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ITIC's superior electron-accepting capacity and efficient oxygen reduction motivated the design of a sensor to enhance sensitivity, selectivity, and stability over conventional oxygen-dependent or fullerene-based systems. As oxygen acts as the terminal reagent in enzymatic glucose oxidation, we developed an ITIC-mediated glucose oxidase (GOx) biosensor on glassy carbon (GCE) and screen-printed carbon electrodes (SPCE). ITIC, a non-fullerene organic semiconductor, was drop-cast onto the electrode to catalyze oxygen reduction, followed by GOx immobilization in a chitosan matrix. Scanning electron microscopy (SEM) confirmed uniform, ultrathin coatings without significant morphological changes upon ITIC and GOx deposition. Electrochemical studies (cyclic (CV) and differential pulse voltammetry (DPV)) revealed a distinct ITIC reduction peak at -0.7 V (vs. Ag/AgCl) and a glucose-dependent current decrease, consistent with mediated electron transfer during enzymatic oxidation. Under optimized conditions, the GCE-based biosensor showed a sensitivity of 10.7 μA L mmol , a linear dynamic range (LDR) of 0.10-1.00 mmol L , and detection (LOD)/quantification (LOQ) limits of 0.02 and 0.06 mmol L , respectively. The SPCE device displayed sensitivity (3.8 μA L mmol ) and maintained excellent linearity (R > 0.99) with LOD and LOQ of 0.05 and 0.16 mmol L . Both platforms showed good precision (RSD < 5%) and reliable recovery in deproteinized plasma and artificial tears (90-104%). The superior performance of the GCE is attributed to higher ITIC loading, faster electron transfer, and reduced background current, while the SPCE offers a low-cost, disposable format with sufficient analytical performance for point-of-care glucose monitoring.

Dupilumab, a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation, has shown efficacy and safety in a phase 3 trial involving patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation and an elevated risk of exacerbation. Whether the findings would be confirmed in a second phase 3 trial was unclear. In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of 300 cells per microliter or higher to receive subcutaneous dupilumab (300 mg) or placebo every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Key secondary end points, analyzed in a hierarchical manner to adjust for multiplicity, included the changes from baseline in the prebronchodilator forced expiratory volume in 1 second (FEV ) at weeks 12 and 52 and in the St. George's Respiratory Questionnaire (SGRQ; scores range from 0 to 100, with lower scores indicating better quality of life) total score at week 52. A total of 935 patients underwent randomization: 470 were assigned to the dupilumab group and 465 to the placebo group. As prespecified, the primary analysis was performed after a positive interim analysis and included all available data for the 935 participants, 721 of whom were included in the analysis at week 52. The annualized rate of moderate or severe exacerbations was 0.86 (95% confidence interval [CI], 0.70 to 1.06) with dupilumab and 1.30 (95% CI, 1.05 to 1.60) with placebo; the rate ratio as compared with placebo was 0.66 (95% CI, 0.54 to 0.82; P<0.001). The prebronchodilator FEV increased from baseline to week 12 with dupilumab (least-squares mean change, 139 ml [95% CI, 105 to 173]) as compared with placebo (least-squares mean change, 57 ml [95% CI, 23 to 91]), with a significant least-squares mean difference at week 12 of 82 ml (P<0.001) and at week 52 of 62 ml (P = 0.02). No significant between-group difference was observed in the change in SGRQ scores from baseline to 52 weeks. The incidence of adverse events was similar in the two groups and consistent with the established profile of dupilumab. In patients with COPD and type 2 inflammation as indicated by elevated blood eosinophil counts, dupilumab was associated with fewer exacerbations and better lung function than placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; NOTUS ClinicalTrials.gov number, NCT04456673.).

In some patients with chronic obstructive pulmonary disease (COPD), type 2 inflammation may increase exacerbation risk and may be indicated by elevated blood eosinophil counts. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation. In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of at least 300 per microliter and an elevated exacerbation risk despite the use of standard triple therapy to receive dupilumab (300 mg) or placebo subcutaneously once every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations of COPD. Key secondary and other end points that were corrected for multiplicity were the change in the prebronchodilator forced expiratory volume in 1 second (FEV ) and in the scores on the St. George's Respiratory Questionnaire (SGRQ; range, 0 to 100, with lower scores indicating a better quality of life) and the Evaluating Respiratory Symptoms in COPD (E-RS-COPD; range, 0 to 40, with lower scores indicating less severe symptoms). A total of 939 patients underwent randomization: 468 to the dupilumab group and 471 to the placebo group. The annualized rate of moderate or severe exacerbations was 0.78 (95% confidence interval [CI], 0.64 to 0.93) with dupilumab and 1.10 (95% CI, 0.93 to 1.30) with placebo (rate ratio, 0.70; 95% CI, 0.58 to 0.86; P<0.001). The prebronchodilator FEV increased from baseline to week 12 by a least-squares (LS) mean of 160 ml (95% CI, 126 to 195) with dupilumab and 77 ml (95% CI, 42 to 112) with placebo (LS mean difference, 83 ml; 95% CI, 42 to 125; P<0.001), a difference that was sustained through week 52. At week 52, the SGRQ score had improved by an LS mean of -9.7 (95% CI, -11.3 to -8.1) with dupilumab and -6.4 (95% CI, -8.0 to -4.8) with placebo (LS mean difference, -3.4; 95% CI, -5.5 to -1.3; P = 0.002). The E-RS-COPD score at week 52 had improved by an LS mean of -2.7 (95% CI, -3.2 to -2.2) with dupilumab and -1.6 (95% CI, -2.1 to -1.1) with placebo (LS mean difference, -1.1; 95% CI, -1.8 to -0.4; P = 0.001). The numbers of patients with adverse events that led to discontinuation of dupilumab or placebo, serious adverse events, and adverse events that led to death were balanced in the two groups. Among patients with COPD who had type 2 inflammation as indicated by elevated blood eosinophil counts, those who received dupilumab had fewer exacerbations, better lung function and quality of life, and less severe respiratory symptoms than those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; BOREAS ClinicalTrials.gov number, NCT03930732.).

Summary Aims Chronic obstructive pulmonary disease (COPD) is usually a progressive condition. Undiagnosed early‐stage disease, particularly in symptomatic patients, is likely to become more severe with time. Hence, prevention or reduction in disease progression is highly relevant. We evaluated the published data and discussed the potential impact of early intervention on the course of COPD. Methods We performed PubMed searches of studies in early or mild COPD, focusing on those relating to lung function decline. Results Smoking cessation reduced lung function decline at all stages of COPD, and the earlier the intervention, the greater the impact on lung function. Accumulating data from placebo‐controlled trials suggested that long‐acting bronchodilators can slow the decline in lung function, as well as reduce exacerbation and mortality rates and improve health‐related quality of life (HRQoL) in patients with mild‐to‐moderate COPD. Inhaled corticosteroids (ICS) do not impact lung function in early COPD, and further research is needed on the role of long‐acting β2‐agonist‐ICS combination therapy in these patients. Conclusions Initiating treatment early in the course of COPD is likely to slow disease progression and improve HRQoL. Current data support maintenance treatment with a long‐acting bronchodilator in this patient group. However, many questions remain unanswered regarding the optimal treatment of mild COPD, and further research is required to develop evidence‐based recommendations in this field.

Recently, two \"fixed triple\" single-inhaler combinations of an inhaled corticosteroid (ICS), a long-acting β -agonist (LABA), and a long-acting muscarinic antagonist (LAMA) have become available for patients with COPD. This review presents the clinical evidence that led to the approval of these triple therapies, discusses the role of ICS in patients with COPD, and presents data on the relative efficacy of \"fixed triple\" (ICS/LAMA/LABA) therapy vs LAMA, ICS/LABA, and LAMA/LABA combinations, and summarizes studies in which ICS/LABAs were combined with LAMAs to form \"open triple\" combinations. Of the five main fixed triple studies completed so far, three evaluated the efficacy and safety of an extrafine formulation of beclometasone dipropionate, formoterol fumarate, and glycopyrronium; the other two studies evaluated fluticasone furoate, vilanterol, and umeclidinium. Overall, compared to LAMA, ICS/LABA, or LAMA/LABA, triple therapy decreased the risk of exacerbations and improved lung function and health status, with a favorable benefit-to-harm ratio. Furthermore, triple therapy showed a promising signal in terms of improved survival. The evidence suggests that triple therapy is the most effective treatment in moderate/severe symptomatic patients with COPD at risk of exacerbations, with marginal if any risk of side effects including pneumonia. Ongoing studies are examining the role of triple therapy in less severe symptomatic patients with COPD and asthma-COPD overlap.

COPD has many hallmarks of autoimmune dysfunction. Driving this autoimmune response are self-antigens, such as highly abundant structural proteins and cellular proteins, which can lead to the production of auto-antibodies. However, controversy surrounds the detection of some of these auto-antibodies as they have often been screened against native, unmodified proteins. Autoantigens arise as a result of a conformational change in the native protein exposing hidden epitopes or by the creation of neo-epitopes through chemical or enzymatic modifications, often caused by oxidative/carbonyl stress. In this study, we screened for auto-antibodies targeting key structural proteins modified by oxidative/carbonyl stress in peripheral blood from stable COPD patients versus control subjects using ELISA. We found an auto-antibody response against unmodified, carbonyl-modified and citrinylated vimentin, with the highest response observed against carbonyl-modified vimentin. Both the IgG and IgM antibody titres against carbonyl-modified were significantly increased in COPD patients compared to healthy non-smokers. Smokers also displayed increased antibody levels against carbonyl-modified vimentin, but only for the IgG isotype. Selectivity analysis indicated that 70% and 63% of COPD patients had higher IgM and IgG titres, respectively, compared to non-smokers. In contrast only 26% and 48% of smokers had higher IgM and IgG titres, respectively, than non-smokers. ROC analysis gave AUC values of 0.78 ( p  < 0.01) and 0.84 ( p  < 0.001) for IgM and IgG, respectively, for COPD versus non-smokers, which fell to 0.70 ( p  < 0.01) and 0.64 (NS), respectively, when asymptomatic smokers were included. No significant increase in antibody titre against carbonyl-modified elastin or collagen was observed in COPD patients or asymptomatic smokers. We conclude that IgM autoantibody responses against carbonyl modified vimentin could serve as a simple blood-based biomarker for COPD, reflecting the disease's pathophysiology, and could help in patient stratification and diagnosis.

AbstractSurface properties of carbon nanotubes in electrochemical sensors can be dramatically altered depending on chemical groups and structural defects present on the surface. The effect of oxidation on structural integrity of multiwalled carbon nanotubes through acidic (nitric/sulfuric acids) and basic (sodium hydroxide) agents has been studied. Chemical modifications of carbon nanotubes structures were evaluated by Raman, Fourier transform infrared spectroscopy and transmission electronic microscopy. Furthermore, these materials were used to construct sensors for electrochemical determination of pesticide methyl parathion (MP). Under optimized conditions, a calibration curve was obtained for MP determination employing a glassy carbon electrode modified with acidic treated and basic treated carbon nanotubes which showed a linear response ranging from 1.0 × 10–7 to 3.4 × 10–5 M with limits of detection of 3.3 × 10–8 and 3.5 ×10–8 M, respectively. Analytical performance of the electrodes showed similar voltammetric behavior providing good sensitivity for the determination of methyl parathion.

Current pharmacological therapies for COPD improve quality of life and symptoms and reduce exacerbations. Given the progressive nature of COPD, it is arguably more important to understand whether the available therapies are able to delay clinical deterioration; the concept of \"clinically important deterioration\" (CID) has therefore been developed. We evaluated the efficacy of the single-inhaler triple combination beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G), using data from three large 1-year studies. The studies compared BDP/FF/G to BDP/FF (TRILOGY), tiotropium (TRINITY), and indacaterol/glycopyrronium (IND/GLY; TRIBUTE). All studies recruited patients with symptomatic COPD, FEV <50%, and an exacerbation history. We measured the time to first CID and to sustained CID, an endpoint combining FEV , St George's Respiratory Questionnaire (SGRQ), moderate-to-severe exacerbations, and death. The time to first CID was based on the first occurrence of any of the following: a decrease of ≥100 mL from baseline in FEV , an increase of ≥4 units from baseline in SGRQ total score, the occurrence of a moderate/severe COPD exacerbation, or death. The time to sustained CID was defined as: a CID in FEV and/or SGRQ total score maintained at all subsequent visits, an exacerbation, or death. Extrafine BDP/FF/G significantly extended the time to first CID vs BDP/FF (HR 0.61, <0.001), tiotropium (0.72, <0.001), and IND/GLY (0.82, <0.001), and significantly extended the time to sustained CID vs BDP/FF (HR 0.64, <0.001) and tiotropium (0.80, <0.001), with a numerical extension vs IND/GLY. In patients with symptomatic COPD, FEV <50%, and an exacerbation history, extrafine BDP/FF/G delayed disease deterioration compared with BDP/FF, tiotropium, and IND/GLY. The studies are registered in ClinicalTrials.gov: TRILOGY, NCT01917331; TRINITY, NCT01911364; TRIBUTE, NCT02579850.

Calverley PMA, Papi A, Page C, et al. 2022;17:1909-1920. The authors wish to correct Figure 1 on page 1912 after it came to their attention an error had been made in the second box of the last row (moderate-to-severe exacerbations), the correct number is 7 not 36. The corrected Figure 1 is shown below: The authors affirm that this error does not affect the results, discussion, and conclusions of the reported study and apologize for any inconvenience caused to the readers.

BackgroundChronic obstructive pulmonary disease (COPD) is characterised by oxidative stress and increased risk of lung carcinoma. Oxidative stress causes DNA damage which can be repaired by DNA-dependent protein kinase complex.ObjectivesTo investigate DNA damage/repair balance and DNA-dependent protein kinase complex in COPD lung and in an animal model of smoking-induced lung damage and to evaluate the effects of oxidative stress on Ku expression and function in human bronchial epithelial cells.MethodsProtein expression was quantified using immunohistochemistry and/or western blotting. DNA damage/repair was measured using colorimetric assays.Results8-OH-dG, a marker of oxidant-induced DNA damage, was statistically significantly increased in the peripheral lung of smokers (with and without COPD) compared with non-smokers, while the number of apurinic/apyrimidinic (AP) sites (DNA damage and repair) was increased in smokers compared with non-smokers (p=0.0012) and patients with COPD (p<0.0148). Nuclear expression of Ku86, but not of DNA-PKcs, phospho-DNA-PKcs, Ku70 or γ-H2AFX, was reduced in bronchiolar epithelial cells from patients with COPD compared with normal smokers and non-smokers (p<0.039). Loss of Ku86 expression was also observed in a smoking mouse model (p<0.012) and prevented by antioxidants. Oxidants reduced (p<0.0112) Ku86 expression in human bronchial epithelial cells and Ku86 knock down modified AP sites in response to oxidative stress.ConclusionsIneffective DNA repair rather than strand breakage per se accounts for the reduced AP sites observed in COPD and this is correlated with a selective decrease of the expression of Ku86 in the bronchiolar epithelium. DNA damage/repair imbalance may contribute to increased risk of lung carcinoma in COPD.