Constraints on the Universal CIV Mass Density at z~6 from Early IR Spectra Obtained with the Magellan FIRE Spectrograph

We present a new determination of the intergalactic CIV mass density at 4.3 < z < 6.3. Our constraints are derived from high signal-to-noise spectra of seven quasars at z > 5.8 obtained with the newly commissioned FIRE spectrograph on the Magellan Baade telescope, coupled with six observations of northern objects taken from the literature. We confirm the presence of a downturn in the CIV abundance at =5.66 by a factor of 4.1 relative to its value at =4.96, as measured in the same sightlines. In the FIRE sample, a strong system previously reported in the literature as CIV at z=5.82 is re-identified as MgII at z=2.78, leading to a substantial downward revision in $\Omega_{CIV}$ for these prior studies. Additionally we confirm the presence of at least two systems with low-ionization CII, SiII, and OI absorption but relatively weak signal from CIV. The latter systems systems may be of interest if the downward trend in $\Omega_{CIV}$ at high redshift is driven in part by ionization effects.Comment: 14 pages, 6 figures, 2 tables. Submitted to Ap

Comparing knowledge, accessibility, and use of evidence-based chronic disease prevention processes across four countries

<p>Background: Evidence-based chronic disease prevention (EBCDP) effectively reduces incidence rates of many chronic diseases, but contextual factors influence the implementation of EBCDP worldwide. This study aims to examine the following contextual factors across four countries: knowledge, access, and use of chronic disease prevention processes.</p><p>Methods: In this cross-sectional study, public health practitioners (N = 400) from Australia (n = 121), Brazil (n = 76), China (n = 102), and the United States (n = 101) completed a 26-question survey on EBCDP. One-way ANOVA and Pearson's Chi-Square tests were used to assess differences in contextual factors of interest by country.</p><p>Results: Practitioners in China reported less knowledge of EBCDP processes (p < 0.001) and less use of repositories of evidence-based interventions, than those from other countries (p < 0.001). Academic journals were the most frequently used method for accessing information about evidence-based interventions across countries. When selecting interventions, Brazilian and Chinese practitioners were more likely to consider implementation ease while the Australian and United States practitioners were more likely to consider effectiveness (p < 0.001).</p><p>Conclusions: These findings can help inform and improve within and across country strategies for implementing EBCDP interventions.</p

Combination Therapy of Brain Natriuretic Peptide and Sildenafil Attenuates Pulmonary Hypertension in Rats [abstract]

Abstract only availableFaculty Mentor: Dr. Vincent DeMarco, Child HealthBackground: Pulmonary arterial hypertension (PAH) is a lethal disease characterized by changes in pulmonary vascular structure and function. We tested the hypothesis that Sildenafil, a phosphodiesterase 5 inhibitor, and brain natriuretic peptide (BNP), a guanosine cyclase stimulator, in combination synergistically attenuates PAH when compared to individual therapy in rats through different mechanisms to increase cGMP while minimizing systemic side effects. Methods: Adult male Sprague-Dawley rats were subcutaneously injected with monocrotaline (n=30, 50 mg/kg). After approximately 5 weeks, rats were anesthetized and instrumented to measure systemic pressure (MAP) and right ventricular systolic pressure (RVSP) during infusions of vehicle solution (n=5), intravenous Sildenafil (84 mg/kg/min; n=8), and intravenous BNP (100 ng/kg/min; n=7) alone and a combination of Sildenafil and BNP (n=10). Results: Sildenafil alone decreased RVSP (-17 ±13.2 mmHg) and had a relatively minimal effect on MAP (-4±9.9 mmHg). BNP decreased RVSP (-19±14 mmHg) but also significantly effected MAP (-11±15.3mmHg). Combination therapy with Sildenafil and BNP lowered RVSP (-20±18.7 mmHg), however it also induced the greatest systemic hypotensive effect (MAP = -19±9.9 mmHg). Conclusion: The combination of Sildenafil and BNP, at these doses, significantly attenuates monocrotaline-induced pulmonary hypertension. However, compared with individual treatment, there is no significant difference in effect on RVSP. Furthermore, additive systemic side effects are too significant to consider combination therapy safe. With a different dosing regime, this combination is a potentially viable option in the treatment of patients with PAH

Five Planets Transiting a Ninth Magnitude Star

The Kepler mission has revealed a great diversity of planetary systems and architectures, but most of the planets discovered by Kepler orbit faint stars. Using new data from the K2 mission, we present the discovery of a five planet system transiting a bright (V = 8.9, K = 7.7) star called HIP 41378. HIP 41378 is a slightly metal-poor late F-type star with moderate rotation (v sin(i) = 7 km/s) and lies at a distance of 116 +/- 18 from Earth. We find that HIP 41378 hosts two sub-Neptune sized planets orbiting 3.5% outside a 2:1 period commensurability in 15.6 and 31.7 day orbits. In addition, we detect three planets which each transit once during the 75 days spanned by K2 observations. One planet is Neptune sized in a likely ~160 day orbit, one is sub-Saturn sized likely in a ~130 day orbit, and one is a Jupiter sized planet in a likely ~1 year orbit. We show that these estimates for the orbital periods can be made more precise by taking into account dynamical stability considerations. We also calculate the distribution of stellar reflex velocities expected for this system, and show that it provides a good target for future radial velocity observations. If a precise orbital period can be determined for the outer Jovian planet through future observations, it will be an excellent candidate for follow-up transit observations to study its atmosphere and measure its oblateness.Comment: Accepted by ApJL. 12 pages, 6 figures, 2 table

Developing, monitoring, and reporting of fidelity in aphasia trials: Core recommendations from the collaboration of aphasia trialists (CATs) trials for aphasia panel

Background: Developing, monitoring, and reporting of fidelity are essential and integral components to the design of randomised controlled trials (RCTs) in stroke and aphasia. Treatment fidelity refers to the degree to which an intervention is delivered as intended and is directly related to the quality of the evidence generated by RCTs. Clear documentation of treatment fidelity in trials assists in the evaluation of the clinical implications of potential benefits attributed to the intervention. Consideration of the implementation requirements of a research-based intervention as intended in a clinical context is necessary to achieve similar outcomes for a clinical population. Despite this, treatment fidelity is rarely reported in RCTs of aphasia intervention. Aim: To describe fidelity strategies and develop core recommendations for developing, monitoring, and reporting of fidelity in aphasia intervention RCTs. Scope: Relevant conceptual frameworks were considered. The Behaviour Change Consortium comprehensive framework of fidelity was adopted. It includes five areas: study design, training providers, delivery of treatment, treatment receipt, and treatment enactment. We explored fidelity in RCTs with a range of complex aphasia interventions (e.g., ASK, Big CACTUS, COMPARE, FCET2EC, POLAR, SUPERB, and VERSE) and described how different trial design factors (e.g., phase of trial, explanatory vs. pragmatic, number and location of sites, and number and type of treatment providers) influenced the fidelity strategies chosen. Strategies were mapped onto the five areas of the fidelity framework with a detailed exploration of how fidelity criteria were developed, measured, and monitored throughout each trial. This information was synthesised into a set of core recommendations to guide aphasia researchers towards the adequate measurement, capture, and reporting of fidelity within future aphasia intervention studies. Conclusions/Recommendations: Treatment fidelity should be a core consideration in planning an intervention trial, a concept that goes beyond treatment adherence alone. A range of strategies should be selected depending on the phase and design of the trial being undertaken and appropriate investment of time and costs should be considered

The glutathione biosynthetic pathway of Plasmodium is essential for mosquito transmission

1Infection of red blood cells (RBC) subjects the malaria parasite to oxidative stress. Therefore, efficient antioxidant and redox systems are required to prevent damage by reactive oxygen species. Plasmodium spp. have thioredoxin and glutathione (GSH) systems that are thought to play a major role as antioxidants during blood stage infection. In this report, we analyzed a critical component of the GSH biosynthesis pathway using reverse genetics. Plasmodium berghei parasites lacking expression of gamma-glutamylcysteine synthetase (γ-GCS), the rate limiting enzyme in de novo synthesis of GSH, were generated through targeted gene disruption thus demonstrating, quite unexpectedly, that γ-GCS is not essential for blood stage development. Despite a significant reduction in GSH levels, blood stage forms of pbggcs− parasites showed only a defect in growth as compared to wild type. In contrast, a dramatic effect on development of the parasites in the mosquito was observed. Infection of mosquitoes with pbggcs− parasites resulted in reduced numbers of stunted oocysts that did not produce sporozoites. These results have important implications for the design of drugs aiming at interfering with the GSH redox-system in blood stages and demonstrate that de novo synthesis of GSH is pivotal for development of Plasmodium in the mosquito

The XQR-30 Metal Absorber Catalog: 778 Absorption Systems Spanning 2 < z < 6.5

Intervening metal absorption lines in the spectra of z > 6 quasars are fundamental probes of the ionization state and chemical composition of circumgalactic and intergalactic gas near the end of the reionization epoch. Large absorber samples are required to robustly measure typical absorber properties and to refine models of the synthesis, transport, and ionization of metals in the early Universe. The "Ultimate XSHOOTER legacy survey of quasars at z~5.8-6.6" (XQR-30) has obtained high signal-to-noise spectra of 30 luminous quasars, nearly quadrupling the existing sample of 12 high quality z~6 quasar spectra. We use this unprecedented sample to construct a catalog of 778 systems showing absorption in one or more of MgII (360 systems), FeII (184), CII (46), CIV (479), SiIV (127), and NV (13) which span 2 < z < 6.5. This catalog significantly expands on existing samples of z > 5 absorbers, especially for CIV and SiIV which are important probes of the ionizing photon background at high redshift. The sample is 50% (90%) complete for rest-frame equivalent widths W > 0.03AA (0.09AA). We publicly release the absorber catalog along with completeness statistics and a Python script to compute the absorption search path for different ions and redshift ranges. This dataset is a key legacy resource for studies of enriched gas from the era of galaxy assembly to cosmic noon, and paves the way for even higher redshift studies with the James Webb Space Telescope and 30m-class telescopes.Comment: 29 pages and 14 figures including 2 appendices. Accepted for publication in MNRAS. The metal absorber catalogue can be downloaded from https://github.com/XQR-30/Metal-catalogue. Contents unchanged from v1 apart from change to author lis

IL-12p70–producing patient DC vaccine elicits Tc1-polarized immunity

Background. Systemic administration of IL-12p70 has demonstrated clinical activity in cancer patients, but dose-limiting toxicities have hindered its incorporation in vaccine formulations. Here, we report on the immunological and clinical outcomes upon vaccination with CD40L/IFN-γ–matured, IL-12p70–producing DCs. Methods. 7 HLA-A*0201(+) newly diagnosed stage IV melanoma patients were immunized against the gp100 melanoma antigen using autologous peptide-pulsed, CD40L/IFN-γ–matured DCs. PBMCs were taken weekly for immune monitoring by tetramer analysis and functional assays. CT imaging was performed at baseline, week 9, and week 18 for clinical assessment using RECIST. Results. 6 of 7 treated patients developed sustained T cell immunity to all 3 melanoma gp100 antigen–derived peptides. 3 of the 6 immunological responders developed confirmed clinical responses (1 complete remission >4 years, 2 partial response). Importantly, DC vaccine–derived IL-12p70 levels positively correlated with time to progression (P = 0.019, log-rank), as did T-cytotoxic 1 (Tc1) immunity, as assessed by IFN-γ/IL-13 and IFN-γ/IL-5 ratios (P = 0.035 and P = 0.030, respectively, log-rank). In contrast, a pathway-specific defect in IL-12p35 transcription was identified upon CD40L/IFN-γ activation in clinical nonresponder patient DCs, and gp100-specific T cells from these patients displayed a Tc2 phenotype. Incorporation of TLR3 and TLR8 agonists into the CD40L/IFN-γ activation protocol corrected the IL-12p70 production defect in DCs derived from clinical nonresponder patients. Conclusion. These findings underscore the essential role of IL-12p70 in the development of therapeutic type 1 antigen–specific CD8(+) T cell immunity in humans with cancer. Trial registration. Clinicaltrials.gov NCT00683670. Funding. Barnes-Jewish Hospital Foundation, Siteman Cancer Frontier Fund, Washington University/JNJ Translational Medicine Award, and NCI (P30 CA91842)

TNF-related apoptosis-inducing ligand, interferon gamma-induced protein 10, and C-reactive protein in predicting the progression of SARS-CoV-2 infection : a prospective cohort study

Background: Early prognostication of COVID-19 severity will potentially improve patient care. Biomarkers, such as TNF-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein 10 (IP-10), and C-reactive protein (CRP), might represent possible tools for point-of-care testing and severity prediction. Methods: In this prospective cohort study, we analyzed serum levels of TRAIL, IP-10, and CRP in patients with COVID-19, compared them with control subjects, and investigated the association with disease sever ity. Results: A total of 899 measurements were performed in 132 patients (mean age 64 years, 40.2% females). Among patients with COVID-19, TRAIL levels were lower (49.5 vs 87 pg/ml, P = 0.0142), whereas IP-10 and CRP showed higher levels (667.5 vs 127 pg/ml, P <0.001; 75.3 vs 1.6 mg/l, P <0.001) than healthy controls. TRAIL yielded an inverse correlation with length of hospital and intensive care unit (ICU) stay, Simplified Acute Physiology Score II, and National Early Warning Score, and IP-10 showed a positive cor relation with disease severity. Multivariable regression revealed that obesity (adjusted odds ratio [aOR] 5.434, 95% confidence interval [CI] 1.005-29.38), CRP (aOR 1.014, 95% CI 1.002-1.027), and peak IP-10 (aOR 1.001, 95% CI 1.00-1.002) were independent predictors of in-ICU mortality

New quasar proximity zone size measurements at z∼6z\sim 6 using the enlarged XQR-30 sample

Proximity zones of high-redshift quasars are unique probes of their central supermassive black holes as well as the intergalactic medium in the last stages of reionization. We present 22 new measurements of proximity zones of quasars with redshifts between 5.8 and 6.6, using the enlarged XQR-30 sample of high-resolution, high-SNR quasar spectra. The quasars in our sample have UV magnitudes of $M_{1450}\sim -27$ and black hole masses of $10^9$\unicode{x2013}$10^{10}$ M$_\odot$. Our inferred proximity zone sizes are 2\unicode{x2013}7 physical Mpc, with a typical uncertainty of less than 0.5 physical Mpc, which, for the first time, also includes uncertainty in the quasar continuum. We find that the correlation between proximity zone sizes and the quasar redshift, luminosity, or black hole mass, indicates a large diversity of quasar lifetimes. Two of our proximity zone sizes are exceptionally small. The spectrum of one of these quasars, with $z=6.02$, displays, unusually for this redshift, damping wing absorption without any detectable metal lines, which could potentially originate from the IGM. The other quasar has a high-ionization absorber $\sim$0.5 pMpc from the edge of the proximity zone. This work increases the number of proximity zone measurements available in the last stages of cosmic reionization to 87. This data will lead to better constraints on quasar lifetimes and obscuration fractions at high redshift, which in turn will help probe the seed mass and formation redshift of supermassive black holes.Comment: 16 pages, 9 figures, Accepted in MNRA