Prone positioning does not improve outcomes of intubated patients with pneumocystis pneumonia and moderate-severe acute respiratory distress syndrome: a single-center, retrospective, observational, cohort study.

BACKGROUND: Pneumocystis pneumonia is an uncommon precipitant of acute respiratory distress syndrome and is associated with high mortality. Prone positioning ventilation has been proven to reduce mortality in patients with moderate-severe acute respiratory distress syndrome. We investigated the effect of prone positioning on oxygenation and mortality in intubated patients with pneumocystis pneumonia comorbid with moderate-severe acute respiratory distress syndrome. METHODS: In this single-center, retrospective, observational, cohort study, eligible patients were enrolled at West China Hospital of Sichuan University from January 1, 2017, to December 31, 2021. Data on demographics, clinical features, ventilation parameters, arterial blood gas, and outcomes were collected. Patients were assigned to the prone cohort or supine cohort according to whether they received prone positioning ventilation. The main outcome was 28-day mortality. FINDINGS: A total of 79 patients were included in the study. Sixty-three patients were enrolled in the prone cohort, and 16 patients were enrolled in the supine cohort. The 28-day mortality was 61.9% in the prone cohort and 68.8% in the supine cohort (P = 0.26), and 90-day mortality was 66.7% in the prone cohort and 68.8% in the supine cohort (P = 0.55). Patients in the supine cohort had fewer invasive mechanical ventilation days and more ventilator-free days. The incidence of complications was higher in the prone cohort than in the supine cohort. CONCLUSIONS: In patients with pneumocystis pneumonia and moderate-severe acute respiratory distress syndrome, prone positioning did not decrease 28-day or 90-day mortality. Trial registration ClinicalTrials.gov number, ChiCTR2200063889. Registered on 20 September 2022, https://www.chictr.org.cn/showproj.html?proj=174886 .

Bibliometric analysis of the pirfenidone and nintedanib in interstitial lung diseases.

Background: At the beginning of 21st century, reclassification of fibrosing interstitial lung diseases (ILD) scored academic concerning, and then propelled development. Decade before, pifenidone and nintedanib were approved for idiopathic pulmonary fibrosis, but no more drugs are yet available. To evaluate the development traits of pirfenidone and nintedanib in fibrosing ILD, including the influential country, institution, authors, keywords, and the major problems or the priorities of the field emerge and evolve, bibliometric analysis was used to summarize and draw scientific knowledge maps. Methods: We confined the words to "pirfenidone", "nintedanib", "pulmonary fibrosis", and "lung disease, interstitial". Publications were retrieved from the Web of Science Core Collection on February 24, 2024 with the search strategies. Citespace and VOSviewer were adopted for bibliometric analysis. Results: For the knowledge map of pirfenidone, a total of 4359 authors from 279 institutions in 58 countries/regions contributed to 538 studies. The United States and Italy are way ahead. Genentech Inc and the University of Turin are the institutions with the strongest influence. AM J RESP CRIT CARE is the maximized influential periodical. Raghu G was the most frequently co-cited scholar. keywords cluster demonstrated that vital capacity, safety, outcome, effectiveness, acute exacerbation, pathway, cell, collagen were the hotspots. The burst timeline of hotspots and references revealed academic transitions of pirfenidone-related studies. About the knowledge map of nintedanib, 3297 authors from 238 institutions in 47 countries/regions published 374 studies. Japan, the United States, and Italy are the most productive countries. Boehringer Ingelheim is the overriding productive institution. New ENGL J MED have important roles in reporting milestones of nintedanib. Richeldi L carried numerous capital publications to support the anti-fibrotic effect of nintedanib. From the network of co-occurrence keywords, idiopathic pulmonary fibrosis, efficacy, and safety were the hotspots. Nintedanib for systemic sclerosis-related ILD and progressive pulmonary fibrosis is the hotspot with sharp evolution recently. Conclusions: We summarized and showed developmental alterations of pirfenidone and nintedanib in fibrosing ILD through bibliographic index-based analysis. Our findings showed just dozen years sharp development period of pirfenidone and nintedanib in ILD, and identifies potential partners for interested researchers. The burst of hotspots demonstrated the evolvement of research priorities and major problems, and we observed the transition of keywords from experimental terms like mouse, bleomycin, cell, pathway, collagen, gene expression, to clinical terms including efficacy, safety, survival, acute exacerbation, and progressive pulmonary fibrosis. In the future, exploration about disparity models of drug administration, differences between early and later initiate anti-fibrotic therapy, both short-term and long-term efficacy of pirfenidone and nintedanib in fibrosing ILD, specifically in connective disease associate ILD would be emphatically concerned by pulmonologists.

Nebulized platelet-derived extracellular vesicles attenuate chronic cigarette smoke-induced murine emphysema.

Chronic obstructive pulmonary disease (COPD) is a prevalent lung disease usually resulting from cigarette smoking (CS). Cigarette smoking induces oxidative stress, which causes inflammation and alveolar epithelial cell apoptosis and represents a compelling therapeutic target for COPD. Purified human platelet-derived exosome product (PEP) is endowed with antioxidant enzymes and immunomodulatory molecules that mediate tissue repair. In this study, a murine model of CS-induced emphysema was used to determine whether nebulized PEP can influence the development of CS-induced emphysema through the mitigation of oxidative stress and inflammation in the lung. Nebulization of PEP effectively delivered the PEP vesicles into the alveolar region, with evidence of their uptake by type I and type II alveolar epithelial cells and macrophages. Lung function testing and morphometric assessment showed a significant attenuation of CS-induced emphysema in mice treated with nebulized PEP thrice weekly for 4 weeks. Whole lung immuno-oncology RNA sequencing analysis revealed that PEP suppressed several CS-induced cell injuries and inflammatory pathways. Validation of inflammatory cytokines and apoptotic protein expression on the lung tissue revealed that mice treated with PEP had significantly lower levels of S100A8/A9 expressing macrophages, higher levels of CD4+/FOXP3+ Treg cells, and reduced NF-κB activation, inflammatory cytokine production, and apoptotic proteins expression. Further validation using in vitro cell culture showed that pretreatment of alveolar epithelial cells with PEP significantly attenuated CS extract-induced apoptotic cell death. These data show that nebulization of exosomes like PEP can effectively deliver exosome cargo into the lung, mitigate CS-induced emphysema in mice, and suppress oxidative lung injury, inflammation, and apoptotic alveolar epithelial cell death.

Clinical characteristics and predictors of pulmonary hypertension in chronic obstructive pulmonary disease at different altitudes.

BACKGROUND: Pulmonary hypertension (PH) is a common complication in patients with chronic obstructive pulmonary disease (COPD) and is closely associated with poor prognosis. However, studies on the predictors of PH in COPD patients are limited, especially in populations living at high altitude (HA). OBJECTIVES: To investigate the differences in the clinical characteristics and predictors of patients with COPD/COPD and PH (COPD-PH) from low altitude (LA, 600 m) and HA (2200 m). METHODS: We performed a cross-sectional survey of 228 COPD patients of Han nationality admitted to the respiratory department of Qinghai People's Hospital (N = 113) and West China Hospital of Sichuan University (N = 115) between March 2019 and June 2021. PH was defined as a pulmonary arterial systolic pressure (PASP) > 36 mmHg measured using transthoracic echocardiography (TTE). RESULTS: The proportion of PH in COPD patients living at HA was higher than that in patients living at LA (60.2% vs. 31.3%). COPD-PH patients from HA showed significantly different in baseline characteristics, laboratory tests and pulmonary function test. Multivariate logistic regression analysis indicated that the predictors of PH in COPD patients were different between the HA and LA groups. CONCLUSIONS: The COPD patients living at HA had a higher proportion of PH than those living at LA. At LA, increased B-type natriuretic peptide (BNP) and direct bilirubin (DB) were predictors for PH in COPD patients. However, at HA, increased DB was a predictor of PH in COPD patients.

Transcriptomic profiles of age-related genes in female trachea and bronchus.

Background: Studies demonstrated that age-related cellular and functional changes of airway significantly contribute to the pathogenesis of many airway diseases. However, our understanding on the age-related molecular alterations of human airway remains inadequate. Methods: Airway (trachea and bronchus) brushing specimens were collected from 14 healthy, female non-smokers with ages ranging from 20 to 60 years. Bulk RNA sequencing was performed on all the specimens (n = 28). Airway cell types and their relative proportions were estimated using CIBERSORTx. The cell type proportions were compared between the younger (age 20-40) and elder group (age 40-60) in the trachea and bronchus respectively. The linear association between cell type proportion and age was assessed using the Pearson correlation coefficient. Differentially expressed genes (DEGs) between the two age groups were identified using DESeq2. Three kinds of enrichment analysis of the age-related DEGs were performed, including Gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and disease enrichment analysis. Results: Sixteen and thirteen cell types were separately identified in tracheal and bronchial brushings, with the airway epithelial cells (including suprabasal, submucosal gland (SMG) goblet, serous, secretory, multiciliated, cycling.basal, basal cells) accounting for 85.1% in the trachea and 92.5% in the bronchus. The lymphatic cell and NK cells had a higher abundance ratio in the trachea, compared with the bronchus. The proportion of basal cells was negatively related to age both in the trachea and bronchus. Thirty-one and fifty-two age-related DEGs (p < 0.1) were identified in the trachea and bronchus, respectively. Among them, five common DEGs (CXCL2, CXCL8, TCIM, P4HA3, AQP10) were identified. Pathway enrichment analysis showed both tracheal and bronchial age-related DEGs were primarily involved in immune regulatory signaling pathways (TNF, NF-kappa B, IL-17 et al.). Disease enrichment analysis suggested that tracheal age-related DEGs significantly related to asthmatic pulmonary eosinophilia, and chronic airflow obstruction et al., and that bronchial age-related DEGs were enriched in airflow obstruction, bronchiectasis, pulmonary emphysema, and low respiratory tract infection et al. Conclusion: We found the proportion of basal cells decreased with age in both the trachea and bronchus, suggesting a weakening of their self-renew ability with age. We identified transcriptomic signature genes associated with the early aging process of the human trachea and bronchus, and provided evidence to support that changes in their immune regulatory function may play critical roles in age-related airway diseases.

Monitoring small airway dysfunction in connective tissue disease-related interstitial lung disease: a retrospective and prospective study.

BACKGROUND: Small airway dysfunction (SAD), a hallmark of early lung function abnormality, is a major component of several chronic respiratory disorders. The role of SAD in patients with connective tissue disease-related interstitial lung disease (CTD-ILD) has not been explored. METHODS: We conducted a two-parts (retrospective and prospective) study to collect pulmonary function tests from CTD-ILD patients. SAD was defined as at least two of the three measures (MMEF, FEF 50%, and FEF 75%) must be 65% of predicted values. Spearman correlation coefficient was used to evaluate association between SAD and other pulmonary function parameters. Mixed effects regression modeling analysis was used to assess response to treatment. RESULTS: CTD-ILD patients with SAD and without SAD were compared in this study. In the retrospective study, pulmonary function tests (PFTs) from 491 CTD-ILD patients were evaluated, SAD were identified in 233 (47.5%). CTD-ILD patients with SAD were less smokers (17.6% vs. 27.9%, p = 0.007) and more females (74.3% vs. 64.0%, p = 0.015) than those without SAD. CTD-ILD patients with SAD had lower vital capacity (% predicted FVC, 70.4 ± 18.3 vs. 80.0 ± 20.9, p < 0.001) and lower diffusion capacity (% predicted DLCO, 58.8 ± 19.7 vs. 63.8 ± 22.1, p = 0.011) than those without SAD. Among 87 CTD-ILD patients prospectively enrolled, significant improvement in % predicted FVC was observed at 12-months follow-up (6.37 ± 1.53, p < 0.001 in patients with SAD; 5.13 ± 1.53, p = 0.002 in patients without SAD), but not in diffusion capacity and SAD parameters. CONCLUSION: In our cohort, about half of CTD-ILD patients have SAD, which is less frequent in smokers and more common in female patients. CTD-ILD patients with SAD have worse pulmonary function compared to those without SAD. Improvement of FVC but no improvement of SAD was observed in CTD-ILD patients after treatment.

The Role of JAK/STAT Pathway in Fibrotic Diseases: Molecular and Cellular Mechanisms.

There are four members of the JAK family and seven of the STAT family in mammals. The JAK/STAT molecular pathway could be activated by broad hormones, cytokines, growth factors, and more. The JAK/STAT signaling pathway extensively mediates various biological processes such as cell proliferation, differentiation, migration, apoptosis, and immune regulation. JAK/STAT activation is closely related to growth and development, homeostasis, various solid tumors, inflammatory illness, and autoimmune diseases. Recently, with the deepening understanding of the JAK/STAT pathway, the relationship between JAK/STAT and the pathophysiology of fibrotic diseases was noticed, including the liver, renal, heart, bone marrow, and lung. JAK inhibitor has been approved for myelofibrosis, and subsequently, JAK/STAT may serve as a promising target for fibrosis in other organs. Therefore, this article reviews the roles and mechanisms of the JAK/STAT signaling pathway in fibrotic diseases.

Rituximab for the treatment of connective tissue disease-associated interstitial lung disease: A systematic review and meta-analysis.

Background: Interstitial lung disease (ILD) is a common pulmonary disease often associated with significant morbidity and mortality in patients with connective tissue diseases (CTD). Currently, no gold-standard therapies are available for CTD-ILD. Recently, several studies have proposed that rituximab (RTX) may be effective for the treatment of CTD-ILD. Objectives: This study aimed to systematically evaluate the efficacy and safety of RTX for the treatment of CTD-ILD. Methods: Studies were selected from PubMed, Embase, and Cochrane Library, up to 20 July 2022. Improvement and stable rates were extracted as the main outcomes and pooled using the weighted mean proportion with fixed or random-effects models, in case of significant heterogeneity (I 2 > 50%). Safety analysis was performed based on the adverse events reported in all of the studies. Results: Thirteen studies (312 patients) were included in the meta-analysis. The follow-up durations ranged from 6 to 36 months. The pooled improvement rate was 35.0% (95% CI: 0.277-0.442), while the pooled stable rate was 59.2% (95% CI: 0.534-0.656). Anti-synthetase syndrome associated with ILD [ASS-ILD, 48.1% (95% CI, 0.373-0.620)] and idiopathic inflammatory myopathies associated with ILD [IIM-ILD, non-ASS, 47.4% (95% CI, 0.266-0.846)] had higher improvement rates than the other types. A total of 106 adverse events associated with RTX or progressive ILD were reported among the 318 patients, 55.7% of which were mild. Among 19 deaths, 17 were due to ILD progression, one to severe pulmonary arterial hypertension, and one to Pneumocystis jirovecii infection. Conclusion: RTX, which exhibits a satisfactory safety profile, is an effective treatment option for CTD-ILD, even in patients who fail to respond to other therapies. Further randomized trials are needed to assess the efficacy of rituximab compared to other treatments for CTD-ILD. Systematic review registration: PROSPERO, identifier (CRD42022363403).

MET-targeted therapies for the treatment of non-small-cell lung cancer: A systematic review and meta-analysis.

Background: Dysregulation of the mesenchymal epithelial transition (MET) pathway contributes to poor clinical outcomes in patients with non-small cell lung cancer (NSCLC). Numerous clinical trials are currently investigating several therapies based on modulation of the MET pathway. Objectives: This study aimed to systematically evaluate the activity and safety of MET inhibitors in patients with NSCLC. Methods: We searched PubMed, Embase, and the Cochrane Library from inception to June 02, 2022. The objective response rate (ORR) and disease control rate (DCR) were extracted as the main outcomes and pooled using the weighted mean proportion with fixed- or random-effects models in cases of significant heterogeneity (I 2>50%). Safety analysis was performed based on adverse events reported in all studies. Results: Eleven studies (882 patients) were included in the meta-analysis. The pooled ORR was 28.1% (95% confidence interval [CI], 0.223-0.354), while the pooled DCR was 69.1% (95% CI, 0.631-0.756). ORRs were higher for tepotinib (44.7% [95% CI, 0.365-0.530]) and savolitinib (42.9% [95% CI, 0.311-0.553]) than for other types of MET inhibitors. Patients with NSCLC with exon 14 skipping exhibited higher ORRs (39.3% (95% CI, 0.296-0.522)) and DCRs (77.8% (95% CI, 0.714-0.847)) than those with MET protein overexpression or amplification. Intracranial response rate and intracranial disease control rates were 40.1% (95% CI, 0.289-0.556) and 95.4% (95% CI, 0.892-0.100), respectively. Adverse events were mild (grade 1 to 2) in 87.2% of patients. Common adverse events above grade 3 included lower extremity edema (3.5% [95% CI, 0.027-0.044]), alanine aminotransferase (ALT) elevation (2.4% [95% CI, 0.014-0.033]), and lipase elevation (2.2% [95% CI, 0.016-0.031]). Conclusion: MET inhibitors, which exhibited a satisfactory safety profile in the current study, may become a new standard of care for addressing MET dysregulation in patients with advanced or metastatic NSCLC, and even in those with brain metastases, particularly tepotinib, savolitinib and capmatinib. Further randomized trials are required to establish standard predictive biomarkers for MET therapies and to compare the effects of different MET inhibitors in NSCLC with MET dysregulation.

Noncanonical JAK1/STAT3 interactions with TGF-ß modulate myofibroblast transdifferentiation and fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with limited survival. Janus kinases (JAKs), tyrosine kinases that transduce cytokine-mediated signals, are known to be involved, but their specific roles in lung fibrosis are not well defined. In this study, the interactions between JAK1/signal transducers and activators of transcription (STAT)3 signaling and transforming growth factor-beta (TGF-ß)-induced fibroblast responses were investigated using both pharmacological and siRNA approaches in human normal and IPF-derived lung fibroblasts. We found that JAK1 directly interacts with the TGF-ß receptor I subunit (TßRI), and silencing JAK1 promotes myofibroblast transdifferentiation. However, the suppression of JAK1 signaling in vitro and in vivo using an inhibitor (upadacitinib) did not alter lung fibroblast activation or fibrosis development. STAT3 was constitutively active in cultured primary lung fibroblasts; this STAT3 activation required JAK1 and repressed myofibroblast transdifferentiation. Loss of phosphorylated STAT3 following transcriptional JAK1 silencing promoted myofibroblast transdifferentiation. In contrast, transcriptional silencing of unphosphorylated STAT3 suppressed TGF-ß signaling, decreased SMAD3 activation, and reduced myofibroblast transdifferentiation and ECM production. Taken together, these observations support a role for JAK1/STAT3 as a direct regulator of TGF-ß signaling in lung fibroblasts. Modulation of JAK1/STAT3 signaling in lung fibroblasts represents a noncanonical approach to regulating TGF-ß-induced fibrosis and suggests the potential for a novel approach to treat pulmonary fibrosis.

Central nervous system infection caused by Mycobacterium houstonense: A case report.

Background: Mycobacterium houstonense is a rapidly growing mycobacterium (RGM) that belongs to the unnamed third biovariant complex of the Mycobacterium fortuitum group, which is rarely responsible for human infection. Approximately 76% of infections caused by the M. fortuitum group occur after open fractures or skin, soft tissue, bone, or puncture wounds. To date, only a few cases of human infectious disease caused by M. houstonense have been reported worldwide. Case presentation: We present a case of a 26-year-old man with a central nervous system (CNS) infection caused by M. houstonense. The patient was transferred to our hospital because of headaches and muscle strength changes. One month prior to presentation at our hospital, the patient was diagnosed with tuberculous meningitis at the other two hospitals, but his condition did not improve after anti-tuberculous treatment, antibiotics, and anti-viral treatment before admission to our hospital. Lumbar puncture was performed at both previous hospitals, as well as at our hospital; the results consistently indicated high cerebrospinal fluid (CSF) opening pressure. M. houstonense was detected in the CSF of the second hospital's lumbar puncture by metagenomic next-generation sequencing (mNGS) but was not identified at our hospital. The patient was discharged from our hospital after receiving non-tuberculous mycobacterium (NTM) treatment for 1 month according to the Chinese NTM guidelines. However, the patient died 20 days after discharge. Conclusion: Since it is difficult to identify M. houstonense, this is the first case of human CNS infection caused by M. houstonense in China. This case may be considered by neurologists and infectious physicians when CNS infection does not respond to conventional treatment, especially in the uncommon type of NTM.

Efficacy and Safety of JAK Inhibitors for Rheumatoid Arthritis: A Meta-Analysis.

Background: More and more trials have been conducted. We aimed to assess the efficacy and safety of different JAKinibs in RA. Methods: A systematic search of randomized controlled trials (RCTs) with JAKinib treatment in RA published in the Medline, Embase, and Cochrane databases up to May 2021 was performed. Results: 37 trials involving 15,174 patients were identified. Pooled analysis revealed that JAKinibs were associated with significant therapeutic improvement in RA patients as determined by ACR20 (RR = 2.03, 95% CI: 1.85 to 2.28) and HAQ-DI (MD = −0.31, 95% CI: −0.33 to −0.28) over placebo. Compared to placebo, JAKinib treatment was also associated with more adverse events (RR = 1.10, p < 0.001; RR = 1.29, p < 0.001; RR = 1.59, p = 0.02). Baricitinib and upadacitinib were related to more frequent adverse events (RR = 1.10; 95% CI: 1.01, 1.21; RR = 1.19; 95% CI: 1.11, 1.28) and infection (RR = 1.22; 95% CI: 1.09, 1.37; RR = 1.38; 95% CI: 1.22, 1.56), whereas only baricitinib was associated with more herpes zoster (RR = 3.15; 95% CI: 1.19, 8.33). Conclusions: JAKinibs were superior to placebo for improving signs, symptoms, and health-related quality of life in RA patients at short term, whereas the overall risk of adverse events and infections were greater with baricitinib and upadacitinib, and a higher risk of herpes zoster was only associated with baricitinib. More trials are needed to investigate the long-term safety.

Canonical and noncanonical regulatory roles for JAK2 in the pathogenesis of rheumatoid arthritis-associated interstitial lung disease and idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated interstitial lung disease (RA-ILD) are two fibrotic interstitial lung diseases that share the usual interstitial pneumonia (UIP) injury pattern. Here, we report that RNA sequencing of lung biopsies from patients with RA-ILD and IPF revealed shared and distinct disease-causing pathways. Analysis of transcriptomic data identified a JAK2 related JAK/STAT signaling pathway gene signature that distinguishes RA-UIP from idiopathic UIP. This was further confirmed by immunohistostaining, which identified JAK2 phosphorylation with two distinct forms of activation: a cytoplasmic form of JAK2 activation in most IPF cases (13/20) and a nuclear form of p-JAK2 in RA-UIP (5/5) and a minority of IPF (6/20) cases. Further immunohistostaining identified STAT5A&B as the downstream transcriptional activator for JAK2-mediated canonical signal transduction and phosphorylation of Tyr41 on histone H3 (H3Y41ph) as the downstream epigenetic regulation site for JAK2-mediated noncanonical signal transduction. Gene Set Enrichment Analysis (GSEA) of the RNA-Seq data further supported this shared pathogenic mechanism for the two diseases with the enrichment of STAT5A&B target gene sets as well as the JAK2 regulated H3Y41ph target gene set. This regulatory role of JAK2 in the pathogenesis of pulmonary fibrosis was further demonstrated by the attenuation of bleomycin-induced murine pulmonary fibrosis using a JAK2-selective pharmacological inhibitor CEP33779. In vitro studies with normal and IPF derived lung fibroblasts revealed a central role for JAK2 as an essential intermediary molecule in TGF-ß-mediated myofibroblast trans-differentiation, proliferation, and extracellular matrix protein production. These observations support a crucial role for JAK2 as an intermediary molecule in fibrotic lung disease development.

Effects of Fly Ash and Hexadecyltrimethoxysilane on the Compressive Properties and Water Resistance of Magnesium Oxychloride Cement.

The application of magnesium oxychloride cement (MOC) is promising, but its poor water resistance seriously hinders its development and application. In this paper, we describe a new type of MOC with excellent water resistance, prepared using fly ash and hexadecyltrimethoxysilane (HDTMS). SEM, XRD, FTIR, TG/DSC, and other microscopic-scale studies were conducted to investigate the mechanism underlying the water-resistance enhancement of the new MOC. It was found that adding 20% fly ash and 3% HDTMS can strengthen the water resistance of MOC while retaining high mechanical properties. In particular, the residual coefficient remained at 0.91 after 7 days of immersion. This is because these two additives, when used together, can increase the content of the gelling 5-phase of MOC, as well as optimize the pore structure of MOC.

A novel humanized model of rheumatoid arthritis associated lung disease.

Cigarette smoking has been implicated in the pathogenesis of seropositive rheumatoid arthritis (RA), as well as RA-associated lung disease. Fibrotic interstitial lung disease as well as emphysema occur in RA and cause substantial morbidity. We used arthritis-susceptible HLA-DQ8 transgenic mice to generate RA-associated lung disease. Mice were exposed to cigarette smoke (CS) prior to induction of arthritis, and subsequently injected with a low dose of bleomycin intra-tracheally to induce lung injury. Exposure of arthritic mice to both CS and bleomycin led to a significant reduction in lung compliance consistent with development of diffuse lung disease. Morphologic evaluation of the lung demonstrated areas of emphysematous change and co-existent fibrosis, consistent with a combined pattern of fibrosis and emphysema. These changes were accompanied by inflammatory cell infiltration and upregulation of fibrosis-associated genes. This humanized mouse model can serve as a valuable research tool to understand the pathogenesis of RA associated lung disease.

AST/ALT ratio as a predictor of mortality and exacerbations of PM/DM-ILD in 1 year-a retrospective cohort study with 522 cases.

OBJECTIVE: To assess the associations between aspartate transaminase/alanine transaminase ratio (DRR) and mortality in patients with polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD). PATIENTS AND METHODS: This was a retrospective cohort study, which included 522 patients with PM/DM-ILD whose DRR on admission were tested at West China Hospital of Sichuan University during the period from January 1, 2008, to December 31, 2018. Cox regression models were used to estimate hazard ratios for mortality in four predefined DRR strata (≤ 0.91, 0.91-1.26, 1.26-1.73, and > 1.73), after adjusting for age, sex, DRR stratum, diagnosis, overlap syndrome, hemoglobin, platelet count, white blood cell count, the percentage of neutrophils, neutrophil/lymphocyte ratio, albumin, creatine kinase, uric acid/creatinine ratio, triglycerides, or low-density lipoprotein. RESULTS: Higher DRR (> 1.73) was an independent predictor of 1-year mortality in multivariate Cox regression analysis (hazard ratio 3.423, 95% CI 1.481-7.911, p = .004). Patients with higher DRR more often required the use of mechanical ventilation and readmission for acute exacerbation of PM/DM-ILD at 1-year follow-up. CONCLUSION: Higher DRR on admission for PM/DM-ILD patients are associated with increased mortality, risk of mechanical ventilation, and hospitalization in 1-year follow-up. This low-cost, easy-to-obtain, rapidly measured biomarker may be useful in the identification of high-risk PM/DM-ILD patients that could benefit from intensive management.

Efficacy and Safety of Tofacitinib, Baricitinib, and Upadacitinib for Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

OBJECTIVE: To assess the efficacy and safety profiles of different dosing regimens of tofacitinib, baricitinib, and upadacitinib, novel selective oral Janus activated kinase inhibitors, in rheumatoid arthritis (RA). METHODS: Randomized controlled trials of tofacitinib (5 and 10 mg twice daily) baricitinib (2 and 4 mg daily), and upadacitinib (15 and 30 mg daily) in RA were identified from MEDLINE, EMBASE, and Cochrane databases through December 11, 2019. Random-effects models were used to estimate pooled mean differences and relative risks (RRs). American College of Rheumatology 20%, Health Assessment Questionnaire-Disability Index, adverse events, risk for infection, venous thromboembolic events, and malignancy were calculated. RESULTS: Twenty trials with an overall low risk of bias involving 8982 patients were identified. Tofacitinib, baricitinib, and upadacitinib improved RA control as determined by American College of Rheumatology 20% (RR, 2.03; 95% CI, 1.87 to 2.20) and Health Assessment Questionnaire-Disability Index scores (mean differences, -0.31; 95% CI, -0.34 to -0.28) compared with placebo. Adverse events were more frequent with upadacitinib, 30 mg, daily (RR, 1.15; 95% CI, 1.02 to 1.30); upadacitinib, 15 mg, daily (RR, 1.14; 95% CI, 1.02 to 1.27); and baricitinib, 4 mg, daily (RR, 1.13; 95% CI, 1.02 to 1.24). The risk for infection was highest with tofacitinib, 10 mg, twice daily (RR, 2.75; 95% CI, 1.72 to 4.41), followed by upadacitinib, 15 mg, daily (RR, 1.35; 95% CI, 1.14 to 1.60) and baricitinib, 4 mg, daily (RR, 1.28; 95% CI, 1.12 to 1.45). Data for venous thromboembolic events were not available for tofacitinib or baricitinib, but there was no increase in risk with upadacitinib (15 mg daily: RR, 2.34; 95% CI, 0.34 to 15.92). CONCLUSION: Tofacitinib, baricitinib, and upadacitinib significantly improve RA control. Head-to-head Janus activated kinase inhibitor clinical trials are needed to further inform decision making.

Molecular characterization of pulmonary defenses against bacterial invasion in allergic asthma: The role of Foxa2 in regulation of ß-defensin 1.

Allergic asthma, characterized by chronic airway Th2-dominated inflammation, is associated with an increased risk of infection; however, the underlying mechanisms are unclear. Forkhead box protein A2 (Foxa2) plays a critical role in Th2 inflammation and is associated with pulmonary defenses. To determining the role of Foxa2 in Th2-dominated lung inflammation against the invading bacteria, we established a mouse OVA-sensitized model, an Escherichia coli lung invasion model, and mice with conditional deletion of Foxa2 in respiratory epithelial cells. The number of bacteria in the lung tissue was counted to assess clearance ability of lung. Lung inflammation and histopathology was evaluated using HE and PAS staining. It was found that OVA-sensitized mice had decreased E. coli clearance, reduced Foxa2 expression, and decreased DEFB1 secretion. Conditional deletion of Foxa2 in respiratory epithelial cells led to decreased clearance of E. coli and impaired secretion of DEFB1, similar to the OVA-induced allergic condition. The impaired secretion of DEFB1 may be responsible for the increased risk of infection in the Th2-dominated airway inflammation. Dual luciferase assay demonstrated that Foxa2 regulates DEFB1 expression by affecting its promoter activity in HBE cells. Our study indicated that Foxa2 plays an important role in Th2-dominated airway inflammation against invading bacteria. Conditional deletion of Foxa2 in respiratory epithelial cells can reduce pulmonary's defense against bacterial invasion by inhibiting DEFB1expression.