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Ultralow-noise microwave amplification and detection play a central role in different applications, going from fundamental physics experiments to the deployment of quantum technologies. In many applications the necessity of reading multiple detectors, or cavities or qubits, calls for large bandwidth amplifiers with the lowest possible noise. Current technologies are based on High Electron Mobility Transistors and Josephson Parametric Amplifiers. Both have limitations, the former in terms of the minimum noise, the latter in terms of bandwidth. Superconducting Traveling Wave Parametric Amplifiers (TWPAs) have the potential of offering quantum limited noise and large bandwidth. These amplifiers are based on the parametric amplification of microwaves traveling along a transmission line with embedded nonlinear elements. We are developing superconducting TWPAs based both on Josephson junction arrays (Traveling Wave Josephson Parametric mplifiers) and on nonlinear kinetic inductance (Dispersion Engineered Traveling Wave Kinetic Inductance Amplifiers). Our goal is to achieve large bandwidth (in the 5 to 10 GHz range), large gain (more than 20 dB), large saturation power (more than -50 dBm), and near quantum limited noise (noise temperature less than 600 mK). Current achievements in the design and development of the high performance TWPAs are here reported and discussed, together with current limitations and possible future developments.

The late archeologist Glynn Isaac first applied the term "muddle in the middle" to a poorly understood period in the Middle Pleistocene human fossil record. This study uses the nasopharyngeal boundaries as a source of traits that may inform this unclear period of human evolution. The nasopharynx lies at the nexus of several vital physiological systems, yet relatively little is known about its importance in human evolution. We analyzed a geographically diverse contemporary Homo sapiens growth series (n = 180 adults, 237 nonadults), Homo neanderthalensis (La Chapelle aux Saints 1, La Ferrassie 1, Forbes Quarry 1, Monte Circeo 1, and Saccopastore 1), mid-Pleistocene Homo (Atapuerca 5, Kabwe 1, Petralona 1, and Steinheim 1), and two Homo erectus sensu lato (KNM-ER 3733 and Sangiran 17). Methods include traditional (Analysis 1) and 3D geometric morphometric analysis (Analysis 2). H. erectus exhibited tall, narrow nasopharyngeal shape, a robust, ancestral morphology. Kabwe 1 and Petralona 1 plotted among H. sapiens in Analysis 2, exhibiting relatively shorter and vertical cartilaginous Eustachian tubes and vertical medial pterygoid plates. Atapuerca 5 and Steinheim 1 exhibited horizontal vomeral orientation similar to H. neanderthalensis, indicating greater relative soft palate length and anteroposterior nasopharynx expansion. They may exhibit synapomorphies with H. neanderthalensis, supporting the accretionary hypothesis. Species-level differences were found among H. sapiens and H. neanderthalensis, including relatively longer dilator tubae muscles and extreme facial airorhynchy among Neanderthals. Furthermore, H. neanderthalensis were autapomorphic in exhibiting horizontal pterygoid plate orientation similar to human infants, suggesting that they may have had inferiorly low placement of the torus tubarius and Eustachian tube orifice on the lateral nasopharyngeal wall in life. This study supports use of osseous nasopharyngeal boundaries both for morphological characters and understanding evolution of otitis media susceptibility in living humans.

Purpose: The azygos system of veins has many anatomical variations that can impact mediastinal and vascular interventions. While radiological reports on these are of great clinical value, this study is among the first to present a high-quality cadaveric dissection of a rare anatomical variant to supplement previously published radiologic studies. The azygos venous system consists of the azygos vein (AV), hemiazygos vein (HAV), and the accessory hemiazygos vein (AHAV), which develop from the last portion of the posterior cardinal veins. The normal anatomical configuration includes drainage of the posterior intercostal veins, vertebral vein, esophageal veins, HAV, and AHAV to an unpaired right-side AV at the level of the 8th/9th thoracic vertebra. Methods: An adult formalin-fixed 70-year-old female Caucasian cadaver was dissected as part of a medical gross anatomy elective course. Results: Gross documentation of a direct connection of the HAV to the AHAV with the AHAV draining into the left brachiocephalic vein. Conclusion: The reported incidence of AHAV draining directly into the left brachiocephalic vein is 1-2%. It is important to note the variations of the azygos system to avoid confusion with a potential pathology such as mediastinal masses. Understanding of the rare variant reported here could be useful in prevention of iatrogenic bleeding from misplacement of venous catheters and help facilitate radiological diagnosis in the incidence of venous clot formation.

Atherosclerosis is a chronic and multifactorial disease accompanied by an imbalance between resolving and pro-inflammatory lipid mediators. Targeting lipid signaling might offer new therapeutical targets for improving the clinical outcome in cardiovascular disease patients. We considered lysophosphatidylinositol (LPI) and its receptor G protein-coupled receptor (GPR)55 as a potential modulator of atherosclerosis. Its role in regulating atherosclerosis and B cell function is unknown. We hypothesize that GPR55 signaling affects atherosclerosis by regulating B cell function. Atherosclerotic plaques were compared between apolipoprotein-E-deficient (ApoE−/−) and ApoE−/−Gpr55−/− mice after 4 to 16 weeks Western Diet (WD; 0.15% cholesterol; n=12–15 per group). To test the role of B cell GPR55, we generated mixed chimeras by irradiating low density lipoprotein receptor deficient (Ldlr−/−) mice and reconstituting with a mixture of μMT and wildtype or μMT and Gpr55−/− bone marrow cells. Circulating B cells were sorted and bulk RNA sequencing analysis was performed. We performed atheroma plaque characterization, qPCR and ELISA of tissue lysates and measure plasma immunoglobulins. Circulating and tissue leukocyte counts were determined. We confirmed Gpr55 expression on circulating B cells, which was higher compared to T and myeloid cells. ApoE−/−Gpr55−/− mice had significantly larger plaques after 4 & 16 weeks WD compared to ApoE−/−, with increased body weight & cholesterol levels. In addition, global Gpr55 deficiency resulted in enhanced aortic pro-inflammatory cytokine mRNA expression, a massively upregulated IgG levels and increased counts of splenic germinal center and plasma cells. ApoE−/−Gpr55−/− B-cell RNA-seq analysis showed 460 differential expressed genes compared to ApoE−/−. The main pathways affected were calcium ion transport, immunoglobulin production, T & B cell activation, and cellular response to stress. B cell specific Gpr55 deficiency blunted the metabolic effects but still translated in larger atherosclerotic plaques and elevated plasma IgG levels. Both global and B cell-restricted Gpr55 deficiency promotes atherosclerosis and is associated with a pro-inflammatory phenotype. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The authors received funds from the Deutsche Forschungsgemeinschaft (STE1053/6-1, STE1053/8-1 to S.S. and SFB1123 to S.S., C.W. and L.M.), the German Ministry of Research and Education (DZHK FKZ 81Z0600205 to S.S.) and the LMU Medical Faculty FöFoLe program (1061 to R.G.P.). I.H. is supported by the DFG (HI1573/2 and CRC1425 #422681845).

The nasopharynx is a region at the nexus of several vital physiological systems, including the nasal cavity, oral cavity, braincase, middle ear, and cervical vertebrae. It has undergone pronounced morphological change over the course of tetrapod, mammalian, and human evolution. However, despite its place in evolutionary history, the nasopharynx has received relatively little attention. This special issue focuses on "the evolution, development, and functional morphology of the nasopharynx and its boundaries." Topics covered here include evolutionary developmental biology (or evo-devo), nasopharyngeal adaptions in bats, the importance of the nasopharynx and adjacent structures over the course of human evolution, normal development, middle ear morphology, clinical importance, and the study of the nasopharynx throughout history. Contributions to this special issue range among reviews and syntheses, descriptive analyses, phylogenetic analysis, traditional morphometrics, three-dimensional geometric morphometrics, and computational fluid dynamics. Here, we discuss the central importance of the nasopharynx as can be seen through vertebrate paleontology and comparative morphology. It is via the composite evolutionary history of the nasopharyngeal boundaries that our origins may be better understood, starting with the derivation of the choanae from the median olfactory pit of jawless fish nearly half a billion years ago to the basicranial flexion and facial reduction that distinguish Homo sapiens from all other living mammals. Indeed, the nasopharynx must be acknowledged for its importance in the processes of encephalization and acquisition of speech that have become the hallmark of our species.

In most individuals, EBV maintains a life-long asymptomatic latent infection. However, EBV can induce the formation of B cell lymphomas in immune suppressed individuals including people living with HIV (PLWH). Most individuals who acquire HIV are already infected with EBV as EBV infection is primarily acquired during childhood and adolescence. Although antiretroviral therapy (ART) has substantially reduced the incidence of AIDS-associated malignancies, EBV positive PLWH are at an increased risk of developing lymphomas compared to the general population. The direct effect of HIV co-infection on EBV replication and EBV-induced tumorigenesis has not been experimentally examined. Using a humanized mouse model of EBV infection, we demonstrate that HIV co-infection enhances systemic EBV replication and immune activation. Importantly, EBV-induced tumorigenesis was augmented in EBV/HIV co-infected mice. Collectively, these results demonstrate a direct effect of HIV co-infection on EBV pathogenesis and disease progression and will facilitate future studies to address why the incidence of certain types of EBV-associated malignancies are stable or increasing in ART treated PLWH.

Industries with a higher return on invested capital (ROIC), or profit for each unit of assets invested, could be particularly appealing to entrepreneurs. Yet, why do some ventures in industries with high ROIC survive while others do not? Drawing on the strategic fit framework, we posit that ventures with a higher sustainable growth rate (i.e., matching internal growth with industry ROIC) or stability (i.e., lower chances of bankruptcy) are more likely to survive in industries with a higher ROIC. We find support for our hypotheses in a sample of 120,816 new ventures established between 2010 and 2016 (15,236 new ventures failed during the period of observation). The findings have implications for the entrepreneurship literature related to the role of industry in explaining venture survival under varying ROIC industry conditions.

Topological insulators are considered new states of quantum matter that cannot be systematically related to conventional insulators and semiconductors. Among them, Bi2Se3 has attracted an increasing interest due to a simple surface band structure and due to a strong contribution of the surface to transport. While the dc electric transport properties have been extensively studied, intrinsic fluctuations and their effect on the surface conduction have received less attention. In order to better investigate these aspects, a detailed characterization of the low-frequency noise, also known as noise spectroscopy, has been made in Bi2Se3 thin films. The experimental results have been obtained for different samples thickness and geometry, in a temperature range from 300 down to 8 K, and as a function of dc bias current and gate voltage. While the observed spectral noise shows a typical thermal and shot noise part, an unusual reduction of the 1/ f noise component is found, especially in the low-temperature region. A correlation of this behavior with structural and dc electric transport investigations suggests that it could be an indication of the occurrence of the topological regime. Flicker noise measurements, therefore, could be considered as a valid alternative technique to standard topological surface state spectroscopy.

Articulated rocker-bogie suspension systems have gained a lot of attention since they were used for rovers destined for space exploration on Mars. This type of suspension allows the vertical load to be distributed equally between the wheels, reducing the risk of the most loaded wheels sinking in the case of soft ground. This peculiarity is verified if the rover moves on flat and horizontal surfaces; if the rover moves on uneven surfaces, the suspension still allows the wheels to be kept in contact with the ground, but the load distribution changes. This paper presents the study of the variation in the distribution of the load among the wheels and the rover stability for different ground geometries; the study involves a preventive kinematic analysis of position to define the configuration of the suspension as a function of the ground geometry.

The COVID-19 pandemic and the need for social distancing have created a demand for new and innovative solutions in healthcare systems worldwide. One of the strategies that have been implemented are chatbots, which can be helpful in providing reliable health information and preventing people from seeking assistance in healthcare centers and being unnecessarily exposed to the virus. In this context, although a high number of chatbots have been implemented worldwide, little has been discussed about the process and challenges in developing and implementing this technology. This paper reports on an action research, which designed a novel chatbot as a prompt response to the COVID-19 pandemic. The chatbot is intended to be a first layer of interaction with the public, performing triage of patients and providing information about COVID-19 on a large scale and without human contact. Our contribution is twofold: (i) we reflected on the development process and discuss lessons learned and recommendations to support a multidisciplinary development and evolution process of the chatbot; and (ii) we identified some interactive and technological features that can be used as a reference framework for this kind of technology. These contributions can be useful to other researchers and multidisciplinary teams facing similar challenges.

The DARTWARS project has the goal of developing high-performing innovative travelling wave parametric amplifiers with high gain, large bandwidth, high saturation power, and nearly quantum-limited noise. The target frequency region for its applications is 5 - 10 GHz, with an expected noise temperature of about 600 mK. The development follows two different approaches, one based on Josephson junctions and one based on kinetic inductance of superconductors. This contribution mainly focuses on the Josephson travelling wave parametric amplifier, presenting its design, preliminary measurements and the test of homogeneity of arrays of Josephson junctions., 4 pages, 5 figures. Proceeding of Pisa15th Meeting conference. arXiv admin note: text overlap with arXiv:2111.03409

In this paper, we will report our recent efforts in achieving high performance in Antimonides type-II superlattice (T2SL) based infrared photodetectors using the barrier infrared detector (BIRD) architecture. The high operating temperature (HOT) BIRD focal plane arrays (FPAs) offer the same high performance, uniformity, operability, manufacturability, and affordability advantages as InSb. However, mid-wavelength infrared (MWIR) HOT-BIRD FPAs can operate at significantly higher temperatures (

Financial markets today are highly computerized -- from software-driven order submission to price determination to straight-through clearing and settlement -- computer technology has displaced manual activities and streamlined functions throughout the trading value chain. The previous chapters examined microeconomic principles that underpin trading and price-setting, and finance theory that provides analytical frameworks for market outcomes. Our analysis introduces real market frictions and examines how transactions costs and heterogeneity among market participants makes market structure and tracing mechanism design crucial determinants of market outcomes and behavior. . In this chapter, we drill down further into the realities of a non-frictionless market in order to focus on how technology can enhance the efficiency of an actual marketplace. Challenging market design issues are encountered when developing and operating an actual trading facility, and as IT professionals know, the devil is in the details. The practical considerations in operating a market system successfully are the next topic this book addresses.

Trading is the implementation of an investment decision. After a portfolio decision has been made by a portfolio manager, it must be implemented, and especially for handling large orders and navigating stressful markets, specific skills and responsibilities are needed that require the expertise of a professional trader. However, the efficiency with which orders are handled and turned into trades depends, not just on traders’ abilities, but also on a market’s liquidity, on the design of the marketplace where shares are traded, and on the regulatory environment. In this chapter, we cover trading costs, liquidity, volatility, price discovery, market structure, and market structure regulation.

Economics encompasses two broad subjects: macroeconomics and microeconomics. Macroeconomics deals with an economy in aggregate and addresses issues such as inflation, unemployment, interest rates, and economic growth. We present a macroeconomic perspective in Chap. 3. Microeconomics, the focus of this chapter, operates, as its name indicates, on the micro level, addressing household consumption decisions and the production decisions of firms. In this chapter, we focus on the parallels (and a few differences) between a standard microeconomics formulation (a household’s selection of an optimal consumption bundle) and a standard finance model (an investor’s selection of a portfolio that optimally combines a riskless asset – cash – and a risky equity portfolio). The finance formulation is the Capital Asset Pricing Model (CAPM). CAPM is a keystone of what is known as modern portfolio theory, the originator of which is Harry Markowitz who was awarded a Nobel Memorial Prize in Economic Sciences in 1990 for having developed the theory of portfolio choice. We then introduce friction (trading costs) and show how CAPM’s frictionless market equilibrium is perturbed. The analysis provides a good lead-in to the next chapter on finance.

This chapter explains how “information shocks” can affect the liquidity of financial markets and stock prices. The focus is on unexpected macroeconomic news as a key type of information shock. The final portion of the chapter discusses some realworld events that demonstrate the effects of these shocks on financial markets and how investors react to unexpected macroeconomic news items.

Trading education is vital for success in the securities and investments industry. Are apprenticeships and time on an institutional trading desk the only way to learn how to trade? Do you need to work with real orders and have real money at risk to gain experience interacting with the dynamic process of price formation? The answers are no and no. Trading simulations that are well-designed can create experiences with price discovery and impose the challenges of illiquidity in ways that replicate the learning accomplished (and pressures felt) on a real trading desk. With TraderEx, you will appreciate the complexity of trading and understand it as a distinct profession within the financial industry, even if it is not always thought of as such in business school curriculum.

In this presentation, we will report our recent efforts in achieving high performance in Antimonides type-II superlattice (T2SL) based infrared photodetectors using the barrier infrared detector (BIRD) architecture. The high operating temperature (HOT) BIRD focal plane arrays (FPAs) offer the same high performance, uniformity, operability, manufacturability, and affordability advantages as InSb. However, mid-wavelength infrared (MWIR) HOT-BIRD FPAs can operate at significantly higher temperatures (

Aqua-AIRS data have been available now for almost 20 years, Suomi-NPP CrIS for 9 years, and JPSS1 CrIS for 4 years. The three instruments satisfy nearly identical functional requirements, and are in very similar polar orbits. However, there are differences in the design, spatial scan pattern and sun-angle, in addition to absolute calibration differences. We compared AIRS, CrIS SNPP and CrIS JPSS data for the 1148 days between 20180217 and 20210430 for the 900 cm-1 channel under clear and random sampled tropical ocean, tropical land, and Arctic conditions. Although JPSS and SNPP are identical designs, the difference between JPSS and SNPP are as large as the differences relative to AIRS. For the day and night tropical ocean at typically 295K and for night tropical land and under the Arctic conditions (265K typical), averaged over all scan angles, detector elements and time, AIRS, JPSS and SNPP agree within 100 mK. Under Antarctic and Antarctic conditions, the difference between JPSS and AIRS and SNPP and AIRS are on average 200 mK, but with a much larger summer/winter correlated pattern. For clear tropical day (318K), AIRS is 500 mK warmer than JPSS, but 150 mK colder than SNPP. The three instruments find 40% fewer clear cases at night than during the day. With JPSS we find 3% fewer clear cases than with AIRS, 9% more than with SNPP day and night. Differences seen in the past three years in the AIRS, SNPP and JPSS data are calibration artifacts. Unless corrected in the construction of merged AIRS/SNPP/JPSS and follow-on time series, they will complicate the interpretation of trends potentially related to climate change.

Hyperspectral infrared measurements of Earth’s atmosphere from space have proven their value for weather forecasting, climate science and atmospheric composition. The CubeSat Infrared Atmospheric Sounder (CIRAS) instrument will demonstrate a fully functional infrared temperature, water vapor and carbon monoxide sounder in a CubeSat sized volume for at least an order of magnitude lower cost than legacy systems. Design for a CubeSat significantly reduces cost of access to space and enables flight in a constellation to reduce revisit time and enable new measurements including 3D winds. A technology demonstration of CIRAS is currently under development at JPL. The effort has completed integration and ambient testing of a high fidelity brassboard, complete with the flight configured optics assembly developed by Ball Aerospace with a JPL Immersion Grating and Black Silicon Entrance Slit. The brassboard includes a flight-configured High Operating Temperature Barrier Infrared Detector (HOT-BIRD) mounted in an Integrated Dewar Cryocooler Assembly (IDCA), enabling testing in the ambient environment. Ambient testing included radiometric testing of the system to characterize the instrument operability and NEdT. Spatial testing was performed to characterize the system line spread function (LSF) in two axes and report FWHM of the LSF. Spectral testing involved an air path test to characterize the spectral/spatial transformation matrix, and an etalon was used to measure the Spectral Response Functions (SRFs). Results of the testing show the CIRAS performs exceptionally well and meets the key performance required of the system. The end result of testing is the CIRAS instrument now meets TRL 4 with confidence in a brassboard configuration ready for thermal vacuum (TVac) testing necessary to achieve TRL 5 for the system.

We use large datasets from the Atmospheric Infrared Sounder (AIRS) and the Moderate Resolution Imaging Spectroradiometer (MODIS) to derive AIRS spatial response functions and study their potential variations over the mission. The new reconstructed spatial response functions can be used to reduce errors in the radiances in non-uniform scenes and improve products generated using both AIRS and MODIS data. AIRS spatial response functions are distinct for each of its 2378 channels and each of its 90 scan angles. We develop the mathematical model and the optimization framework for deriving spatial response functions for two AIRS channels with low water vapor absorption and various scan angles. We quantify uncertainties in the derived reconstructions and study how they differ from pre-flight spatial response functions. We show that our approach generates reconstructions that agree with the data more accurately compared to pre-flight spatial responses. We derive spatial response functions using data collected during successive dates in order to ascertain the repeatability of the reconstructed spatial response functions. We also compare the derived spatial response functions based on data collected in the beginning, the middle, and at the current state of the mission in order to study changes in reconstructions over time.

Rationale & Objective In the general population, cognitive impairment is associated with increased mortality, and higher levels of education are associated with lower risks for cognitive impairment and mortality. These associations are not well studied in patients receiving long-term hemodialysis and were the focus of the current investigation. Study Design Prospective cohort study. Setting & Participants Adult hemodialysis patients treated in 20 Italian dialysis clinics. Exposures Patients’ cognitive function across 5 domains (memory, attention, executive function, language, and perceptual-motor function), measured using a neuropsychological assessment comprising 10 tests; and patients’ self-reported years of education. Outcome All-cause mortality. Analytical Approach Nested multivariable Cox regression models were used to examine associations of cognition (any domain impaired, number of domains impaired, and global function score from principal components analysis of unadjusted test scores) and education with mortality and whether there were interactions between them. Results 676 (70.6%) patients participated, with a median age of 70.9 years and including 38.8% women. Cognitive impairment was present in 79.4% (527/664; 95% CI, 76.3%-82.5%). During a median follow-up of 3.3 years (1,874 person-years), 206 deaths occurred. Compared to no cognitive impairment, adjusted HRs for mortality were 1.77 (95% CI, 1.07-2.93) for any impairment, 1.48 (95% CI, 0.82-2.68) for 1 domain impaired, 1.88 (95% CI, 1.01-3.53) for 2 domains, and 2.01 (95% CI, 1.14-3.55) for 3 to 5 domains. The adjusted HR was 0.68 (95% CI, 0.51-0.92) per standard deviation increase in global cognitive function score. Compared with primary or lower education, adjusted HRs were 0.79 (95% CI, 0.53-1.20) for lower secondary and 1.13 (95% CI, 0.80-1.59) for upper secondary or higher. The cognition-by-education interaction was not significant (P = 0.7). Limitations Potential selection bias from nonparticipation and missing data; no data for cognitive decline; associations with education were not adjusted for other socioeconomic factors. Conclusions Cognitive impairment is associated with premature mortality in hemodialysis patients. Education does not appear to be associated with mortality.

The purpose of this work is to use data from the Atmospheric Infrared Sounder (AIRS) and the Moderate Resolution Imaging Spectroradiometer (MODIS) to refine our knowledge of post-launch AIRS point spread functions (PSFs), including suspected changes over the mission. We develop methodology, by deriving mathematical optimization formulation based on variational principles and Sobolev gradient descent, for reconstruction of AIRS spatial response functions. We use the data over the ocean, collected for the duration of a day, to reconstruct a single PSF. We examine the repeatability of our reconstructions by computing PSFs based on data collected during two consecutive days, and also investigating the change in the reconstructions by comparing the reconstructed PSF based on data collected in the beginning and the middle of the mission. We also quantify uncertainties in our reconstruction results.

In this presentation, we will report our recent efforts in achieving high performance in Antimonides type-II superlattice (T2SL) based infrared photodetectors using the barrier infrared detector (BIRD) architecture. The high operating temperature (HOT) BIRD focal plane arrays (FPAs) offer the same high performance, uniformity, operability, manufacturability, and affordability advantages as InSb. However, mid-wavelength infrared (MWIR) HOT-BIRD FPAs can operate at significantly higher temperatures (

The evolution of the Amazon forest is tightly coupled to its terrestrial water balance (evapotranspiration minus precipitation, or ET-P), as an increase in ET-P reduces soil moisture, increasing water stress. However, large differences of ~ 50% between current monthly estimates of ET-P make it challenging to confidently quantify its spatio-temporal distribution and evolution. Here, we show that new satellite observations of the HDO/H2O ratio of water vapor, spanning 2003 to 2020, constrain estimates of the Amazon water balance with monthly precision of ~ 20%. The HDO/H2O ratio of water vapor is sensitive to the difference between ET and P, rather than to either flux alone, because lighter isotopes preferentially evaporate and heavier isotopes preferentially condense. Consequently, variable bias and sensitivity errors that result from combining different ET and precipitation products are minimized with this proxy. Our analysis demonstrates these data can quantify the spatial patterns of Amazon water balance from monthly to interannual time scales.

Infiltration with inflammatory T-cells and accumulation of cardiac myofibroblasts are hallmarks of cardiac fibrosis and maladaptive remodeling. The origin, identity, and functions of the resident cardiac cells involved in this process are, however, unclear. To determine the identity of cells contained in regions exhibiting fibrosis, mass cytometry profiling was performed using resident human ventricular cardiac fibroblasts and right ventricle autopsy tissues from individuals diagnosed with pulmonary hypertension and SUGEN/hypoxia rats. Results showed that a subpopulation of resident myocardial fibroblasts expresses increased levels of CD4+, a helper T-cell surface marker, in addition to mesenchymal markers in humans and rats. Characterization of the resident cardiac fibroblast subpopulation, both structurally and functionally, using transcriptome and secretome analysis of the secreted cytokines, chemokines, proteins, and metabolites, evidenced that IL-1β induces a phenotypic switch of human cardiac fibroblasts from mesenchymal to CD4+ lymphoidal lineage in vitro. RNA sequencing (RNA-seq) analysis of FACS-sorted CD4-expressing cardiac fibroblasts further revealed that the transcriptome of such IL-1β-induced CD4+ fibroblast population exhibited classical lymphoidal and stem cell-like signatures. Lastly, reversal of cell clustering, phosphorylation of MAPK p38 and NF-κB p65, and phenotypic switching was achieved with the administration of an IL-1R antagonist. In conclusion, we have identified a subpopulation of cardiac fibroblasts which exhibits structural and functional attributes of both mesenchymal and lymphoid cells which is induced by IL-1b-IL-1R-NFkB pathway for differentiation of cardiac fibroblast cells. These data suggest that cardiac fibroblast transdifferentiation during inflammation may form the basis for maladaptive remodeling during myocardial fibrosis. Non-standard abbreviations: IL-1B; Interleukin-1-beta, CD4; Cluster of differentiation, aSMA; alpha smooth muscle actin, MAPK; mitogen activated protein kinases, NFkB; Nuclear Factor kappa-light-chain- enhancer of activated B cells; IL-1R; Interleukin-1-receptor

BackgroundLower seroconversion rates have been reported in patients with rheumatic diseases receiving immunomodulatory therapies following a standard mRNA-based vaccine regimen. Data with regard to immunogenicity and safety of a 3rd vaccine dose in this patient population is limited1.ObjectivesWe aim to study immunogenicity, vaccine associated side effects and the occurrence of flares in RA patients unresponsive to a standard vaccine regimen eligible for a 3rd vaccine dose.MethodsRA patients who had a low or absent anti-S1 response after 12 (Cohort A) or 24 weeks (Cohort B) following a standard vaccination regimen received a 3rd vaccine dose. Temporary discontinuation of DMARD therapy was recommended. Serum samples were collected before, 2, 12, and 24 weeks after the 3rd vaccine dose. Quantitative measurement of anti-S was performed using the Roche Elecsys Anti-SARS-CoV-2 spike subunit assay. Neutralizing activity (NT50) against Wuhan WT and αasβ-, γ-, and δ- variants was assessed by using a HIV-based pseudovirus system.ResultsBaseline characteristics are shown in Table 1. 45/47 patients temporarily discontinued DMARD therapy: Mtx and JAKi were paused one 1 week before/restarted 2 weeks after the 3rd vaccine dose, bDMARDs were paused 2 weeks before/restarted 2 weeks after the 3rd dose. Local pain and/or systemic vaccine associated side effects following the 3rd vaccine dose were reported in 12/17 (71%) in Cohort A, and 10/29 (35%) patients in Cohort B (p = 0.018). Flares were defined as loss of low disease activity (LDA), subsequent to the 3rd vaccine dose and occurred in 17/47 (36%) patients (p = 0.0332) with comparable frequencies in both cohorts (41% Cohort A, 33% Cohort B (NS)).Table 1.Baseline characteristics of RA patients in Cohort A and Cohort BRA patients (n = 17) Cohort ARA patients (n = 30) Cohort Bp-valueAge (yrs), mean (± SD)69 (8)63.9 (8)NSFemale sex, n (%)9 (53)13 (43)NSVaccination type/schedulemRNA-1273/BNT162b2, n=3/145/25NSRA disease characteristicsACPA ± RF, n (%)13 (77)12 (40)0.02*Disease activity (CDAI)Remission (≤ 2.8), n (%)3 (18)6 (20)NSLDA (2.9 - 10), n (%)11 (64)18 (60)NSModerate CDAI (10.1 - 22.0), n (%)2 (12)3 (10)NSHigh CDAI (22.1 - 76.0), n (%)1 (6)3 (10)NSDMARD therapyNSMonotherapy of csDMARDs, n (%)2/17 (12)10/30 (33)NSbDMARDs ± csDMARDs, n (%)8/17 (47)14/30 (47)NSJAKi ± csDMARDs, n (%)7/17 (41)6/30 (20)NSPrednisone, n (%)5/17 (29)11/30 (37)NSMean daily dose prednisone (mg ± SD)4.1 ± 1.64.1 ± 1.5NSLow or absent anti-S titers were confirmed before the third vaccination (Cohort A: median 19.5 U/ml, IQR 0.47-57; cohort B: median 65.9 U/ml, IQR 22-154) (p = 0.0018). Two weeks after the 3rd dose, a rapid and significant increase in anti-S were observed in 12/17 (82%) and 25/28 (89%) patients (Cohort A: median 2500 U/ml, IQR 798-2500; Cohort B: median 2500 U/ml, IQR 2500-2500) (NS). High levels of anti-S were maintained in the majority of patients 55% (11/20) until week 12 in both cohorts (Figure 1). NT50 against Wuhan-WT and other variants was assessed in 21 patients 2 weeks after the 3rd vaccine dose revealing a low or absent NT50 against delta in 38% of patients despite a median anti-S response of 2500 U/ml (IQR 798-2500). 14/21 patients had peak anti-S titres of 2500 U/ml, of those 12/14 developed a strong NT50 response against the delta variant.Figure 1.ConclusionOur data demonstrate that a 3rd vaccine dose, maybe complimented by temporary discontinuation of DMARD therapy, may lead to a rapid increase in anti-S antibodies when using a homologous vaccine and profound neutralizing activity in the majority of RA patients previously unresponsive to a standard two dose regimen. This seems to be independent of the interval to the previous standard vaccine regimen. As flares occurred in 36% of all patients, the necessity and length of DMARD discontinuation should be explored in more detail to balance between sustained control of disease activity and optimized vaccine induced immune responses.References[1]Schmiedeberg K, et al. Lancet Rheumatol 2022; 4(1): e11-e13Disclosure of InterestsKristin Schmiedeberg: None declared, Irene A. Abela: None declared, Nicolas Vuilleumier: None declared, Sabrina Pagano: None declared, Johannes von Kempis Speakers bureau: Lilly, Consultant of: Abbvie, BMS, Pfizer, and Sanofi, Andrea Rubbert-Roth Speakers bureau: Abbvie, Pfizer, Sanofi, UCB, BMS, Lilly, Gilead and Roche, Consultant of: Abbvie, Gilead, Lilly, BMS, and Sanofi

BackgroundVaccines are highly effective in preventing COVID-19 associated hospitalization and deaths. Strong and persistent immune responses are critical to provide protection for patients with immunomodulatory therapies.ObjectivesTo assess humoral and cellular immune responses following 2 doses of an anti-SARS-CoV-2 mRNA based vaccine in rheumatoid arthritis (RA). Immune responses in patients treated with csDMARDs, bDMARDs (with the exception of rituximab) and JAK inhibitors were compared to healthy controls (HC) over 24 weeks. In addition, disease activity by CDAI and vaccine-induced side effects were prospectively monitored.MethodsThe RECOVER trial (Rheumatoid Covid-19 Vaccine Immune Response) is a non-randomised, prospective observational control group trial and enrolled 77 RA patients on DMARD therapy and 21 HC. Clinical assessment and blood sampling was performed at baseline, 3 weeks after the 1st and 2 weeks after the 2nd vaccine dose and at week 12 and 24 after the 1st. Antibody response to the receptor binding domain (RBD) within the SARS-CoV-2 S1 protein was measured with the Elecsys Anti-SARS-CoV-2-S (Roche Diagnostics GmbH) test. The seroprofiling assay ABCORA, which has been suggested as a surrogate for neutralization,1 was used to determine IgG, IgA and IgM responses to RBD, S1, S2 and N. The neutralizing activity NT50 at week 12 was assessed against Wuhan-Hu-1 pseudoviruses (HIV-based). IFN-y ELISpots were applied to detect spike-reactive T cell responses after in vitro stimulation with a spike peptide mix.ResultsBaseline characteristics of participants are detailed in Table 1. Vaccination was well tolerated with no differences between RA patients and HC. At baseline, the majority of RA patients were in remission/LDA (57/77, 74%), this proportion decreased to 51% (39/77) after the second vaccine dose (p = 0.005). Treatment adjustments were required in 11/77 patients. The immunogenicity analyses were based on 73 RA patients after exclusion of 4 patients with previously unnoticed SARS-CoV-2 infection (positive for anti-nucleoprotein). In contrast to HC, anti-S titers were lower at all timepoints with significantly reduced titers observed in patients on abatacept and JAK inhibitors (Figure 1). Potent neutralizing activity (NT50 ≥ 250)) was detected in all HC at week 12, in contrast to 62% RA patients. NT50 correlated to the results based on the ABCORA assay. Peak anti-S titers (2 weeks after 2nd vaccine) were predictive of NT50 ≥ 250 at week 12 (p < 0.0001). In contrast to marked differences in the humoral immune responses, spike-protein specific IFN-α secreting T cells were largely unaltered by different DMARD regimen.Table 1.Baseline characteristicsRA patients (n = 77)HC (n = 21)p-valueAge (yrs), mean (± SD)64 (13)44 (14)< 0.0001Female, n (%)46 (60)15 (71)NSVaccination typemRNA-1273, n (%)12 (16)0 (0)0.06BNT162b2, n (%)65 (84)21 (100)Disease activity (CDAI)Remission (≤ 2.8), n (%)17/77 (22)Low (2.9 - 10), n (%)40/77 (52)Moderate (10.1 - 22.0), n (%)15/77 (20)High (22.1 - 76.0), n (%)5/77 (7)DMARD therapyMono csDMARDs, n (%)22/77 (29)bDMARDs, n (%)35/77 (46)Mono bDMARDs, n (%)14/35 (40)JAKi, n (%)20/77 (26)Mono JAKi, n (%)8/20 (40)Prednisone, n (%)25/77 (33)Mean daily dose (mg ± SD)5.6 ± 3.6ConclusionRA patients, in comparison with HC, revealed a slower kinetic and lower magnitude of humoral immune responses depending on the treatment regimen while T cell responses were largely maintained. Peak anti-S responses two weeks after the second vaccine were able to predict the development of potent neutralizing activity and should therefore be considered to individually tailor vaccination strategies.References[1]Abela I et al. Nature Commun 2021. doi.org/10.1038/s41467-021-27040-xDisclosure of InterestsKristin Schmiedeberg: None declared, Irene A. Abela: None declared, Natalia Barbara Pikor: None declared, Nicolas Vuilleumier: None declared, Magdalena Schwarzmueller: None declared, Selina Epp: None declared, Sabrina Pagano: None declared, Sarah Grabherr: None declared, Angelica Brooke Patterson: None declared, Madalina Nussberger: None declared, Alexandra Trkola: None declared, Burkhard Ludewig: None declared, Johannes von Kempis: None declared, Andrea Rubbert-Roth Speakers bureau: Abbvie, Pfizer, Sanofi, UCB, BMS, Lilly, Gilead, Roche, Consultant of: Abbvie, Gilead, Lilly, BMS, Sanofi