Emergence and dynamics of influenza super-strains

Abstract Background Influenza super-strains can emerge through recombination of strains from birds, pigs, and humans. However, once a new recombinant strain emerges, it is not clear whether the strain is capable of sustaining an outbreak. In certain cases, such strains have caused major influenza pandemics. Methods Here we develop a multi-host (i.e., birds, pigs, and humans) and multi-strain model of influenza to analyze the outcome of emergent strains. In the model, pigs act as “mixing vessels” for avian and human strains and can produce super-strains from genetic recombination. Results We find that epidemiological outcomes are predicted by three factors: (i) contact between pigs and humans, (ii) transmissibility of the super-strain in humans, and (iii) transmissibility from pigs to humans. Specifically, outbreaks will reoccur when the super-strain intections are less frequent between humans (e.g., R0=1.4) but grequent from pigs to humans, and a large-scale outbreak followed by successively damping outbreaks will occur when human transmissibility is high (e.g., R0=2.3). The average time between the initial outbreak and the first resurgence varies from 41 to 82 years. We determine the largest outbreak will occur when 2.

Directional Reflectance Studies in Support of the Radiometric Calibration Test Site (RadCaTS) at Railroad Valley

The Radiometric Calibration Test Site (RadCaTS) is a suite of commercial and custom instruments used to make measurements of the surface reflectance and atmosphere throughout the day at Railroad Valley, Nevada. It was developed in response to the need for daily radiometric calibration data for the vast array of Earth-observing sensors on orbit, which is continuously increasing as more nations and private companies launch individual environmental satellites as well as large constellations. The current suite of instruments at RadCaTS includes five ground-viewing radiometers (GVRs), four of which view the surface in a nadir-viewing configuration. Many sensors such as those on Landsat-7 and Landsat-8 view Railroad Valley within 3 of nadir, while others such as those on Sentinel-2A and -2B, RapidEye, Aqua, Suomi NPP, and Terra can view Railroad Valley at off-nadir angles. Past efforts have shown that the surface bidirectional reflectance distribution function (BRDF) has minimal impact on vicarious calibration uncertainties for views <10, but the desire to use larger view angles has prompted the effort to develop a BRDF correction for data from RadCaTS. The current work investigates the application of Railroad Valley BRDF data derived from a BRF camera developed at the University of Arizona in the 1990s (but is no longer in use) to the current RadCaTS surface reflectance measurements. Also investigated are early results from directional reflectance studies using a mobile spectro-goniometer system during a round-robin field campaign in 2018. This work describes the preliminary results, the effects on current measurements, and the approach for future measurements

Calculating the potential for within-flight transmission of influenza A (H1N1)

Abstract Background Clearly air travel, by transporting infectious individuals from one geographic location to another, significantly affects the rate of spread of influenza A (H1N1). However, the possibility of within-flight transmission of H1N1 has not been evaluated; although it is known that smallpox, measles, tuberculosis, SARS and seasonal influenza can be transmitted during commercial flights. Here we present the first quantitative risk assessment to assess the potential for within-flight transmission of H1N1. Methods We model airborne transmission of infectious viral particles of H1N1 within a Boeing 747 using methodology from the field of quantitative microbial risk assessment. Results The risk of catching H1N1 will essentially be confined to passengers travelling in the same cabin as the source case. Not surprisingly, we find that the longer the flight the greater the number of infections that can be expected. We calculate that H1N1, even during long flights, poses a low to moderate within-flight transmission risk if the source case travels First Class. Specifically, 0-1 infections could occur during a 5 hour flight, 1-3 during an 11 hour flight and 2-5 during a 17 hour flight. However, within-flight transmission could be significant, particularly during long flights, if the source case travels in Economy Class. Specifically, two to five infections could occur during a 5 hour flight, 5-10 during an 11 hour flight and 7-17 during a 17 hour flight. If the aircraft is only partially loaded, under certain conditions more infections could occur in First Class than in Economy Class. During a 17 hour flight, a greater number of infections would occur in First Class than in Economy if the First Class Cabin is fully occupied, but Economy class is less than 30% full. Conclusions Our results provide insights into the potential utility of air travel restrictions on controlling influenza pandemics in the winter of 2009/2010. They show travel by one infectious individual, rather than causing a single outbreak of H1N1, could cause several simultaneous outbreaks. These results imply that, during a pandemic, quarantining passengers who travel in Economy on long-haul flights could potentially be an important control strategy. Notably, our results show that quarantining passengers who travel First Class would be unlikely to be an effective control strategy

Modeling influenza epidemics and pandemics: insights into the future of swine flu (H1N1)

Here we present a review of the literature of influenza modeling studies, and discuss how these models can provide insights into the future of the currently circulating novel strain of influenza A (H1N1), formerly known as swine flu. We discuss how the feasibility of controlling an epidemic critically depends on the value of the Basic Reproduction Number (R0). The R0 for novel influenza A (H1N1) has recently been estimated to be between 1.4 and 1.6. This value is below values of R0 estimated for the 1918–1919 pandemic strain (mean R0~2: range 1.4 to 2.8) and is comparable to R0 values estimated for seasonal strains of influenza (mean R0 1.3: range 0.9 to 2.1). By reviewing results from previous modeling studies we conclude it is theoretically possible that a pandemic of H1N1 could be contained. However it may not be feasible, even in resource-rich countries, to achieve the necessary levels of vaccination and treatment for control. As a recent modeling study has shown, a global cooperative strategy will be essential in order to control a pandemic. This strategy will require resource-rich countries to share their vaccines and antivirals with resource-constrained and resource-poor countries. We conclude our review by discussing the necessity of developing new biologically complex models. We suggest that these models should simultaneously track the transmission dynamics of multiple strains of influenza in bird, pig and human populations. Such models could be critical for identifying effective new interventions, and informing pandemic preparedness planning. Finally, we show that by modeling cross-species transmission it may be possible to predict the emergence of pandemic strains of influenza

NuSTAR discovery of a luminosity dependent cyclotron line energy in Vela X-1

We present NuSTAR observations of Vela X-1, a persistent, yet highly variable, neutron star high-mass X-ray binary (HMXB). Two observations were taken at similar orbital phases but separated by nearly a year. They show very different 3–79 keV flux levels as well as strong variability during each observation, covering almost one order of magnitude in flux. These observations allow, for the first time ever, investigations on kilo-second time-scales of how the centroid energies of cyclotron resonant scattering features (CRSFs) depend on flux for a persistent HMXB. We find that the line energy of the harmonic CRSF is correlated with flux, as expected in the sub-critical accretion regime. We argue that Vela X-1 has a very narrow accretion column with a radius of around 0.4 km that sustains a Coulomb interaction dominated shock at the observed luminosities of L_x ~ 3 × 10^36 erg s^−1. Besides the prominent harmonic line at 55 keV the fundamental line around 25 keV is clearly detected. We find that the strengths of the two CRSFs are anti-correlated, which we explain by photon spawning. This anti-correlation is a possible explanation for the debate about the existence of the fundamental line. The ratio of the line energies is variable with time and deviates significantly from 2.0, also a possible consequence of photon spawning, which changes the shape of the line. During the second observation, Vela X-1 showed a short off-state in which the power-law softened and a cut-off was no longer measurable. It is likely that the source switched to a different accretion regime at these low mass accretion rates, explaining the drastic change in spectral shape

The smooth cyclotron line in her x-1 as seen with nuclear spectroscopic telescope array

Her X-1, one of the brightest and best studied X-ray binaries, shows a cyclotron resonant scattering feature (CRSF) near 37 keV. This makes it an ideal target for a detailed study with the Nuclear Spectroscopic Telescope Array (NuSTAR), taking advantage of its excellent hard X-ray spectral resolution. We observed Her X-1 three times, coordinated with Suzaku, during one of the high flux intervals of its 35 day superorbital period. This paper focuses on the shape and evolution of the hard X-ray spectrum. The broadband spectra can be fitted with a power law with a high-energy cutoff, an iron line, and a CRSF. We find that the CRSF has a very smooth and symmetric shape in all observations and at all pulse phases. We compare the residuals of a line with a Gaussian optical-depth profile to a Lorentzian optical-depth profile and find no significant differences, strongly constraining the very smooth shape of the line. Even though the line energy changes dramatically with pulse phase, we find that its smooth shape does not. Additionally, our data show that the continuum only changes marginally between the three observations. These changes can be explained with varying amounts of Thomson scattering in the hot corona of the accretion disk. The average, luminosity-corrected CRSF energy is lower than in past observations and follows a secular decline. The excellent data quality of NuSTAR provides the best constraint on the CRSF energy to date

Transcriptional Priming of Salmonella Pathogenicity Island-2 Precedes Cellular Invasion

Invasive salmonellosis caused by Salmonella enterica involves an enteric stage of infection where the bacteria colonize mucosal epithelial cells, followed by systemic infection with intracellular replication in immune cells. The type III secretion system encoded in Salmonella Pathogenicity Island (SPI)-2 is essential for intracellular replication and the regulators governing high-level expression of SPI-2 genes within the macrophage phagosome and in inducing media thought to mimic this environment have been well characterized. However, low-level expression of SPI-2 genes is detectable in media thought to mimic the extracellular environment suggesting that additional regulatory pathways are involved in SPI-2 gene expression prior to cellular invasion. The regulators involved in this activity are not known and the extracellular transcriptional activity of the entire SPI-2 island in vivo has not been studied. We show that low-level, SsrB-independent promoter activity for the ssrA-ssrB two-component regulatory system and the ssaG structural operon encoded in SPI-2 is dependent on transcriptional input by OmpR and Fis under non-inducing conditions. Monitoring the activity of all SPI-2 promoters in real-time following oral infection of mice revealed invasion-independent transcriptional activity of the SPI2 T3SS in the lumen of the gut, which we suggest is a priming activity with functional relevance for the subsequent intracellular host-pathogen interaction

Mechanisms and in vivo functions of contact inhibition of locomotion

Contact inhibition of locomotion (CIL) is a process whereby a cell ceases motility or changes its trajectory upon collision with another cell. CIL was initially characterized more than half a century ago and became a widely studied model system to understand how cells migrate and dynamically interact. Although CIL fell from interest for several decades, the scientific community has recently rediscovered this process. We are now beginning to understand the precise steps of this complex behaviour and to elucidate its regulatory components, including receptors, polarity proteins and cytoskeletal elements. Furthermore, this process is no longer just in vitro phenomenology; we now know from several different in vivo models that CIL is essential for embryogenesis and in governing behaviours such as cell dispersion, boundary formation and collective cell migration. In addition, changes in CIL responses have been associated with other physiological processes, such as cancer cell dissemination during metastasis

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707