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Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous disease with a variety of symptoms including, persistent coughing and mucus production, shortness of breath, wheezing, and chest tightness. As the disease advances, exacerbations, i.e. acute worsening of respiratory symptoms, may increase in frequency, leading to potentially life-threatening complications. Exposure to air pollutants may trigger COPD exacerbations. Literature predictive models for COPD exacerbations, while promising, may be constrained by their reliance on fixed air quality sensor data that may not fully capture individuals’ dynamic exposure to air pollution. To address this, we designed a machine learning (ML) framework that leverages data from personal air quality monitors, health records, lifestyle, and living condition information to build models that perform short-term prediction of COPD exacerbations. The framework employs (i) k-means clustering to uncover potentially distinct patient sub-types, (ii) supervised ML techniques (Logistic Regression, Random Forest, and eXtreme Gradient Boosting) to train and test predictive models for each patient sub-type and (iii) an explainable artificial intelligence technique (SHAP) to interpret the final models. The framework was tested on data collected in 101 COPD patients monitored for up to 6 months with occurrence of exacerbation in 10.7% of total samples. Two different patient sub-types have been identified, characterised by different disease severity. The best performing models were Random Forest in cluster 1, with area under the receiver operating characteristic curve (AUC) of 0.90, and area under the precision/recall curve (AUPRC) of 0.7; and Random Forest model in cluster 2, with AUC of 0.82 and AUPRC of 0.56. The model interpretability analysis identified previous symptoms and cumulative pollutant exposure as key predictors of exacerbations. The results of our study set a premise for a predictive framework in COPD exacerbations, particularly investigating the potential influence of environmental features. The SHAP analysis revealed that the contribution of environmental features is not uniform across all subjects. For instance, cumulative exposure to pollutants demonstrated greater predictive power in cluster 1. The SHAP analysis also shown that overall clinical factors and individual symptomatology play the most significant role in this setup to determine exacerbation risk.

Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are the leading causes of death in systemic sclerosis (SSc). Until now, no prospective biomarker to predict new onset of SSc-ILD or SSc-PAH in patients with SSc has reached clinical application. In homeostasis, the receptor for advanced glycation end products (RAGE) is expressed in lung tissue and involved in cell-matrix adhesion, proliferation and migration of alveolar epithelial cells, and remodeling of the pulmonary vasculature. Several studies have shown that sRAGE levels in serum and pulmonary tissue vary according to the type of lung-related complication. Therefore, we investigated levels of soluble RAGE (sRAGE) and its ligand high mobility group box 1 (HMGB1) in SSc and their abilities to predict SSc-related pulmonary complications. One hundred eighty-eight SSc patients were followed retrospectively for the development of ILD, PAH, and mortality for 8 years. Levels of sRAGE and HMGB1 were measured in serum by ELISA. Kaplan-Meier survival curves were performed to predict lung events and mortality and event rates were compared with a log-rank test. Multiple linear regression analysis was performed to examine the association between sRAGE and important clinical determinants. At baseline, levels of sRAGE were significantly higher in SSc-PAH-patients (median 4099.0 pg/ml [936.3-6365.3], p = 0.011) and lower in SSc-ILD-patients (735.0 pg/ml [IQR 525.5-1988.5], p = 0.001) compared to SSc patients without pulmonary involvement (1444.5 pg/ml [966.8-2276.0]). Levels of HMGB1 were not different between groups. After adjusting for age, gender, ILD, chronic obstructive pulmonary disease, anti-centromere antibodies, the presence of puffy fingers or sclerodactyly, use of immunosuppression, antifibrotic therapy, or glucocorticoids, and use of vasodilators, higher sRAGE levels remained independently associated with PAH. After a median follow-up of 50 months (25-81) of patients without pulmonary involvement, baseline sRAGE levels in the highest quartile were predictive of development of PAH (log-rank p = 0.01) and of PAH-related mortality (p = 0.001). High systemic sRAGE at baseline might be used as a prospective biomarker for patients with SSc at high risk to develop new onset of PAH. Moreover, high sRAGE levels could predict lower survival rates due to PAH in patients with SSc.

Raynaud’s Phenomenon (RP) leading to repetitive ischemia and reperfusion (IR) stress, is the first recognizable sign of systemic sclerosis (SSc) leading to increased oxidative stress. High-mobility group box-1 (HMGB1) is a nuclear factor released by apoptotic and necrotic cells after oxidative stress. Since HMGB1 can signal through the receptor for advanced glycation end products (RAGE), we investigated whether an RP attack promotes the release of HMGB1, leading to fibroblast activation and the upregulation of interferon (IFN)-inducible genes. A cold challenge was performed to simulate an RP attack in patients with SSc, primary RP (PRP), and healthy controls. We measured levels of HMGB1 and IFN gamma-induced Protein 10 (IP-10) at different time points in the serum. Digital perfusion was assessed by photoplethysmography. In vitro, HMGB1 or transforming growth factor (TGF-β1) (as control) was used to stimulate healthy human dermal fibroblasts. Inflammatory, profibrotic, and IFN-inducible genes, were measured by RT-qPCR. In an independent cohort, sera were obtained from 20 patients with SSc and 20 age- and sex-matched healthy controls to determine HMGB1 and IP-10 levels. We found that HMGB1 levels increased significantly 30 min after the cold challenge in SSc compared to healthy controls. In vitro stimulation with HMGB1 resulted in increased mRNA expression of IP-10, and interleukin-6 (IL-6) while TGF-β1 stimulation promoted IL-6 and Connective Tissue Growth Factor (CTGF). In serum, both HMGB1 and IP-10 levels were significantly higher in patients with SSc compared to healthy controls. We show that cold challenge leads to the release of HMGB1 in SSc patients. HMGB1 induces IP-10 expression in dermal fibroblasts partly through the soluble RAGE (sRAGE) axis suggesting a link between RP attacks, the release of HMGB1 and IFN-induced proteins as a putative early pathogenetic mechanism in SSc.

BackgroundSystemic sclerosis-interstitial lung disease (SSc-ILD) is a severe complication that affects most SSc patients causing one-third of SSc-related deaths [1]. There is an unmet need for predictive biomarkers of ILD to identify patients at risk, prior to clinical manifestation. Activated IFN-induced chemokines and proteins are implicated in the early inflammatory phase of SSc-ILD [2]. CXCL10 is an IFN-induced chemokine that is important in the chemoattraction of inflammatory cells in SSc-affected tissue [3,4].ObjectivesWe investigated CXCL10 serum levels in SSc, SSc-ILD, and healthy controls (HCs) to understand whether CXCL10 levels differ between groups and potentially play a role in ILD pathogenesis. We also sought whether CXCL10 levels in serum mirror those in the lungs to investigate whether systemic levels reflect those of the affected organ locally. The transcriptomic study investigated CXCL10 expression in inflammatory SSc-ILD lung sections compared to fibrotic sections to show whether CXCL10 is more prominent in early disease. We also assessed whether CXCL10 could serve as a predictive biomarker for the new onset of SSc-ILD. Finally, to better comprehend the clinical observations, in vitro studies aimed to reveal the inflammatory/fibrotic effects of local and systemic fluids of SSc-ILD patients compared to SSc without ILD and controls.MethodsOne-hundred sixty-five SSc patients (SSc-ILD = 41) and 13 age- and sex- matched HCs were retrospectively followed from 2013 to 2020. Furthermore, 15 SSc patients (SSc-ILD = 7) were prospectively recruited for bronchoalveolar lavage (BAL) procedure. CXCL10 mRNA and protein levels were measured on various levels (serum, BAL, and SSc-ILD lung tissues) by ELISA and nanoString transcriptomic assay. Spearman’s correlations were performed between CXCL10 levels in serum and lungs. Kaplan-Meier analyses were performed to evaluate predictability of SSc-ILD using CXCL10 levels at baseline. Human primary lung fibroblasts were treated with BAL fluid or serum from SSc without ILD or SSc-ILD patients. After stimulation, inflammatory (IL-6 and CXCL10)/fibrotic (α-SMA and TGF-β) genes were assessed using qPCR.ResultsAt baseline, serum CXCL10 was significantly higher in SSc-ILD patients compared to SSc without ILD [Median (IQR): 126 (66-282) vs 79 (50-122), p = 0.004] and HCs [Median (IQR): vs. 4 (4-9), p < 0.0001]. BAL fluid CXCL10 levels in SSc-ILD patients were not significantly higher than those in SSc without ILD [Median (IQR): 457 (42-725) vs 134 (72-333), p = 0.2). However, BAL CXCL10 levels significantly correlated with serum levels (r = 0.7, p = 0.007). The nanoString showed that CXCL10 gene expression is significantly higher in inflammatory lung tissue compared to fibrotic tissue (fold change = 2.3, p = 0.029). Kaplan-Meier survival analysis (Figure 1) revealed that CXCL10 levels >3rd quartile at baseline in SSc patients significantly predicted new onset of ILD (p = 0.023). The in vitro studies showed that CXCL10 and IL-6 were significantly overexpressed in lung fibroblasts treated with SSc-ILD BAL fluid or serum compared to SSc without ILD [(CXCL10: p = 0.0043; p = 0.0087), (IL-6: p = 0.0022; p = 0.0043), respectively) and controls (all: p = 0.0022). On the contrary, TGF-β and α-SMA expression did not change after treatment in all groups.Figure 1.Kaplan-Meier survival curve according to baseline CXCL10 levels quartiles.ConclusionCXCL10 is a potential predictive biomarker for new onset of ILD in SSc patients. Further longitudinal studies with larger sample sizes are needed to verify the capability of CXCL10 to predict ILD. Additionally, our nanoString and in vitro data suggest that CXCL10 may play a significant role in the early development of SSc-ILD which might be amenable to therapeutic interventions.References[1]Volkmann et al, Journal of Sclero and Rel Dis. 2021; 10.1177/2397198320915042[2]Wu et al, Frontiers in Immunology, 2013; 10.3389/fimmu.2013.00266[3]Fujii, et al, J Dermatol Sci, 2004; 10.1016/j.jdermsci.2004.03.001[4]Antonelli et al, Rheumatology, 2008; 10.1093/rheumatology/kem313AcknowledgementsThis collaboration project is co-financed by the Ministry of Economic Affairs and Climate Policy by means of the PPP-allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships. The Health-Holland communication toolkit is available on “Communication Toolkit” | Health-Holland (health-holland.com). Part of this project is funded by Sanofi Genzyme.Disclosure of InterestsYehya Al-Adwi: None declared, Isabella M. Atzeni: None declared, Berber Doornbos- van der Meer: None declared, Marcel Van der Leij: None declared, Bart-Jan Kroesen: None declared, Alja J. Stel: None declared, Harry van Goor: None declared, Tji-Joong Gan: None declared, Wim Timens: None declared, Johanna Westra: None declared, Douwe J Mulder Grant/research support from: Dr DJ Mulder as an employee of the UMCG received research grants from Sanofi which were paid to the UMCG.

A search for the doubly-charmed-baryon decay $$ {\\Xi}_{cc}^{++}\\to {\\Xi}_c^0{\\pi}^{+}{\\pi}^{+} $$ Ξ cc + + → Ξ c 0 π + π + is performed using proton-proton collision data collected by the LHCb experiment at a centre-of-mass energy of 13 TeV and corresponding to an integrated luminosity of 5 . 4 fb − 1 . A significant structure consistent with the $$ {\\Xi}_{cc}^{++} $$ Ξ cc + + baryon is observed in the $$ {\\Xi}_c^0{\\pi}^{+}{\\pi}^{+} $$ Ξ c 0 π + π + invariant-mass spectrum. Using the $$ {\\Xi}_{cc}^{++}\\to {\\Lambda}_c^{+}{K}^{-}{\\pi}^{+}{\\pi}^{+} $$ Ξ cc + + → Λ c + K − π + π + decay as the normalisation channel, the branching fraction ratio, $$ \\frac{\\mathcal{B}\\left({\\Xi}_{cc}^{++}\\to {\\Xi}_c^0{\\pi}^{+}{\\pi}^{+}\\right)}{\\mathcal{B}\\left({\\Xi}_{cc}^{++}\\to {\\Lambda}_c^{+}{K}^{-}{\\pi}^{+}{\\pi}^{+}\\right)} $$ B Ξ cc + + → Ξ c 0 π + π + B Ξ cc + + → Λ c + K − π + π + , is measured to be 1 . 37 ± 0 . 18 (stat) ± 0 . 09 (syst) ± 0 . 35 (ext). This measurement provides critical input for testing QCD factorisation methods in the weak decays of doubly-heavy baryons, particularly in quantifying nonperturbative effects such as final-state interactions and resonance contributions to the hadronisation process.

The elliptic and triangular flow of charged particles are measured using two-particle angular correlations in p Pb collisions in the pseudorapidity range 2.0 < | η | < 4.8. The data sample was collected by the LHCb experiment in 2016 at a centre-of-mass energy per nucleon pair of $$ \\sqrt{s_{\\textrm{NN}}}=8.16 $$ s NN = 8.16 TeV, containing in total approximately 1.5 billion collision events. Non-flow contributions are obtained in low-multiplicity collisions and subtracted to extract the flow harmonics. The results are presented as a function of event multiplicity and hadron transverse momentum. Comparisons with a full (3+1)D dynamic model indicate that it overestimates the measured elliptic flow. A comparison between the forward and backward regions reveals no significant differences in flow parameters, suggesting that final-state effects may dominate over initial-state effects in the origin of flow in small systems.

The lifetimes of the $$ {\\varOmega}_c^0 $$ Ω c 0 and $$ {\\Xi}_c^0 $$ Ξ c 0 baryons are measured using a pp collision dataset collected by the LHCb experiment, corresponding to an integrated luminosity of 9 fb − 1 . The charm baryons are produced in the fully reconstructed decay chains $$ {\\varOmega}_b^{-}\\to {\\varOmega}_c^0\\left(\\to p{K}^{-}{K}^{-}{\\pi}^{+}\\right){\\pi}^{-} $$ Ω b − → Ω c 0 → p K − K − π + π − and $$ {\\Xi}_b^{-}\\to {\\Xi}_c^0\\left(\\to p{K}^{-}{K}^{-}{\\pi}^{+}\\right){\\pi}^{-} $$ Ξ b − → Ξ c 0 → p K − K − π + π − . The measurement uses topologically and kinematically similar B − → D 0 (→ K − K + π − π + ) π − decays for normalisation. The measured lifetimes are $$ {\\displaystyle \\begin{array}{c}{\\tau}_{\\varOmega_c^0}=276.3\\pm 19.4\\left(\\textrm{stat}\\right)\\pm 1.8\\left(\\textrm{syst}\\right)\\pm 0.7\\left({\\tau}_{D^0}\\right)\\textrm{fs},\\\ {}{\\tau}_{\\Xi_c^0}=149.2\\pm 2.5\\left(\\textrm{stat}\\right)\\pm 0.9\\left(\\textrm{syst}\\right)\\pm 0.4\\ \\left({\\tau}_{D^0}\\right)\\textrm{fs},\\end{array}} $$ τ Ω c 0 = 276.3 ± 19.4 stat ± 1.8 syst ± 0.7 τ D 0 fs , τ Ξ c 0 = 149.2 ± 2.5 stat ± 0.9 syst ± 0.4 τ D 0 fs , where the first uncertainty is statistical, the second systematic and the third due to the uncertainty of the D 0 lifetime. These results are consistent with previous measurements performed by the LHCb experiment.

A time-integrated angular analysis of the decay $$ {B}_s^0\\to J/\\psi {\\overline{K}}^{\\ast }{(892)}^0 $$ B s 0 → J / ψ K ¯ ∗ 892 0 , with J / ψ → μ + μ − and $$ {\\overline{K}}^{\\ast }{(892)}^0\\to {K}^{-}{\\pi}^{+} $$ K ¯ ∗ 892 0 → K − π + , is presented. The analysis employs a sample of proton-proton collision data collected by the LHCb experiment during 2015–2018 at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 6 fb − 1 . A simultaneous maximum-likelihood fit is performed to the angular distributions in bins of the K − π + mass. This fit yields measurements of the CP -averaged polarisation fractions and CP asymmetries for the P-wave component of the K − π + system. The longitudinal and parallel polarisation fractions are determined to be f 0 = 0.534 ± 0.012 ± 0.009 and f || = 0.211 ± 0.014 ± 0.005, respectively, where the first uncertainty is statistical and the second is systematic. The CP asymmetries are measured with 3–7% precision and are found to be consistent with zero. These measurements, along with an updated determination of the branching fraction relative to the B 0 → J / ψK *0 decay, are combined with previous LHCb results, providing the most precise values for these observables to date.

A study of $$ {\\Lambda}_b^0 $$ Λ b 0 and $$ {\\Xi}_b^0 $$ Ξ b 0 baryon decays to the final states $$ p{K}_{\\textrm{S}}^0{\\pi}^{-} $$ p K S 0 π − and $$ p{K}_{\\textrm{S}}^0{K}^{-} $$ p K S 0 K − is performed using pp collision data collected by the LHCb experiment, corresponding to an integrated luminosity of 9 fb − 1 . The decays $$ {\\Lambda}_b^0\\to p{K}_{\\textrm{S}}^0{K}^{-} $$ Λ b 0 → p K S 0 K − and $$ {\\Xi}_b^0\\to p{K}_{\\textrm{S}}^0{K}^{-} $$ Ξ b 0 → p K S 0 K − are observed for the first time, with significances reaching eight standard deviations. The branching fractions and integrated CP asymmetries are measured for the $$ {\\Lambda}_b^0\\to p{K}_{\\textrm{S}}^0{\\pi}^{-} $$ Λ b 0 → p K S 0 π − , $$ {\\Lambda}_b^0\\to p{K}_{\\textrm{S}}^0{K}^{-} $$ Λ b 0 → p K S 0 K − , and $$ {\\Xi}_b^0\\to p{K}_{\\textrm{S}}^0{K}^{-} $$ Ξ b 0 → p K S 0 K − decays. For the decay $$ {\\Lambda}_b^0\\to p{K}_{\\textrm{S}}^0{\\pi}^{-} $$ Λ b 0 → p K S 0 π − , the CP asymmetries are measured in different regions of the Dalitz plot. No evidence of CP violation is observed.

Branching fraction ratios between the decays $$ {B}_{(s)}^0\\to J/\\psi {\\eta}^{\\left(\\prime \\right)} $$ B s 0 → J / ψ η ′ are measured using proton-proton collision data collected by the LHCb experiment at centre-of-mass energies of 7, 8 and 13 TeV, corresponding to an integrated luminosity of 9 fb − 1 . The measured ratios of these branching fractions are $$ {\\displaystyle \\begin{array}{c}\\frac{\\mathcal{B}\\left({B}^0\\to J/{\\psi \\eta}^{\\prime}\\right)}{\\mathcal{B}\\left({B}^0\\to J/\\psi \\eta \\right)}=0.48\\pm 0.06\\pm 0.02\\pm 0.01,\\\ {}\\frac{\\mathcal{B}\\left({B}_s^0\\to J/{\\psi \\eta}^{\\prime}\\right)}{\\mathcal{B}\\left({B}_s^0\\to J/\\psi \\eta \\right)}=0.80\\pm 0.02\\pm 0.02\\pm 0.01,\\end{array}} $$ B B 0 → J / ψη ′ B B 0 → J / ψη = 0.48 ± 0.06 ± 0.02 ± 0.01 , B B s 0 → J / ψη ′ B B s 0 → J / ψη = 0.80 ± 0.02 ± 0.02 ± 0.01 , where the uncertainties are statistical, systematic and related to the precision of the η (′) branching fractions, respectively. They are used to constrain the η/η ′ mixing angle, ϕ P , and to probe the presence of a possible glueball component in the η ′ meson, described by the gluonic mixing angle ϕ G . The obtained results are $$ {\\displaystyle \\begin{array}{c}{\\phi}_{\\textrm{P}}={\\left({41.6}_{-1.2}^{+1.0}\\right)}^{\\circ },\\\ {}{\\phi}_{\\textrm{G}}={\\left({28.1}_{-4.0}^{+3.9}\\right)}^{\\circ },\\end{array}} $$ ϕ P = 41.6 − 1.2 + 1.0 ∘ , ϕ G = 28.1 − 4.0 + 3.9 ∘ , where the uncertainties are statistically dominated. While the value of ϕ P is compatible with existing experimental determinations and theoretical calculations, the angle ϕ G differs from zero by more than four standard deviations, which points to a substantial glueball component in the η ′ meson and/or unexpectedly large contributions from gluon-mediated processes in these decays. The absolute branching fractions are also measured relative to that of the well-established $$ {B}_s^0\\to J/\\psi \\phi $$ B s 0 → J / ψϕ decay, which serves as the normalisation channel. These results supersede the previous LHCb measurements and are the most precise to date.