Prolonged mechanical ventilation (PMV) is associated with poor outcomes and a high economic cost. The association between protein intake and PMV has rarely been investigated in previous studies. This ...study aimed to investigate the impact of protein intake on weaning from mechanical ventilation. Patients with the PMV (mechanical ventilation ≥6 h/day for ≥21 days) at our hospital between December 2020 and April 2022 were included in this study. Demographic data, nutrition records, laboratory data, weaning conditions, and survival data were retrieved from the patient’s electronic medical records. A total of 172 patients were eligible for analysis. The patients were divided into two groups: weaning success (n = 109) and weaning failure (n = 63). Patients with daily protein intake greater than 1.2 g/kg/day had significant shorter median days of ventilator use than those with less daily protein intake (36.5 vs. 114 days, respectively, p < 0.0001). Daily protein intake ≥1.065 g/kg/day (odds ratio: 4.97, p = 0.033), daily protein intake ≥1.2 g/kg/day (odds ratio: 89.07, p = 0.001), improvement of serum albumin (odds ratio: 3.68, p = 0.027), and BMI (odds ratio: 1.235, p = 0.014) were independent predictor for successful weaning. The serum creatinine level in the 4th week remained similar in patients with daily protein intake either >1.065 g/kg/day or >1.2 g/kg/day (p = 0.5219 and p = 0.7796, respectively). Higher protein intake may have benefits in weaning in patients with PMV and had no negative impact on renal function.
Differences in the clinical phenotypes and outcomes of fungus-associated asthma remain unclear. We aimed to investigate the presentation of asthmatics with fungal sensitization and/or positive fungal ...isolates.
Clinical characteristics, pulmonary function, microbiological data, allergy test reports, emergency department (ED) visits and hospitalizations were retrieved from the Chang Gung Research Database between 2010 and 2018; the largest electronic medical record-based database in Taiwan. Follow-up care was provided to each patient for 3 years.
A total of 30,754 asthmatics were enrolled, and 7976 were eligible for analysis after applying the exclusion criteria. Of these patients, 694 had sputum examinations for fungi. The patients were divided into four groups: group 1, neither fungal sensitization nor fungal isolates in the sputum (n = 386); group 2, positive fungal sensitization (n = 58); group 3, positive fungal isolates (n = 217); and group 4, concomitant positive fungal sensitization and positive fungal isolates (n = 33). Asthmatic patients with fungal sensitization (groups 2 and 4) demonstrated significantly higher IgE levels compared with those without (groups 1 and 3). Group 4 patients had a higher frequency of hospitalization. Amongst patients under Global Initiative for Asthma (GINA) step 4–5 therapies, group 4 asthmatics possessed significantly higher incidence of respiratory failure.
The prevalence of fungal sensitization and fungal isolates from sputum were even across asthmatic severities, but the clinical impact of fungi may be more significant among patients with more severe disease.
Background
Treatment responsiveness to corticosteroids is excellent for cryptogenic organizing pneumonia (COP) and sarcoidosis, but suboptimal for idiopathic pulmonary fibrosis (IPF)/usual ...interstitial pneumonia (UIP). We hypothesise that the differential expression of IL-17 contributes to variable corticosteroid sensitivity in different interstitial lung diseases.
Objective
To determine the associations among expression of IL-17, glucocorticoid receptor-β and responsiveness to corticosteroid treatment in interstitial lung diseases.
Methods
Immunohistochemical (IHC) staining was performed on formalin-fixed paraffin-embedded (FFPE) lung tissues obtained by bronchoscopic, CT-guided or surgical biopsies, and quantified by both cell counting (% positive cells) by individuals and by software IHC Profiler plugin of ImageJ (opacity density score). We studied the effect of IL-17 on corticosteroid sensitivity in human fibroblast MRC5 cell line.
Results
Compared with specimens from patients with COP (n =13) and sarcoidosis (n =13), those from IPF patients (n = 21) had greater GR-β and IL-17 expression and neutrophil infiltration. Radiographic progression after oral corticosteroid treatment was positively correlated with the expression in IL-17 and GR-β/GR-α ratio in all patients (COP, sarcoidosis and IPF) and also within the IPF subgroup only. IL-17 expression level was positively associated with GR-β and GR-β/GR-α ratio. In MRC5 cells, exogenous IL-17 increased the production of collagen I and up-regulated GR-β expression and dexamethasone’s suppressive effect on collagen I production was impaired by IL-17, and silencing IL-17 receptor A gene attenuated the effect of IL-17.
Conclusion
Up-regulation of GR-β/GR-α ratio by IL-17 could be associated with the relative corticosteroid-insensitivity of IPF.
Semiconductor crystals have generally shown facet‐dependent electrical, photocatalytic, and optical properties. These phenomena have been proposed to result from the presence of a surface layer with ...bond‐level deviations. To provide experimental evidence of this structural feature, synchrotron X‐ray sources are used to obtain X‐ray diffraction (XRD) patterns of polyhedral cuprous oxide crystals. Cu2O rhombic dodecahedra display two distinct cell constants from peak splitting. Peak disappearance during slow Cu2O reduction to Cu with ammonia borane differentiates bulk and surface layer lattices. Cubes and octahedra also show two peak components, while diffraction peaks of cuboctahedra are comprised of three components. Temperature‐varying lattice changes in the bulk and surface regions also show shape dependence. From transmission electron microscopy (TEM) images, slight plane spacing deviations in surface and inner crystal regions are measured. Image processing provides visualization of the surface layer with depths of about 1.5–4 nm giving dashed lattice points instead of dots from atomic position deviations. Close TEM examination reveals considerable variation in lattice spot size and shape for different particle morphologies, explaining why facet‐dependent properties are emerged. Raman spectrum reflects the large bulk and surface lattice difference in rhombic dodecahedra. Surface lattice difference can change the particle bandgap.
High‐resolution X‐ray diffraction patterns reveal bulk and surface layer components for polyhedral Cu2O crystals, while transmission electron microscopy analysis provides first visual evidence of the surface layer contributing to their various facet‐dependent properties. The surface layer can affect Raman spectra and tune the crystal bandgap.
Bronchiectasis is characterized by systemic inflammation and multiple comorbidities. This study aimed to investigate the clinical outcomes based on the bronchiectasis etiology comorbidity index ...(BACI) score in patients hospitalized for severe bronchiectasis exacerbations. We included non-cystic fibrosis patients hospitalized for severe bronchiectasis exacerbations between January 2008 and December 2016 from the Chang Gung Research Database (CGRD) cohort. The main outcome was the 1-year mortality rate after severe exacerbations. We used the Cox regression model to assess the risk factors of 1-year mortality. Of 1,235 patients who were hospitalized for severe bronchiectasis exacerbations, 641 were in the BACI < 6 group and 594 in the BACI ≥ 6 group. The BACI ≥ 6 group had more previous exacerbations and a lower FEV
.
(19.1%) was the most common bacterium, followed by
(7.5%). Overall, 11.8% of patients had respiratory failure and the hospital mortality was 3.0%. After discharge, compared to the BACI < 6 group, the BACI ≥ 6 group had a significantly higher cumulative incidence of respiratory failure and mortality in a 1-year follow-up. The risk factors for 1-year mortality in a multivariate analysis include age hazard ratio (HR) 4.38,
= 0.01, being male (HR 4.38,
= 0.01), and systemic corticosteroid usage (HR 6.35,
= 0.001), while airway clearance therapy (ACT) (HR 0.50,
= 0.010) was associated with a lower mortality risk. An increased risk of respiratory failure and mortality in a 1-year follow-up after severe exacerbations was observed in bronchiectasis patients with multimorbidities, particularly older age patients, male patients, and patients with a history of systemic corticosteroid use. ACT could effectively improve the risk for 1-year mortality.
The development of drug resistance in oral squamous cell carcinoma (OSCC) that frequently leads to recurrence and metastasis after initial treatment remains an unresolved challenge. Presence of ...cancer stem cells (CSCs) has been increasingly reported to be a critical contributing factor in drug resistance, tumor recurrence and metastasis. Thus, unveiling of mechanisms regulating CSCs and potential targets for developing their inhibitors will be instrumental for improving OSCC therapy.
siRNA, shRNA and miRNA that specifically target keratin 17 (KRT17) were used for modulation of gene expression and functional analyses. Sphere-formation and invasion/migration assays were utilized to assess cancer cell stemness and epithelial mesenchymal transition (EMT) properties, respectively. Duolink proximity ligation assay (PLA) was used to examine molecular proximity between KRT17 and plectin, which is a large protein that binds cytoskeleton components. Cell proliferation assay was employed to evaluate growth rates and viability of oral cancer cells treated with cisplatin, carboplatin or dasatinib. Xenograft mouse tumor model was used to evaluate the effect of KRT17- knockdown in OSCC cells on tumor growth and drug sensitization.
Significantly elevated expression of KRT17 in highly invasive OSCC cell lines and advanced tumor specimens were observed and high KRT17 expression was correlated with poor overall survival. KRT17 gene silencing in OSCC cells attenuated their stemness properties including markedly reduced sphere forming ability and expression of stemness and EMT markers. We identified a novel signaling cascade orchestrated by KRT17 where its association with plectin resulted in activation of integrin β4/α6, increased phosphorylation of FAK, Src and ERK, as well as stabilization and nuclear translocation of β-catenin. The activation of this signaling cascade was correlated with enhanced OSCC cancer stemness and elevated expression of CD44 and epidermal growth factor receptor (EGFR). We identified and demonstrated KRT17 to be a direct target of miRNA-485-5p. Ectopic expression of miRNA-485-5p inhibited OSCC sphere formation and caused sensitization of cancer cells towards cisplatin and carboplatin, which could be significantly rescued by KRT17 overexpression. Dasatinib treatment that inhibited KRT17-mediated Src activation also resulted in OSCC drug sensitization. In OSCC xenograft mouse model, KRT17 knockdown significantly inhibited tumor growth, and combinatorial treatment with cisplatin elicited a greater tumor inhibitory effect. Consistently, markedly reduced levels of integrin β4, active β-catenin, CD44 and EGFR were observed in the tumors induced by KRT17 knockdown OSCC cells.
A novel miRNA-485-5p/KRT17/integrin/FAK/Src/ERK/β-catenin signaling pathway is unveiled to modulate OSCC cancer stemness and drug resistance to the common first-line chemotherapeutics. This provides a potential new therapeutic strategy to inhibit OSCC stem cells and counter chemoresistance.
Influenza infection is a cause of exacerbations in patients with chronic pulmonary diseases. The aim of this study was to investigate the clinical outcomes and identify risk factors associated with ...hospitalization and mortality following influenza infection in adult patients with bronchiectasis. Using the Chang Gung Research Database, we identified patients with bronchiectasis and influenza-related infection (ICD-9-CM 487 and anti-viral medicine) between 2008 and 2017. The main outcomes were influenza-related hospitalization and in-hospital mortality rate. Eight hundred sixty-five patients with bronchiectasis and influenza infection were identified. Five hundred thirty-six (62%) patients with bronchiectasis were hospitalized for influenza-related infection and 118 (22%) patients had respiratory failure. Compared to the group only seen in clinic, the hospitalization group was older, with more male patients, a lower FEV
higher bronchiectasis aetiology comorbidity index (BACI), and more acute exacerbations in the previous year. Co-infections were evident in 55.6% of hospitalized patients, mainly caused by
(15%), fungus (7%), and
(6%). The respiratory failure group developed acute kidney injury (36% vs. 16%;
< 0.001), and shock (47% vs. 6%;
< 0.001) more often than influenza patients without respiratory failure. The overall mortality rate was 10.8% and the respiratory failure group exhibited significantly higher in-hospital mortality rates (27.1% vs. 6.2%;
< 0.001). Age, BACI, and previous exacerbations were independently associated with influenza-related hospitalization. Age, presence of shock, and low platelet counts were associated with increased hospital mortality. Influenza virus caused severe exacerbation in bronchiectasis, especially in those who were older and who had high BACI scores and previous exacerbations. A high risk of respiratory failure and mortality were observed in influenza-related hospitalization in bronchiectasis. We highlight the importance of preventing or treating influenza infection in bronchiectasis.
Background and objective
Circulating fibrocytes act as precursors of myofibroblasts, contribute to airway remodelling in chronic asthma and migrate to injured tissues by expressing CXCR4 and CCR7. ...Anti‐IgE therapy improves severe allergic asthma (SAA) control and airway remodelling in T2‐high SAA. The effects of anti‐IgE therapy on fibrocyte activities were investigated in this study.
Methods
The expression of CCR7, CXCR4, ST2 and α‐SMA (α‐smooth muscle actin) in both circulating and cultured fibrocytes from all patients with asthma was measured, and was repeated after omalizumab treatment in SAA. Fibrocytes recruitment, proliferation and transformation were also measured in response to anti‐IgE therapy.
Results
Omalizumab effectively improved asthma control and pulmonary function in T2‐high SAA, associated with a decline in serum levels of IL‐33 and IL‐13. Omalizumab down‐regulates CXCR4 and CCR7 expression of fibrocytes, which could suppress fibrocyte recruitment into the lungs. Omalizumab also suppressed the increased number of fibrocytes and α‐SMA+ fibrocytes within the cultured non‐adherent non‐T (NANT) cells after 3–7 days of culture. The decrease in serum levels of IL‐33 by omalizumab contributed to the effectiveness in inhibiting fibrocyte recruitment, proliferation and myofibroblast transformation through IL‐33/ST2 axis. The elevated IL‐13 expression in SAA patients potentiated the effects of IL‐33 by increasing ST2 expression.
Conclusion
Omalizumab reduced the number of circulating fibrocytes, cell and number of fibrocytes as well as α‐SMA+ fibrocytes after 3–7 days of culture in SAA patients. IL‐33 and IL‐13 may be implicated in the effectiveness of omalizumab in inhibiting fibrocyte activation contributing partly to the clinical benefits in reducing lamina propria and basement membrane thickening.
Omalizumab suppressed fibrocyte chemotaxis, proliferation and myofibroblast transformation in severe allergic asthma patients. IL‐33 and IL‐13 may be implicated in the effectiveness of omalizumab in inhibiting fibrocyte activation contributing partly to the clinical benefits in reducing lamina propria and basement membrane thickening.
See related Editorial
Glucoregulatory efficiency and ATP production are key regulators for neuronal plasticity and memory formation. Besides its chemotactic and neuroinflammatory functions, the CC chemokine--CCL5 displays ...neurotrophic activity. We found impaired learning-memory and cognition in CCL5-knockout mice at 4 months of age correlated with reduced hippocampal long-term potentiation and impaired synapse structure. Re-expressing CCL5 in knockout mouse hippocampus restored synaptic protein expression, neuronal connectivity and cognitive function. Using metabolomics coupled with FDG-PET imaging and seahorse analysis, we found that CCL5 participates in hippocampal fructose and mannose degradation, glycolysis, gluconeogenesis as well as glutamate and purine metabolism. CCL5 additionally supports mitochondrial structural integrity, purine synthesis, ATP generation, and subsequent aerobic glucose metabolism. Overexpressing CCL5 in WT mice also enhanced memory-cognition performance as well as hippocampal neuronal activity and connectivity through promotion of de novo purine and glutamate metabolism. Thus, CCL5 actions on glucose aerobic metabolism are critical for mitochondrial function which contribute to hippocampal spine and synapse formation, improving learning and memory.
Bronchiectasis is a chronic infectious respiratory disease with diverse causes and ethnic or geographic differences. However, few large-scale studies of its etiology have been conducted in Asia. This ...study aimed to determine the etiology and clinical features of bronchiectasis in Taiwan.
This longitudinal cohort study investigated the etiology and clinical features of newly diagnosed non-cystic fibrosis bronchiectasis patients from January 2002 to December 2016. The clinical, functional and microbiological data of patients were retrieved from the Chang Gung Research Database, which includes seven medical facilities throughout Taiwan. The index date was the date of the first bronchiectasis diagnosis. Known diseases that were diagnosed before the index date were regarded as etiologies of bronchiectasis.
The cohort comprised 15,729 adult patients with bronchiectasis. Idiopathic (32%) was the most common cause, followed by post-pneumonia (24%). Other causes included post-tuberculosis (12%), chronic obstructive pulmonary disease (14%), asthma (10%), gastroesophageal reflux disease (2%) and rheumatic diseases (2%). At diagnosis, 8487 patients had sputum culture. Pseudomonas aeruginosa (5.3%) was the most common bacteria, followed by non-tuberculosis mycobacteria (3.6%), Haemophilus influenzae (3.4%) and Klebsiella pneumoniae (3.1%), but 6155 (72.1%) had negative sputum cultures. Patients with post-tuberculosis had a higher sputum isolation rate of non-tuberculosis mycobacteria than P. aeruginosa. Patients with post-tuberculosis and post-pneumonia bronchiectasis had a higher frequency of chronic lung infection than other groups (p < 0.05). Clinical characteristics, such as gender, lung function, comorbidities and microbiology, were significantly different between idiopathic and known etiologies.
Idiopathic, post-infection and tuberculosis constitute major bronchiectasis etiologies in Taiwan. Clinical characteristics and sputum microbiology were distinct among separate etiology phenotypes.
PDF
