tbuckley/cabot-search huggingface dataset:
Proteomic Signatures for Risk Prediction of Atrial Fibrillation
Authors: Hanjin Park, Faye L. Norby, Daehoon Kim, Eunsun Jang, Hee Tae Yu, Tae-Hoon Kim, Jae-Sun Uhm, Jung-Hoon Sung, Hui-Nam Pak, Moon-Hyoung Lee, Pil-Sung Yang, Boyoung Joung
Journal: Circulation (2025)

BACKGROUND: Proteomic signatures might improve disease prediction and enable targeted disease prevention and management. We explored whether a protein risk score derived from large-scale proteomics data improves risk prediction of atrial fibrillation (AF). METHODS: A total of 51 680 individuals with 1459 unique plasma protein measurements and without a history of AF were included from the UKB-PPP (UK Biobank Pharma Proteomics Project). A protein risk score was developed with lasso-penalized Cox regression from a random subset of 70% (36 176 individuals, 54.4% women, 2155 events) and was tested on the remaining 30% (15 504 individuals, 54.4% women, 910 events). The protein risk score was externally replicated with the ARIC study (Atherosclerosis Risk in Communities; 11 012 individuals, 54.8% women, 1260 events). RESULTS: The protein risk score formula developed from the UKB-PPP derivation set was composed of 165 unique plasma proteins, and 15 of them were associated with atrial remodeling. In the UKB-PPP test set, a 1-SD increase in protein risk score was associated with a hazard ratio of 2.20 (95% CI, 2.05–2.41) for incident AF. The C index for a model including CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology Atrial Fibrillation), NT-proBNP (N-terminal B-type natriuretic peptide), polygenic risk score, and protein risk score was 0.816 (95% CI, 0.802–0.829) compared with 0.771 (95% CI, 0.755–0.787) for a model including CHARGE-AF, NT-proBNP, and polygenic risk score (C-index change, 0.044 [95% CI, 0.039–0.055]). Protein risk score added to CHARGE-AF, NT-proBNP, and polygenic risk score resulted in a risk reclassification of 5.4% (95% CI, 2.9%–7.9%) with a 5-year risk threshold of 5%. In the decision curve, the predicted net benefit before and after the addition of protein risk score to a model including CHARGE-AF, NT-proBNP, and polygenic risk score was 3.8 and 5.4 per 1000 people, respectively, at a 5-year risk threshold of 5%. External replication of a protein risk score in the ARIC study showed consistent improvement in risk stratification of AF. CONCLUSIONS: Protein risk score derived from a single plasma sample improved risk prediction of AF. Further research using proteomic signatures in AF screening and prevention is needed.
A survey of sequence-to-graph mapping algorithms in the pangenome era
Authors: Yingbo Cui, Chenchen Peng, Zeyu Xia, Canqun Yang, Yifei Guo
Journal: Genome biology (2025)

Abstract A pangenome can reveal the genetic diversity across different individuals simultaneously. It offers a more comprehensive reference for genome analysis compared to a single linear genome that may introduce allele bias. Pangenomes are often represented as genome graphs, making sequence-to-graph mapping a fundamental task for pangenome construction and analysis. Numerous sequence-to-graph mapping algorithms have been developed over the past few years. Here, we provide a review of the advancements in sequence-to-graph mapping algorithms in the pangenome era. We also discuss the challenges and opportunities that arise in the context of pangenome graphs.
Early Detection of β-Cell Decline Using Home Dried-Blood-Spot C-Peptide Levels in New-Onset Type 1 Diabetes
Authors: A. Emile J. Hendriks, M. Loredana Marcovecchio, Mark L. Evans, Peter Barker, Keith Burling, Lut Overbergh, Chantal Mathieu
Journal: Diabetes Care (2025)

OBJECTIVE There is a need for early detection of β-cell decline in people with newly diagnosed (ND) type 1 diabetes. The gold standard mixed-meal tolerance test (MMTT) is an invasive and time-consuming procedure that requires participants to travel to clinical sites. We assessed the feasibility of measuring dried blood spot (DBS) C-peptide levels collected at home as an alternative to the MMTT to detect early β-cell decline. RESEARCH DESIGN AND METHODS Individuals with ND type 1 diabetes were recruited within 6 weeks of diagnosis as part of the INNODIA cohort. They collected finger-prick DBS C-peptide data at home, both while fasting and 60 min after a liquid meal. At 12 months, an MMTT was conducted to measure the area under the curve (AUC) of venous C-peptide. RESULTS Data of 292 people were analyzed (mean age 12.7 years; range 1.2–43.8 years). The median number of DBS card pairs per participant was 6.5 (interquartile range = 2, 9) over 12 months. The slopes of stimulated DBS C-peptide levels in the first 6 months significantly predicted venous MMTT AUC C-peptide and peak C-peptide levels at 12 months (P &amp;lt; 0.01). The models were adjusted for simultaneous glucose levels, age, and baseline fasting C-peptide level. However, the 6-month fasting DBS C-peptide slope did not predict 12-month MMTT AUC C-peptide. CONCLUSIONS Home DBS C-peptide assessment is a feasible method to monitor β-cell function in ND type 1 diabetes. The early prognostic utility of stimulated DBS C-peptide highlights its potential for optimizing trial design. However, further validation is needed to confirm its reliability and broader applicability.
Comparability, acceptability and longitudinal adherence with digital emPHasis-10 in pulmonary arterial hypertension
Authors: Joseph Newman, Frances Varian, Felicity Hitchcock, Rebecca Burney, Gregg Harry Rawlings, John Harrington, Ze Ming Goh, Jenna Ablott, David G Kiely, Iain Armstrong, A A Roger Thompson, Jill Carlton, Elin Haf Davies, Alexander Rothman, Mark Toshner
Journal: European Respiratory Journal (2025)
Impaired IgA Mucosal Immunity Following Lung Transplantation: A Potential Trigger for Bronchiolitis Obliterans Syndrome
Authors: François M Carlier, Bruno Detry, Jérôme Ambroise, Nicolas Heddebaut, Thomas Planté-Bordeneuve, Aurélie Daumerie, Elisabeth Longchampt, Loïc Falque, Martine Reynaud-Gaubert, Sandrine Hirschi, Jean-François Mornex, Xavier Demant, Adrien Tissot, Jérôme Le Pavec, Vincent Bunel, David Lair, Marina Pretolani, Alexandre Vallée, Charles Pilette, Olivier Brugière
Journal: European Respiratory Journal (2025)

Rationale. Bronchiolitis obliterans syndrome (BOS) limits long-term survival after lung transplantation (LuTx) and may be triggered by infections. As immunoglobulin (Ig)A is crucial to ensure adequate mucosal immunity, we explored whether IgA-related mucosal immunity is impaired in BOS. Methods. Sixty LuTx recipients from the COLT cohort were retrospectively included. All participants were in stable condition within the first year post-transplant. At 3.5 years post-LuTx, 30 remained stable and 30 had developed BOS. Bronchoalveolar lavage fluid (BALF) and sera collected pre-transplant and at 6 (M6) and 12 months (M12) post-transplant were assessed for monomeric IgA, secretory (S)-IgA, secretory component (SC) and cytokine profiling. Second, bronchiolar polymeric Ig receptor (pIgR) expression and subepithelial IgA-producing B-cell numbers were compared across graft tissue samples from 54 LuTx recipients classified as stable, pre-BOS, BOS or end-stage BOS. Results. S-IgA levels in BALF decreased between M6 and M12 (p=0.0001) and were reduced in BOS patients at M12 (p=0.0018). Patients with lower S-IgA levels had higher infection rates. BOS patients exhibited elevated SC levels in serum (p&lt;0.01). Both reduced S-IgA in BALF and increased SC in serum were associated with higher risk of BOS. Lastly, a reduction in bronchiolar pIgR expression was observed in BOS patients (p=0.0001), that paralleled BOS severity. Conclusions. This study demonstrates an early impairment of mucosal IgA immunity in LuTx patients, which was linked to the later development of BOS, suggesting that IgA-related markers may serve as early predictors of BOS onset.
Particulate matter–related ITIH4 deficiency is associated with an emphysema phenotype of chronic obstructive pulmonary disease through JNK-dependent and JNK-independent signaling
Authors: Sheng-Ming Wu, Kuan-Yuan Chen, Hsiao-Chi Chuang, Shu-Chuan Ho, Cheng-Wei Lin, Chia-Li Han, Wei-Lun Sun, Po-Hao Feng, Shiou-Fu Lin, Yueh-Hsi Chen, Tzu-Tao Chen, Chien-Hua Tseng, Wen-Te Liu, Kang-Yun Lee
Journal: European Respiratory Journal (2025)

Rationale : Prolonged exposure to airborne particulate matter (PM) is associated with emphysema and chronic obstructive pulmonary disease (COPD); however, the precise underlying mechanism remains unclear. Objectives In a previous high-throughput screen, we identified inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) as a biomarker of long-term PM exposure. We hypothesized that ITIH4 is implicated in PM-related emphysema. Methods We investigated the association between ITIH4 expression and ambient PM exposure through a clinical cohort analysis (220 patients with COPD and 61 healthy participants) and in vitro studies. Measurements and Main Results The COPD cohort studies revealed significant correlations between emphysema severity, ambient PM exposure, and serum ITIH4 levels. In primary small airway epithelial cells from COPD patients with low basal levels of ITIH4, exposure to PM and oxidative stress led to increased apoptosis. However, ITIH4 overexpression significantly inhibited oxidative stress–induced apoptosis in normal and COPD airway epithelial cells. Acute exposure to hydrogen peroxide resulted in the rapid degradation of ITIH4 protein with no effect on transcriptional level, although ITIH4 gene expression is downregulated in the lung tissue of patients with COPD. A human apoptosis antibody array revealed that ITIH4 overexpression attenuated hydrogen peroxide–induced apoptotic signaling. Furthermore, extracellular ITIH4 protein confers cytoprotective functions in cells exposed to PM or oxidative stress. Mechanistically, ITIH4 attenuated oxidative stress–induced JNK activation and β-catenin decrease. A deficiency of ITIH4 exacerbated the effects of oxidative stress. Conclusions We identified a novel pathogenetic mechanism involving ITIH4, where chronic exposure to air pollution induces or promotes emphysema.
How do people with COPD walk? A European study on digitally measured real-world gait
Authors: Laura Delgado-Ortiz, Joren Buekers, Nikolaos Chynkiamis, Heleen Demeyer, Anja Frei, Elena Gimeno-Santos, Clint Hansen, Jeffrey M Hausdorff, Nicholas S Hopkinson, Carl-Philipp Jansen, Anne Kirsten, Sarah Koch, Walter Maetzler, Dimitrios Megaritis, Milo A Puhan, David Singleton, Ioannis Vogiatzis, Henrik Watz, Silvia Del Din, Brian Caulfield, Clemens Becker, Lynn Rochester, Thierry Troosters, Judith Garcia-Aymerich
Journal: European Respiratory Journal (2025)

The amount of walking that people with chronic obstructive pulmonary disease (COPD) do is reduced. However, data on their manner of walking ( i.e. , gait) is still lacking. We characterised real-world gait in COPD by assessing levels and distributions of gait parameters, and comparing them across COPD severity, and with healthy peers. 549 people with COPD from seven European sites and 19 healthy older adults wore single wearable devices (either Axivity AX6 or Dynaport MM+) continuously for one week, from which we identified walking bouts (WBs), calculated 15 digital mobility outcomes (DMOs) aggregated at weekly level, and compared them across COPD severity levels and with healthy peers. Participants with COPD were 37% female, and had mean( sd ) age 68(8)years and post-bronchodilator FEV 1 54(20)% predicted. All gait DMOs were normally distributed and exhibited variability between participants ( e.g. , mean walking speed of 0.83(0.12)m·s −1 , ranging from 0.48 to 1.20 m·s −1 ). Walking speed and cadence DMOs were lower with increasing disease severity ( e.g. , mean walking speed of 0.88(0.11), 0.85(0.12), 0.80(0.12), and 0.78(0.14) m·s −1 in GOLD 1–4, p &lt;0.001; mean cadence 93(6), 91(6), and 89(7) steps/min in GOLD A, B and E, p =0.013). Stride length and duration varied across COPD severity levels. Walking speed and cadence bout-to-bout variability only varied across dyspnoea severity levels. In a secondary analysis, we compared DMO data from people with COPD to a convenience sample of 19 healthy older adults (47% women, mean age 71(6) years) and found that walking speed and cadence varied between COPD and healthy adults ( e.g. , mean walking speed 0.83(0.12) versus 0.90(0.12) m·s −1 , p =0.041). In people with COPD, gait DMOs are normally distributed and worsen as disease advances. Moreover, walking speed and cadence DMOs are significantly altered when compared to healthy peers. Further research should elucidate which DMOs can be improved with treatments to enhance mobility and reduce adverse events.
Sputum metagenomics in bronchiectasis reveals pan-European variation: an EMBARC-BRIDGE study
Authors: Kai Xian Thng, Pei Yee Tiew, Micheál Mac Aogáin, Jayanth Kumar Narayana, Tavleen Kaur Jaggi, Fransiskus Xaverius Ivan, Morven Shuttleworth, Merete B Long, Hollian Richardson, Holly Lind, Daniela Alferes de Lima Headley, Kara Robertson, Jennifer Pollock, Pieter C Goeminne, Michal Shteinberg, Anthony De Soyza, Stefano Aliberti, Josje Altenburg, Charles S Haworth, Oriol Sibila, Eva Polverino, Michael R Loebinger, Felix C Ringshausen, Natalie Lorent, Katerina Dimakou, Amelia Shoemark, James D Chalmers, Sanjay H Chotirmall
Journal: European Respiratory Journal (2025)

Background The EMBARC registry shows considerable variation in culturable microbes in sputum between different European countries. The additive role of next generation metagenomic sequencing remains unexplored and association with antimicrobial resistomes unknown. Methods We prospectively assessed sputum from N=349 individuals recruited into the EMBARC-BRIDGE study with next-generation shotgun metagenomic sequencing including three European regions: Northern and Western Europe, Southern Europe and the United Kingdom, including samples from ten European countries. Microbiome and resistome profiles were assessed in relation to clinical outcomes. Results Next generation metagenomic sequencing reproduced differences between countries in microbial profiles previously shown by culture in the EMBARC study. Metagenomics provided enhanced detection for some bronchiectasis pathogens including P. aeruginosa , H. influenzae and S. pneumoniae . Three metagenomic microbial clusters dominated by the genera Pseudomonas, Streptococcus and Haemophilus demonstrated pan-European but variable distribution. Diverse resistomes, linked to underlying microbiomes, were identified across Europe, with significantly higher diversity of resistance gene determinants in Southern Europe. Resistome composition significantly differed between regions characterised by regionally contrasting multi-drug-resistant profiles. The EMBARC-BRIDGE cohort validated established bronchiectasis resistotypes: RT1 and RT2, which occur at varying frequency across regions. Despite geographic variation in microbiome and resistome profiles in bronchiectasis across Europe, analogous antimicrobial resistance gene profiles associate with the key bronchiectasis genera Pseudomonas, Streptococcus and Haemophilus, independent of country or region. Conclusion Sputum metagenomics confirms and extends prior observations of regional variation in bronchiectasis microbiology. Important variation in the distribution of pathogens and antimicrobial resistance genes has implications for antimicrobial practices across Europe.
Renal dysfunction and outcomes in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: an individual participant data meta-analysis
Authors: Amber Meservey, Nadine Al-Naamani, Jasleen Minhas, Jason S Fritz, Dina Appleby, Guillaume Baudry, Nicolas Girerd, Rui Feng, Steven M Kawut, Jude Moutchia
Journal: European Respiratory Journal (2025)

Background Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) cause right ventricular dysfunction with extrapulmonary sequalae including renal dysfunction. We sought to characterize renal dysfunction in PAH and CTEPH and to assess the effect of pulmonary hypertension treatment on renal function. Methods We performed an individual participant data meta-analysis of 6694 participants from 18 phase III randomized clinical trials of pulmonary hypertension therapies. We calculated estimated glomerular filtration rate (eGFR) using the race-agnostic 2021 CKD-EPI equation. Results The mean age was 49.6±15.5 years, 78% were female and 58% had idiopathic PAH. A total of 907 participants (13.5%) had a baseline eGFR&lt;60 mL·min −1 ·1.73 m −2 . Lower baseline eGFR correlated with higher mean right atrial pressure (mRAP) and lower cardiac index. At 12–16 weeks, a 10 mmHg decrease in mRAP from baseline or a 1 L·min −1 ·m −2 increase in cardiac index was associated with only a 1.7 mL·min −1 ·1.73 m −2 (95% CI: −2.9, −0.5; p=0.006) or a 1.4 mL·min −1 ·1.73 m −2 (95% CI: 0.5, 2.4; p=0.003) increase in eGFR, respectively. A 10 mL·min −1 ·1.73 m −2 lower baseline eGFR was associated with an increased risk of all-cause mortality (aHR: 1.16 [95% CI:1.08, 1.23]; p &lt;0.001). Interestingly, pulmonary hypertension treatment was associated with only a small improvement in eGFR at 12–16 weeks (aβ: 2.0 mL·min −1 ·1.73 m −2 [95% CI: 1.4, 2.6]; p &lt;0.001). Conclusion Renal dysfunction remains highly prevalent in PAH and CTEPH and is associated with worse hemodynamics and worse clinical outcomes. In this cohort with relatively preserved renal function, pulmonary hypertension treatment was associated with only a minimal improvement in eGFR.
Endocrine-disrupting chemicals and female reproductive health: a growing concern
Authors: Anne-Simone Parent, Pauliina Damdimopoulou, Hanna K L Johansson, Nora Bouftas, Monica K Draskau, Delphine Franssen, Julie Fudvoye, Majorie van Duursen, Terje Svingen
Journal: Nature Reviews Endocrinology (2025)
Cross-species tropism of AAV.CPP.16 in the respiratory tract and its gene therapies against pulmonary fibrosis and viral infection
Authors: Zhi Yang, Yizheng Yao, Xi Chen, Victoria Madigan, Shanrui Pu, Xianqun Fan, Jun Pu, Fengfeng Bei
Journal: Cell Reports Medicine (2025)

Efficient gene delivery vectors are crucial for respiratory and lung disease therapies. We report that AAV.CPP.16, an engineered adeno-associated virus (AAV) variant derived from AAV9, efficiently transduces airway and lung cells in mice and non-human primates via intranasal administration. AAV.CPP.16 outperforms AAV6 and AAV9, two wild-type AAVs with demonstrated tropism for respiratory tissues, and efficiently targets key respiratory cell types. It supports gene supplementation and editing therapies in two clinically relevant mouse models of respiratory and lung diseases. A single intranasal dose of AAV.CPP.16 expressing a dual-target, vascular endothelial growth factor (VEGF)/transforming growth factor (TGF)-β1-neutralizing protein protected lungs from idiopathic pulmonary fibrosis, while a similar application of AAV.CPP.16 carrying an "all-in-one" CRISPR-Cas13d system inhibited transcription of the SARS-CoV-2-derived RNA-dependent RNA polymerase (Rdrp) gene. Our findings highlight AAV.CPP.16 as a promising vector for respiratory and lung gene therapy.
Benmelstobart plus anlotinib and chemotherapy in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: A phase 2 study
Authors: Liangyu Bie, Chen Wei, Suxia Luo, Shuailei Dong, Zhiwei Gu, Yijie Ma, Qingxin Xia, He Zhang, Jing Li, Wenying Deng, Ning Li
Journal: Cell Reports Medicine (2025)

This phase 2 study investigates first-line benmelstobart plus anlotinib and chemotherapy in human epidermal growth factor receptor 2 (HER2)-negative unresectable locally advanced/metastatic gastric or gastroesophageal junction (G/GEJ) cancer. Twenty-five eligible patients receive benmelstobart plus anlotinib and chemotherapy for 6 cycles, followed by benmelstobart and anlotinib maintenance. Of 24 patients with post-treatment imaging, objective response rate (ORR) is 75.0% (95% confidence interval [CI], 53.3%-90.2%; partial response [PR], 18 [75.0%]), and disease control rate (DCR) is 100.0%. The median duration of response (DoR) is 10.9 months. By the date cutoff, the median follow-up is 15.8 months. Median progression-free survival (PFS) and overall survival (OS) among all 25 patients are 10.3 and 18.2 months, respectively. Survival outcomes are not associated with programmed death-ligand 1 (PD-L1) expression. Lymphocytes, T cells, and CD3+CD8+ T cells are enriched in patients with long-term response (PFS > 12 months). Most common grade ≥3 treatment-related adverse event (TRAE) is neutrophil count decreased (12%). This study shows promising efficacy and safety, representing a potential first-line option in patients with HER2-negative advanced G/GEJ cancer, regardless of PD-L1 expressions. The study was registered at ClinicalTrials.gov (NCT04891900).
Unravelling the Brain Resilience Following Stroke: From injury to rewiring of the brain through pathway activation, drug targets, and therapeutic interventions
Authors: Ankit Singh, Khalandar Dhalayat, Shradhey Dhobale, Bijoyani Ghosh, Aishika Datta, Anupom Borah, Pallab Bhattacharya
Journal: Ageing Research Reviews (2025)
Autoamputation in Mismatch Repair–Deficient Colon Cancer
Authors: Michael Flanagan, Michael Kelly, Paul McCormick
Journal: JAMA Oncology (2025)

A woman in her 50s with a history of hemochromatosis, psoriasis, and type 2 diabetes presented with a 3-month history of abdominal pain, weight loss, and a large palpable fixed abdominal mass. What is your diagnosis?
Medical School Faculty Diversity and the Liaison Committee on Medical Education’s Diversity Standards
Authors: Mytien Nguyen, Tonya L. Fancher, Sarwat I. Chaudhry, Alan Dardik, Laura Castillo-Page, Gbenga Ogedegbe, Paris Butler, Mayur M. Desai, Shruthi Venkataraman, Olivia Marie Campa, Amy Sage, Dowin Boatright
Journal: JAMA Network Open (2025)

This cross-sectional study evaluates US medical school faculty diversity before and after introduction of the Liaison Committee on Medical Education’s diversity standards.
Long-Term Follow-Up of Extracranial-Intracranial Bypass Surgery for Symptomatic Cerebral Artery Occlusion
Authors: Yan Ma, Tao Wang, Wei Ni, Haibo Wang, Delin Liu, Xinyi Sun, Xiaoguang Tong, Liyong Zhang, Zhiyong Tong, Yufeng Wang, Yiling Cai, Jun Ren, Donghai Wang, Lian Duan, Aisha Maimaitili, Chunhua Hang, Jiasheng Yu, Feng Ling, Yangfeng Wu, Colin P. Derdeyn, Yuxiang Gu, Guoguang Zhao, Liqun Jiao
Journal: JAMA (2025)

This study examines extracranial-intracranial bypass surgery plus medical treatment vs medical treatment alone in symptomatic patients with hemodynamically compromised internal carotid artery or middle carotid artery occlusion.