A novel coronavirus pneumonia (COVID-19) has caused significant life loss and healthcare burden globally. COVID-19 is known to cause a cytokine release syndrome (CRS) like response, and interleukin-6 ...(IL-6) is one of the cytokines involved. Clinicians are using IL-6 inhibitors to CRS, and researchers are investigating the use of IL-6 inhibitors, namely tocilizumab, sarilumab, siltuximab, in COVID-19 management.
In this article, we will discuss the pharmacology of these three inhibitors and summarize available clinical data via literature search on PubMed with keywords of tocilizumab, sarilumab, siltuximab, and COVID-19. While awaiting more data from randomized clinical trials on these drugs, observational studies and clinical reports have demonstrated IL-6 inhibitors showed some benefits in improving clinical outcome and a well-tolerated safety profile.
There is a role for suppressing the immune response with IL-6 inhibitors that will continue to require investigation. These agents are available and have demonstrated a mild safety profile. There may be advantages to a targeted approach to suppressing the hyperinflammatory state of the disease. Timing, the long-term effects, and what cocktail of medications demonstrates the strongest outcomes are all important considerations as IL-6 inhibitors continue to be evaluated in this global pandemic.
Among this cohort, we found that 25 (46%) patients were asymptomatic (admitted to hospital for a non-COVID-19-related diagnosis but with an incidental positive PCR test for SARS-CoV-2), four (7%) had ...mild disease, 11 (20%) had moderate disease, and 14 (26%) had severe or critical illness. In our real-world assessment of patients admitted to hospital with a positive SARS-CoV-2 PCR test, we found that nearly a fifth of patients had received at least one dose of the vaccine, and we observed that many patients had not completed the full vaccine course. The finding that more than a quarter of fully vaccinated patients admitted to hospital with SARS-CoV-2 were severely or critically ill with COVID-19 could be reflective of numerous factors, including the emergence of SARS-CoV-2 variants that might confer decreased vaccine effectiveness and an ineffective immune response mounted against vaccines among those with comorbidities—eg, older age, overweight, and use of immunosuppressive agents.
Tocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series.
The goal of this study ...was to determine if tocilizumab benefits patients hospitalized with COVID-19.
This observational study of consecutive COVID-19 patients hospitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020, was conducted by chart review. Patients were treated with tocilizumab using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified according to disease severity designated at admission (severe, ≥ 3 L supplemental oxygen to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were conducted for race/ethnicity.
Among the 239 patients, median age was 64 years; 36% and 19% were black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P = .003). Tocilizumab-treated patients (n = 153 64%) comprised 90% of those with severe disease; 44% of patients with nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P < .001) and received tocilizumab sooner (2 vs 3 days; P < .001), but their survival was similar to that of patients with nonsevere disease (83% vs 91%; P = .11). For tocilizumab-treated patients requiring MV, survival was 75% (95% CI, 64-89). Following tocilizumab treatment, few adverse events occurred, and oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor (also termed CD25) levels increased significantly. Survival in black and Hispanic patients, after controlling for age, was significantly higher than in white patients (log-rank test, P = .002).
A treatment algorithm that included tocilizumab to target CRS may influence MV and survival outcomes. In tocilizumab-treated patients, oxygenation and inflammatory biomarkers improved, with higher than expected survival. Randomized trials must confirm these findings.
ABSTRACT
We present the results of a search for high-redshift (z > 9) galaxy candidates in the JWST UNCOVER survey, using deep NIRCam and NIRISS imaging in seven bands over ∼45 arcmin2 and ancillary ...Hubble Space Telescope (HST) observations. The NIRCam observations reach a 5σ limiting magnitude of ∼29.2 AB. The identification of high-z candidates relies on a combination of a dropout selection and photometric redshifts. We find 16 candidates at 9 < z < 12 and three candidates at 12 < z < 13, eight candidates are deemed very robust. Their lensing amplification ranges from μ = 1.2 to 11.5. Candidates have a wide range of (lensing corrected) luminosities and young ages, with low stellar masses 6.8 < log(M⋆/M⊙) < 9.5 and low star formation rates (SFR = 0.2–7 M⊙ yr−1), confirming previous findings in early JWST observations of z > 9. A few galaxies at z ∼ 9−10 appear to show a clear Balmer break between the F356W and F444W/F410M bands, which helps constrain their stellar mass. We estimate blue UV continuum slopes between β = −1.8 and −2.3, typical for early galaxies at z > 9 but not as extreme as the bluest recently discovered sources. We also find evidence for a rapid redshift-evolution of the mass-luminosity relation and a redshift evolution of the UV continuum slope for a given range of intrinsic magnitude, in line with theoretical predictions. These findings suggest that deeper JWST observations are needed to reach the fainter galaxy population at those early epochs, and follow-up spectroscopy will help better constrain the physical properties and star formation histories of a larger sample of galaxies.
Abstract We report JWST/NIRSpec spectra of three distant T-type brown dwarfs identified in the Ultradeep NIRSpec and NIRCam ObserVations before the Epoch of Reionization (UNCOVER) survey of the Abell ...2744 lensing field. One source was previously reported as a candidate T dwarf on the basis of NIRCam photometry, while two sources were initially identified as candidate active galactic nuclei. Low-resolution 1–5 μ m spectra confirm the presence of molecular features consistent with T dwarf atmospheres, and comparison to spectral standards infers classifications of sdT1, T6, and T8–T9. The warmest source, UNCOVER-BD-1, shows evidence of subsolar metallicity, and atmosphere model fits indicate T eff = 1300 K and M/H ∼ −1.0, making this one of the few spectroscopically confirmed T subdwarfs known. The coldest source, UNCOVER-BD-3, is near the T/Y dwarf boundary with T eff = 550 K, and our analysis indicates the presence of PH 3 in the 3–5 μ m region, favored over CO 2 and a possible indicator of subsolar metallicity. We estimate distances of 0.9–4.5 kpc from the Galactic midplane, making these the most distant brown dwarfs with spectroscopic confirmation. Population simulations indicate high probabilities of membership in the Galactic thick disk for two of these brown dwarfs, and potential halo membership for UNCOVER-BD-1. Our simulations indicate that there are approximately 5 T dwarfs and 1–2 L dwarfs in the Abell 2744 field down to F444W = 30 AB mag, roughly one-third of which are thick disk members. These results highlight the utility of deep JWST/NIRSpec spectroscopy for identifying and characterizing the oldest metal-poor brown dwarfs in the Milky Way.
IMPORTANCE: Emerging evidence suggests that risk of bacterial sexually transmitted infections (STIs) increases among gay and bisexual men following initiation of HIV preexposure prophylaxis (PrEP). ...OBJECTIVE: To describe STI incidence and behavioral risk factors among a cohort of predominantly gay and bisexual men who use PrEP, and to explore changes in STI incidence following PrEP commencement. DESIGN, SETTING, AND PARTICIPANTS: The Pre-exposure Prophylaxis Expanded (PrEPX) Study, a multisite, open-label intervention study, was nested within the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance (ACCESS) clinic network. A total of 4275 participants were enrolled (July 26, 2016–April 1, 2018) in Victoria, Australia. Of these, 2981 enrolled at 5 ACCESS clinics (3 primary care, 1 sexual health, and 1 community-based HIV rapid testing service), had at least 1 follow-up visit, and were monitored until April 30, 2018. EXPOSURES: Upon enrollment, participants received daily oral tenofovir disoproxil fumurate and emtricitabine for HIV PrEP, quarterly HIV and STI testing, and clinical monitoring. MAIN OUTCOMES AND MEASURES: The primary outcome was incidence of chlamydia, gonorrhea, or syphilis. Incidence rates and hazard ratios describing behavioral risk factors of STI diagnosis were calculated. Incidence rate ratios (IRRs), adjusted for change in testing frequency, described changes in STI incidence from 1-year preenrollment to study follow-up among participants with preenrollment testing data (n = 1378). RESULTS: Among the 2981 individuals (median age, 34 years interquartile range, 28-42), 98.5% identified as gay or bisexual males, 29% used PrEP prior to enrollment, 89 (3%) withdrew and were censored at date of withdrawal, leaving 2892 (97.0%) enrolled at final follow-up. During a mean follow-up of 1.1 years (3185.0 person-years), 2928 STIs were diagnosed among 1427 (48%) participants (1434 chlamydia, 1242 gonorrhea, 252 syphilis). STI incidence was 91.9 per 100 person-years, with 736 participants (25%) accounting for 2237 (76%) of all STIs. Among 2058 participants with complete data for multivariable analysis, younger age, greater partner number, and group sex were associated with greater STI risk, but condom use was not. Among 1378 participants with preenrollment testing data, STI incidence increased from 69.5 per 100 person-years prior to enrollment to 98.4 per 100 person-years during follow-up (IRR, 1.41 95% CI, 1.29-1.56). After adjusting for testing frequency, the increase in incidence from 1 year preenrollment to follow-up was significant for any STI (adjusted IRR, 1.12 95% CI, 1.02-1.23) and for chlamydia (adjusted IRR, 1.17 95% CI, 1.04-1.33). CONCLUSIONS AND RELEVANCE: Among gay and bisexual men using PrEP, STIs were highly concentrated among a subset, and receipt of PrEP after study enrollment was associated with an increased incidence of STIs compared with preenrollment. These findings highlight the importance of frequent STI testing among gay and bisexual men using PrEP.
Abstract The era of the James Webb Space Telescope ushers stellar population models into uncharted territories, particularly at the high-redshift frontier. In a companion paper, we apply the ...Prospector Bayesian framework to jointly infer galaxy redshifts and stellar population properties from broadband photometry as part of the UNCOVER survey. Here we present a comprehensive error budget in spectral energy distribution (SED) modeling. Using a sample selected to have photometric redshifts higher than 9, we quantify the systematic shifts stemming from various model choices in inferred stellar mass, star formation rate (SFR), and age. These choices encompass different timescales for changes in the star formation history (SFH), nonuniversal stellar initial mass functions (IMF), and the inclusion of variable nebular abundances, gas density, and ionizing photon budget. We find that the IMF exerts the strongest influence on the inferred properties: the systematic uncertainties can be as much as 1 dex, 2–5 times larger than the formal reported uncertainties in mass and SFR, and importantly, exceed the scatter seen when using different SED fitting codes. Although the assumptions on the lower end of the IMF induce degeneracy, our findings suggest that a common practice in the literature of assessing uncertainties in SED-fitting processes by comparing multiple codes is substantively underestimating the true systematic uncertainty. Highly stochastic SFHs change the inferred SFH by much larger than the formal uncertainties, and introduce ∼0.8 dex systematics in SFR averaged over a short timescale and ∼0.3 dex systematics in average age. Finally, employing a flexible nebular emission model causes ∼0.2 dex systematic increase in mass and SFR, comparable to the formal uncertainty. This paper constitutes an initial step toward a complete uncertainty estimate in SED modeling.
Challenges in using cytokine data are limiting Coronavirus Disease 2019 (COVID-19) patient management and comparison among different disease contexts. We suggest mitigation strategies to improve the ...accuracy of cytokine data, as we learn from experience gained during the COVID-19 pandemic.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Peanuts are the most common food to provoke fatal or near-fatal anaphylactic reactions. Treatment with an anti-hIgE mAb is efficacious but requires frequent parenteral administration. ...Objective Based on the knowledge that peanut allergy is mediated by peanut-specific IgE, we hypothesized that a single administration of an adeno-associated virus (AAV) gene transfer vector encoding for anti-hIgE would protect against repeated peanut exposure in the host with peanut allergy. Methods We developed a novel humanized murine model of peanut allergy that recapitulates the human anaphylactic response to peanuts in NOD- scid IL2Rgammanull mice transferred with blood mononuclear cells from donors with peanut allergy and then sensitized with peanut extract. As therapy, we constructed an adeno-associated rh.10 serotype vector coding for a full-length, high-affinity, anti-hIgE antibody derived from the Fab fragment of the anti-hIgE mAb omalizumab (AAVrh.10anti-hIgE). In the reconstituted mice peanut-specific IgE was induced by peanut sensitization and hypersensitivity, and reactions were provoked by feeding peanuts to mice with symptoms similar to those of human subjects with peanut allergy. Results A single administration of AAVrh.10anti-hIgE vector expressed persistent levels of anti-hIgE. The anti-hIgE vector, administered either before sensitization or after peanut sensitization and manifestation of the peanut-induced phenotype, blocked IgE-mediated alterations in peanut-induced histamine release, anaphylaxis scores, locomotor activity, and free IgE levels and protected animals from death caused by anaphylaxis. Conclusion If this degree of persistent efficacy translates to human subjects, AAVrh.10anti-hIgE could be an effective 1-time preventative therapy for peanut allergy and possibly other severe, IgE-mediated allergies.
Abstract
Recent JWST/NIRCam imaging taken for the ultra-deep UNCOVER program reveals a very red dropout object at
z
phot
≃ 7.6, triply imaged by the galaxy cluster A2744 (
z
d
= 0.308). All three ...images are very compact, i.e., unresolved, with a delensed size upper limit of
r
e
≲ 35 pc. The images have apparent magnitudes of
m
F444W
∼ 25−26 AB, and the magnification-corrected absolute UV magnitude of the source is
M
UV,1450
= −16.81 ± 0.09. From the sum of observed fluxes and from a spectral energy distribution (SED) analysis, we obtain estimates of the bolometric luminosities of the source of
L
bol
≳ 10
43
erg s
−1
and
L
bol
∼ 10
44
–10
46
erg s
−1
, respectively. Based on its compact, point-like appearance, its position in color–color space, and the SED analysis, we tentatively conclude that this object is a UV-faint dust-obscured quasar-like object, i.e., an active galactic nucleus at high redshift. We also discuss other alternative origins for the object’s emission features, including a massive star cluster, Population III, supermassive, or dark stars, or a direct-collapse black hole. Although populations of red galaxies at similar photometric redshifts have been detected with JWST, this object is unique in that its high-redshift nature is corroborated geometrically by lensing, that it is unresolved despite being magnified—and thus intrinsically even more compact—and that it occupies notably distinct regions in both size–luminosity and color–color space. Planned UNCOVER JWST/NIRSpec observations, scheduled in Cycle 1, will enable a more detailed analysis of this object.
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