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Increased plasma mitochondrial DNA concentrations are associated with poor outcomes in multiple critical illnesses, including COVID-19. However, current methods of cell-free mitochondrial DNA quantification in plasma are time-consuming and lack reproducibility. Here, we used next-generation sequencing to characterize the size and genome location of circulating mitochondrial DNA in critically ill subjects with COVID-19 to develop a facile and optimal method of quantification by droplet digital PCR. Sequencing revealed a large percentage of small mitochondrial DNA fragments in plasma with wide variability in coverage by genome location. We identified probes for the mitochondrial DNA genes, cytochrome B and NADH dehydrogenase 1, in regions of relatively high coverage that target small sequences potentially missed by other methods. Serial assessments of absolute mitochondrial DNA concentrations were then determined in plasma from 20 critically ill subjects with COVID-19 without a DNA isolation step. Mitochondrial DNA concentrations on the day of enrollment were increased significantly in patients with moderate or severe acute respiratory distress syndrome (ARDS) compared with those with no or mild ARDS. Comparisons of mitochondrial DNA concentrations over time between patients with no/mild ARDS who survived, patients with moderate/severe ARDS who survived, and nonsurvivors showed the highest concentrations in patients with more severe disease. Absolute mitochondrial DNA quantification by droplet digital PCR is time-efficient and reproducible; thus, we provide a valuable tool and rationale for future studies evaluating mitochondrial DNA as a real-time biomarker to guide clinical decision-making in critically ill subjects with COVID-19.

Background Increased inflammation has been well defined in coronavirus disease 2019 (COVID-19), while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases, and acute respiratory distress syndrome, a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets. Methods Blood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis, and cytokine levels were assessed. Lung tissue was obtained immediately postmortem for immunostaining. PubMed searches for neutrophils, lung, and COVID-19 yielded 10 peer-reviewed research articles in English. Results Elevations in neutrophil-associated cytokines interleukin 8 (IL-8) and interleukin 6, and general inflammatory cytokines IFN-inducible protien-19, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 1β, interleukin 10, and tumor necrosis factor, were identified both at first measurement and across hospitalization (P Conclusions Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. Importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data show that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.

Adeno-associated virus (AAV) vectors are currently investigated as gene transfer agents for the treatment of a variety of diseases. However, activation of the host immune response upon vector administration limits the use of AAV in the clinical setting. To decrease host detection of AAVs, we tested the CD47-based “don’t-eat-me” signal in the context of the AAV capsid. We genetically incorporated the bioactive region of CD47, named “self-peptide” (SP), onto the surface of the AAV2 capsid. AAV mutants were structurally and functionally characterized for vector production, SP and linker incorporation into the capsid, transduction efficiency, and phagocytic susceptibility. We demonstrate that utilizing linkers improves the AAV2 capsid’s tolerance to SP insertion. Notably, the SP significantly decreases the phagocytic susceptibility of AAV2 in vitro. Collectively, these results suggest that display of the SP motif on the AAV capsid surface can inhibit phagocytosis of the vector in vitro via the “don’t-eat-me” signaling.

Infection by SARS-CoV-2 and subsequent COVID-19 can cause viral sepsis and septic shock. Several complications have been observed in patients admitted to the intensive care unit (ICU) with COVID-19, one of those being bacterial superinfection. Based on prior evidence that dysregulated systemwide proteolysis is associated with death in bacterial septic shock, we investigated whether protease activity and proteolysis could be elevated in COVID-19-induced sepsis with bacterial superinfection. In particular, we sought to assess the possible implications on the regulation of protein systems, such as for instance the proteins and enzymes involved in the clotting cascade.Blood samples collected at multiple time points during the ICU stay of four COVID-19 patients were analyzed to quantify: a) the circulating proteome and peptidome by mass spectrometry; b) plasma enzymatic activity of trypsin-like substrates and five clotting factors (plasmin, thrombin, factor VII, factor IX, factor X) by a fluorogenic assay.Of the four patients, one was diagnosed with bacterial superinfection on day 7 after beginning of the study and later died. The other three patients all survived (ICU length-of-stay 11.25±6.55 days, hospital stay of 15.25±7.18 days). Spikes in protease activity (factor VII, trypsin-like activity) were detected on day 7 for the patient who died. Corresponding increases in the total intensity of peptides derived by hydrolysis of plasma proteins, especially of fibrinogen degradation products, and a general reduction of coagulation proteins, were measured as well. A downregulation of endogenous enzymatic inhibitors, in particular trypsin inhibitors, characterized the non-surviving patient throughout her ICU stay. Enzymatic activity was stable in the patients who survived.Our study highlights the potential of multiomics approaches, combined with quantitative analysis of enzymatic activity, to i) shed light on proteolysis as a possible pathological mechanism in sepsis and septic shock, including COVID-19-induced sepsis; ii) provide additional insight into malfunctioning protease-mediated systems, such as the coagulation cascade; and iii) describe the progression of COVID-19 with bacterial superinfection.

Introduction Patient experience, satisfaction, perception and expectation are some related measures valued by patient-centered health care. Patient experience (PE) usually refers to objective, observable events or facts; while patient satisfaction, perception and expectation (PS) are measures which focus on a patient's subjective evaluation of the health care process. These concepts have been studied in osteopathic manipulative treatment (OMT), a therapeutic intervention practiced by osteopathic practitioners in many countries and by some medical doctors in USA and Canada. Objective To systematically review and summarize the primary research literature pertaining to PE and PS of OMT. Methods A comprehensive literature search was performed on seven databases: Ovid MEDLINE, Embase, Cochrane Central, Cinahl, AMED, Osteopathic Research Web, and OSTMED.DR to identify primary research that surveyed the PE or PS of OMT. Findings from relevant studies were summarized. Results The literature search identified 322 references, of which 16 were included in this review, including 7 qualitative, 8 quantitative and 1 dual-method study. The quantitative studies with various research instruments reported on a number of PE & PS aspects, with data showing mostly positive responses from patients. The qualitative studies revealed patients' perception of OMT which may be summarized as being patient-centered, holistic, thorough, a treatment option that could be effective for certain conditions and one that offered good clinician-patient partnership but with possible adverse effects and futility. Conclusion The primary literature reported mainly positive PE and PS of OMT. OMT as a treatment was found to have many positive characteristics.

Adeno-associated virus (AAV) has emerged as a promising gene delivery vector because of its non-pathogenicity, simple structure and genome, and low immunogenicity compared to other viruses. However, its adoption as a safe and effective delivery vector for certain diseases relies on altering its tropism to deliver transgenes to desired cell populations. To this end, we have developed a protease-activatable AAV vector, named provector, that responds to elevated extracellular protease activity commonly found in diseased tissue microenvironments. The AAV9-based provector is initially inactive, but then it can be switched on by matrix metalloproteinases (MMP)-2 and -9. Cryo-electron microscopy and image reconstruction reveal that the provector capsid is structurally similar to that of AAV9, with a flexible peptide insertion at the top of the 3-fold protrusions. In an in vivo model of myocardial infarction (MI), the provector is able to deliver transgenes site specifically to high-MMP-activity regions of the damaged heart, with concomitant decreased delivery to many off-target organs, including the liver. The AAV provector may be useful in the future for enhanced delivery of transgenes to sites of cardiac damage.

BackgroundIncreased inflammation is a hallmark of COVID-19, with pulmonary and systemic inflammation identified in multiple cohorts of patients. Definitive cellular and molecular pathways driving severe forms of this disease remain uncertain. Neutrophils, the most numerous leukocytes in blood circulation, can contribute to immunopathology in infections, inflammatory diseases and acute respiratory distress syndrome (ARDS), a primary cause of morbidity and mortality in COVID-19. Changes in multiple neutrophil functions and circulating cytokine levels over time during COVID-19 may help define disease severity and guide care and decision making.MethodsBlood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil oxidative burst, neutrophil extracellular trap formation (NETosis), phagocytosis and cytokine levels were assessed ex vivo. Lung tissue was obtained immediately post-mortem for immunostaining.ResultsElevations in neutrophil-associated cytokines IL-8 and IL-6, and general inflammatory cytokines IP-10, GM-CSF, IL-1b, IL-10 and TNF, were identified in COVID-19 plasma both at the first measurement and at multiple timepoints across hospitalization (p < 0.0001). Neutrophils had exaggerated oxidative burst (p < 0.0001), NETosis (p < 0.0001) and phagocytosis (p < 0.0001) relative to controls. Increased NETosis correlated with both leukocytosis and neutrophilia. Neutrophils and NETs were identified within airways and alveoli in the lung parenchyma of 40% of SARS-CoV-2 infected lungs. While elevations in IL-8 and ANC correlated to COVID-19 disease severity, plasma IL-8 levels alone correlated with death.ConclusionsCirculating neutrophils in COVID-19 exhibit an activated phenotype with increased oxidative burst, NETosis and phagocytosis. Readily accessible and dynamic, plasma IL-8 and circulating neutrophil function may be potential COVID-19 disease biomarkers.

We search NANOGrav's 12.5-year data set for evidence of a gravitational wave background (GWB) with all the spatial correlations allowed by general metric theories of gravity. We find no substantial evidence in favor of the existence of such correlations in our data. We find that scalar-transverse (ST) correlations yield signal-to-noise ratios and Bayes factors that are higher than quadrupolar (tensor transverse, TT) correlations. Specifically, we find ST correlations with a signal-to-noise ratio of 2.8 that are preferred over TT correlations (Hellings and Downs correlations) with Bayesian odds of about 20:1. However, the significance of ST correlations is reduced dramatically when we include modeling of the Solar System ephemeris systematics and/or remove pulsar J0030$+$0451 entirely from consideration. Even taking the nominal signal-to-noise ratios at face value, analyses of simulated data sets show that such values are not extremely unlikely to be observed in cases where only the usual TT modes are present in the GWB. In the absence of a detection of any polarization mode of gravity, we place upper limits on their amplitudes for a spectral index of $\gamma = 5$ and a reference frequency of $f_\text{yr} = 1 \text{yr}^{-1}$. Among the upper limits for eight general families of metric theories of gravity, we find the values of $A^{95\%}_{TT} = (9.7 \pm 0.4)\times 10^{-16}$ and $A^{95\%}_{ST} = (1.4 \pm 0.03)\times 10^{-15}$ for the family of metric spacetime theories that contain both TT and ST modes., Comment: 24 pages, 18 figures, 3 appendices. Please send any comments/questions to Nima Laal (laaln@oregonstate.edu)

We report results from continued timing observations of PSR J0740+6620, a high-mass, 2.8-ms radio pulsar in orbit with a likely ultra-cool white dwarf companion. Our data set consists of combined pulse arrival-time measurements made with the 100-m Green Bank Telescope and the Canadian Hydrogen Intensity Mapping Experiment telescope. We explore the significance of timing-based phenomena arising from general-relativistic dynamics and variations in pulse dispersion. When using various statistical methods, we find that combining $\sim 1.5$ years of additional, high-cadence timing data with previous measurements confirms and improves upon previous estimates of relativistic effects within the PSR J0740+6620 system, with the pulsar mass $m_{\rm p} = 2.08^{+0.07}_{-0.07}$ M$_\odot$ (68.3\% credibility) determined by the relativistic Shapiro time delay. For the first time, we measure secular variation in the orbital period and argue that this effect arises from apparent acceleration due to significant transverse motion. After incorporating contributions from Galactic differential rotation and off-plane acceleration in the Galactic potential, we obtain a model-dependent distance of $d = 1.14^{+0.17}_{-0.15}$ kpc (68.3\% credibility). This improved distance confirms the ultra-cool nature of the white dwarf companion determined from recent optical observations. We discuss the prospects for future observations with next-generation facilities, which will likely improve the precision on $m_{\rm p}$ for J0740+6620 by an order of magnitude within the next few years., Final version after minor corrections during referee process. Published in the Astrophysical Journal Letters on 1 July 2021

The NANOGrav Collaboration reported strong Bayesian evidence for a common-spectrum stochastic process in its 12.5-yr pulsar timing array dataset, with median characteristic strain amplitude at periods of a year of $A_{\rm yr} = 1.92^{+0.75}_{-0.55} \times 10^{-15}$. However, evidence for the quadrupolar Hellings \& Downs interpulsar correlations, which are characteristic of gravitational wave signals, was not yet significant. We emulate and extend the NANOGrav dataset, injecting a wide range of stochastic gravitational wave background (GWB) signals that encompass a variety of amplitudes and spectral shapes, and quantify three key milestones: (I) Given the amplitude measured in the 12.5 yr analysis and assuming this signal is a GWB, we expect to accumulate robust evidence of an interpulsar-correlated GWB signal with 15--17 yrs of data, i.e., an additional 2--5 yrs from the 12.5 yr dataset; (II) At the initial detection, we expect a fractional uncertainty of $40\%$ on the power-law strain spectrum slope, which is sufficient to distinguish a GWB of supermassive black-hole binary origin from some models predicting more exotic origins;(III) Similarly, the measured GWB amplitude will have an uncertainty of $44\%$ upon initial detection, allowing us to arbitrate between some population models of supermassive black-hole binaries. In addition, power-law models are distinguishable from those having low-frequency spectral turnovers once 20~yrs of data are reached. Even though our study is based on the NANOGrav data, we also derive relations that allow for a generalization to other pulsar-timing array datasets. Most notably, by combining the data of individual arrays into the International Pulsar Timing Array, all of these milestones can be reached significantly earlier., 15 pages, 7 figures

The American Thoracic Society Core Curriculum updates clinicians annually in adult and pediatric pulmonary disease, medical critical care, and sleep medicine, in a 3-4-year recurring cycle of topics. These topics will be presented at the 2020 Virtual Conference. Below is the adult sleep medicine core that includes topics pertinent to sleep-disordered breathing and insomnia.

Citation:McSharry D, Lam MT, Malhotra AT. OSA as a probable risk factor for severe COVID-19. J Clin Sleep Med. 2020;16(9):1649.

When galaxies merge, the supermassive black holes in their centers may form binaries and emit low-frequency gravitational radiation in the process. In this paper, we consider the galaxy 3C 66B, which was used as the target of the first multimessenger search for gravitational waves. Due to the observed periodicities present in the photometric and astrometric data of the source, it has been theorized to contain a supermassive black hole binary. Its apparent 1.05-year orbital period would place the gravitational-wave emission directly in the pulsar timing band. Since the first pulsar timing array study of 3C 66B, revised models of the source have been published, and timing array sensitivities and techniques have improved dramatically. With these advances, we further constrain the chirp mass of the potential supermassive black hole binary in 3C 66B to less than (1.65 ± 0.02) × 109 M ⊙ using data from the NANOGrav 11-year data set. This upper limit provides a factor of 1.6 improvement over previous limits and a factor of 4.3 over the first search done. Nevertheless, the most recent orbital model for the source is still consistent with our limit from pulsar timing array data. In addition, we are able to quantify the improvement made by the inclusion of source properties gleaned from electromagnetic data over “blind” pulsar timing array searches. With these methods, it is apparent that it is not necessary to obtain exact a priori knowledge of the period of a binary to gain meaningful astrophysical inferences.

While observations of many high-precision radio pulsars of order $\lesssim1~\mu$s across the sky are needed for the detection and characterization of a stochastic background of low-frequency gravitational waves (GWs), sensitivity to single sources of GWs requires even higher timing precision. The Argentine Institute of Radio Astronomy (IAR; Instituto Argentino de Radioastronom\'ia) has begun observations of the brightest-known millisecond pulsar, J0437$-$4715. Even though the two antennas are smaller than other single-dish telescopes previously used for pulsar timing array (PTA) science, the IAR's capability to monitor this pulsar daily coupled with the pulsar's brightness allows for high-precision pulse arrival-time measurements. While upgrades of the facility are currently underway, we show that modest improvements beyond current plans will provide IAR with unparalleled sensitivity to this pulsar. The most stringent upper limits on single GW sources come from the North American Nanohertz Observatory for Gravitational Waves (NANOGrav). Observations of PSR J0437$-$4715 will provide a significant sensitivity increase in NANOGrav's "blind spot" in the sky where fewer pulsars are currently being observed. With state-of-the-art instrumentation installed, we estimate the array's sensitivity will improve by a factor of $\approx$2-4 over 10 years for 20% of the sky with the inclusion of this pulsar as compared to a static version of the PTA used in NANOGrav's most recent limits. More modest instrumentation result in factors of $\approx$1.4-3. We identify four other candidate pulsars as suitable for inclusion in PTA efforts. International PTA efforts will also benefit from inclusion of these data given the potential achievable sensitivity., Comment: 14 pages, 2 figures, 4 tables, published in ApJ

An ensemble of inspiraling supermassive black hole binaries should produce a stochastic background of very low frequency gravitational waves. This stochastic background is predicted to be a power law, with a spectral index of -2/3, and it should be detectable by a network of precisely timed millisecond pulsars, widely distributed on the sky. This paper reports a new "time slicing" analysis of the 11-year data release from the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) using 34 millisecond pulsars. Methods to flag potential "false positive" signatures are developed, including techniques to identify responsible pulsars. Mitigation strategies are then presented. We demonstrate how an incorrect noise model can lead to spurious signals, and show how independently modeling noise across 30 Fourier components, spanning NANOGrav's frequency range, effectively diagnoses and absorbs the excess power in gravitational-wave searches. This results in a nominal, and expected, progression of our gravitational-wave statistics. Additionally we show that the first interstellar medium event in PSR J1713+0747 pollutes the common red noise process with low-spectral index noise, and use a tailored noise model to remove these effects., 14 pages, 13 figures, fixed typo in abstract of earlier version

The mergers of supermassive black hole binaries (SMBHBs) promise to be incredible sources of gravitational waves (GWs). While the oscillatory part of the merger gravitational waveform will be outside the frequency sensitivity range of pulsar timing arrays (PTAs), the non-oscillatory GW memory effect is detectable. Further, any burst of gravitational waves will produce GW memory, making memory a useful probe of unmodeled exotic sources and new physics. We searched the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) 11-year data set for GW memory. This dataset is sensitive to very low frequency GWs of $\sim3$ to $400$ nHz (periods of $\sim11$ yr $-$ $1$ mon). Finding no evidence for GWs, we placed limits on the strain amplitude of GW memory events during the observation period. We then used the strain upper limits to place limits on the rate of GW memory causing events. At a strain of $2.5\times10^{-14}$, corresponding to the median upper limit as a function of source sky position, we set a limit on the rate of GW memory events at $, Comment: 10 pages, 6 figures, submitted to ApJ

We extract interstellar scintillation parameters for pulsars observed by the NANOGrav radio pulsar timing program. Dynamic spectra for the observing epochs of each pulsar were used to obtain estimates of scintillation timescales, scintillation bandwidths, and the corresponding scattering delays using a stretching algorithm to account for frequency-dependent scaling. We were able to measure scintillation bandwidths for 28 pulsars at 1500 MHz and 15 pulsars at 820 MHz. We examine scaling behavior for 17 pulsars and find power-law indices ranging from $-0.7$ to $-3.6$, though these may be biased shallow due to insufficient frequency resolution at lower frequencies. We were also able to measure scintillation timescales for six pulsars at 1500 MHz and seven pulsars at 820 MHz. There is fair agreement between our scattering delay measurements and electron-density model predictions for most pulsars. We derive interstellar scattering-based transverse velocities assuming isotropic scattering and a scattering screen halfway between the pulsar and earth. We also estimate the location of the scattering screens assuming proper motion and interstellar scattering-derived transverse velocities are equal. We find no correlations between variations in scattering delay and either variations in dispersion measure or flux density. For most pulsars for which scattering delays were measurable, we find that time of arrival uncertainties for a given epoch are larger than our scattering delay measurements, indicating that variable scattering delays are currently subdominant in our overall noise budget but are important for achieving precisions of tens of ns or less., Comment: Accepted to ApJ

We have constructed a new timescale, TT(IPTA16), based on observations of radio pulsars presented in the first data release from the International Pulsar Timing Array (IPTA). We used two analysis techniques with independent estimates of the noise models for the pulsar observations and different algorithms for obtaining the pulsar timescale. The two analyses agree within the estimated uncertainties and both agree with TT(BIPM17), a post-corrected timescale produced by the Bureau International des Poids et Mesures (BIPM). We show that both methods could detect significant errors in TT(BIPM17) if they were present. We estimate the stability of the atomic clocks from which TT(BIPM17) is derived using observations of four rubidium fountain clocks at the US Naval Observatory. Comparing the power spectrum of TT(IPTA16) with that of these fountain clocks suggests that pulsar-based timescales are unlikely to contribute to the stability of the best timescales over the next decade, but they will remain a valuable independent check on atomic timescales. We also find that the stability of the pulsar-based timescale is likely to be limited by our knowledge of solar-system dynamics, and that errors in TT(BIPM17) will not be a limiting factor for the primary goal of the IPTA, which is to search for the signatures of nano-Hertz gravitational waves., Comment: accepted by MNRAS

We present a new analysis of the profile data from the 47 millisecond pulsars comprising the 12.5-year data set of the North American Nanohertz Observatory for Gravitational Waves (NANOGrav), which is presented in a parallel paper (Alam et al. 2021a; NG12.5). Our reprocessing is performed using "wideband" timing methods, which use frequency-dependent template profiles, simultaneous time-of-arrival (TOA) and dispersion measure (DM) measurements from broadband observations, and novel analysis techniques. In particular, the wideband DM measurements are used to constrain the DM portion of the timing model. We compare the ensemble timing results to NG12.5 by examining the timing residuals, timing models, and noise model components. There is a remarkable level of agreement across all metrics considered. Our best-timed pulsars produce encouragingly similar results to those from NG12.5. In certain cases, such as high-DM pulsars with profile broadening, or sources that are weak and scintillating, wideband timing techniques prove to be beneficial, leading to more precise timing model parameters by 10-15%. The high-precision, multi-band measurements of several pulsars indicate frequency-dependent DMs. Compared to the narrowband analysis in NG12.5, the TOA volume is reduced by a factor of 33, which may ultimately facilitate computational speed-ups for complex pulsar timing array analyses. This first wideband pulsar timing data set is a stepping stone, and its consistent results with NG12.5 assure us that such data sets are appropriate for gravitational wave analyses., Comment: 62 pages, 55 figures, 5 tables, 3 appendices. Data available at http://nanograv.org/data/ and via DOI 10.5281/zenodo.4312887

Background: Increased inflammation is a hallmark of COVID-19, with pulmonary and systemic inflammation identified in multiple cohorts of patients. Definitive cellular and molecular pathways driving severe forms of this disease remain uncertain. Neutrophils, the most numerous leukocytes in blood circulation, can contribute to immunopathology in infections, inflammatory diseases and acute respiratory distress syndrome (ARDS), a primary cause of morbidity and mortality in COVID-19. Neutrophilia, elevated neutrophil:lymphocyte ratios, and elevated neutrophil-associated cytokines are present in COVID-19, but changes in neutrophil functions have not been characterized. Here we analyzed the functional state of circulating neutrophils in COVID-19. Methods: Blood was obtained from critically ill COVID-19 patients over two weeks and healthy controls across multiple timepoints. Plasma cytokine profiles were assessed by bead array. Neutrophils were isolated and tested ex vivo for oxidative burst, neutrophil extracellular trap formation (NETosis) and phagocytosis. Lung tissue was obtained immediately post-mortem from COVID-19 patients for immunostaining. Results: Elevations in neutrophil-associated cytokines IL-8 and IL-6 were identified in COVID-19 plasma both at the first measurement and across their hospitalization (p < 0.0001). Elevations in cytokines IP-10, GM-CSF, IL-1b, IL-10 and TNF were also present at the first measurement and across hospital stays. Functionally, circulating neutrophils from COVID-19 patients had exaggerated oxidative burst (p < 0.0001), NETosis (p < 0.0001) and phagocytosis (p < 0.0001) relative to controls. Increased NETosis was found to be correlated with both leukocytosis and neutrophilia in COVID-19 patients. Neutrophils and NETs were identified within airways and alveoli in lung parenchyma. While elevations in IL-8 and ANC correlated to COVID-19 disease severity, plasma IL-8 levels alone correlated with death. Conclusions: Circulating neutrophils in COVID-19 exhibit an activated phenotype with increased oxidative burst, NETosis and phagocytosis. Readily accessible and dynamic, plasma IL-8 and circulating neutrophil function can be explored as potential COVID-19 disease biomarkers. Funding Statement: This work was supported by the Department of Veterans Affairs (salary support and VA Merit Award, PI Crotty Alexander) and NIH NHLBI (PI Crotty Alexander). Declaration of Interests: The authors report no conflicts of interest. Ethics Approval Statement: The research protocol was approved by the UCSD, VASDHS and Rady Children’s Hospital institutional review boards (IRBs) and all participants or designated family member gave written informed consent.

Radio pulsar signals are significantly perturbed by their propagation through the ionized interstellar medium. In addition to the frequency-dependent pulse times of arrival due to dispersion, pulse shapes are also distorted and shifted, having been scattered by the inhomogeneous interstellar plasma, affecting pulse arrival times. Understanding the degree to which scattering affects pulsar timing is important for gravitational wave detection with pulsar timing arrays (PTAs), which depend on the reliability of pulsars as stable clocks with an uncertainty of ~100ns or less over ~10yr or more. Scattering can be described as a convolution of the intrinsic pulse shape with an impulse response function representing the effects of multipath propagation. In previous studies, the technique of cyclic spectroscopy has been applied to pulsar signals to deconvolve the effects of scattering from the original emitted signals. We present an analysis of simulated data to test the quality of deconvolution using cyclic spectroscopy over a range of parameters characterizing interstellar scattering and pulsar signal-to-noise ratio. We show that cyclic spectroscopy is most effective for high-S/N and/or highly scattered pulsars. We conclude that cyclic spectroscopy could play an important role in scattering correction to distant populations of highly scattered pulsars not currently included in PTAs. For future telescopes and for current instruments such as the Green Bank Telescope upgraded with the ultrawide bandwidth (UWB) receiver, cyclic spectroscopy could potentially double the number of PTA-quality pulsars., Comment: 21 pages, 10 figures. Typo fixed, conclusions unchanged. Accepted for publication in ApJ

Over the past few decades, the measurement precision of some pulsar-timing experiments has advanced from ~10 us to ~10 ns, revealing many subtle phenomena. Such high precision demands both careful data handling and sophisticated timing models to avoid systematic error. To achieve these goals, we present PINT (PINT Is Not Tempo3), a high-precision Python pulsar timing data analysis package, which is hosted on GitHub and available on Python Package Index (PyPI) as pint-pulsar. PINT is well-tested, validated, object-oriented, and modular, enabling interactive data analysis and providing an extensible and flexible development platform for timing applications. It utilizes well-debugged public Python packages (e.g., the NumPy and Astropy libraries) and modern software development schemes (e.g., version control and efficient development with git and GitHub) and a continually expanding test suite for improved reliability, accuracy, and reproducibility. PINT is developed and implemented without referring to, copying, or transcribing the code from other traditional pulsar timing software packages (e.g., TEMPO and TEMPO2) and therefore provides a robust tool for cross-checking timing analyses and simulating pulse arrival times. In this paper, we describe the design, usage, and validation of PINT, and we compare timing results between it and TEMPO and TEMPO2., Comment: Re-submitted to the Astrophysical Journal at December 31st, 2020

We present time-of-arrival (TOA) measurements and timing models of 47 millisecond pulsars (MSPs) observed from 2004 to 2017 at the Arecibo Observatory and the Green Bank Telescope by the North American Nanohertz Observatory for Gravitational Waves (NANOGrav). The observing cadence was three to four weeks for most pulsars over most of this time span, with weekly observations of six sources. These data were collected for use in low-frequency gravitational wave searches and for other astrophysical purposes. We detail our observational methods and present a set of TOA measurements, based on "narrowband" analysis, in which many TOAs are calculated within narrow radio-frequency bands for data collected simultaneously across a wide bandwidth. A separate set of "wideband" TOAs will be presented in a companion paper. We detail a number of methodological changes compared to our previous work which yield a cleaner and more uniformly processed data set. Our timing models include several new astrometric and binary pulsar measurements, including previously unpublished values for the parallaxes of PSRs J1832-0836 and J2322+2057, the secular derivatives of the projected semi-major orbital axes of PSRs J0613-0200 and J2229+2643, and the first detection of the Shapiro delay in PSR J2145-0750. We report detectable levels of red noise in the time series for 14 pulsars. As a check on timing model reliability, we investigate the stability of astrometric parameters across data sets of different lengths. We report flux density measurements for all pulsars observed. Searches for stochastic and continuous gravitational waves using these data will be subjects of forthcoming publications., Comment: 54 pages, 52 figures, 7 tables, 1 appendix. Data are available at http://nanograv.org/data/ and via the DOI 10.5281/zenodo.4312297

We search for extrasolar planets around millisecond pulsars using pulsar timing data and seek to determine the minimum detectable planetary masses as a function of orbital period. Using the 11-year data set from the North American Nanohertz Observatory for Gravitational Waves (NANOGrav), we look for variations from our models of pulse arrival times due to the presence of exoplanets. No planets are detected around the millisecond pulsars in the NANOGrav 11-year data set, but taking into consideration the noise levels of each pulsar and the sampling rate of our observations, we develop limits that show we are sensitive to planetary masses as low as that of the moon. We analyzed potential planet periods, P, in the range 7 days < P < 2000 days, with somewhat smaller ranges for some binary pulsars. The planetary mass limit for our median-sensitivity pulsar within this period range is 1 M_moon (P / 100 days)^(-2/3)., Revised and accepted by ApJ Letters