. The response in those receiving a third biologic was less pronounced, as might be expected in this relatively treatment-refractory population. In this group, only patients treated with tocilizumab had maintained remission at one year. Conclusion: Patients who do not respond to an anti-TNF agent often benefit from being switched to a second, or even third, biologic. Importantly, it may take longer than expected to fully assess the effectiveness of a second or third agent in patients with refractory disease

Emerging Evidence and Treatment Perspectives from Randomized Clinical Trials in Systemic Sclerosis: Focus on Interstitial Lung Disease

Systemic sclerosis (SSc) is a complex rare autoimmune disease with heterogeneous clinical manifestations. Currently, interstitial lung disease (ILD) and cardiac involvement (including pulmonary arterial hypertension) are recognized as the leading causes of SSc-associated mortality. New molecular targets have been discovered and phase II and phase III clinical trials published in the last 5 years on SSc-ILD will be discussed in this review. Details on the study design; the drug tested and its dose; the inclusion and exclusion criteria of the study; the concomitant immunosuppression; the outcomes and the duration of the study were reviewed. The two most common drugs used for the treatment of SSc-ILD are cyclophosphamide and mycophenolate mofetil, both supported by randomized controlled trials. Additional drugs, such as nintedanib and tocilizumab, have been approved to slow pulmonary function decline in SSc-ILD. In this review, we discuss the therapeutic alternatives for SSc management, offering the option to customize the design of future studies to stratify SSc patients and provide a patient-specific treatment according to the new emerging pathogenic features of SSc-ILD

The COVID-19 Assessment for Survival at Admission (CASA) Index: A 12 Months Observational Study

Objective: Coronavirus disease 2019 (COVID-19) is a disease with a high rate of progression to critical illness. However, the stratification of patients at risk of mortality is not well defined. In this study, we aimed to define a mortality risk index to allocate patients to the appropriate intensity of care. Methods: This is a 12 months observational longitudinal study designed to develop and validate a pragmatic mortality risk score to stratify COVID-19 patients aged ≥18 years and admitted to hospital between March 2020 and March 2021. Main outcome was in-hospital mortality. Results: 244 patients were included in the study (mortality rate 29.9%). The Covid-19 Assessment for Survival at Admission (CASA) index included seven variables readily available at admission: respiratory rate, troponin, albumin, CKD-EPI, white blood cell count, D-dimer, Pa02/Fi02. The CASA index showed high discrimination for mortality with an AUC of 0.91 (sensitivity 98.6%; specificity 69%) and a better performance compared to SOFA (AUC = 0.76), age (AUC = 0.76) and 4C mortality (AUC = 0.82). The cut-off identified (11.994) for CASA index showed a negative predictive value of 99.16% and a positive predictive value of 57.58%. Conclusions: A quick and readily available index has been identified to help clinicians stratify COVID-19 patients according to the appropriate intensity of care and minimize hospital admission to patients at high risk of mortality

Design and implementation of a seismic Newtonian-noise cancellation system for the Virgo gravitational-wave detector

Terrestrial gravity perturbations caused by seismic fields produce the so-called Newtonian noise in gravitational-wave detectors, which is predicted to limit their sensitivity in the upcoming observing runs. In the past, this noise was seen as an infrastructural limitation, i.e., something that cannot be overcome without major investments to improve a detector's infrastructure. However, it is possible to have at least an indirect estimate of this noise by using the data from a large number of seismometers deployed around a detector's suspended test masses. The noise estimate can be subtracted from the gravitational-wave data; a process called Newtonian-noise cancellation (NNC). In this article, we present the design and implementation of the first NNC system at the Virgo detector as part of its AdV+ upgrade. It uses data from 110 vertical geophones deployed inside the Virgo buildings in optimized array configurations. We use a separate tiltmeter channel to test the pipeline in a proof-of-principle. The system has been running with good performance over months

Characterizing the Sardinia candidate site for the Einstein Telescope

Due to its unique geophysical features and to the low density population of the area, Sos Enattos is a promising candidate site to host the Einstein Telescope (ET), the third-generation Gravitational Wave Observatory. The geophysical characterization of the Sos Enattos former mine, close to one of the proposed ET corners, started in 2010 with the deployment of seismic and environmental sensors underground. Since 2019 a new extensive array of seismometers, magnetometers and acoustic sensors have been installed in three stations along the underground tunnels, with one additional station at the surface. Beside a new geological survey over a wider area, two boreholes about 270 m deep each were excavated at the other two corners, determining the good quality of the drilled granite and orthogneiss rocks and the absence of significant thoroughgoing fault zones. These boreholes are instrumented with broadband seismometers that revealed an outstanding low level of vibrational noise in the low-frequency band of ET-LF (2-10Hz), significantly lower than the Peterson's NLNM and resulting among the quietest seismic stations in the world in that frequency band. The low seismic background and the reduced number of seismic glitches ensure that just a moderated Newtonian noise subtraction would be needed to achieve the ET target sensitivity. Geoelectrical and active seismic campaigns have been carried out to reveal the features of the subsurface, revealing the presence of small-sized fractured areas with limited water circulation. Finally, temporary arrays of seismometers, magnetometers and acoustic sensors are deployed in the area to study the local sources of environmental noise

Array analysis of seismic noise at the Sos Enattos mine, the Italian candidate site for the Einstein Telescope

The area surrounding the dismissed mine of Sos Enattos (Sardinia, Italy) is the Italian candidate site for hosting Einstein Telescope (ET), the third-generation gravitational wave (GW) observatory. One of the goals of ET is to extend the sensitivity down to frequencies well below those currently achieved by GW detectors, i.e. down to 2 Hz. In the bandwidth [1,10] Hz, the seismic noise of anthropogenic origin is expected to represent the major perturbation to the operation of the infrastructure, and the site that will host the future detector must fulfill stringent requirements on seismic disturbances. In this paper we describe the operation of a temporary, 15-element, seismic array deployed in close proximity to the mine. Signals of anthropogenic origin have a transient nature, and their spectra are characterized by a wide spectral lobe spanning the [3,20] Hz frequency interval. Superimposed to this wide lobe are narrow spectral peaks within the [3,8] Hz frequency range. Results from slowness analyses suggest that the origin of these peaks is related to vehicle traffic along the main road running east of the mine. Exploiting the correlation properties of seismic noise, we derive a dispersion curve for Rayleigh waves, which is then inverted for a shallow velocity structure down to depths of ≈≈ 150 m. This data, which is consistent with that derived from analysis of a quarry blast, provide a first assessment of the elastic properties of the rock materials at the site candidate to hosting ET

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level