Selective Replacement of Cholesterol with Cationic Amphiphilic Drugs Enables the Design of Lipid Nanoparticles with Improved RNA Delivery.

The delivery of RNA across biological barriers can be achieved by encapsulation in lipid nanoparticles (LNPs). Cationic amphiphilic drugs (CADs) are pharmacologically diverse compounds with ionizable lipid-like features. In this work, we applied CADs as a fifth component of state-of-the-art LNPs via microfluidic mixing. Improved cytosolic delivery of both siRNA and mRNA was achieved by partly replacing the cholesterol fraction of LNPs with CADs. The LNPs could cross the mucus layer in a mucus-producing air-liquid interface model of human primary bronchial epithelial cells following nebulization. Moreover, CAD-LNPs demonstrated improved epithelial and endothelial targeting following intranasal administration in mice, without a marked pro-inflammatory signature. Importantly, quantification of the CAD-LNP molar composition, as demonstrated for nortriptyline, revealed a gradual leakage of the CAD from the formulation during LNP dialysis. Altogether, these data suggest that the addition of a CAD prior to the rapid mixing process might have an impact on the composition, structure, and performance of LNPs.

Epigenomic partitioning of a polygenic risk score for asthma reveals distinct genetically driven disease pathways.

BACKGROUND: Individual differences in susceptibility to developing asthma, a heterogeneous chronic inflammatory lung disease, are poorly understood. Whether genetics can predict asthma risk and how genetic variants modulate the complex pathophysiology of asthma are still debated. AIM: To build polygenic risk scores for asthma risk prediction and epigenomically link predictive genetic variants to pathophysiological mechanisms. METHODS: Restricted polygenic risk scores were constructed using single nucleotide variants derived from genome-wide association studies and validated using data generated in the Rotterdam Study, a Dutch prospective cohort of 14 926 individuals. Outcomes used were asthma, childhood-onset asthma, adulthood-onset asthma, eosinophilic asthma and asthma exacerbations. Genome-wide chromatin analysis data from 19 disease-relevant cell types were used for epigenomic polygenic risk score partitioning. RESULTS: The polygenic risk scores obtained predicted asthma and related outcomes, with the strongest associations observed for childhood-onset asthma (2.55 odds ratios per polygenic risk score standard deviation, area under the curve of 0.760). Polygenic risk scores allowed for the classification of individuals into high-risk and low-risk groups. Polygenic risk score partitioning using epigenomic profiles identified five clusters of variants within putative gene regulatory regions linked to specific asthma-relevant cells, genes and biological pathways. CONCLUSIONS: Polygenic risk scores were associated with asthma(-related traits) in a Dutch prospective cohort, with substantially higher predictive power observed for childhood-onset than adult-onset asthma. Importantly, polygenic risk score variants could be epigenomically partitioned into clusters of regulatory variants with different pathophysiological association patterns and effect estimates, which likely represent distinct genetically driven disease pathways. Our findings have potential implications for personalised risk mitigation and treatment strategies.

Clinical response and on-treatment clinical remission with tezepelumab in a broad population of patients with severe, uncontrolled asthma: results over 2 years from the NAVIGATOR and DESTINATION studies.

BACKGROUND: In asthma, clinical response is characterized by disease improvement with treatment, whereas clinical remission is characterized by long-term disease stabilization with or without ongoing treatment. The proportion of patients receiving tezepelumab who responded to treatment and those who achieved on-treatment clinical remission was assessed in the NAVIGATOR (NCT03347279) and DESTINATION (NCT03706079) studies of severe, uncontrolled asthma. METHODS: NAVIGATOR and DESTINATION were phase 3, randomized, double-blind, placebo-controlled studies; DESTINATION was an extension of NAVIGATOR. Complete clinical response was defined as achieving all of the following: ≥50% reduction in exacerbations versus the previous year, improvements in pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV1) of ≥100 mL or ≥5%, improvements in Asthma Control Questionnaire (ACQ)-6 score of ≥0.5 and physicians' assessment of asthma improvement. On-treatment clinical remission was defined as an ACQ-6 total score ≤1.5, stable lung function (pre-BD FEV1 >95% of baseline) and no exacerbations or use of oral corticosteroids during the time periods assessed. RESULTS: Higher proportions of tezepelumab than placebo recipients achieved complete clinical response over weeks 0-52 (46% versus 24%; OR: 2.83 [95% CI: 2.10-3.82]), and on-treatment clinical remission over weeks 0-52 (28.5% versus 21.9%; OR: 1.44 [95% CI: 0.95-2.19]) and weeks >52-104 (33.5% versus 26.7%; OR: 1.44 [95% CI: 0.97-2.14]). Tezepelumab recipients who achieved on-treatment clinical remission versus complete clinical response at week 52 had better preserved lung function and lower inflammatory biomarkers at baseline, and fewer exacerbations in the 12 months before the study. CONCLUSIONS: Among patients with severe, uncontrolled asthma, tezepelumab treatment was associated with an increased likelihood of achieving complete clinical response and on-treatment clinical remission compared with placebo. Both are clinically important outcomes but may be driven by different patient characteristics.

Genome-wide association study of preserved ratio impaired spirometry (PRISm).

BACKGROUND: Preserved ratio impaired spirometry (PRISm) is defined as a forced expiratory volume in 1 s (FEV1) <80% predicted and FEV1/forced vital capacity ≥0.70. PRISm is associated with respiratory symptoms and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities. METHODS: We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected single nucleotide polymorphisms (SNPs) reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait linkage disequilibrium score regression to estimate genome-wide genetic correlation between PRISm and pulmonary and extrapulmonary traits. Phenome-wide association studies of top SNPs were performed. RESULTS: 22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (rg) between PRISm and spirometric COPD (rg=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (rg=0.12, p=0.007). Phenome-wide association studies showed that 18 of 22 signals were associated with diabetic traits and seven with blood pressure traits. CONCLUSION: This is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals, rs7652391 (nearest gene MECOM), rs9431040 (HLX), rs62018863 (TMEM114) and rs185937162 (HLA-B), have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extrapulmonary comorbidity.

The AGE-RAGE axis associates with chronic pulmonary diseases and smoking in the Rotterdam study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and asthma associate with high morbidity and mortality. High levels of advanced glycation end products (AGEs) were found in tissue and plasma of COPD patients but their role in COPD and asthma is unclear. METHODS: In the Rotterdam Study (n = 2577), AGEs (by skin autofluorescence (SAF)), FEV1 and lung diffusing capacity (DLCOc and DLCOc /alveolar volume [VA]) were measured. Associations of SAF with asthma, COPD, GOLD stage, and lung function were analyzed using logistic and linear regression adjusted for covariates, followed by interaction and stratification analyses. sRAGE and EN-RAGE associations with COPD prevalence were analyzed by logistic regression. RESULTS: SAF associated with COPD prevalence (OR = 1.299 [1.060, 1.591]) but not when adjusted for smoking (OR = 1.106 [0.89, 1.363]). SAF associated with FEV1% predicted (ß=-3.384 [-4.877, -1.892]), DLCOc (ß=-0.212 [-0.327, -0.097]) and GOLD stage (OR = 4.073, p = 0.001, stage 3&4 versus 1). Stratified, the association between SAF and FEV1%predicted was stronger in COPD (ß=-6.362 [-9.055, -3.670]) than non-COPD (ß=-1.712 [-3.306, -0.118]). Association of SAF with DLCOc and DLCOc/VA were confined to COPD (ß=-0.550 [-0.909, -0.191]; ß=-0.065 [-0.117, -0.014] respectively). SAF interacted with former smoking and COPD prevalence for associations with lung function. Lower sRAGE and higher EN-RAGE associated with COPD prevalence (OR = 0.575[0.354, 0.931]; OR = 1.778[1.142, 2.768], respectively). CONCLUSIONS: Associations between SAF, lung function and COPD prevalence were strongly influenced by smoking. SAF associated with COPD severity and its association with lung function was more prominent within COPD. These results fuel further research into interrelations and causality between SAF, smoking and COPD. TAKE-HOME MESSAGE: Skin AGEs associated with prevalence and severity of COPD and lung function in the general population with a stronger effect in COPD, calling for further research into interrelations and causality between SAF, smoking and COPD.

Targeting the IL-5 pathway in eosinophilic asthma: A comparison of anti-IL-5 versus anti-IL-5 receptor agents.

Eosinophilic asthma is characterized by frequent exacerbations, poor symptom control and accelerated lung function decline. It is now recognized that the immune response underlying eosinophilic asthma involves a complex network of interconnected pathways from both the adaptive and innate immune systems. Within this response, interleukin-5 (IL-5) plays a central role in eosinophil differentiation, activation and survival and has emerged as a key target for therapies treating severe asthma. The monoclonal antibodies mepolizumab and reslizumab target the ligand IL-5, preventing its interaction with eosinophils; in contrast, benralizumab binds to the IL-5 receptor (IL-5R), preventing IL-5 from binding and leading to substantially greater eosinophil reduction by enhanced antibody-dependent cell-mediated cytotoxicity. Although no direct head-to-head clinical trials of asthma have been published to formally evaluate the clinical significance of these different therapeutic approaches, the potential benefits of partial versus complete eosinophil depletion continue to remain an important area of study and debate. Here, we review the existing real-world and clinical study data of anti-IL-5/anti-IL-5R therapies in severe eosinophilic asthma.

Real-world biologics response and super-response in the International Severe Asthma Registry cohort.

BACKGROUND: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma. METHODS: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV1) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day. RESULTS: 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria. CONCLUSIONS: Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria.

Smoking-related dysregulation of plasma circulating microRNAs: the Rotterdam study.

BACKGROUND: MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Differential miRNA expression, which is widely shown to be associated with the pathogenesis of various diseases, can be influenced by lifestyle factors, including smoking. This study aimed to investigate the plasma miRNA signature of smoking habits, the potential effect of smoking cessation on miRNA levels, and relate the findings with lung cancer incidence. RESULTS: A targeted RNA-sequencing approach measured plasma miRNA levels in 2686 participants from the population-based Rotterdam study cohort. The association between cigarette smoking (current versus never) and 591 well-expressed miRNAs was assessed via adjusted linear regression models, identifying 41 smoking-associated miRNAs that passed the Bonferroni-corrected threshold (P < 0.05/591 = 8.46 × 10-5). Moreover, we found 42 miRNAs with a significant association (P < 8.46 × 10-5) between current (reference group) and former smokers. Then, we used adjusted linear regression models to explore the effect of smoking cessation time on miRNA expression levels. The expression levels of two miRNAs were significantly different within 5 years of cessation (P < 0.05/41 = 1.22 × 10-3) from current smokers, while for cessation time between 5 and 15 years we found 19 miRNAs to be significantly different from current smokers, and finally, 38 miRNAs were significantly different after more than 15 years of cessation time (P < 1.22 × 10-3). These results imply the reversibility of the smoking effect on plasma levels of at least 38 out of the 41 smoking-miRNAs following smoking cessation. Next, we found 8 out of the 41 smoking-related miRNAs to be nominally associated (P < 0.05) with the incidence of lung cancer. CONCLUSIONS: This study demonstrates smoking-related dysregulation of plasma miRNAs, which might have a potential for reversibility when comparing different smoking cessation groups. The identified miRNAs are involved in several cancer-related pathways and include 8 miRNAs associated with lung cancer incidence. Our results may lay the groundwork for further investigation of miRNAs as potential mechanism linking smoking, gene expression and cancer.

The Rotterdam Study. Design update and major findings between 2020 and 2024.

The Rotterdam Study is a population-based cohort study, started in 1990 in the district of Ommoord in the city of Rotterdam, the Netherlands, with the aim to describe the prevalence and incidence, unravel the etiology, and identify targets for prediction, prevention or intervention of multifactorial diseases in mid-life and elderly. The study currently includes 17,931 participants (overall response rate 65%), aged 40 years and over, who are examined in-person every 3 to 5 years in a dedicated research facility, and who are followed-up continuously through automated linkage with health care providers, both regionally and nationally. Research within the Rotterdam Study is carried out along two axes. First, research lines are oriented around diseases and clinical conditions, which are reflective of medical specializations. Second, cross-cutting research lines transverse these clinical demarcations allowing for inter- and multidisciplinary research. These research lines generally reflect subdomains within epidemiology. This paper describes recent methodological updates and main findings from each of these research lines. Also, future perspective for coming years highlighted.

Clinical course of suspected familial and sporadic idiopathic pulmonary fibrosis: Data from the PROOF-Next registry.

BACKGROUND AND OBJECTIVE: Real-life data on suspected familial fibrosis, defined as the occurrence of the disease in a patient younger than 50 and/or having at least one relative affected by pulmonary fibrosis remain scarce. METHODS: The Belgian and Luxembourg IPF registry (PROOF-Next) is a multicentric prospective longitudinal and observational study set in Belgium and Luxembourg. We compared characteristics and clinical course of patients with suspected familial pulmonary fibrosis (FPF) and sporadic IPF. RESULTS: We included 618 patients in the analysis, of whom 76 (12%) fulfilled criteria for FPF. They were significantly younger than sIPF (median age (range) 65 (43-87), vs. 72 (51-98), p = 0.0001). Male gender proportion and smoking status did not differ between groups, but the number of pack-year among current and former smokers was lower in FPF (20 vs. 25, p = 0.02). Besides, 87% of FPF and 76% of sIPF were treated with antifibrotic (p = 0.047). Baseline pulmonary function tests were similar in both groups, as well as median time before progression and transplant-free survival. Finally, genetic testing, performed in a minority, led to the identification of 10 telomerase-related gene variants. CONCLUSION: Although younger and exposed to less tobacco, patients with FPF show an equally aggressive progression as observed in sporadic IPF patients. These results warrant early referral of FPF patients to expert centres for optimal management.

Real-Life Response to Biologics in Severe Asthma with Nasal Polyposis: Insights from the Belgian Severe Asthma Registry.

BACKGROUND: Nasal polyposis (NP) is a comorbidity of type 2 severe asthma (SA) which could influence response to SA biologics. METHODS: We evaluated (super-) response in SA patients with (NP +) and without NP (NP-) enrolled in the Belgian Severe Asthma Registry (BSAR). RESULTS: 914 patients, of whom 31% NP + , were included. At enrollment, NP + patients had higher annual exacerbation rates, higher number of emergency room visits and more elevated type 2 biomarkers. In the longitudinal subanalysis of 104 patients, both groups had significant and similar asthma responses to asthma biologics, except for a greater increase in FEV1 in the NP + group. Super-response was achieved in 33 patients (32%), irrespective of NP status or type of biologic. CONCLUSION: In conclusion, both NP + and NP - patients had positive treatment responses, with some able to achieve super-response. In SA patients with NP, a greater FEV1 improvement as compared to SA patients without NP was observed.

Deep learning predicted perceived age is a reliable approach for analysis of facial ageing: A proof of principle study.

BACKGROUND: Perceived age (PA) has been associated with mortality, genetic variants linked to ageing and several age-related morbidities. However, estimating PA in large datasets is laborious and costly to generate, limiting its practical applicability. OBJECTIVES: To determine if estimating PA using deep learning-based algorithms results in the same associations with morbidities and genetic variants as human-estimated perceived age. METHODS: Self-supervised learning (SSL) and deep feature transfer (DFT) deep learning (DL) approaches were trained and tested on human-estimated PAs and their corresponding frontal face images of middle-aged to elderly Dutch participants (n = 2679) from a population-based study in the Netherlands. We compared the DL-estimated PAs with morbidities previously associated with human-estimated PA as well as genetic variants in the gene MC1R; we additionally tested the PA associations with MC1R in a new validation cohort (n = 1158). RESULTS: The DL approaches predicted PA in this population with a mean absolute error of 2.84 years (DFT) and 2.39 years (SSL). In the training-test dataset, we found the same significant (p < 0.05) associations for DL PA with osteoporosis, ARHL, cognition, COPD and cataracts and MC1R, as with human PA. We also found a similar but less significant association for SSL and DFT PAs (0.69 and 0.71 years per allele, p = 0.008 and 0.011, respectively) with MC1R variants in the validation dataset as that found with human, SSL and DFT PAs in the training-test dataset (0.79, 0.78 and 0.71 years per allele respectively; all p < 0.0001). CONCLUSIONS: Deep learning methods can automatically estimate PA from facial images with enough accuracy to replicate known links between human-estimated perceived age and several age-related morbidities. Furthermore, DL predicted perceived age associated with MC1R gene variants in a validation cohort. Hence, such DL PA techniques may be used instead of human estimations in perceived age studies thereby reducing time and costs.

Novel genetic variants associated with inhaled corticosteroid treatment response in older adults with asthma.

INTRODUCTION: Older adults have the greatest burden of asthma and poorest outcomes. The pharmacogenetics of inhaled corticosteroid (ICS) treatment response is not well studied in older adults. METHODS: A genome-wide association study of ICS response was performed in asthmatics of European ancestry in Genetic Epidemiology Research on Adult Health and Aging (GERA) by fitting Cox proportional hazards regression models, followed by validation in the Mass General Brigham (MGB) Biobank and Rotterdam Study. ICS response was measured using two definitions in asthmatics on ICS treatment: (1) absence of oral corticosteroid (OCS) bursts using prescription records and (2) absence of asthma-related exacerbations using diagnosis codes. A fixed-effect meta-analysis was performed for each outcome. The validated single-nucleotide polymorphisms (SNPs) were functionally annotated to standard databases. RESULTS: In 5710 subjects in GERA, 676 subjects in MGB Biobank, and 465 subjects in the Rotterdam Study, four novel SNPs on chromosome six near PTCHD4 validated across all cohorts and met genome-wide significance on meta-analysis for the OCS burst outcome. In 4541 subjects in GERA and 505 subjects in MGB Biobank, 152 SNPs with p<5 × 10-5 were validated across these two cohorts for the asthma-related exacerbation outcome. The validated SNPs included methylation and expression quantitative trait loci for CPED1, CRADD and DST for the OCS burst outcome and GM2A, SNW1, CACNA1C, DPH1, and RPS10 for the asthma-related exacerbation outcome. CONCLUSIONS: Multiple novel SNPs associated with ICS response were identified in older adult asthmatics. Several SNPs annotated to genes previously associated with asthma and other airway or allergic diseases, including PTCHD4.

European Respiratory Society short guidelines for the use of as-needed ICS/formoterol in mild asthma.

Recent clinical trials of as-needed fixed-dose combination of inhaled corticosteroid (ICS)/formoterol have provided new evidence that may warrant a reconsideration of current practice. A Task Force was set up by the European Respiratory Society to provide evidence-based recommendations on the use of as-needed ICS/formoterol as treatment for mild asthma. The Task Force defined two questions that were assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. The Task Force utilised the outcomes to develop recommendations for a pragmatic guideline for everyday clinical practice. The Task Force suggests that adults with mild asthma use as-needed ICS/formoterol instead of regular ICS maintenance treatment plus as-needed short-acting ß2-antagonist (SABA) and that adolescents with mild asthma use either as-needed ICS/formoterol or ICS maintenance treatment plus as-needed SABA (conditional recommendation; low certainty of evidence). The recommendation for adults places a relatively higher value on the reduction of systemic corticosteroid use and the outcomes related to exacerbations, and a relatively lower value on the small differences in asthma control. Either treatment option is suggested for adolescent patients as the balance is very close and data more limited. The Task Force recommends that adult and adolescent patients with mild asthma use as-needed ICS/formoterol instead of as-needed SABA (strong recommendation; low certainty of evidence). This recommendation is based on the benefit of as-needed ICS/formoterol in mild asthma on several outcomes and the risks related to as-needed SABA in the absence of anti-inflammatory treatment. The implementation of this recommendation is hampered in countries (including European Union countries) where as-needed ICS/formoterol is not approved for mild asthma.

Collaboration between explainable artificial intelligence and pulmonologists improves the accuracy of pulmonary function test interpretation.

BACKGROUND: Few studies have investigated the collaborative potential between artificial intelligence (AI) and pulmonologists for diagnosing pulmonary disease. We hypothesised that the collaboration between a pulmonologist and AI with explanations (explainable AI (XAI)) is superior in diagnostic interpretation of pulmonary function tests (PFTs) than the pulmonologist without support. METHODS: The study was conducted in two phases, a monocentre study (phase 1) and a multicentre intervention study (phase 2). Each phase utilised two different sets of 24 PFT reports of patients with a clinically validated gold standard diagnosis. Each PFT was interpreted without (control) and with XAI's suggestions (intervention). Pulmonologists provided a differential diagnosis consisting of a preferential diagnosis and optionally up to three additional diagnoses. The primary end-point compared accuracy of preferential and additional diagnoses between control and intervention. Secondary end-points were the number of diagnoses in differential diagnosis, diagnostic confidence and inter-rater agreement. We also analysed how XAI influenced pulmonologists' decisions. RESULTS: In phase 1 (n=16 pulmonologists), mean preferential and differential diagnostic accuracy significantly increased by 10.4% and 9.4%, respectively, between control and intervention (p<0.001). Improvements were somewhat lower but highly significant (p<0.0001) in phase 2 (5.4% and 8.7%, respectively; n=62 pulmonologists). In both phases, the number of diagnoses in the differential diagnosis did not reduce, but diagnostic confidence and inter-rater agreement significantly increased during intervention. Pulmonologists updated their decisions with XAI's feedback and consistently improved their baseline performance if AI provided correct predictions. CONCLUSION: A collaboration between a pulmonologist and XAI is better at interpreting PFTs than individual pulmonologists reading without XAI support or XAI alone.

RIPK1 kinase-dependent inflammation and cell death contribute to the pathogenesis of COPD.

BACKGROUND: Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of regulated cell death (including apoptosis and necroptosis) and inflammation, both drivers of COPD pathogenesis. We aimed to define the contribution of RIPK1 kinase-dependent cell death and inflammation in the pathogenesis of COPD. METHODS: We assessed RIPK1 expression in single-cell RNA sequencing (RNA-seq) data from human and mouse lungs, and validated RIPK1 levels in lung tissue of COPD patients via immunohistochemistry. Next, we assessed the consequences of genetic and pharmacological inhibition of RIPK1 kinase activity in experimental COPD, using Ripk1 S25D/S25D kinase-deficient mice and the RIPK1 kinase inhibitor GSK'547. RESULTS: RIPK1 expression increased in alveolar type 1 (AT1), AT2, ciliated and neuroendocrine cells in human COPD. RIPK1 protein levels were significantly increased in airway epithelium of COPD patients compared with never-smokers and smokers without airflow limitation. In mice, exposure to cigarette smoke (CS) increased Ripk1 expression similarly in AT2 cells, and further in alveolar macrophages and T-cells. Genetic and/or pharmacological inhibition of RIPK1 kinase activity significantly attenuated airway inflammation upon acute and subacute CS exposure, as well as airway remodelling, emphysema, and apoptotic and necroptotic cell death upon chronic CS exposure. Similarly, pharmacological RIPK1 kinase inhibition significantly attenuated elastase-induced emphysema and lung function decline. Finally, RNA-seq on lung tissue of CS-exposed mice revealed downregulation of cell death and inflammatory pathways upon pharmacological RIPK1 kinase inhibition. CONCLUSIONS: RIPK1 kinase inhibition is protective in experimental models of COPD and may represent a novel promising therapeutic approach.

Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA).

BACKGROUND: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies. METHODS: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria. RESULTS: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately). CONCLUSIONS: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.

Patient-centered digital biomarkers for allergic respiratory diseases and asthma: The ARIA-EAACI approach - ARIA-EAACI Task Force Report.

Biomarkers for the diagnosis, treatment and follow-up of patients with rhinitis and/or asthma are urgently needed. Although some biologic biomarkers exist in specialist care for asthma, they cannot be largely used in primary care. There are no validated biomarkers in rhinitis or allergen immunotherapy (AIT) that can be used in clinical practice. The digital transformation of health and health care (including mHealth) places the patient at the center of the health system and is likely to optimize the practice of allergy. Allergic Rhinitis and its Impact on Asthma (ARIA) and EAACI (European Academy of Allergy and Clinical Immunology) developed a Task Force aimed at proposing patient-reported outcome measures (PROMs) as digital biomarkers that can be easily used for different purposes in rhinitis and asthma. It first defined control digital biomarkers that should make a bridge between clinical practice, randomized controlled trials, observational real-life studies and allergen challenges. Using the MASK-air app as a model, a daily electronic combined symptom-medication score for allergic diseases (CSMS) or for asthma (e-DASTHMA), combined with a monthly control questionnaire, was embedded in a strategy similar to the diabetes approach for disease control. To mimic real-life, it secondly proposed quality-of-life digital biomarkers including daily EQ-5D visual analogue scales and the bi-weekly RhinAsthma Patient Perspective (RAAP). The potential implications for the management of allergic respiratory diseases were proposed.

Younger facial looks are associate with a lower likelihood of several age-related morbidities in the middle-aged to elderly.

BACKGROUND: Looking older for one's chronological age is associated with a higher mortality rate. Yet it remains unclear how perceived facial age relates to morbidity and the degree to which facial ageing reflects systemic ageing of the human body. OBJECTIVES: To investigate the association between ΔPA and age-related morbidities of different organ systems, where ΔPA represents the difference between perceived age (PA) and chronological age. METHODS: We performed a cross-sectional analysis on data from the Rotterdam Study, a population-based cohort study in the Netherlands. High-resolution facial photographs of 2679 men and women aged 51.5-87.8 years of European descent were used to assess PA. PA was estimated and scored in 5-year categories using these photographs by a panel of men and women who were blinded for chronological age and medical history. A linear mixed model was used to generate the mean PAs. The difference between the mean PA and chronological age was calculated (ΔPA), where a higher (positive) ΔPA means that the person looks younger for their age and a lower (negative) ΔPA that the person looks older. ΔPA was tested as a continuous variable for association with ageing-related morbidities including cardiovascular, pulmonary, ophthalmological, neurocognitive, renal, skeletal and auditory morbidities in separate regression analyses, adjusted for age and sex (model 1) and additionally for body mass index, smoking and sun exposure (model 2). RESULTS: We observed 5-year higher ΔPA (i.e. looking younger by 5 years for one's age) to be associated with less osteoporosis [odds ratio (OR) 0.76, 95% confidence interval (CI) 0.62-0.93], less chronic obstructive pulmonary disease (OR 0.85, 95% CI 0.77-0.95), less age-related hearing loss (model 2; B = -0.76, 95% CI -1.35 to -0.17) and fewer cataracts (OR 0.84, 95% CI 0.73-0.97), but with better global cognitive functioning (g-factor; model 2; B = 0.07, 95% CI 0.04-0.10). CONCLUSIONS: PA is associated with multiple morbidities and better cognitive function, suggesting that systemic ageing and cognitive ageing are, to an extent, externally visible in the human face.

Modelling ASthma TrEatment Responses (MASTER): Effect of individual patient characteristics on the risk of exacerbation in moderate or severe asthma: A time-to-event analysis of randomized clinical trials.

AIMS: There is limited understanding of how clinical and demographic characteristics are associated with exacerbation risk in patients with moderate-to-severe asthma, and how these factors correlate with symptom control and treatment response. Here we assess the relationship between baseline characteristics and exacerbation risk during regular dosing with inhaled corticosteroids (ICS) monotherapy or in combination with long-acting beta2-agonists (ICS/LABA) in clinical trial patients with varying levels of symptom control, as assessed by the asthma control questionnaire (ACQ-5). METHODS: A time-to-event model was developed using pooled patient data (N = 16 282) from nine clinical studies [Correction added on 26 July 2023, after first online publication: The N value in the preceding sentence has been corrected in this version.]. A parametric hazard function was used to describe the time-to-first exacerbation. Covariate analysis included the assessment of the effect of seasonal variation, clinical and demographic baseline characteristics on baseline hazard. Predictive performance was evaluated by standard graphical and statistical methods. RESULTS: An exponential hazard model best described the time-to-first exacerbation in moderate-to-severe asthma patients. Body mass index, smoking status, sex, ACQ-5, % predicted forced expiratory volume over 1 s (FEV1 p) and season were identified as statistically significant covariates affecting baseline hazard irrespective of ICS or ICS/LABA use. Fluticasone propionate/salmeterol (FP/SAL) combination therapy resulted in a significant reduction in the baseline hazard (30.8%) relative to FP monotherapy. CONCLUSIONS: Interindividual differences at baseline and seasonal variation affect the exacerbation risk independently from drug treatment. Moreover, it appears that even when a comparable level of symptom control is achieved in a group of patients, each individual may have a different exacerbation risk, depending on their baseline characteristics and time of the year. These findings highlight the importance of personalized interventions in moderate-to-severe asthma patients.