72 research outputs found
Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on the IL23/IFNg axis
Immune checkpoint inhibitors (CPIs) have revolutionised cancer treatment, with previously untreatable disease now amenable to potential cure. Combination regimens of anti-CTLA-4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. CPI-induced colitis is a common and serious complication. To probe the impact of immune checkpoints on intestinal homeostasis, mice were challenged with combination anti-CTLA-4/anti-PD-1 immunotherapy and manipulation of the intestinal microbiota. Colonic immune responses were profiled using bulk and single-cell RNA-sequencing and flow cytometry. CPI-colitis was dependent on the composition of the intestinal microbiota and was characterized by remodelling of mucosal lymphocytes with induction of polyfunctional lymphocyte responses characterized by increased expression of interferon-γ (IFNγ), other pro-inflammatory cytokines/chemokines (Il22, Il17a Ccl3, Ccl4 and Ccl9), cytotoxicity molecules (Gzmb, Gzma, Prf1, Nkg7) and the chemokine receptor Cxcr6. In comparison with mucosal lymphocytes in the steady state, polyfunctional lymphocytes from both CD4+ and CD8+ lineages upregulated costimulatory molecules and checkpoint molecules in CPI-colitis, indicating that these cells are tightly regulated. CPI-colitis was attenuated following depletion of effector lymphocytes or following blockade of the IL23/IFNγ axis. This study provides new mechanistic insights into CPI-colitis, identifying polyfunctional, cytotoxic lymphocytes as key mediators of disease. Therapeutic targeting of their effector response or regulatory networks, including the IL23/IFNγ axis likely holds the key to preventing and reversing CPI-colitis
Measuring our universe from galaxy redshift surveys
Galaxy redshift surveys have achieved significant progress over the last
couple of decades. Those surveys tell us in the most straightforward way what
our local universe looks like. While the galaxy distribution traces the bright
side of the universe, detailed quantitative analyses of the data have even
revealed the dark side of the universe dominated by non-baryonic dark matter as
well as more mysterious dark energy (or Einstein's cosmological constant). We
describe several methodologies of using galaxy redshift surveys as cosmological
probes, and then summarize the recent results from the existing surveys.
Finally we present our views on the future of redshift surveys in the era of
Precision Cosmology.Comment: 82 pages, 31 figures, invited review article published in Living
Reviews in Relativity, http://www.livingreviews.org/lrr-2004-
Large Scale Structure of the Universe
Galaxies are not uniformly distributed in space. On large scales the Universe
displays coherent structure, with galaxies residing in groups and clusters on
scales of ~1-3 Mpc/h, which lie at the intersections of long filaments of
galaxies that are >10 Mpc/h in length. Vast regions of relatively empty space,
known as voids, contain very few galaxies and span the volume in between these
structures. This observed large scale structure depends both on cosmological
parameters and on the formation and evolution of galaxies. Using the two-point
correlation function, one can trace the dependence of large scale structure on
galaxy properties such as luminosity, color, stellar mass, and track its
evolution with redshift. Comparison of the observed galaxy clustering
signatures with dark matter simulations allows one to model and understand the
clustering of galaxies and their formation and evolution within their parent
dark matter halos. Clustering measurements can determine the parent dark matter
halo mass of a given galaxy population, connect observed galaxy populations at
different epochs, and constrain cosmological parameters and galaxy evolution
models. This chapter describes the methods used to measure the two-point
correlation function in both redshift and real space, presents the current
results of how the clustering amplitude depends on various galaxy properties,
and discusses quantitative measurements of the structures of voids and
filaments. The interpretation of these results with current theoretical models
is also presented.Comment: Invited contribution to be published in Vol. 8 of book "Planets,
Stars, and Stellar Systems", Springer, series editor T. D. Oswalt, volume
editor W. C. Keel, v2 includes additional references, updated to match
published versio
The dependence of clustering on galaxy properties
(abridged)We use a sample of ~200,000 galaxies drawn from the Sloan Digital
Sky Survey to study how clustering depends on properties such as stellar mass
(M*), colour (g-r), 4000A break strength (D4000), concentration index (C), and
stellar surface mass density (\mu_*). We find that more massive galaxies
cluster more strongly than less massive galaxies, with the difference
increasing above the characteristic stellar mass of the Schechter mass
function. When divided by physical quantities, galaxies with redder colours,
larger D4000, higher C and larger \mu_* cluster more strongly. The clustering
differences are largest on small scales and for low mass galaxies. At fixed
stellar mass,the dependences of clustering on colour and 4000A break strength
are similar. Different results are obtained when galaxies are split by
concentration or surface density. The dependence of w(r_p) on g-r and D4000
extends out to physical scales that are significantly larger than those of
individual dark matter haloes (> 5 Mpc/h). This large-scale clustering
dependence is not seen for the parameters C or \mu_*. On small scales (< 1
Mpc/h), the amplitude of the correlation function is constant for ``young''
galaxies with 1.1 < D4000< 1.5 and a steeply rising function of age for
``older'' galaxies with D4000>1.5. In contrast, the dependence of the amplitude
of w(r_p) on concentration on scales less than 1 Mpc/h is strongest for
disk-dominated galaxies with C<2.6. This demonstrates that different processes
are required to explain environmental trends in the structure and in star
formation history of galaxies.Comment: 17 pages, 14 figures; reference updated and text slightly changed to
match the published version; Tables 5 and 6 are available at
http://www.mpa-garching.mpg.de/~leech/papers/clustering
Impact of clinical phenotypes on management and outcomes in European atrial fibrillation patients: a report from the ESC-EHRA EURObservational Research Programme in AF (EORP-AF) General Long-Term Registry
Background: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients\u2019 clinical phenotypes and analyse the differential clinical course. Methods: We performed a hierarchical cluster analysis based on Ward\u2019s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients\u2019 prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P <.001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27\u20133.62; HR 3.42, 95%CI 2.72\u20134.31; HR 2.79, 95%CI 2.32\u20133.35), and Cluster 1 (HR 1.88, 95%CI 1.48\u20132.38; HR 2.50, 95%CI 1.98\u20133.15; HR 2.09, 95%CI 1.74\u20132.51) reported a higher risk for the three outcomes respectively. Conclusions: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes
Clinical complexity and impact of the ABC (Atrial fibrillation Better Care) pathway in patients with atrial fibrillation: a report from the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry
Background: Clinical complexity is increasingly prevalent among patients with atrial fibrillation (AF). The ‘Atrial fibrillation Better Care’ (ABC) pathway approach has been proposed to streamline a more holistic and integrated approach to AF care; however, there are limited data on its usefulness among clinically complex patients. We aim to determine the impact of ABC pathway in a contemporary cohort of clinically complex AF patients. Methods: From the ESC-EHRA EORP-AF General Long-Term Registry, we analysed clinically complex AF patients, defined as the presence of frailty, multimorbidity and/or polypharmacy. A K-medoids cluster analysis was performed to identify different groups of clinical complexity. The impact of an ABC-adherent approach on major outcomes was analysed through Cox-regression analyses and delay of event (DoE) analyses. Results: Among 9966 AF patients included, 8289 (83.1%) were clinically complex. Adherence to the ABC pathway in the clinically complex group reduced the risk of all-cause death (adjusted HR [aHR]: 0.72, 95%CI 0.58–0.91), major adverse cardiovascular events (MACEs; aHR: 0.68, 95%CI 0.52–0.87) and composite outcome (aHR: 0.70, 95%CI: 0.58–0.85). Adherence to the ABC pathway was associated with a significant reduction in the risk of death (aHR: 0.74, 95%CI 0.56–0.98) and composite outcome (aHR: 0.76, 95%CI 0.60–0.96) also in the high-complexity cluster; similar trends were observed for MACEs. In DoE analyses, an ABC-adherent approach resulted in significant gains in event-free survival for all the outcomes investigated in clinically complex patients. Based on absolute risk reduction at 1 year of follow-up, the number needed to treat for ABC pathway adherence was 24 for all-cause death, 31 for MACEs and 20 for the composite outcome. Conclusions: An ABC-adherent approach reduces the risk of major outcomes in clinically complex AF patients. Ensuring adherence to the ABC pathway is essential to improve clinical outcomes among clinically complex AF patients
Impact of renal impairment on atrial fibrillation: ESC-EHRA EORP-AF Long-Term General Registry
Background: Atrial fibrillation (AF) and renal impairment share a bidirectional relationship with important pathophysiological interactions. We evaluated the impact of renal impairment in a contemporary cohort of patients with AF. Methods: We utilised the ESC-EHRA EORP-AF Long-Term General Registry. Outcomes were analysed according to renal function by CKD-EPI equation. The primary endpoint was a composite of thromboembolism, major bleeding, acute coronary syndrome and all-cause death. Secondary endpoints were each of these separately including ischaemic stroke, haemorrhagic event, intracranial haemorrhage, cardiovascular death and hospital admission. Results: A total of 9306 patients were included. The distribution of patients with no, mild, moderate and severe renal impairment at baseline were 16.9%, 49.3%, 30% and 3.8%, respectively. AF patients with impaired renal function were older, more likely to be females, had worse cardiac imaging parameters and multiple comorbidities. Among patients with an indication for anticoagulation, prescription of these agents was reduced in those with severe renal impairment, p <.001. Over 24 months, impaired renal function was associated with significantly greater incidence of the primary composite outcome and all secondary outcomes. Multivariable Cox regression analysis demonstrated an inverse relationship between eGFR and the primary outcome (HR 1.07 [95% CI, 1.01–1.14] per 10 ml/min/1.73 m2 decrease), that was most notable in patients with eGFR <30 ml/min/1.73 m2 (HR 2.21 [95% CI, 1.23–3.99] compared to eGFR ≥90 ml/min/1.73 m2). Conclusion: A significant proportion of patients with AF suffer from concomitant renal impairment which impacts their overall management. Furthermore, renal impairment is an independent predictor of major adverse events including thromboembolism, major bleeding, acute coronary syndrome and all-cause death in patients with AF
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