tbuckley/cabot-search huggingface dataset:
A proof-of-mechanism trial in asthma with lunsekimig, a bispecific nanobody® molecule
Authors: Annemie Deiteren, Emmanuel Krupka, Lieselot Bontinck, Karine Imberdis, Griet Conickx, Selcuk Bas, Naimish Patel, Heribert W. Staudinger, Benjamin T. Suratt
Journal: European Respiratory Journal (2025)

Background Monovalent biologics blocking thymic stromal lymphopoietin or interleukin-13 have been shown to elicit pharmacodynamic responses in asthma following a single dose. Therefore, dual blockade of these cytokines may result in an enhanced response compared to single targeting and has the potential to break efficacy ceilings in asthma. This study assessed the safety and tolerability of lunsekimig, a bispecific NANOBODY ® molecule that blocks thymic stromal lymphopoietin and interleukin-13, and its effect on Type 2 inflammatory biomarkers and lung function in asthma. Methods This was a Phase 1b, single-dose (subcutaneous lunsekimig 400 mg or placebo), randomised (2:1), double-blind, proof-of-mechanism study in 36 participants with mild-to-moderate asthma and elevated fractional exhaled nitric oxide (≥25 ppb), a marker of airway inflammation. The primary endpoint was safety and tolerability through Day 71. The main pharmacodynamic secondary endpoint was change from baseline in fractional exhaled nitric oxide at Day 29. Results Lunsekimig was well tolerated, with no serious treatment-emergent adverse events. Fractional exhaled nitric oxide was significantly reduced from Day 8 through Day 29 after a single dose, with change from baseline of −40.9 ppb (90% CI: −55.43 to −26.39; p&lt;0.0001) versus placebo at Day 29. Blood-based Type 2 biomarkers at Day 29 were significantly reduced from baseline. Lung function, particularly small airway dysfunction, was numerically improved at Day 29, most notably in participants with impaired lung function at baseline. Conclusions A single dose of lunsekimig was well tolerated, significantly suppressed Type 2 inflammation, and improved lung function in mild-to-moderate asthma.
Role of inflammasomes in acute respiratory distress syndrome
Authors: Luke Flower, Emilio G Vozza, Clare E Bryant, Charlotte Summers
Journal: Thorax (2025)

Acute respiratory distress syndrome (ARDS) is present in &gt;10% of all people admitted to critical care and is associated with severe morbidity and mortality. Despite more than half a century since its first description, no efficacious pharmacological therapies have been developed, and little progress has been made in improving clinical outcomes. Neutrophils are the principal drivers of ARDS, with their priming and subsequent aberrant downstream functions, including interleukin (IL) 1β and IL-18 secretion, central to the disease pathogenesis. The dominant pathways through which IL-1β and IL-18 are believed to be elaborated are multimeric protein structures called inflammasomes that consist of sensor proteins, adaptor proteins and an effector enzyme. The inflammasome’s initial activation depends on one of a variety of damage-associated (DAMP) or pathogen-associated (PAMP) molecular patterns. However, once activated, a common downstream inflammatory pathway is initiated regardless of the specific DAMP or PAMP involved. Several inflammasomes exist in humans. The nucleotide-binding domain leucine-rich repeat (NLR) family, pyrin domain-containing 3 (NLRP3), inflammasome is the best described in the context of ARDS and is known to be activated in both infective and sterile cases. The NLR family, caspase activation and recruitment domain-containing 4 (NLRC4) and absent in melanoma 2 (AIM2) inflammasomes have also been implicated in various ARDS settings, as have inflammasome-independent pathways. Further work is required to understand human biology as much of our knowledge is extrapolated from rodent experimental models. Experimental lung injury models have demonstrated beneficial responses to inflammasome, IL-1β and IL-18 blockade. However, findings have yet to be successfully translated into humans with ARDS, likely due to an underappreciation of the central role of the neutrophil inflammasome. A thorough understanding of inflammasome pathways is vital for critical care clinicians and researchers and for the development of beneficial therapies. In this review, we describe the central role of the inflammasome in the development of ARDS and its potential for immunomodulation, highlighting key areas for future research.
<sup>129</sup>Xenon MR Imaging and Spectroscopy Detects Response to Therapy in Pulmonary Hypertension
Authors: Fawaz Alenezi, Anna Costelle, Prerna Sharma, Megan Barrett, Elianna A. Bier, Bastiaan Driehuys, Sudarshan Rajagopal
Journal: European Respiratory Journal (2025)

<title>Extract</title> <sup>129</sup>Xe gas-exchange magnetic resonance imaging/MR spectroscopy (<sup>129</sup>Xe MRI/MRS) is an emerging functional lung imaging technology with the potential to provide precise, spatial, quantitative metrics of pulmonary ventilation, interstitial membrane uptake, transfer to capillary red blood cells (RBCs) and hemodynamics [1–3]. When used in concert, these <sup>129</sup>Xe MRI/MRS metrics can be used to differentiate between patients with chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH) and post-capillary pulmonary hypertension (PH) [3]. Incorporation of cardiogenic <sup>129</sup>Xe-RBC signal oscillations and RBC transfer defects into an initial diagnostic algorithm revealed good sensitivity and specificity in differentiating between pre- and post-capillary PH [4]. However, it is not known whether these <sup>129</sup>Xe-RBC metrics are sensitive to changes associated with PAH targeted therapies. Here, we addressed this question by performing a descriptive proof-of-concept study using these markers to measure therapy response in PH patients treated with inhaled treprostinil (iTRE).
Effectiveness and safety of tofacitinib<i>versus</i>calcineurin inhibitor in interstitial lung disease secondary to anti-MDA5-positive dermatomyositis: a multi-centre cohort study
Authors: Wanlong Wu, Bingpeng Guo, Wenjia Sun, Dan Chen, Wenwen Xu, Zhiwei Chen, Yakai Fu, Yan Ye, Xia Lyu, Zhixin Xue, Kaiwen Wang, Jiangfeng Zhao, Cuiying Xie, Yi Chen, Chunhua Ye, Min Dai, Wei Fan, Jia Li, Xiaodong Wang, Yu Xue, Weiguo Wan, Li Sun, Huaxiang Wu, Qun Luo, Qian Han, Qiong Fu, Shuang Ye
Journal: European Respiratory Journal (2025)

Objective To compare the effectiveness and safety of tofacitinib (TOF) versus calcineurin inhibitor (CNI) as initial immunosuppressive regimen for anti-melanoma differentiation-associated gene 5-positive dermatomyositis with interstitial lung disease (MDA5+DM-ILD). Methods Adult Chinese patients with newly-diagnosed MDA5+DM-ILD (ILD course&lt;3 months) from five tertiary referral centres between April 2014 and January 2023 were included for this retrospective cohort study. The primary effectiveness endpoint was lung transplantation-free survival within 1 year. Propensity score-based inverse probability of treatment weighting (IPTW) was applied for adjustment in this real-world study. Results : In the eligible cohort, a total of 94 (32.4%) and 105 (46.7%) patients died or underwent lung transplantation within 1 year in the TOF group (n=290) and the CNI group (n=225), respectively. After adjustment by IPTW, patients’ lung transplantation-free survival rate within 1 year was significantly higher in the TOF group compared to the CNI group (log-rank p=0.013). Multivariable Cox analysis performed in the IPTW dataset revealed the hazard ratio of TOF versus CNI for 1-year survival was 0.72 (95% CI, 0.56 to 0.94, p=0.013). The adjusted difference of survival rate was 9.3% (95%CI 2.8% to 15.8%). Alternative analytic strategies yielded consistent results in sensitivity analyses. Patients less than 60 years old, without RPILD, or with baseline PaO 2 /FiO 2 ≥300 mmHg might benefit more from TOF. Opportunistic infection was the major treatment-related serious adverse event, with generally comparable incidence (42.4% versus 45.3%). Conclusion In this large multi-centre cohort study, tofacitinib showed significantly more benefits for 1-year lung transplantation-free survival than calcineurin inhibitors in MDA5+DM-ILD.
Protein biomarkers of interstitial lung abnormalities in relatives of patients with pulmonary fibrosis
Authors: Jonathan A. Rose, Mark P. Steele, Esteban J. Kosak Lopez, Gisli Thor Axelsson, Andrea G. Galecio Chao, Alan Waich, Katie Regan, Swati Gulati, Anthony H. Maeda, Sharmin Sultana, Claire Cutting, Ann-Marcia C. Tukpah, Andrew J. Synn, Mary B. Rice, Hilary J. Goldberg, Joyce S. Lee, David A. Lynch, Rachel K. Putman, Hiroto Hatabu, Benjamin A. Raby, David A. Schwartz, Ivan O. Rosas, Gary M. Hunninghake
Journal: European Respiratory Journal (2025)

Rationale First-degree relatives of patients with pulmonary fibrosis (relatives) are at high risk for interstitial lung abnormalities (ILA), highlighting the need for biomarkers for risk prediction. We aimed to identify blood proteins associated with and predictive of ILA among relatives of patients with pulmonary fibrosis. Methods Relatives enrolled in two independent cohorts had protein levels measured using an aptamer-based proteomic platform. ILA was assessed with CT scans per Fleischner Society recommendations. Protein associations with ILA were assessed using regression, and significant proteins were used with clinical variables to detect ILA. Results Of 237 relatives from two independent cohorts, 26% had ILA. Seven proteins were associated with ILA in the discovery cohort after FDR-adjustment, and all remained significant after adjusting for age, gender, and smoking status. Six of seven were significant in the validation cohort including GDF15, SFTPD, and SFTPB. In a multivariable model, six proteins combined with basic demographics in the discovery cohort had AUC=0.92 (0.88 in validation cohort). LASSO modelling identified three proteins and age as predictors with an AUC=0.89. When applied to the combined cohorts, this simple model would reduce the need for CT imaging in one of every three relatives screened. Conclusion Peripheral blood proteins are associated with ILA in relatives of patients with pulmonary fibrosis and can be used to detect ILA. Our findings demonstrate the potential utility of blood biomarkers in this high-risk group and suggests molecular targets for future investigation.
Contemporary pulmonary hypertension hemodynamic definitions stratify mortality risk in candidates for advanced heart failure therapies
Authors: Stephen P. Wright, Elizabeth Karvasarki, Tayler A. Buchan, Vikram Gurtu, Michael Zarathus-Cook, Michael McDonald, Ana C. Alba, Susanna Mak
Journal: European Respiratory Journal (2025)

<title>Extract</title> Right heart catheterization (<bold>RHC</bold>) is performed to evaluate pulmonary hypertension (<bold>PH</bold>) in patients with Stage C-D chronic heart failure (<bold>HF</bold>) being considered for advanced therapies. However, the recommended thresholds of hemodynamic criteria at which to test PH reversibility (<italic>e.g.</italic>, pulmonary artery systolic pressure (<bold>PASP</bold>) ≥50 mmHg) are relatively high, [1] considering that mean pulmonary artery pressure (<bold>mPAP</bold>) and pulmonary vascular resistance (<bold>PVR</bold>) are very low in healthy adults, [2, 3] and mortality increases with even mild PH. [4, 5] Contemporary guidelines have thus set the mPAP threshold for PH diagnosis at 20 mmHg, and reduced the PVR threshold indicating a pre-capillary component to 2 WU. [6–8] As a step toward incorporating current PH guidelines into advanced HF care, we grouped patients in our Canadian center by PH severity using specific criteria prompting reversibility testing and the broader hemodynamic definition. We then tested whether these PH groups were associated with 3-year mortality.
Initial therapy in patients with pulmonary arterial hypertension and cardiovascular comorbidities
Authors: Athénaïs Boucly, David Montani, Fabrice Bauer, Elise Artaud-Macari, Emmanuel Bergot, Clément Boissin, Ari Chaouat, Vincent Cottin, Claire Dauphin, Bruno Degano, Pascal De Groote, Camille du Roure, Nicolas Favrolt, Delphine Horeau-Langlard, Xavier Jaïs, Mitja Jevnikar, Thomas Lacoste-Palasset, François Picard, Grégoire Prévôt, Martine Reynaud-Gaubert, Anne Roche, Ségolène Turquier, Marc Humbert, Olivier Sitbon, Laurent Savale
Journal: European Respiratory Journal (2025)

Background European guidelines recommend initial monotherapy in PAH patients with cardiovascular (CV) comorbidities based on the limited of evidence for combination therapy in this growing population. Methods A retrospective analysis was conducted on incident PAH patients enrolled in the French Pulmonary Hypertension Registry between 2009 and 2020. Propensity score matching was used to investigate initial dual oral combination therapy versus oral monotherapy in patients with at least one CV comorbidity ( i.e. , hypertension, obesity, diabetes and coronary artery disease). Results Of the 1784 patients identified, 1088 had ≥1 CV comorbidity, including 20% with ≥3 comorbidities. In the propensity score matched population (N=708), the majority of patients were female, with idiopathic/heritable/drug-induced PAH, at intermediate 1-year mortality risk. At first follow-up, initial dual therapy led to larger improvements in symptoms, exercise capacity, hemodynamics, and risk status than initial monotherapy, with no differences in long-term survival. Treatment discontinuations were observed in 23% of patients initiated on dual therapy and 24% of those initiated on monotherapy. Conclusions Initial dual oral combination therapy may be beneficial and well tolerated in most PAH patients with CV comorbidities.
Efficacy and safety of the activin signalling inhibitor, sotatercept, in a pooled analysis of PULSAR and STELLAR studies
Authors: Marius M. Hoeper, Mardi Gomberg-Maitland, David B. Badesch, J. Simon R. Gibbs, Ekkehard Grünig, Grzegorz Kopeć, Vallerie V. McLaughlin, Gisela Meyer, Karen M. Olsson, Ioana R. Preston, Stephan Rosenkranz, Rogerio Souza, Aaron B. Waxman, Loïc Perchenet, James Strait, Aiwen Xing, Solaiappan Manimaran, Xuelong Wang, Barry Miller, Alexandra G. Cornell, Janethe de Oliveira Pena, H. Ardeschir Ghofrani, Marc Humbert
Journal: European Respiratory Journal (2025)

Introduction Pulmonary arterial hypertension (PAH) is a progressive disease associated with significant morbidity and mortality. Sotatercept is a first-in-class activin signalling inhibitor that acts to restore the balance between the growth-promoting and growth-inhibiting signalling pathways. Methods This post-hoc, exploratory, pooled analysis combines data from the double-blind placebo periods of the phase 2 PULSAR ( NCT03496207 ) and phase 3 STELLAR ( NCT04576988 ) studies. Both studies were international, multicentre, randomised, double-blind, placebo-controlled trials in patients with PAH. Efficacy and safety parameters common to both studies were analysed. Results A total of 429 patients were randomised and treated; 237 received sotatercept and 192 received placebo. Adding sotatercept to background PAH therapy for 24 weeks improved exercise capacity (as assessed by 6-min walk distance), pulmonary vascular resistance, World Health Organization functional class, and delayed time to first occurrence of death or clinical worsening event. There were clinically important reductions in both pulmonary and right heart pressures; improvements in right ventricle (RV) size during both systole and diastole; and enhancements in RV contractility and RV-pulmonary artery coupling. The number of patients who experienced at least one adverse event of interest or special interest (increased haemoglobin, thrombocytopenia, bleeding events [mostly epistaxis], increased blood pressure, and telangiectasia) was higher in the sotatercept group than the placebo group. Discussion This pooled analysis confirms that sotatercept delivers therapeutic benefit across a range of efficacy endpoints and has favourable safety in patients with PAH. Increased duration of follow-up will provide further insight into long-term outcomes of sotatercept in patients with PAH.
Accelerated epigenetic aging worsens survival and mediates environmental stressors in fibrotic interstitial lung disease
Authors: Gillian C. Goobie, Daniel-Costin Marinescu, Ayodeji Adegunsoye, Jean Bourbeau, Christopher Carlsten, Rachel L. Clifford, Dany Doiron, Qingling Duan, Kevin F. Gibson, Amanda Grant-Orser, Ana I. Hernandez Cordero, Kerri A. Johannson, Daniel J. Kass, Sharon E. Kim, Janice M. Leung, Xiaoyun Li, Wan Tan, Chen Xi Yang, S. Mehdi Nouraie, Christopher J. Ryerson, Tillie L Hackett, Yingze Zhang
Journal: European Respiratory Journal (2025)

Background The role of epigenetic aging in the environmental pathogenesis and prognosis of fibrotic interstitial lung disease (fILD) is unclear. We evaluated whether ambient particulate matter ≤2.5 μm (PM 2.5 ) and neighbourhood disadvantage exposures are associated with accelerated epigenetic aging, and whether epigenetic age is associated with adverse clinical outcomes in patients with fILD. Methods This multicentre, international, cohort study included patients with fILD from the University of Pittsburgh (UPitt, n=306) and University of British Columbia (UBC, n=170). Five-year PM 2.5 exposures were estimated using satellite-derived models. Neighbourhood disadvantage was calculated using U.S. and Canadian Census-based metrics. Epigenetic age difference (EAD=epigenetic age – chronological age) was calculated using GrimAge analysis of blood DNA methylation data. Linear models assessed associations of exposures with EAD. Cox models assessed associations of EAD with transplant-free survival. Causal mediation analysis evaluated EAD mediation of exposure-survival relationships. Results Median epigenetic age was 11.7 years older than chronological age in patients with fILD. In combined cohort analysis, each interquartile range (IQR) PM 2.5 increase was associated with 2.88 years (95%CI 1.39–4.38, p&lt;0.001) increased EAD. In UPitt, each IQR neighbourhood disadvantage increase was associated with 1.16 years (95%CI 0.22–2.09, p=0.02) increased EAD. Increased EAD was associated with worse transplant-free survival (HR=1.17 per 1-year increase EAD, 95%CI 1.10–1.24, p&lt;0.001), with EAD mediating 40% of PM 2.5 -survival relationship and 59% of neighbourhood disadvantage-survival relationships. Epigenetic age was also more strongly associated with transplant-free survival than chronological age. Conclusions Epigenetic age acceleration is associated with worse survival and mediates adverse exposure impacts in fILD.
Spatial Variation in the Association between Extreme Heat Events and Warm Season Pediatric Acute Care Utilization: A Small-Area Assessment of Multiple Health Conditions and Environmental Justice Implications in California (2005–2019)
Authors: Allan Ndovu, Chen Chen, Lara Schwarz, Emma Lasky, Sheri D. Weiser, Tarik Benmarhnia
Journal: Environmental Health Perspectives (2025)

The increasing frequency and severity of extreme heat events due to climate change present unique risks to children and adolescents. There is a lack of evidence regarding how heat's impacts on pediatric patients vary spatially and how structural and sociodemographic factors drive this heterogeneity. We examined the association between extreme heat events and pediatric acute care utilization in California for 19 distinct health conditions. We then assessed how extreme heat's consequences varied at the ZIP code level and identified environmental justice metrics that modulated children's vulnerability to extreme heat. This study analyzed 7.2 million unscheduled hospitalizations and emergency department visits for children <19 years old in California between May and September from 2005 to 2019. We first utilized a time-stratified case-crossover design to generate statewide estimates for the association between extreme heat events and care utilization. We then implemented a within-community matched design coupled with a Bayesian hierarchical model to generate spatially varying effect estimates. Finally, we conducted a random effects meta-regression to examine how community-level characteristics modified heat's impacts across ZIP codes. Extreme heat events were associated with substantial increases in acute care utilization for all causes [odds ratio (OR)=1.03; 95% confidence interval (CI): 1.03, 1.04] and were attributable for over 30,000 excess acute care utilizations during the study period. Extreme heat events were also associated with increases in heat-related illness (OR=1.53; 95% CI: 1.49, 1.58); endocrine, nutritional, and metabolic disorders (OR=1.13; 95% CI: 1.1, 1.16); other signs and symptoms (OR=1.07; 95% CI: 1.06, 1.08); and injury and poisoning (OR=1.07; 95% CI: 1.05, 1.08). There was substantial spatial heterogeneity in extreme heat events effects, especially in coastal metropolitan areas. Communities with lower incomes and education levels, less access to insurance and air conditioning, and higher percentages of Black, Hispanic, and Pacific Islander residents were most vulnerable during extreme heat events. Extreme heat events in California are associated with increased pediatric care utilization. There is significant variation in heat's consequences, and historically disadvantaged and under-resourced communities are most impacted. These findings suggest that interventions designed to improve heat resilience should be targeted to protect vulnerable children. https://doi.org/10.1289/EHP14236.
Segmental post-PCI physiological gradients using ultrasonic or optical flow ratio: Insights from ASET JAPAN Study
Authors: Pruthvi C Revaiah, Kotaro Miyashita, Tsung-Ying Tsai, Retesh Bajaj, Nozomi Kotoku, Akihiro Tobe, Takashi Muramatsu, Kengo Tanabe, Ken Kozuma, Yukio Ozaki, Scot Garg, Shengxian Tu, Jouke Dijkstra, Christos V Bourantas, Yoshinobu Onuma, Patrick W Serruys
Journal:  (2025)

Abstract Background Segmental pressure gradients post percutaneous coronary intervention (PCI) can detect residual disease and optimization targets. Ultrasonic flow ratio (UFR) or optical flow ratio (OFR) offer simultaneous physiological and morphological assessment using a single imaging catheter. This study evaluated the utility of UFR and OFR in identifying residual disease post-PCI. Methods and Results The study include patients from the ASET JAPAN Pilot study with complete intra-vascular imaging pullback data, where UFR or OFR was obtained post-PCI. Anatomical focal lesions distal and proximal to the stent were analyzed in segments ≥5mm long. UFR or OFR virtual pullback curves assessed intra-stent pressure gradients, defining physiological focal or diffuse by segmental pressure drops ≥0.05 over lengths &amp;lt;10mm or ≥10mm, respectively. The median post-PCI UFR/OFR was 0.93 (0.88-0.96) with 35.4% (69/195) vessels having a UFR/OFR&amp;lt;0.91. There were significantly more focal lesions, both anatomical and physiological, proximal and distal to the stent in vessels with UFR/OFR&amp;lt;0.91 compared to those ≥0.91. Agreement between anatomical and physiological focal lesions was moderate proximally (kappa=0.553, p&amp;lt;0.001) and fair distally (kappa=0.219, p=0.002). The in-stent gradient poorly predicted significant stent under-expansion. However, the virtual FFR gradient performed well in detecting proximal or distal focal disease (AUC=0.835 and 0.877, respectively) Conclusions UFR/OFR effectively identifies suboptimal vessel physiology post-PCI and locates precise anatomical issues, validated by intra-vascular imaging.