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Background: Preserved ratio impaired spirometry (PRISm) refers to decreased forced expiratory volume in 1 s (FEV 1 ) in the setting of preserved ratio. Little is known about the role of PRISm and its complex relation with small airway dysfunction (SAD) and lung volume. Therefore, we aimed to investigate the associations between PRISm and SAD and lung volume. Methods: We conducted a cross-sectional community-dwelling study in China. Demographic data, standard respiratory epidemiology questionnaire, spirometry, impulse oscillometry (IOS) and computed tomography (CT) data were collected. PRISm was defined as post-bronchodilator FEV 1 /FVC ≥ 0.70 and FEV 1  < 80% predicted. Spirometry-defined SAD was defined as at least two of three of the post-bronchodilator maximal mid-expiratory flow (MMEF), forced expiratory flow 50% (FEF50), and forced expiratory flow 75% (FEF75) less than 65% of predicted. IOS-defined SAD and CT-defined gas trapping were defined by the fact that the cutoff value of peripheral airway resistance R5–R20 > 0.07 kPa/L/s and LAA − 856 >20%, respectively. Analysis of covariance and logistic regression were used to determine associations between PRISm and SAD and lung volume. We then repeated the analysis with a lower limit of normal definition of spirometry criteria and FVC definition of PRISm. Moreover, we also performed subgroup analyses in ever smoker, never smoker, subjects without airway reversibility or self-reported diagnosed asthma, and subjects with CT-measured total lung capacity ≥70% of predicted. Results: The final analysis included 1439 subjects. PRISm had higher odds and more severity in spirometry-defined SAD (pre-bronchodilator: odds ratio [OR]: 5.99, 95% confidence interval [95%CI]: 3.87–9.27, P < 0.001; post-bronchodilator: OR: 14.05, 95%CI: 8.88–22.24, P < 0.001), IOS-defined SAD (OR: 2.89, 95%CI: 1.82–4.58, P < 0.001), and CT-air trapping (OR: 2.01, 95%CI: 1.08–3.72, P = 0.027) compared with healthy control after adjustment for confounding factors. CT-measured total lung capacity in PRISm was lower than that in healthy controls (4.15 ± 0.98 vs. 4.78 ± 1.05 L, P < 0.05), after adjustment. These results were robust in repeating analyses and subgroup analyses. Conclusion: Our finding revealed that PRISm was associated with SAD and reduced total lung capacity. Future studies to identify the underlying mechanisms and longitudinal progression of PRISm are warranted.

Background Atherogenic index of plasma (AIP) at baseline has been associated with increased morbidity and mortality from cardiovascular disease (CVD). However, the relationship between long-term AIP trajectories and CVD remains unclear. Therefore, this study aimed to investigate the associations between AIP trajectories and the incidence of CVD in the English population. Method The study data analysis was based on the English Longitudinal Study of Aging (ELSA) from 2004 to 2017. The study population consisted of individuals aged 50 years and older in England. AIP was calculated as log 10 (triglycerides/high-density lipoprotein cholesterol). Group-based trajectory model (GBTM) was applied to identify the trajectory of the AIP index from Wave 2 to 8 over a 12-year follow-up. Cox proportional hazard models were then used to analyze the associations between different AIP index trajectory groups and the incidence of CVD. Results A total of 3976 participants with completed AIP data in Wave 2 and more than two AIP measurements between Wave 2 and Wave 8 were enrolled in the ELSA cohort. The participants were divided into three groups [low-stable group ( n  = 1146), moderate-stable group ( n  = 2110), high-stable group ( n  = 720)] using a GBTM model. After adjusting for potential confounders, participants in the high-stable group indicated an increased risk of developing incident of CVD compared to those in the low-stable AIP group [Hazard Ratio (HR) 1.33; 95% Confidence Interval (CI) 1.02–1.74, P  = 0.033]. However, no differences in the incidence of CVD (HR 1.20, 95%CI 0.98–1.48, P  = 0.082) were observed in the moderate-stable group. Subgroup analysis indicated similar results for participants under 63 years old and those with high alcohol consumption. Conclusions A high and sustainable level of the AIP index may contribute to the incidence of CVD. The trajectories of the AIP index can help identify older English individuals at increased risk of CVD who deserve primitive preventive and therapeutic approaches.

Background Ferroptosis therapy has emerged as a promising antitumor strategy by utilizing the Fenton reaction to destroy cancer cells, where Fe 2+ catalyzes the decomposition of H 2 O 2 into hydroxyl radicals (•OH). Despite the great potential of ferroptosis therapy in suppressing tumor growth, inadequate catalysts and reactants within tumors remains a major challenge before its clinical translation. Herein, we developed glucose oxidase (GOx)-loaded phase-transition nanodroplets (PND) modified with Fe-tannic acid (TA) networks (PND@GOx@Fe-TA) for enhanced antitumor efficacy of ferroptosis therapy via synergistic photothermal and starvation therapy. Results PND@GOx@Fe-TA can convert glucose into H 2 O 2 , which not only provides sufficient H 2 O 2 for Fenton reaction, but also consumes glucose to exert starvation therapy. In addition, the Fe-TA networks of PND@GOx@Fe-TA can be degraded upon reaching the tumor site, thus generating Fe 2+ from Fe 3+ via reduction by the overexpressed glutathione (GSH) in the tumor microenvironment. The Fe 2+ then reacts with the in situ-generated H 2 O 2 for enhanced Fenton reaction and induces ferroptosis of cancer cells. Additionally, the PND@GOx@Fe-TA exhibits photothermal effects under 808 nm laser irradiation, which not only accelerates the Fe 2+ -mediated Fenton reaction but also gasifies the liquid core of the PND, enabling its use as a contrast agent for contrast-enhanced ultrasound (CEUS), photoacoustic imaging (PAI) and magnetic resonance imaging (MRI). Conclusions In summary, the PND@GOx@Fe-TA represents a promising approach for multimodal imaging-guided antitumor therapy by synergistic starvation, photothermal and enhanced ferroptosis therapy. Graphical Abstract

Chronic obstructive pulmonary disease (COPD) is a prevalent condition that significantly impacts public health. Unfortunately, there are few effective treatment options available. Mendelian randomization (MR) has been utilized to repurpose existing drugs and identify new therapeutic targets. The objective of this study is to identify novel therapeutic targets for COPD. Cis-expression quantitative trait loci (cis-eQTL) were extracted for 4,317 identified druggable genes from genomics and proteomics data of whole blood (eQTLGen) and lung tissue (GTEx Consortium). Genome-wide association studies (GWAS) data for doctor-diagnosed COPD, spirometry-defined COPD (Forced Expiratory Volume in one second [FEV1]/Forced Vital Capacity [FVC] <0.7), and FEV1 were obtained from the cohort of FinnGen, UK Biobank and SpiroMeta consortium. We employed Summary-data-based Mendelian Randomization (SMR), HEIDI test, and colocalization analysis to assess the causal effects of druggable gene expression on COPD and lung function. The reliability of these druggable genes was confirmed by eQTL two-sample MR and protein quantitative trait loci (pQTL) SMR, respectively. The potential effects of druggable genes were assessed through the phenome-wide association study (PheWAS). Information on drug repurposing for COPD was collected from multiple databases. A total of 31 potential druggable genes associated with doctor-diagnosed COPD, spirometry-defined COPD, and FEV1 were identified through SMR, HEIDI test, and colocalization analysis. Among them, 22 genes (e.g., MMP15, PSMA4, ERBB3, and LMCD1) were further confirmed by eQTL two-sample MR and protein SMR analyses. Gene-level PheWAS revealed that ERBB3 expression might reduce inflammation, while GP9 and MRC2 were associated with other traits. The drugs Montelukast (targeting the MMP15 gene) and MARIZOMIB (targeting the PSMA4 gene) may reduce the risk of spirometry-defined COPD. Additionally, an existing small molecule inhibitor of the APH1A gene has the potential to increase FEV . Our findings identified 22 potential drug targets for COPD and lung function. Prioritizing clinical trials that target these identified druggable genes with existing drugs or novel medications will be beneficial for the development of COPD treatments.

Background: Despite the clinical efficacy of immunotherapy in treating malignant tumors, its effectiveness is often hampered by the immunosuppressive nature of the tumor microenvironment (TME). In this study, we propose the design of a nanoscale ultrasound contrast agent capable of triggering macrophage polarization and immunogenic cell death (ICD) for the treatment of hepatocellular carcinoma (HCC) through sonodynamic treatment (SDT) and immunotherapy. Methods: The re-educator (designated as ICG@C3F8-R848 NBs) is composed of the Toll-like receptor agonist resiquimod (R848) and the sonosensitizer Indocyanine green (ICG), utilizing nanobubbles (NBs) as carriers. The technique known as ultrasound-targeted nanobubble destruction (UTND) employs nanosized microbubbles and low-frequency ultrasound (LFUS) to ensure accurate drug delivery and enhance safety. Results: Following intravenous delivery, ICG@C3F8-R848 NBs have the potential to selectively target and treat primary tumors using SDT in conjunction with ultrasonography. Importantly, R848 can enhance antitumor immunity by inducing the polarization of macrophages from an M2 to an Ml phenotype. Conclusion: The SDT-initiated immunotherapy utilizing ICG@C3F8-R848 NBs demonstrates significant tumor suppression effects with minimal risk of systemic toxicity. The utilization of this self-delivery re-education technique would contribute to advancing the development of nanomedicine for the treatment of hepatocellular carcinoma. Keywords: hepatocellular carcinoma, synergistic sono-immunotherapy strategy, tumor-associated-macrophage

Background Small airway dysfunction (SAD) is common but little is known about the longitudinal prognosis of spirometry-defined SAD. Therefore, we aimed to evaluate the risk of lung function decline and incident chronic obstructive pulmonary disease (COPD) of spirometry-defined SAD. Methods It was a population-based prospective cohort study conducted in Guangdong, China. Participants were enrolled in the years 2002, 2008, 2012, 2017, and 2019, and those who completed baseline demographic data, a standardized epidemiological questionnaire for COPD, and spirometry were included. Follow-up visits were conducted every three years after enrolment, with a maximum follow-up time of 15 years and a minimum follow-up time of 3 years. Spirometry-defined SAD was defined as having at least two out of three parameters (maximal mid-expiratory flow, forced expiratory flow 50%, and forced expiratory flow 75%) below 65% of the predicted value. Non-obstructive SAD and obstructive SAD were further differentiated based on the presence of airflow obstruction (forced expiratory volume in one second [FEV 1 ]/forced vital capacity [FVC] < 0.70). Pre- and post-bronchodilator spirometry measurements were analyzed separately. Results Pre-bronchodilator spirometry dataset included 4680 participants (mean age 55.3 [10.8] years, 2194 [46.9%] males). Participants with pre-bronchodilator SAD had a significantly faster annual decline of FEV 1 % of predicted value (0.31 ± 0.05 vs. 0.20 ± 0.03 %/year; difference: 0.12 [95% confidence interval: 0.01–0.23]; P = 0.023), FVC, and FVC % of predicted value compared to those without pre-bronchodilator SAD. The annual decline of lung function in participants with pre-bronchodilator non-obstructive SAD was not significantly different from that in pre-bronchodilator healthy controls, but they were more likely to progress to spirometry-defined COPD (adjusted hazard ratio: 2.92 [95% confidence interval: 2.28–3.76], P < 0.001). Post-bronchodilator spirometry dataset yielded similar results. Conclusions Individuals with spirometry-defined SAD have a faster decline in lung function compared to those without SAD, and non-obstructive SAD is more likely to progress to spirometry-defined COPD. Trial registration Chinese Clinical Trials Registration ChiCTR1900024643. Registered on 19 July 2019.

Background The clinical significance of the impulse oscillometry-defined small airway bronchodilator response (IOS-BDR) is not well-known. Accordingly, this study investigated the clinical characteristics of IOS-BDR and explored the association between lung function decline, acute respiratory exacerbations, and IOS-BDR. Methods Participants were recruited from an Early Chronic Obstructive Pulmonary Disease (ECOPD) cohort subset and were followed up for two years with visits at baseline, 12 months, and 24 months. Chronic obstructive pulmonary disease (COPD) was defined as a post-bronchodilator forced expiratory volume in 1 s (FEV 1 )/forced vital capacity (FVC) ratio < 0.70. IOS-BDR was defined as meeting any one of the following criteria: an absolute change in respiratory system resistance at 5 Hz ≤ − 0.137 kPa/L/s, an absolute change in respiratory system reactance at 5 Hz ≥ 0.055 kPa/L/s, or an absolute change in reactance area ≤ − 0.390 kPa/L. The association between IOS-BDR and a decline in lung function was explored with linear mixed-effects model. The association between IOS-BDR and the risk of acute respiratory exacerbations at the two-year follow-up was analyzed with the logistic regression model. Results This study involved 466 participants (92 participants with IOS-BDR and 374 participants without IOS-BDR). Participants with IOS-BDR had higher COPD assessment test and modified Medical Research Council dyspnea scale scores, more severe emphysema, air trapping, and rapid decline in FVC than those without IOS-BDR over 2-year follow-up. IOS-BDR was not associated with the risk of acute respiratory exacerbations at the 2-year follow-up. Conclusions The participants with IOS-BDR had more respiratory symptoms, radiographic structural changes, and had an increase in decline in lung function than those without IOS-BDR. Trial registration Chinese Clinical Trial Registry, ChiCTR1900024643. Registered on 19 July, 2019.

Background The association between diurnal temperature range (DTR) and hospitalization for exacerbation of chronic respiratory diseases (CRD) was rarely reported. Objectives To examine the association between DTR and daily hospital admissions for exacerbation of CRD and find out the potential effect of modifications on this association. Method Data on daily hospitalization for exacerbation of chronic obstructive pulmonary disease (COPD), asthma and bronchiectasis and meteorology measures from 2013 through 2017 were obtained from 21 cities in South China. After controlling the effects of daily mean temperature, relative humidity (RH), particulate matter < 2.5 μm diameter (PM 2.5 ) and other confounding factors, a standard generalized additive model (GAM) with a quasi-Poisson distribution was performed to evaluate the relationships between DTR and daily hospital admissions of CRD in a two-stage strategy. Subgroup analysis was performed to find potential modifications, including seasonality and population characteristics. Result Elevated risk of hospitalization for exacerbation of CRD (RR = 1.09 [95%CI: 1.08 to 1.11]) was associated with the increase in DTR (the 75th percentile versus the 25th percentile of DTR at lag0–6). The effects of DTR on hospital admissions for CRD were strong at low DTR in the hot season and high DTR in the cold season. The RR (the 75th percentile versus the 25th percentile of DTR at lag0–6) of hospitalization was 1.11 (95%CI: 1.08 to 1.12) for exacerbations of COPD and 1.09 (95%CI: 1.05 to 1.13) for asthma. The adverse effect of DTR on hospitalization for bronchiectasis was only observed in female patients (RR = 1.06 [95%CI: 1.03 to 1.10]). Conclusion Our study provided additional evidence for the association between DTR and daily hospitalization for exacerbation of CRD, and these associations are especially stronger in COPD patients and in the cold season than the hot season. Preventive measures to reduce the adverse impacts of DTR were needed for CRD patients.

BackgroundThe prognostic value of respiratory symptom profiles for predicting exacerbation risk and lung function decline remains unclear in mild-to-moderate chronic obstructive pulmonary disease (COPD).Research questionAre respiratory symptom profiles associated with both exacerbation risk and lung function decline in mild-to-moderate COPD?Study design and methodsThis was a posthoc analysis of data from participants with mild-to-moderate COPD from the SubPopulations and InteRmediate Outcome Measures in COPD Study. Respiratory symptom profiles were identified through latent class analysis. Outcomes included exacerbation rates evaluated by zero-inflated negative binomial regressions, time-to-first exacerbation evaluated by Cox regression and longitudinal forced expiratory volume in 1 second (FEV1) decline evaluated by linear mixed-effects models.ResultsAmong the 954 participants with mild-to-moderate COPD, five distinct respiratory symptom profiles were identified. Compared with the ‘minimal respiratory’ profile, the ‘productive cough’ profile was associated with a higher rate of any respiratory exacerbations (relative ratio [RR] 1.84; 95% confidence interval [CI] 1.29 to 2.64) and severe respiratory exacerbations (RR 2.05; 95% CI 1.12 to 3.74). Similarly, the ‘Wheeze’ profile was associated with higher rates of any (RR 1.55; 95% CI 1.12 to 2.15) and severe exacerbations (RR 1.73; 95% CI 1.00 to 2.98). The ‘nearly all respiratory symptoms’ profile was associated with a higher rate of exacerbations (any exacerbation: RR 2.12; 95% CI 1.56 to 2.89; severe exacerbations: RR 2.07; 1.23 to 3.47) and an accelerated annual FEV1 decline (−15.41 mL/year; 95% CI −30.33 to −0.51 mL/year). The ‘dry cough’ profile exhibited the lowest FEV1 trajectory despite a non-significant annual decline.InterpretationRespiratory symptom profiles identifies distinct prognostic outcomes in mild-to-moderate COPD. The productive cough is associated with increased exacerbation risk, while the dry cough is associated with a lower lung function trajectory.Trial registration numberNCT0196934.

The immunosuppressive tumor microenvironment (TME) has become a major challenge in cancer immunotherapy, with abundant tumor-associated macrophages (TAMs) playing a key role in promoting tumor immune escape by displaying an immunosuppressive (M2) phenotype. Recently, it was reported that M1 macrophage-derived nanovesicles (M1NVs) can reprogram TAMs to an anti-tumor M1 phenotype, thereby significantly alleviating the immunosuppressive TME and enhancing the anti-tumor efficacy of immunotherapy. Herein, we developed M1NVs loaded with mesoporous dopamine (MPDA) and indocyanine green (ICG), which facilitated the recruitment of M2 TAMs through synergistic photothermal and photodynamic therapy. Thereafter, M1NVs can induce M1 repolarization of TAMs, resulting in increased infiltration of cytotoxic T lymphocytes within the tumor to promote tumor regression. This study investigated the effect of phototherapy on the immune environment of liver cancer using single-cell RNA sequencing (scRNA-seq) by comparing HCC tissues before and after MPDA/ICG@M1NVs + NIR treatment. The results showed significant shifts in cell composition and gene expression, with decreases in epithelial cells, B cells, and macrophages and increases in neutrophils and myeloid cells. Additionally, gene analysis indicated a reduction in pro-inflammatory signals and immunosuppressive functions, along with enhanced B-cell function and anti-tumor immunity, downregulation of the Gtsf1 gene in the epithelial cells of the MPDA/ICG @M1NVs + NIR group, and decreased expression of the lars2 gene in immune subpopulations. Eno3 expression is reduced in M1 macrophages, whereas Clec4a3 expression is downregulated in M2 macrophages. Notably, the B cell population decreased, whereas Pou2f2 expression increased. These genes regulate cell growth, death, metabolism, and tumor environment, indicating their key role in HCC progression. This study highlights the potential for understanding cellular and molecular dynamics to improve immunotherapy.