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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.

Reduction of albumin excretion rate in normotensive microalbuminuric type 2 diabetic patients during long-term simvastatin treatment. G Tonolo , M Ciccarese , P Brizzi , L Puddu , G Secchi , P Calvia , M M Atzeni , M G Melis and M Maioli Servizio Diabetologia, University of Sassari, Italy. Abstract OBJECTIVE: To study the long-term effects of simvastatin on urinary albumin excretion rate (AER) in normotensive microalbuminuric type 2 diabetic patients with hypercholesterolemia. RESEARCH DESIGN AND METHODS: A total of 19 normotensive microalbuminuric hypercholesterolemic type 2 diabetic patients entered a double-blind crossover study for 2 years, receiving either simvastatin (20 mg/day) or placebo (each treatment for 1 year). RESULTS: Simvastatin significantly decreased plasma cholesterol (total and LDL) after 52 weeks of treatment. A concomitant significant decrease of AER (25% from basal) with no significant changes in creatinine clearance was observed during the same period. CONCLUSIONS: Our data are in keeping with the hypothesis that simvastatin might be used as an additional means to preserve renal function in microalbuminuric hypercholesterolemic type 2 diabetic patients.

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.

IntroductionPeople with mental health conditions and psychosocial disabilities frequently experience human rights violations. This study assessed the efficacy of the WHO QualityRights e-training in promoting their rights within the mental healthcare system.MethodsIn this cluster-randomised trial in three psychiatric hospitals in Ghana, we randomly selected units within each hospital and randomised them 1:1 to the intervention (WHO QualityRights e-training) or control arm (COVID-19 e-training). The intervention included presentations, videos, interactive exercises and forum discussions. Mental health professionals in these facilities were eligible participants. Primary outcomes were changes in knowledge about the rights of persons with mental health conditions and in the attitudes towards them, measured post-intervention using the WHO QualityRights Knowledge and Attitudes questionnaires. Secondary outcomes included changes at 3 and 6 months in knowledge, attitudes and mental health professionals’ practices related to substitute decision-making and coercion. Data analysts were masked to group assignment.ResultsBetween 11 August 2021 and 13 April 2022, 28 clusters (14 per arm) were randomised and 252 participants enrolled (126 per arm); 179 (71%) were women. 206 (81.8%) completed the post-training follow-up. The intervention group showed significantly greater improvements in scores on the WHO QualityRights Knowledge (mean difference: 4.61 [95% CI 3.49 to 5.72], d=1.12) and Attitudes (−7.99 [95% CI −10.32 to −5.66], d=0.92) compared with the control group, with similarly significant results at 3 and 6 months. Additionally, intervention participants reported less frequent use of substitute decision-making and restraint (−2.60 [95% CI −4.05 to −1.16], d=0.52 at 3 months; −1.76 [95% CI −3.11 to −0.40], d=0.36 at 6 months).ConclusionThis study showed that the WHO QualityRights e-training effectively improves mental health professionals’ knowledge and attitudes and can lead to reduction in providers’ use of substitute decision-making and coercion practices, thus suggesting a need for improved investment in rights-based interventions and further research.Trial registration numberNCT04728243.

A measurement of CP-violating observables is performed using the decays B $^{±}$→ DK $^{±}$and B $^{±}$→ Dπ $^{±}$ , where the D meson is reconstructed in one of the self-conjugate three-body final states$ {K}_{\\mathrm{S}}^0 $ π $^{+}$ π $^{−}$and$ {K}_{\\mathrm{S}}^0 $ K $^{+}$ K $^{−}$(commonly denoted$ {K}_{\\mathrm{S}}^0 $ h $^{+}$ h $^{−}$ ). The decays are analysed in bins of the D-decay phase space, leading to a measurement that is independent of the modelling of the D-decay amplitude. The observables are inter- preted in terms of the CKM angle γ. Using a data sample corresponding to an integrated luminosity of 9 fb $^{−1}$collected in proton-proton collisions at centre-of mass energies of 7, 8, and 13 TeV with the LHCb experiment, γ is measured to be$ \\left({68.7}_{-5.1}^{+5.2}\\right){}^{\\circ} $ . The hadronic parameters$ {r}_B^{D K},{r}_B^{D\\pi},{\\delta}_B^{D K},\\kern0.5em \\mathrm{and}\\kern0.5em {\\delta}_B^{D\\pi} $ , which are the ratios and strong-phase differences of the suppressed and favoured B $^{±}$decays, are also reported.[graphic not available: see fulltext]

Background:Calcinosis cutis is a major daily challenge to patients with longstanding systemic sclerosis (SSc), negatively affecting their quality of life. Unfortunately, treatment options are very limited due to lack of understanding of the pathogenetic process. Currently, calcinosis cutis is only detected at its irreversible end-stage. Early detection of calcinosis cutis could putatively allow early disease-modifying interventions and monitor treatment effects.Objectives:The aim of the current study is to assess the feasibility of visualising “active” micro-calcifications with 18-F Sodium Fluoride (NaF) PET scanning, compared to low-dose CT in patients with clinically overt calcinosis cutis.Methods:This was a cross-sectional, observational, pilot study. All patients met 2013 ACR/EULAR criteria for SSc. Patients underwent a whole body NaF PET/low-dose CT scan, scanned 90 minutes post-injection. (Sub)cutaneous calcifications were described and assessed on NaF PET, which was compared to CT images by two independent investigators.Results:A total of 10 female patients with limited cutaneous SSc [median age 56 years (IQR 52-66), median disease duration 17 years (8-19), PAH 10%, ILD 20%] were included, and compared to 10 controls [70 years (65-73)]. NaF uptake showed normal distribution throughout the skeletal bones, arterial tree, and visceral organs, which was comparable between patients and controls. Additionally, NaF uptake was visible in the skin of all SSc patients, but in none of the controls. Cutaneous NaF uptake largely correlated with clinical calcifications. Most common sites of cutaneous NaF uptake were fingers (6 patients) and knees (7 patients). Only 5% of the NaF positive lesions were not accompanied by visible calcifications on CT. Furthermore, of all calcified lesions seen on CT, 51% showed uptake on NaF PET. Small lesions (<1 cm), were generally only visible on CT, due to lower resolution of NaF PET.Conclusion:Imaging of “active” calcinosis cutis in limited cutaneous systemic sclerosis is feasible using NaF PET scanning. Most clinically overt calcifications and half of those seen on CT were positive for NaF uptake. Whether these “active” calcifications behave differently in terms of faster progression, clinical complaints, and infection risk, and whether these are potentially suitable for disease modifying interventions is subject to future study.Disclosure of Interests:None declared

A measurement of Z → τ ⁺ τ ⁻production cross-section is presented using data, corresponding to an integrated luminosity of 2 fb ⁻¹ , from pp collisions at √s̅=8 TeV collected by the LHCb experiment. The τ ⁺ τ ⁻candidates are reconstructed in final states with the first tau lepton decaying leptonically, and the second decaying either leptonically or to one or three charged hadrons. The production cross-section is measured for Z bosons with invariant mass between 60 and 120 GeV/c ² , which decay to tau leptons with transverse momenta greater than 20 GeV/c and pseudorapidities between 2.0 and 4.5. The cross-section is determined to be σ_(pp)_(→ Z→ τ⁺)_(τ⁻)=95.8 ± 2.1 ± 4.6 ± 0.2 ± 1.1 pb, where the first uncertainty is statistical, the second is systematic, the third is due to the LHC beam energy uncertainty, and the fourth to the integrated luminosity uncertainty. This result is compatible with NNLO Standard model predictions. The ratio of the cross-sections for Z → τ ⁺ τ ⁻to Z → μ ⁺ μ ⁻(Z → e ⁺ e ⁻ ), determined to be 1.01 ± 0.05 (1.02 ± 0.06), is consistent with the lepton-universality hypothesis in Z decays.

Biliopancreatic diversion (BPD), a gastrectomy with a long ROUX en Y reconstruction, reduces intestinal absorption by delaying the mixing of food and biliopancreatic juices, and induces persistent weight loss in obese patients unresponsive to medical treatments. The levels of leptin (a plasma protein synthesised in human adipose tissue) are increased in obese subjects and significantly decrease after a major weight loss. A possible role of thyroid hormones in regulating adipose tissue metabolism in humans has been proposed, but it is not universally accepted and the relationship between thyroid function and leptin levels has not yet been clearly defined. We studied serum leptin, TSH, fT4 and fT3 levels in 38 obese patients (26 women and 12 men), before and 12 months after BPD. There was a significant post-surgical decrease in BMI and circulating leptin levels in all of the treated subjects, but thyroid function did not seem to be affected (TSH and fT4 levels were unchanged). However, fT3 levels significantly decreased after surgery. Our data suggest that BPD-induced malabsorption has no direct effect on thyroid function, but possibly reduces the peripheral conversion of thyroxine to T3. Further studies seem to be necessary to clarify the clinical relevance of these observations.