The candidate TB vaccine, MVA85A, induces highly durable Th1 responses

BACKGROUND: Vaccination against tuberculosis (TB) should provide long-term protective immunity against Mycobacterium tuberculosis ( M.tb ). The current TB vaccine, Bacille Calmette-Guerin (BCG), protects against disseminated childhood TB, but protection against lung TB in adolescents and adults is variable and mostly poor. One potential reason for the limited durability of protection may be waning of immunity through gradual attrition of BCG-induced T cells. We determined if a MVA85A viral-vector boost could enhance the durability of mycobacteria-specific T cell responses above those induced by BCG alone. METHODS: We describe a long-term follow-up study of persons previously vaccinated with MVA85A. We performed a medical history and clinical examination, a tuberculin skin test and measured vaccine-specific T cell responses in persons previously enrolled as adults, adolescents, children or infants into three different Phase II trials, between 2005 and 2011. RESULTS: Of 252 potential participants, 183 (72.6%) consented and completed the study visit. Vaccine-induced Ag85A-specific CD4+ T cell responses were remarkably persistent in healthy, HIV-uninfected adults, adolescents, children and infants, up to 6 years after MVA85A vaccination. Specific CD4+ T cells expressed surface markers consistent with either CD45RA−CCR7+ central memory or CD45RA−CCR7− effector memory T cells. Similarly durable Ag85A-specific CD4+ T cell responses were detected in HIV-infected persons who were on successful antiretroviral therapy when MVA85A was administered. By contrast, Ag85A-specific CD4+ T cell frequencies in untreated MVA85A-vaccinated HIV-infected persons were mostly undetectable 3-5 years after vaccination. CONCLUSION: MVA85A induces remarkably durable T cell responses in immunocompetent persons. However, results from a recent phase IIb trial of MVA85A, conducted in infants from the same geographic area and study population, showed no vaccine efficacy, suggesting that these durable T cell responses do not enhance BCG-induced protection against TB in infants

Coronary atherosclerosis scoring with semiquantitative CCTA risk scores for prediction of major adverse cardiac events: Propensity score-based analysis of diabetic and non-diabetic patients.

AIMS:We aimed to compare semiquantitative coronary computed tomography angiography (CCTA) risk scores - which score presence, extent, composition, stenosis and/or location of coronary artery disease (CAD) - and their prognostic value between patients with and without diabetes mellitus (DM). Risk scores derived from general chest-pain populations are often challenging to apply in DM patients, because of numerous confounders. METHODS:Out of a combined cohort from the Leiden University Medical Center and the CONFIRM registry with 5-year follow-up data, we performed a secondary analysis in diabetic patients with suspected CAD who were clinically referred for CCTA. A total of 732 DM patients was 1:1 propensity-matched with 732 non-DM patients by age, sex and cardiovascular risk factors. A subset of 7 semiquantitative CCTA risk scores was compared between groups: 1) any stenosis ≥50%, 2) any stenosis ≥70%, 3) stenosis-severity component of the coronary artery disease-reporting and data system (CAD-RADS), 4) segment involvement score (SIS), 5) segment stenosis score (SSS), 6) CT-adapted Leaman score (CT-LeSc), and 7) Leiden CCTA risk score. Cox-regression analysis was performed to assess the association between the scores and the primary endpoint of all-cause death and non-fatal myocardial infarction. Also, area under the receiver-operating characteristics curves were compared to evaluate discriminatory ability. RESULTS:A total of 1,464 DM and non-DM patients (mean age 58 ± 12 years, 40% women) underwent CCTA and 155 (11%) events were documented after median follow-up of 5.1 years. In DM patients, the 7 semiquantitative CCTA risk scores were significantly more prevalent or higher as compared to non-DM patients (p ≤ 0.022). All scores were independently associated with the primary endpoint in both patients with and without DM (p ≤ 0.020), with non-significant interaction between the scores and diabetes (interaction p ≥ 0.109). Discriminatory ability of the Leiden CCTA risk score in DM patients was significantly better than any stenosis ≥50% and ≥70% (p = 0.003 and p = 0.007, respectively), but comparable to the CAD-RADS, SIS, SSS and CT-LeSc that also focus on the extent of CAD (p ≥ 0.265). CONCLUSION:Coronary atherosclerosis scoring with semiquantitative CCTA risk scores incorporating the total extent of CAD discriminate major adverse cardiac events well, and might be useful for risk stratification of patients with DM beyond the binary evaluation of obstructive stenosis alone

Clinical risk factors and atherosclerotic plaque extent to define risk for major events in patients without obstructive coronary artery disease: the long-term coronary computed tomography angiography CONFIRM registry.

AimsIn patients without obstructive coronary artery disease (CAD), we examined the prognostic value of risk factors and atherosclerotic extent.Methods and resultsPatients from the long-term CONFIRM registry without prior CAD and without obstructive (≥50%) stenosis were included. Within the groups of normal coronary computed tomography angiography (CCTA) (N = 1849) and non-obstructive CAD (N = 1698), the prognostic value of traditional clinical risk factors and atherosclerotic extent (segment involvement score, SIS) was assessed with Cox models. Major adverse cardiac events (MACE) were defined as all-cause mortality, non-fatal myocardial infarction, or late revascularization. In total, 3547 patients were included (age 57.9 ± 12.1 years, 57.8% male), experiencing 460 MACE during 5.4 years of follow-up. Age, body mass index, hypertension, and diabetes were the clinical variables associated with increased MACE risk, but the magnitude of risk was higher for CCTA defined atherosclerotic extent; adjusted hazard ratio (HR) for SIS >5 was 3.4 (95% confidence interval [CI] 2.3-4.9) while HR for diabetes and hypertension were 1.7 (95% CI 1.3-2.2) and 1.4 (95% CI 1.1-1.7), respectively. Exclusion of revascularization as endpoint did not modify the results. In normal CCTA, presence of ≥1 traditional risk factors did not worsen prognosis (log-rank P = 0.248), while it did in non-obstructive CAD (log-rank P = 0.025). Adjusted for SIS, hypertension and diabetes predicted MACE risk in non-obstructive CAD, while diabetes did not increase risk in absence of CAD (P-interaction = 0.004).ConclusionAmong patients without obstructive CAD, the extent of CAD provides more prognostic information for MACE than traditional cardiovascular risk factors. An interaction was observed between risk factors and CAD burden, suggesting synergistic effects of both

UNCOVER: A NIRSpec Identification of a Broad-line AGN at z = 8.50

Deep observations with the James Webb Space Telescope (JWST) have revealed an emerging population of red pointlike sources that could provide a link between the postulated supermassive black hole seeds and observed quasars. In this work, we present a JWST/NIRSpec spectrum from the JWST Cycle 1 UNCOVER Treasury survey of a massive accreting black hole at z = 8.50 displaying a clear broad-line component as inferred from the Hβ line with FWHM = 3439 ± 413 km s−1, typical of the broad-line region of an active galactic nucleus (AGN). The AGN nature of this object is further supported by high ionization, as inferred from emission lines, and a point-source morphology. We compute a black hole mass of and a bolometric luminosity of Lbol ∼ 6.6 × 1045 erg s−1. These values imply that our object is accreting at ∼40% of the Eddington limit. Detailed modeling of the spectral energy distribution in the optical and near-infrared, together with constraints from ALMA, indicate an upper limit on the stellar mass of , which would lead to an unprecedented ratio of black hole to host mass of at least ∼30%. This is orders of magnitude higher compared to the local QSOs but consistent with recent AGN studies at high redshift with JWST. This finding suggests that a nonnegligible fraction of supermassive black holes either started out from massive seeds and/or grew at a super-Eddington rate at high redshift. Given the predicted number densities of high-z faint AGN, future NIRSpec observations of larger samples will allow us to further investigate galaxy–black hole coevolution in the early Universe

DUALZ: Deep UNCOVER-ALMA Legacy High-Z Survey

We present the survey design and initial results of the ALMA Cycle 9 program of DUALZ, which aims to establish a joint ALMA and JWST public legacy field targeting the massive galaxy cluster Abell 2744. DUALZ features a contiguous $4'\times6'$ ALMA 30-GHz-wide mosaic in Band 6, covering areas of $\mu>2$ down to a sensitivity of $\sigma=32.7~\mu$Jy. Through a blind search, we identified 69 dust continuum sources at S/N $\gtrsim5.0$ with median redshift and intrinsic 1.2-mm flux of $z=2.30$ and $S_{\rm 1.2mm}^{\rm int}=0.24$~mJy. Of these, 27 have been spectroscopically confirmed, leveraged by the latest NIRSpec observations, while photometric redshift estimates are constrained by the comprehensive HST, NIRCam, and ALMA data for the remaining sources. With priors, we further identify a [CII]158 $\mu$m line emitter at $z=6.3254\pm0.0004$, confirmed by the latest NIRSpec spectroscopy. The NIRCam counterparts of the 1.2-mm continuum exhibit undisturbed morphologies, denoted either by disk or spheroid, implying the triggers for the faint mm emission are less catastrophic than mergers. We have identified 8 HST-dark galaxies (F150W$>$27mag, F150W$-$F444W$>$2.3) and 2 JWST-dark (F444W$>$30mag) galaxy candidates among the ALMA continuum sources. The former includes face-on disk galaxies, hinting that substantial dust obscuration does not always result from inclination. We also detect a marginal dust emission from an X-ray-detected galaxy at $z_{\rm spec}=10.07$, suggesting an active co-evolution of the central black hole and its host. We assess the infrared luminosity function up to $z\sim10$ and find it consistent with predictions from galaxy formation models. To foster diverse scientific outcomes from the community, we publicly release reduced ALMA mosaic maps, cubes, and the source catalog.Comment: 33 pages, 16 figures, and 5 tables. Submitted to ApJS. The ALMA products are fully available from here: https://jwst-uncover.github.io/DR2.html#DUAL

UNCOVER: A NIRSpec Identification of a Broad Line AGN at z = 8.50

Deep observations with JWST have revealed an emerging population of red point-like sources that could provide a link between the postulated supermassive black hole seeds and observed quasars. In this work we present a JWST/NIRSpec spectrum from the JWST Cycle 1 UNCOVER Treasury survey, of a massive accreting black hole at $z=8.50$, displaying a clear broad-line component as inferred from the H$\beta$ line with FWHM = $3439\pm413$ km s$^{-1}$, typical of the broad line region of an active galactic nucleus (AGN). The AGN nature of this object is further supported by high ionization, as inferred from emission lines, and a point-source morphology. We compute the black hole mass of log$_{10}(M_{\rm BH}/M_\odot)=8.17\pm0.42$, and a bolometric luminosity of $L_{\rm bol}\sim6.6\times10^{45}$ erg s$^{-1}$. These values imply that our object is accreting at $\sim 40\%$ of the Eddington limit. Detailed modeling of the spectral energy distribution in the optical and near-infrared, together with constraints from ALMA, indicate an upper limit on the stellar mass of log$_{10}(M_{\rm *}/M_\odot)<8.7$, which would lead to an unprecedented ratio of black hole to host mass of at least $\sim 30 \%$. This is orders of magnitude higher compared to the local QSOs, but is consistent with recent AGN studies at high redshift with JWST. This finding suggests that a non-negligible fraction of supermassive black holes either started out from massive seeds and/or grew at a super-Eddington rate at high redshift. Given the predicted number densities of high-$z$ faint AGN, future NIRSpec observations of larger samples will allow us to further investigate the galaxy-black hole co-evolution in the early Universe.Comment: 14 pages, 6 figures, 2 tables. Submitted to ApJ

A telephone survey of parental attitudes and behaviours regarding teenage drinking

<p>Abstract</p> <p>Background</p> <p>Irish teenagers demonstrate high rates of drunkenness and there has been a progressive fall in age of first drinking in recent decades. International research indicates that parents exert substantial influence over their teenager's drinking. We sought to determine the attitudes and behaviours of Irish parents towards drinking by their adolescent children.</p> <p>Methods</p> <p>We conducted a telephone survey of a representative sample of of 234 parents who had a teenager aged between 13 and 17 years.</p> <p>Results</p> <p>Six per cent reported that they would be unconcerned if their son or daughter was to binge drink once per month. On the issue of introducing children to alcohol in the home, 27% viewed this as a good idea while 63% disagreed with this practice. Eleven per cent of parents reported that they had given a drink to their teenager at home. Parents who drank regularly themselves, who were from higher socio-demographic groups and who lived in the east of Ireland demonstrated more permissive attitudes to teenage drinking.</p> <p>Conclusions</p> <p>We found no evidence of widespread permissive attitudes and behaviours among Irish parents. Given that parental influences have been demonstrated to exert substantial impact on teenage drinking, it may be possible to harness the concerns of Irish parents more effectively to reverse the trends of escalating alcohol related harm in Ireland.</p