Tacrolimus alleviates pulmonary fibrosis progression through inhibiting the activation and interaction of ILC2 and monocytes.

Idiopathic pulmonary fibrosis (IPF) is a heterogeneous group of lung diseases with different etiologies and characterized by progressive fibrosis. This disease usually causes pulmonary structural remodeling and decreased pulmonary function. The median survival of IPF patients is 2-5 years. Predominantly accumulation of type II innate immune cells accelerates fibrosis progression by secreting multiple pro-fibrotic cytokines. Group 2 innate lymphoid cells (ILC2) and monocytes/macrophages play key roles in innate immunity and aggravate the formation of pro-fibrotic environment. As a potent immunosuppressant, tacrolimus has shown efficacy in alleviating the progression of pulmonary fibrosis. In this study, we found that tacrolimus is capable of suppressing ILC2 activation, monocyte differentiation and the interaction of these two cells. This effect further reduced activation of monocyte-derived macrophages (Mo-M), thus resulting in a decline of myofibroblast activation and collagen deposition. The combination of tacrolimus and nintedanib was more effective than either drug alone. This study will reveal the specific process of tacrolimus alleviating pulmonary fibrosis by regulating type II immunity, and explore the potential feasibility of tacrolimus combined with nintedanib in the treatment of pulmonary fibrosis. This project will provide new ideas for clinical optimization of anti-pulmonary fibrosis drug strategies.

Nickel-catalyzed C(sp2)-C(sp3) coupling via photoactive electron donor-acceptor complexes.

We have developed a novel Ni-catalyzed reductive cross-coupling reaction of aryl bromides and alkyl iodides via a photoactive electron donor-acceptor (EDA) complex. This photo-induced process enables the efficient construction of C(sp2)-C(sp3) bonds in the absence of an external photocatalyst. Electronically and structurally diverse aryl bromides, as well as secondary and primary alkyl iodides could undergo this transformation smoothly. Natural product derivatives were employed successfully, and UV-vis spectroscopy was utilized to gain mechanistic insight.

The Clinical Analysis of Checkpoint Inhibitor Pneumonitis with Different Severities in Lung Cancer Patients: A Retrospective Study.

Immune-related adverse events (irAEs) of immunotherapy would lead to the temporary or permanent discontinuation of immune checkpoint inhibitors (ICIs). Among them, checkpoint inhibitor pneumonitis (CIP) is a potentially life-threatening irAE. This study aimed to identify the differences between patients with low-grade CIPs (grades 1-2) and high-grade CIPs (grades 3-5) and to explore the prognostic factors. We retrospectively reviewed the medical records of 916 lung cancer patients who were treated with ICIs. Patients with CIPs were identified after multidisciplinary discussion, and their clinical, laboratory, radiological, and follow-up data were analyzed. Among the 74 enrolled CIP patients, there were 31 low-grade CIPs and 43 high-grade CIPs. Compared with low-grade CIP patients, patients with high-grade CIPs were older (65.8 years vs. 61.5 years) and had lower serum albumin (35.2 g/L vs. 37.9 g/L), higher D-dimer (5.1 mg/L vs. 1.7 mg/L), and more pulmonary infectious diseases (32.6% vs. 6.5%) during follow-up. In addition, complication with pulmonary infectious diseases, management with intravenous immunoglobulin, tocilizumab, and longer duration of large dosage corticosteroids might be associated with worse outcomes for patients with CIPs. This study highlights potential risk factors for high-grade CIP and poor prognosis among lung cancer patients who were treated with anti-cancer ICIs.

Immunotherapy of microsatellite stable colorectal cancer: resistance mechanisms and treatment strategies.

In recent years, immunotherapy strategies based on immune checkpoint inhibitors have yielded good efficacy in colorectal cancer (CRC)especially in colorectal cancer with microsatellite instability-high. However, microsatellite-stable (MSS) CRCs account for about 85% of CRCs and are resistant to immunotherapy. Previous studies have shown that compared with MSS CRC, high microsatellite instability CRC possesses a higher frequency of mutations and can generate more neoantigens. Therefore, improving the sensitivity of immunotherapy to MSS CRC is a hot topic which is crucial for the treatment of MSS CRC. This review aims to discuss the factors contributing to MSS CRC insensitivity to immunotherapy and explored potential solutions to overcome immunotherapy resistance.

Estrogen/Progesterone Receptor Expression and Cancer Antigen 125 Level as Preoperative Predictors to Estimate Lymph Node Metastasis in Endometrioid Endometrial Cancer.

Loss of estrogen receptor/progesterone receptor (ER/PR) in endometrial cancer (EC) is associated with tumor progression and poor outcomes. Elevated pretreatment cancer antigen 125 (CA 125) level is a risk factor for lymph node metastasis (LNM). We evaluated whether the combination of ER/PR expression and CA 125 level could be used as a biomarker to predict LNM. We retrospectively investigated patients with endometrioid EC who underwent complete staging surgery during January 2015 to December 2020. We analyzed ER/PR status using immunohistochemical staining, and quantified its expression using the sum of both ER/PR H-scores. Receiver operating characteristic curves were used to identify optimal cutoff values of H-score and CA 125 levels for predicting LNM. A nomogram for predicting LNM was constructed and validated by bootstrap resampling. In 396 patients, the optimal cutoff values of the ER/PR H-score and CA 125 were 407 (area under the receiver operating characteristic curve: 0.645, P=0.001) and 40 U/mL (area under the receiver operating characteristic curve: 0.762, P<0.001), respectively. Multivariate analysis showed that CA 125 ≥40 UmL (odds ratio: 10.02; 95% CI: 4.74-21.18) and ER/PR H-score <407 (odds ratio: 4.20; 95% CI: 1.55-11.32) were independent predictors. An LNM predictive nomogram was constructed using these 2 variables and our model yielded a negative predictive value and negative likelihood ratio of 98.3% and 0.14, respectively. ER/PR expression with pretreatment CA 125 levels can help estimate LNM risk and aid in decision-making regarding the need for lymphadenectomy in patients with endometrioid EC.

Apoptotic Cell-Derived CD14(+) Microparticles Promote the Phagocytic Activity of Neutrophilic Precursor Cells in the Phagocytosis of Apoptotic Cells.

Membranous CD14 is crucial in the phagocytic activity of neutrophils. However, the role of CD14(+) microparticles (MPs) derived from apoptotic neutrophils (apo-MP) during the phagocytic process is not clear. All trans-retinoic acid (ATRA) induces acute promyelocytic leukemic NB4 cells along granulocytic differentiation. In this study, we investigated the role of CD14(+)apo-MP in the cell-cell interaction during the phagocytic process of apoptotic cells by viable ATRA-NB4 cells. We firstly demonstrate that CD14 expression and phagocytic activity of NB4 cells were upregulated simultaneously after ATRA treatment in a time-dependent manner, and both were significantly enhanced via concurrent lipopolysaccharide treatment. The phagocytic activity of ATRA-NB4 cells and lipopolysaccharide-treated ATRA-NB4 cells were both significantly attenuated by pre-treating cells with an antibody specific to either CD14 or TLR4. Further flow cytometric analysis demonstrates that apoptotic ATRA-NB4 cells release CD14(+)apo-MP in an idarubicin dosage-dependent manner. Both CD14 expression and the phagocytic activity of viable ATRA-NB4 cells were significantly enhanced after incubation with apo-MP harvested from apoptotic ATRA-NB4 cells, and the apo-MP-enhanced phagocytic activity was significantly attenuated by pre-treating apo-MP with an anti-CD14 antibody before incubation with viable cells. We conclude that CD14(+)apo-MP derived from apoptotic ATRA-NB4 cells promotes the phagocytic activity of viable ATRA-NB4 cells in engulfing apoptotic cells.

Discovery of HDAC6, HDAC8, and 6/8 Inhibitors and Development of Cell-Based Drug Screening Models for the Treatment of TGF-ß-Induced Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis is incurable, and its progression is difficult to control and thus can lead to pulmonary deterioration. Pan-histone deacetylase inhibitors such as SAHA have shown potential for modulating pulmonary fibrosis yet with off-target effects. Therefore, selective HDAC inhibitors would be beneficial for reducing side effects. Toward this goal, we designed and synthesized 24 novel HDAC6, HDAC8, or dual HDAC6/8 inhibitors and established a two-stage screening platform to rapidly screen for HDAC inhibitors that effectively mitigate TGF-ß-induced pulmonary fibrosis. The first stage consisted of a mouse NIH-3T3 fibroblast prescreen and yielded five hits. In the second stage, human pulmonary fibroblasts (HPFs) were used, and four out of the five hits were tested for caco-2 permeability and liver microsome stability to give two potential leads: J27644 (15) and 20. This novel two-stage screen platform will accelerate the discovery and reduce the cost of developing HDAC inhibitors to mitigate TGF-ß-induced pulmonary fibrosis.

Pretreatment carcinoembryonic antigen combined with cancer antigen-125 for predicting lymph node metastasis in endometrial carcinoma: a retrospective cohort study.

PURPOSE: To investigate whether the cost-effective, pretreatment tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen-125 (CA-125) can be used to predict lymph node metastasis (LNM) in endometrioid-type endometrial cancer (EC) and to develop a predictive model. METHODS: This was a single-center retrospective study of patients with endometrioid-type EC who underwent complete staging surgery between January 2015 and June 2022. We identified the optimal cut-off values of CEA and CA-125 for predicting LNM using receiver operating characteristic (ROC) curves. Stepwise multivariate logistic regression analysis was used to identify independent predictors. A nomogram for predicting LNM was constructed and validated by bootstrap resampling. RESULTS: The optimal cut-off values of CEA and CA-125 were 1.4 ng/mL (area under the ROC curve (AUC) 0.62) and 40 U/mL (AUC 0.75), respectively. Multivariate analysis showed that CEA (odds ratio (OR) 1.94; 95% confidence interval (CI) 1.01-3.74) and CA-125 (OR 8.75; 95% CI 4.42-17.31) were independent predictors of LNM. Our nomogram showed adequate discrimination with a concordance index of 0.78. Calibration curves for the probability of LNM showed optimal agreement between the predicted and actual probabilities. The risk of LNM for markers below the cut-offs was 3.6%. The negative predictive value and negative likelihood ratio were 96.6% and 0.26, respectively, with moderate ability to rule out the possibility of LNM. CONCLUSION: We report a cost-effective method of using pretreatment CEA and CA-125 levels to identify patients with endometrioid-type EC who are at a low risk for LNM, which may guide decision-making regarding aborting lymphadenectomy.

All-shot Aspirations in Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) Are Associated With Malignancy.

Background: Aspirations without a tissue core are common in endobronchial ultrasound-guided transbronchial needle aspiration procedures. However, the diagnostic value of all-shot aspirations and no-tissue-core aspirations is unclear. Patients and Methods: A retrospective analysis of patients who underwent endobronchial ultrasound-guided transbronchial needle aspiration with the description of all-shot or no-tissue-core aspirations was conducted at a tertiary hospital between January 2017 and March 2021. Patients' pathologic and clinical diagnoses were retrieved and compared between all-shot patients (all aspirations had a tissue core) and no-tissue-core patients (at least one aspiration had no tissue core). Results: Among all 505 patients with 1402 aspirations, 356 (70.5%) patients, and 1184 (84.5%) aspirations were all-shot. Pathologic diagnosis after endobronchial ultrasound-guided transbronchial needle aspiration revealed neoplasms in 46.1% of all-shot patients, but 33.6% of no-tissue-core patients (odds ratio, 1.69; 95% confidence interval, 1.14-2.52; P = .009). Final clinical diagnosis revealed malignancy in 53.1% of all-shot patients, but 37.6% of no-tissue-core patients (odds ratio, 1.88; 95% confidence interval, 1.27-2.78; P = .001). In 133 patients with pathologic nonspecific findings, a clinical diagnosis of malignancy was proven in 25 of 79 (31.6%) of all-shot patients, but only 6 of 54 (11.1%) of no-tissue-core patients (odds ratio, 3.70; 95% confidence interval, 1.40-9.79; P = .006). Conclusions: Patients with all-shot aspirations in endobronchial ultrasound-guided transbronchial needle aspiration are more likely to have the pathologic and clinical diagnosis of malignancy. More measures should be taken to exclude malignancy in all-shot patients when the endobronchial ultrasound-guided transbronchial needle aspiration was nondiagnostic.

Astrocyte-associated fibronectin promotes the proinflammatory phenotype of astrocytes through ß1 integrin activation.

Astrocytes are key players in neuroinflammation. In response to central nervous system (CNS) injury or disease, astrocytes undergo reactive astrogliosis, which is characterized by increased proliferation, migration, and glial fibrillary acidic protein (GFAP) expression. Activation of the transcription factor nuclear factor-κB (NF-κB) and upregulation of downstream proinflammatory mediators in reactive astrocytes induce a proinflammatory phenotype in astrocytes, thereby exacerbating neuroinflammation by establishing an inflammatory loop. In this study, we hypothesized that excessive fibronectin (FN) derived from reactive astrocytes would induce this proinflammatory phenotype in astrocytes in an autocrine manner. We exogenously treated astrocytes with monomer FN, which can be incorporated into the extracellular matrix (ECM), to mimic plasma FN extravasated through a compromised blood-brain barrier in neuroinflammation. We also induced de novo synthesis and accumulation of astrocyte-derived FN through tumor necrosis factor-α (TNF-α) stimulation. The excessive FN deposition resulting from both treatments initiated reactive astrogliosis and triggered NF-κB signaling in the cultured astrocytes. In addition, inhibition of FN accumulation in the ECM by the FN inhibitor pUR4 strongly attenuated the FN- and TNF-α-induced GFAP expression, NF-κB activation, and proinflammatory mediator production of astrocytes by interrupting FN-ß1 integrin coupling and thus the inflammatory loop. In an in vivo experiment, intrathecal injection of pUR4 considerably ameliorated FN deposition, GFAP expression, and NF-κB activation in inflamed spinal cord, suggesting the therapeutic potential of pUR4 for attenuating neuroinflammation and promoting neuronal function restoration.

Safety and Tolerability of High-Resolution Esophageal Manometry in Children and Adults.

INTRODUCTION: While high-resolution manometry (HRM) is widely accepted as a safe procedure, no study has assessed the safety profile of HRM in clinical practice. This study aimed to determine the safety and tolerability of HRM and to investigate potential determinants of intolerability. METHODS: We obtained HRM procedure reports, demographics, and clinical data (2005-2022) at a tertiary center using electronic chart review. Our primary outcome was HRM tolerability. Multivariable regression was performed to identify associations between the outcome and covariates including age, sex, race, and comorbidities. RESULTS: A total of 5,107 patients (60.3% female) were included. Of them, 5,050 patients (98.9%) tolerated HRM well and 57 patients (1.1%) did not. Age had a statistically significant effect on tolerance: those younger than 18 years had more than a 5-fold increase in not tolerating HRM compared with those aged 18-79 years (5.77% vs 0.99%; odds ratio [OR] = 5.44, 95% confidence interval [CI] 1.60-18.45; P = 0.007), and those aged 80 years or older were also more likely to terminate HRM (2.43% vs 0.99%; OR = 2.56, 95% CI 1.13-5.76; P = 0.024). While prior foregut surgery had a significant effect on tolerance (OR = 8.06, 95% CI 2.29-28.39; P = 0.001), other factors of race, sex, body mass index, and psychological or cognitive disorders had no significant impact. No serious complications were identified. DISCUSSION: HRM is safe and well-tolerated with approximately 1 in every 100 patients being unable to tolerate HRM. Intolerance was more commonly seen in children and seniors due to minor symptoms of discomfort without serious complications. These data points are crucial to counsel patients in whom HRM is being considered.

Clinical spectrum of Chinese hospitalized lung cancer patients with concomitant interstitial lung disease: before and after the new era of LC treatment.

This study aimed to explore the general characteristics and spectrum of hospitalized Chinese patients suffering from lung cancer with concomitant interstitial lung disease (LC-ILD). Furthermore, we compared their features before and after the period of immunotherapy for lung cancer. A retrospective analysis of the clinical characteristics of hospitalized LC patients with definite pathological diagnoses was performed from 2014 to 2021. ILD was defined after the review of chest CT imaging. There were 13,085 hospitalized LC patients. Among them, 509 patients (3.89%) had 551 cases of ILD. There were variable underlying causes of ILD, including idiopathic interstitial pneumonia (360 patients), LC treatment-associated ILD (134 cases), and connective tissue disease-associated ILD (55 patients). Although most LC-ILD patients were suffering from adenocarcinoma (204/40.1%), SCLC patients were prone to concomitant ILD (10.8% of all SCLC cases), followed by SCC (9.6% of all SCC cases). All but 10 LC-ILD patients received anti-LC treatment; however, only 39 (10.8%) LC-IIP patients received anti-ILD treatment. There were more LC-ILD patients in the 2018-2021 group than in the 2014-2017 group (5.16% vs. 2.03%, p < 0.001). The underlying causes of ILD were significantly different between the 2018-2021 group and the 2014-2017 group (p < 0.001). After adjusting for the number of hospitalized patients having the same LC pathological pattern, SCLC was determined to be the most likely to be concomitant with ILD, followed by SCC. Most LC-ILD patients were scheduled for anti-LC therapy; however, treatments for concomitant IIP were usually ignored. LC treatment-associated ILD should receive more attention than before.

Tacrolimus ameliorates bleomycin-induced pulmonary fibrosis by inhibiting M2 macrophage polarization via JAK2/STAT3 signaling.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown cause and characterized by excessive proliferation of fibroblasts and the irregular remodeling of extracellular matrix (ECM), which ultimately cause the severe distortion of the alveolar architecture. The median survival of IPF patients is 2-5 years. IPF patients are predominantly infiltrated by M2 macrophages during the course of disease development and progression. Predominantly accumulation of M2 macrophages accelerates fibrosis progression by secreting multiple cytokines that promote fibroblast to myofibroblast transition. In the process of M2 macrophage polarization, JAK2/STAT3 signaling plays a key role, thus, targeting activated macrophages to inhibit the pro-fibrotic phenotype is considered as an approach to the potential treatment of IPF. Tacrolimus is a macrolide antibiotic that as a specific inhibitor of T-lymphocyte function and has been used widely as an immunosuppressant in human organ transplantation. In this study we explored the potential effect and mechanism of tacrolimus on pulmonary fibrosis in vivo and vitro. Here, we found that tacrolimus is capable of suppressing M2 macrophages polarization by inhibiting pro-fibrotic factors secreted by M2 macrophages. This effect further alleviates M2-induced myofibroblast activation, thus resulting in a decline of collagen deposition, pro-fibrotic cytokines secretion, recovering of lung function, ultimately relieving the progression of fibrosis in vivo. Mechanistically, we found that tacrolimus can inhibit the activation of JAK2/STAT3 signaling by targeting JAK2. Our findings indicate a potential anti-fibrotic effect of tacrolimus by regulating macrophage polarization and might be meaningful in clinical settings.

Serum Cystatin C Levels Could Predict Rapid Kidney Function Decline in A Community-Based Population.

BACKGROUND: Several biomarkers have been correlated with the prevalence and severity of chronic kidney disease (CKD); however, the association between biomarkers and rapid kidney function decline (RKFD) is unknown. This study aimed to evaluate the predictive performance of biomarkers to determine who is likely to develop RKFD in a healthy population. METHODS: A community-based cohort of 2608 people residing in northern Taiwan were enrolled, and their renal function was followed annually from January 2014 to December 2019. The outcomes of interest were RKFD, defined as a 15% decrease in the estimated glomerular filtration rate (eGFR) within the first 4 years, and a decrease in eGFR without improvement in the fifth year. Clinical variables and potential predictors of RKFD, namely adiponectin, leptin, tumor necrosis factor-alpha, and cystatin C, were measured and analyzed. RESULTS: The incidence of RKFD was 17.0% (105/619). After matching for age and sex at a 1:1 ratio, a total of 200 subjects were included for analysis. The levels of cystatin C and total vitamin D were significantly negatively correlated with eGFR. eGFR was negatively correlated with the levels of cystatin C and total vitamin D. Among the biomarkers, cystatin C showed the best predictive performance for RKFD (area under the receiver operating characteristic curve: 0.789). Lower serum cystatin C was associated with a higher rate of RKFD in healthy subjects. A generalized additive model showed that 0.82 mg/L was an adequate cut-off value of cystatin C to predict RKFD. Multivariable logistic regression analysis further indicated that low cystatin C and eGFR were independent predictors of the possibility of RKFD. CONCLUSIONS: Serum cystatin C level could predict the possibility of RKFD. We suggest that a low cystatin C level should be considered as a risk factor for RKFD in healthy subjects.

Does surgical plethysmographic index-guided analgesia affect opioid requirement and extubation time? A systematic review and meta-analysis.

PURPOSE: This meta-analysis of all relevant clinical trials investigated surgical plethysmographic index (SPI)-guided analgesia's efficacy under general anesthesia for perioperative opioid requirement and emergence time after anesthesia. METHODS: PubMed, Embase, Web of Science, and Cochrane Library were searched up to January 2022 to identify clinical trials comparing SPI-guided and conventional clinical practice for patients who underwent general anesthesia. With the random-effects model, we compared intraoperative opioid consumption, emergence time, postoperative pain, analgesia requirement, and incidence of postoperative nausea and vomiting (PONV). RESULTS: Thirteen randomized controlled trials (RCTs) (n = 1314) met our selection criteria. The overall pooled effect sizes of all RCTs indicated that SPI-guided analgesia could not significantly reduce opioid consumption during general anesthesia. SPI-guided analgesia accompanied with hypnosis monitoring could decrease intraoperative opioid consumption (standardized mean difference [SMD] - 0.31, 95% confidence interval [CI] - 0.63 to 0.00) more effectively than SPI without hypnosis monitoring (SMD 1.03, 95% CI 0.53-1.53), showing a significant difference (p < 0.001). SPI-guided analgesia could significantly shorten the emergence time, whether assessed by extubation time (SMD - 0.36, 95% CI - 0.70 to - 0.03, p < 0.05, I2 = 67%) or eye-opening time (SMD - 0.40, 95% CI - 0.63 to - 0.18, p < 0.001, I2 = 54%). SPI-guided analgesia did not affect the incidence of PONV, postoperative pain, and analgesia management. CONCLUSION: SPI-guided analgesia under general anesthesia could enhance recovery after surgery without increasing the postoperative complication risk. However, it did not affect intraoperative opioid requirement. Notably, SPI-guided analgesia with hypnosis monitoring could effectively reduce intraoperative opioid requirement.

Synergistic Benefit of Adoptive T Cells in Combination With Chemoradiotherapy Against Metastatic Prostate Cancer Cells.

BACKGROUND/AIM: Prostate cancer (PC) is one of the major diseases that affects male health and ranks as the second most frequent cancer in men worldwide. Although most newly-diagnosed PCs are well-differentiated tumors with a high cure probability, there are some patients with aggressive malignancies that show potential for recurrence and metastasis. Cytotoxic T lymphocytes are a specific immune effector cell population that mediates immune responses against cancer. MATERIALS AND METHODS: In the present study, the cytotoxicity of peripheral blood mononuclear cells (PBMCs)-derived γδ T cells and cytokine-induced killer (CIK) cells in combination with chemoradiotherapy against PC cells was evaluated using Alamar blue cell viability and cell membrane permeability assays. RESULTS: Advanced PC-3 cells, which were more resistant to docetaxel (Doc), also showed higher viability following pretreatment with radiation. The cell proliferation inhibition was significantly increased upon additional γδ T or CIK treatment. Furthermore, the proportion of apoptotic cells was significantly (p<0.05) increased in the Doc-γδ T cell co-treatment group as compared with the Doc or γδ T cell treated alone group. CONCLUSION: γδ T cell therapy may provide additional benefit compared to traditional chemoradiotherapy for PC treatment.

Severe asthma as the initial clinical manifestation of IgG4-related disease: a retrospective clinical study.

BACKGROUND: Respiratory involvement is common in immunoglobulin G4-related disease (IgG4-RD). However, severe asthma as the initial clinical manifestation of IgG4-RD is rare and might be neglected by respiratory clinicians. We aimed to explore the clinical characteristics and prognoses of patients with immunoglobulin G4-related disease (IgG4-RD) manifesting as severe asthma. METHODS: A retrospective analysis of the clinical characteristics and prognoses of patients with severe asthma who were eventually diagnosed with IgG4-RD was performed in the Peking Union Medical College Hospital from 2013 to 2019. RESULTS: Twelve patients (5males, 7 females) were included. The mean age at enrollment and age of asthma onset were 59.4 ± 10.1 and 53.8 ± 10.4 years, respectively. The mean duration of asthma symptoms was 5.7 ± 2.0 years. In all patients, the proportion (25.1 ± 10.3%) and count (2.0 ± 1.1) × 109/L of eosinophils in peripheral blood increased. Additionally, all patients exhibited elevated total immunoglobulin E [IgE, (1279.3 ± 1257.9) KU/L] and IgG4 (9155.8 ± 9247.6) mg/dL. Bronchial wall thickening (n = 11) and mediastinal/hilar lymphadenopathy (n = 11) were major chest CT manifestations. All were pathologically diagnosed through surgical biopsy; submandibular gland (n = 8), supraclavicular lymph node (n = 2), stomach (n = 1), rashes (n = 1), lacrimal gland (n = 1) and thoracoscopic lung (n = 1) biopsies were performed. Asthma was well controlled by oral glucocorticoids (GCs), but some patients relapsed during tapering (n = 11). The refractory condition was controlled after increasing the dosage of GCs and add-on immunosuppressants. CONCLUSIONS: For patients with middle age-onset severe asthma with elevated eosinophils, total IgE and IgG4 levels and available salivary gland ultrasound imaging, ruling out IgG4-RD is recommended. GCs used in combination with immunosuppressants is recommended to prevent relapse.

Potential or contraindicated drug-drug interactions with antiretroviral therapy in real-world settings in Taiwan.

BACKGROUND/PURPOSE: Given the complex metabolic pathway of antiretroviral therapy (ART), polypharmacy may increase the risk of drug-drug interactions (DDIs). Therefore, we investigated the frequency of DDIs during ART exposure to improve medical care for patients with human immunodeficiency virus (HIV). METHODS: This was a nationwide cross-sectional study using claims data from the National Health Insurance in Taiwan in 2016. Potential or contraindicated DDIs with recommended first-line ART (1L-ART) or protease inhibitors (PIs) were identified from the University of Liverpool drug interaction database. Fisher's exact or chi-square test was used to determine the significance of categorical variables. RESULTS: A total of 25,863 HIV-infected individuals were identified. Regarding 1L-ART users, patients with contraindicated DDIs accounted for 1-4%, whereas those with potential DDIs accounted for 15-50%. The most frequently coprescribed medications related to potential DDIs were diclofenac and polyvalent cation-containing antacids. Among PI users, 8-10% of them had contraindicated DDIs while 44-50% of them had potential DDIs. The medications related to potential DDIs with PIs were zolpidem, betamethasone, polyvalent cation-containing antacids, and loperamide. CONCLUSION: Our study showed a low prevalence of contraindicated DDIs in the HIV population; however, more attention should be paid to a high proportion of potential DDIs. Strategies to avoid these DDIs should be implemented if possible. Further research that focuses on the long-term clinical impact of potential DDIs is warranted.

Myositis specific antibodies are associated with isolated anti-Ro-52 associated interstitial lung disease.

OBJECTIVES: Anti-Ro-52 antibody positivity might be associated with the presence of interstitial lung disease (ILD) among patients with autoimmune features. However, the clinical significance of isolated anti-Ro-52 positivity (i.e. the presence of anti-Ro-52 antibodies but the absence of anti-Ro-60 antibodies; anti-Ro-52+Ro-60-) in patients with ILD is not clear. METHODS: This is a prospective and observational study of Chinese ILD patients with isolated anti-Ro-52 positivity. According to their myositis specific antibody (MSA) status, patients were split into groups, and their clinical and radiological features were compared. RESULTS: Of the 158 enrolled patients with ILD and isolated anti-Ro-52 positivity (isolated anti-Ro-52-ILD), there were 130 patients with a positive MSA status and 28 patients with a negative MSA status. Anti-synthetase antibodies (ASAs) were found in 61.5% of patients with MSA+-ILD, and anti-melanoma differentiation associated protein 5 (anti-MDA-5) antibodies were found in the remaining 38.5% of patients. The anti-nuclear antibody (ANA) pattern was associated with ASA and anti-MDA-5 positivity (x2 = 70.7, P < 0.001; Cramer's value 0.47, P < 0.001): ANA negativity was associated with anti-MDA-5 positivity, and cytoplasmic ANA positivity was associated with ASA positivity. There were statistically significant differences in the high-resolution CT patterns between patients with isolated anti-Ro-52 positivity with different MSA statuses (x2 = 29.8, P < 0.001; Cramer's value 0.31, P < 0.001): OP pattern was more common in patients with anti-MDA-5 antibodies than in those without anti-MDA-5 antibodies. CONCLUSIONS: Patients with isolated anti-Ro-52-ILD showed high positivity of MSA. Isolated anti-Ro-52 positivity with cytoplasmic ANA positivity was strongly associated with ASA+-ILD, while ANA negativity was associated with anti-MDA-5+-ILD.

Circulating Fibroblast Growth Factor-23 Levels Can Predict Rapid Kidney Function Decline in a Healthy Population: A Community-Based Study.

BACKGROUND: Fibroblast growth factor-23 (FGF-23) associates with decreased kidney function in patients with chronic kidney disease (CKD). However, the correlation between circulating FGF-23 levels and the rate of renal function decline in healthy individuals is largely unknown. We aimed to evaluate the predictive performance of FGF-23 for rapid kidney function decline (RKFD) in a community-based study. METHODS: A total of 2963 people residing in northern Taiwan were enrolled from August 2013 to May 2018 for an annual assessment of kidney function for five years. The baseline estimated glomerular filtration rates (eGFR) were calculated using the 2009 and 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, which aggregates the values of serum creatinine and cystatin C (eGFRcr-cys). The outcome was RKFD-a 15% decrease in estimated glomerular filtration rate (eGFR) within the first four years, and a reduction in eGFR without improvement in the 5th year. A generalized additive model (GAM) was used to determine the cut-off value of FGF-23 to predict RKFD. RESULTS: The incidence of RKFD was 18.0% (114/634). After matching for age and sex at a 1:1 ratio, a total of 220 subjects were analyzed. eGFRcr-cys was negatively correlated with total vitamin D level but seemed irrelevant to FGF-23. Multivariable logistic regression analysis showed that FGF-23, eGFRcr-cys, and urine albumin-to-creatinine ratio (UACR) were independent predictors of the possibility of RKFD. FGF-23 showed the best predictive performance for RKFD (AUROC: 0.803), followed by baseline eGFRcr-cys (AUROC: 0.639) and UACR (AUROC: 0.591). From the GAM, 32 pg/mL was the most appropriate cut-off value of FGF-23 with which to predict RKFD. The subgroup and sensitivity analyses showed consistent results that high-FGF-23 subjects had higher risks of RKFD. CONCLUSIONS: Circulating FGF-23 level could be a helpful predictor for RKFD in this community-based population.