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Purpose: Ventilator-associated pneumonia (VAP) is a common ICU complication linked to high morbidity and mortality. Inhaled antibiotics may offer targeted prophylaxis, but their effectiveness has shown mixed results. This study aims to further evaluate whether inhaled antibiotics reduce VAP incidence and ICU mortality through a systematic review and meta-analysis of the most updated available evidence.

Methods: A systematic review was conducted following PRISMA 2020 guidelines. Multiple databases were searched for studies published up to November 14, 2024. Ten studies including 2876 patients (1485 intervention; 1391 control) met inclusion criteria. A random-effects meta-analysis was performed to estimate pooled risk ratios (RR) for VAP incidence and ICU mortality. Risk of bias was assessed using ROBINS-I and certainty of evidence via GRADE.

Results: Inhaled antibiotics significantly reduced the incidence of VAP compared to controls (RR = 0.67; 95% CI: 0.58-0.77; p < 0.001), but showed no significant effect on ICU mortality (RR = 0.92; 95% CI: 0.79-1.06; p = 0.25). Moderate heterogeneity was observed in VAP outcomes (I² = 46.8%), while mortality analysis showed no heterogeneity. Funnel plot analysis suggested minimal publication bias, and GRADE rated the evidence as moderate in certainty.

Conclusion: Inhaled antibiotics significantly reduce VAP incidence but show no clear mortality benefit. While promising for prevention, their survival impact remains uncertain. Clinical use should consider patient context and microbial patterns for targeted approach. Future research should identify high-risk subgroups, assess long-term outcomes, and evaluate antibiotic resistance.

Background: The methacholine challenge requires a 20% fall in forced expiratory volume in one second (FEV₁). The fall is measured as litre (L) change from the pre-challenge (baseline) value. A higher baseline FEV₁ requires a greater volume change to reach a 20% fall. The aim of this study was to evaluate change using percent predicted, which may remove dependence on the baseline value.

Methods: Challenge data from a cohort of 114 asthma patients was re-analysed. The dose causing an 20% fall from baseline (PD₂₀) was compared to a 15% fall in predicted value (PD_15%) for the classification of bronchial hyperresponsiveness.

Results: There was significant agreement between PD₂₀ and PD_15% (r = 0.95, p < 0.0001), with an ICC of 0.97. PD₂₀ was significantly higher than PD_15% (0.0055 mg, p < 0.0001). Greater decreases in FEV₁ were observed with PD₂₀ versus PD_15% (21.4% pred vs 19.1% pred respectively, p = 0.0004), with 29% of patients requiring at least one additional dose of methacholine to achieve PD₂₀ compared to PD_15%. A higher baseline FEV₁ resulted in higher PD₂₀ values, whereas no relationship was found for PD_15%. Variability in FEV₁ between repeated visits (n = 15) was associated with the change in PD₂₀, but not the change in PD_15%.

Conclusion: We suggest a PD criteria based on 15% predicted change should be used for bronchial challenge testing. This method is less influenced by baseline airflow obstruction, and is a more efficient and safer way of measuring airway hyperresponsiveness.

Purpose: Acute respiratory distress syndrome (ARDS)/Acute lung injury (ALI), characterized by severe hypoxemia and pulmonary edema, involves mitochondrial dysfunction. Cytidine/uridine monophosphate kinase 2 (Cmpk2), a mitochondrial metabolic enzyme, modulates inflammation and senescence, yet its role in ARDS remains unclear. We investigated Cmpk2's function in Pseudomonas aeruginosa (P. aeruginosa)-induced ALI using Cmpk2 global knockout (KO) mice.

Methods: Cmpk2 was identified through mitochondrial gene expression analysis of ARDS datasets (GEO). Murine ALI was induced by intratracheal P. aeruginosa injection. Lung pathology (hematoxylin and eosin staining), leukocyte recruitment (flow cytometry), and cytokines (ELISA) were assessed. GO/KEGG analyses were conducted to identify Cmpk2-associated biological processes and pathways. The expression of Cmpk2 in leukocyte populations was analyzed using single-cell RNA sequencing (scRNA-seq) data from ARDS patient samples. Mouse neutrophils' phagocytosis of P. aeruginosa was quantified by flow cytometry. Zebrafish embryos were infected with P. aeruginosa and Staphylococcus aureus for bacterial burden and survival assays.

Results: Cmpk2 expression was significantly upregulated in ARDS. Cmpk2 KO exacerbated P. aeruginosa-induced ALI in mice, as evidenced by increased pathological damage and permeability, elevated proinflammatory cytokines and enhanced neutrophil infiltration. GO/KEGG analyses linked Cmpk2 to innate immunity. scRNA-seq analysis revealed an enriched expression of Cmpk2 in neutrophils. Cmpk2 deficiency impaired neutrophil phagocytosis and reduced host survival during bacterial infection, accomplished by decreased STING expression. The differences in phagocytosis between the wild-type and Cmpk2 KO mouse neutrophils/zebrafish embryos were eliminated by STING inhibitor C176.

Conclusion: Cmpk2 protects against pneumonia by attenuating neutrophil recruitment and enhancing bacterial phagocytosis via STNG-dependent mechanisms.

Introduction/purpose: Right ventricle (RV) dysfunction in the setting of acute pulmonary embolism (PE) is associated with worse outcomes. The ratio of tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) provides an estimate of right ventricular-arterial (RV-PA) coupling and has been associated with adverse outcomes in patients with pulmonary hypertension. In this study, we examined if RV-PA uncoupling can further risk stratify acute PE.

Methods: This is a single-center, retrospective analysis of patients admitted to a tertiary center with the diagnosis of acute PE. The Kruskal-Wallis Rank Sum, Wilcoxon Rank Sum, and Chi-square tests were used to identify clinical features associated with reduced RV-PA uncoupling at three distinct thresholds, severe (< 0.31), moderate (0.31-0.4) and mild (> 0.4-1.75) derived from prior studies.

Results: 146 patients were included in our analysis. Patients with severely impaired RV-PA uncoupling ratios were more likely to have RV dysfunction by CT defined as CT RV/LV ratio > 0.9 (p < 0.01) and were more likely to need veno-arterial extracorporeal membrane oxygenation (VA-ECMO) compared to those that had moderate or mild impairment (p < 0.01). We also found a correlation between BNP (r = - 0.44, p < 0.01), lactate levels (r = - 0.18 p = 0.04), and the TAPSE/PASP ratio. European Society of Cardiology, sPESI, and BOVA risk stratification scores did not distinguish between patients with mild, moderate, or severe RV-PA uncoupling.

Conclusion: Patients with acute PE who have severely impaired RV-PA uncoupling ratios have more severe disease, characterized by elevated biomarkers and need for VA-ECMO. TAPSE/PASP values can be used to risk stratify and guide treatment of acute PE.

Background: Smoking is a major risk factor for lung function decline and chronic obstructive pulmonary disease (COPD), but the individual susceptibility to these traits cannot be explained solely by environmental risk factors.

Aim: To estimate the relative contribution of genetic and environmental factors to lung function, chronic bronchitis and COPD.

Methods: 12,449 twins aged 40-80 years participated in a nationwide survey using the Danish Twin Registry, which included a questionnaire, clinical examination and spirometry. Clinical COPD was defined by respiratory symptoms plus airflow obstruction. Biometric models of genetic and environmental latent factors were used to estimate the heritability after adjusting for sex, age, and height.

Results: Mean (SD) age of the study population was 58.4 (9.6) years and mean BMI (kg/m²) was 26.6 (4.4); 20% were current smokers and 52% were females. The heritability of FEV₁, FVC and FEV₁/FVC was 64% (60-67%), 61% (57-65%), and 50% (46-55%), respectively. Genetic factors explained 48% (24-72%) and 47% (16-78%), respectively, of the individual susceptibility to chronic bronchitis and clinical COPD.

Conclusion: Genetic factors explain at least half of the variation in lung function and around half of the individual susceptibility to chronic bronchitis and clinical COPD, respectively, when adjusted for sex, age, height.

Background: Macrophage polarization is essential for inflammatory regulation in COPD. The precise role of BPI Fold-Containing Family B Member 4 (BPIFB4) in regulating the inflammatory processes underlying COPD pathogenesis remains to be fully elucidated. This investigation seeks to clarify how BPIFB4 modulates macrophage polarization by activating the phosphoinositide 3-kinase (PI3K)-AKT1 signaling pathway, thereby influencing inflammatory progression in COPD.

Methods: In a COPD mouse model induced by cigarette smoke (CS) and lipopolysaccharide (LPS) and in cigarette smoke extract (CSE)-treated THP-1 cells, BPIFB4 was overexpressed or silenced. Bronchoalveolar lavage fluid, lung tissues, and serum were collected. qPCR and western blots assessed BPIFB4 and PI3K-AKT1 pathway expression in lung tissues and THP-1 cells. Flow cytometry evaluated M1/M2 macrophage polarization, and enzyme-linked immunosorbent assay (ELISA) measured related cytokine levels.

Results: The results demonstrated how BPIFB4 gene silencing resulted in more pronounced lung tissue and functional damage compared to BPIFB4 overexpression, alongside an elevated presence of M1 macrophages and associated pro-inflammatory factors. In contrast, BPIFB4 overexpression in both COPD mice and CSE-treated THP-1 cells significantly enhanced p-AKT1 and p-PI3K levels while reducing the number of M1 macrophages. In addition, inhibition of the PI3K-AKT1 pathway reversed these effects, resulting in a marked increase in M1 macrophages and their associated cytokines.

Conclusion: BPIFB4 overexpression alleviates M1 macrophage polarization by activating the PI3K-AKT1 pathway, thereby reducing lung tissue damage and dysfunction in COPD mice.

Pyruvate kinase M2 (PKM2) is a critical enzyme regulating cell metabolism and growth under different physiological conditions. In its metabolic role, PKM2 catalyzes the final and also a rate-limiting reaction in the glycolytic pathway, converting phosphoenolpyruvate (PEP) to pyruvate while phosphorylating adenosine diphosphate (ADP) to pyruvate and adenosine-triphosphate (ATP). Also, PKM2 has been reported to function as a protein kinase that regulates gene transcription and expression involved in cellular growth and survival. Current studies have focused on the glycolytic and non‑glycolytic functions of PKM2 in various tissues and organs. In this review, we summarize the in-depth role of PKM2 in the pathogenesis in pulmonary diseases including chronic obstructive pulmonary disease (COPD), asthma, pulmonary arterial hypertension (PAH), acute lung injury (ALI), pulmonary fibrosis, infectious lung disease and lung cancer. We also discuss its potential applications in disease diagnosis and therapies.

Poor or worsening functional status of lung transplant (LTx) candidates is a key risk factor for waitlist and post-transplant mortality. As more critically ill adults and children are listed for LTx, the use of extracorporeal membrane oxygenation (ECMO) as bridge to LTx is also increasing. Sustaining optimal functional status while on the waitlist to LTx is crucial for LTx candidates as deterioration in functional status can negatively impact pre- and post-LTx outcomes. We conducted an analysis of the United Network for Organ Sharing Registry which showed that most patients (70%) on ECMO successfully bridged to LTx. The majority had severely limited functional status at the time of waitlisting but 96% of adults requiring ECMO on the waitlist for LTx either maintained or improved functional status from the time of waitlist to the time of LTx while all children on ECMO maintained or improved their functional status. With continuing medical and technical advances, the use of ECMO may also evolve to improve LTx candidates' functional status.

Purpose: Pregnancy is a risk factor for the development of obstructive sleep apnea (OSA) and for worsening of asthma; the interaction between the two disorders is not well described. We aimed to examine airway mechanics in pregnant patients with and without OSA and asthma.

Methods: We studied 217 women with BMI above 25 early in the second trimester of pregnancy. Airways resistance was measured using the forced oscillation technique at 5 Hz (R5), 20 Hz (R20), and 35 Hz (R35). All values were expressed as % predicted. level III sleep studies were scored according to the recommended AASM rules; OSA was diagnosed by AHI ≥ 5 events per hour. Asthma was defined by medical history and record review.

Results: Of the 217 women tested, 53 had OSA and 66 had asthma. R20 and R35 were increased in women with both OSA and asthma compared to those with neither asthma nor OSA (adjusted mean difference (aMD) for R20 was 19.7, CI 3.4-36.0, p value = 0.02; aMD for R35 was 36.9 CI 12.4-61.5, p value = 0.003). There was a significant increase in R35 for women with OSA as opposed to those without (aMD 17.6 (CI 1.4-33.8; p value = 0.03).

Conclusion: Pregnant women with both OSA and asthma have higher central airways resistance and upper airway resistance as measured at R20 and R35, respectively, compared to those with neither OSA nor asthma. Further work is needed to understand mechanisms underlying the synergistic effects of OSA and asthma on airways mechanics.