Synergistic B and T lymphocyte interaction: prognostic implications in non-small cell lung cancer.

While T-cell-mediated immune responses in solid tumors have been well-established and have driven major therapeutic advances, our understanding of B-cell biology in cancer is comparatively less developed. A total of 60 lung cancer patients were included, of which 53% were diagnosed at an early stage while 47% were diagnosed at an advanced stage. Flow cytometry was used to analyze the proportion of T and B cells in all blood samples, and the levels of human serum cytokines were also assessed. Compared to the control group, cancer patients showed lower frequencies of IgD+CD27+ marginal B cells and CD32+ B cells, and higher frequencies of T cells with lower CD8+ T cells and higher central memory and naïve CD4+ T cells. Additionally, advanced-stage cancer patients exhibited higher levels of cytokines, a higher proportion of effector memory CD8+ T cells, and a lower frequency of CD27+CD28+CD4+/CD8+ T cells. Linear regression analysis revealed significant correlations between cancer stage and the frequency of B and T cell subsets, leukocyte count, and cytokine levels. Survival analysis demonstrated that patients with higher frequency of class-switched B cells had a worse prognosis, while patients with higher frequency of CD8+ effector T cells and lower frequency of CD4+57+ T cells appeared to have a better survival rate. These findings provide valuable insight into the immunological changes that occur during lung cancer progression and have the potential to inform the development of new immunotherapeutic strategies.

Exploring the evolution of T cell function and diversity across different stages of non-small cell lung cancer.

The immune system plays a key role in detecting and fighting cancerous tumors. T cells are a crucial component in both natural and therapeutic cancer immunoediting responses, but it is unclear if they are the primary agents of these processes. In this study, patients with lung lesions detected by CT scan were selected, and their peripheral blood samples were analyzed for T cell population and serum cytokines/chemokines. T cell subtypes (CD3, CD4, CD8, CD27, CD28, CD45, CD45RA, CD57, CCR7, and PD1) and serum cytokines/chemokines (IL-2, IL-6, IL-10, IFN-γ, TGF-ß, TNFα, CXCL1, CXCL9, and CXCL12) were measured by flow cytometry and analysis before surgical resection or other cancer treatments. The frequency of T cell subpopulations in patients with lung cancer (n = 111) corresponded to those seen in patients with T cell exhaustion. As lung cancer progressed, the proportion of effector memory T cells decreased, while the proportion of naive T cells, PD-1, CD57+, CD28+CD27+, CD45RA+, and CD3+CD4+CCR7 increased. Circulating CD8+PD1+ T cells were positively correlated with intra-tumoral PD-L1 expression. Concurrently, serum levels of IL-2, TGF-ß, and CXCL9 decreased, while IL-6, IL-10, IFN-γ, and CXCL12 increased during the progression of lung cancer. In conclusion, T cell dysfunction is associated with cancer progression, particularly in advanced-stage lung cancer, and cancer immunoediting will provide early-stage cancer detection and further therapeutic strategies.

The impact of nontuberculous mycobacterial lung disease in critically ill patients: Significance for survival and ventilator use.

BACKGROUND: This study investigates the impact of nontuberculous mycobacterial lung disease (NTM-LD) on mortality and mechanical ventilation use in critically ill patients. METHODS: We enrolled patients with NTM-LD or tuberculosis (TB) in intensive care units (ICU) and analysed their association with 30-day mortality and with mechanical ventilator-free survival (VFS) at 30 days after ICU admission. RESULTS: A total of 5996 ICU-admitted patients were included, of which 541 (9.0 %) had TB and 173 (2.9 %) had NTM-LD. The overall 30-day mortality was 22.2 %. The patients with NTM-LD had an adjusted hazard ratio (aHR) of 1.49 (95 % CI, 1.06-2.05), and TB patients had an aHR of 2.33 (95 % CI, 1.68-3.24), compared to ICU patients with negative sputum mycobacterial culture by multivariable Cox proportional hazard (PH) regression. The aHR of age<65 years, obesity, idiopathic pulmonary fibrosis, end-stage kidney disease, active cancer and autoimmune disease and diagnosis of respiratory failure were also significantly positively associated with ICU 30-day mortality. In multivariable Cox PH regression for VFS at 30 days in patients requiring invasive mechanical ventilation, NTM-LD was negatively associated with VFS (aHR 0.71, 95 % CI: 0.56-0.92, p = 0.009), while TB showed no significant association. The diagnosis of respiratory failure itself predicted unfavourable outcome for 30-day mortality and a negative impact on VFS at 30 days. CONCLUSIONS: NTM-LD and TB were not uncommon in ICU and both were correlated with increasing 30-day mortality in ICU patients. NTM-LD was associated with a poorer outcome in terms of VFS at 30 days.

Increased Tuberculosis Reactivation Risk in Patients Receiving Immune Checkpoint Inhibitor-Based Therapy.

OBJECTIVE: Reports of tuberculosis (TB) during anticancer treatment with immune checkpoint inhibitors (ICIs) are increasing. However, it is not clear whether the use of ICIs is a significant risk factor for TB, including reactivation or latent TB infection (LTBI). METHODS: To determine the risk of TB reactivation in patients with lung cancer who use ICIs or tyrosine kinase inhibitors (TKIs), we conducted a retrospective study using a hospital-based cancer registry. In addition, we monitored patients with cancer using ICI or TKI in a multicenter prospective study to check the incidence of LTBI. RESULTS: In the retrospective study, several demographic factors were imbalanced between the ICI and TKI groups: the ICI group was younger, had more males, exhibited more squamous cell carcinoma in histology rather than adenocarcinoma, had fewer EGFR mutations, and received more chemotherapy. Propensity score matching was used to control for confounding factors, and we found that the incidence of TB was higher among patients with lung cancer who received ICIs than among those who received TKIs (2298 vs 412 per 100 000 person-years, P = .0165). Through multivariable analysis, group (ICI vs TKI) was the independent risk factor for TB development (adjusted hazard ratio (aHR): 6.29, 95% CI, 1.23-32.09, P = .0269). In the prospective cohort, which included 72 patients receiving ICIs and 50 receiving TKIs, we found that the incidence of positive seroconversion of LTBI by interferon gamma release assay (IGRA) was significantly higher in patients receiving ICIs (18% vs 0%, aHR: 9.88, P = 0.035) under multivariable Cox regression. CONCLUSION: The use of ICIs may be linked to a higher likelihood of TB reactivation and LTBI than individuals solely receiving TKIs as anticancer therapy. Consequently, the implementation of a screening program for TB reactivation and LTBI among patients undergoing ICI treatment could prove advantageous by enabling early detection and prompt treatment of the infection.

Comprehensive Genomic Analysis of Patients With Non-Small-Cell Lung Cancer Using Blood-Based Circulating Tumor DNA Assay: Findings From the BFAST Database of a Single Center in Taiwan.

PURPOSE: The Blood First Assay Screening Trial (BFAST) is a prospective study using next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) in treatment-naïve advanced/metastatic non-small-cell lung cancer (NSCLC). We compared liquid biopsy to tissue testing and analyzed genomic alterations in Taiwanese patients with NSCLC using the BFAST database. MATERIALS AND METHODS: A total of 269 patients underwent FoundationOne Liquid Companion Diagnostic (F1LCDx) assay at the National Taiwan University Hospital, of whom 264 underwent tissue-based genetic testing also. We analyzed the actionable mutations and the concordance between tissue-based genetic testing, which was limited to EGFR, ALK, ROS1, and BRAF, in a real-life clinical setting and blood-based NGS in the clinical trial. Additionally, we analyzed the co-occurring genomic alterations from the blood-based ctDNA assay. RESULTS: A total of 76.2% patients showed actionable mutations. Standard tissue testing did not detect known driver alterations in about 22.7% of the patients (sensitivity, 70.24%). Liquid NGS detected additional mutations (RET, KRAS, MET, and ErbB2) in 14% of the patients, which went undetected by the standard-of-care testing. The complementary use of ctDNA NGS increased the detection rate by 42%. The F1LCDx assay had a sensitivity of 83.41%. Lower tumor and metastasis stages predicted nondetected blood-based NGS ctDNA results. Common co-occurring mutations in the blood-based NGS ctDNA assay were TP53, DNMT3A, TET2, PIK3CA, CTNNB1, and RB1. Among the patients with EGFR-mutated NSCLC, TET2 co-occurring alterations correlated with shorter progression-free survival of EGFR tyrosine kinase inhibitor treatment. CONCLUSION: NGS ctDNA analysis in comprehensive genetic testing improves actionable mutation identification, vital for treating Asian NSCLC cases with high actionable mutation rates. Lower stages correlated with undetected blood-based NGS ctDNA assay results.

Prescription pattern and effectiveness of antihypertensive drugs in patients with aortic dissection who underwent surgery.

Background: Surgical patients with aortic dissection often require multiple antihypertensive drugs to control blood pressure. However, the prescription pattern and effectiveness of antihypertensive drugs for these patients are unclear. We aimed to investigate the prescription pattern and effectiveness of different classes of antihypertensive drugs in surgical patients with aortic dissection. Methods: Newly diagnosed aortic dissection patients who underwent surgery, aged >20 years, from 1 January 2012 to 31 December 2017 were identified. Patients with missing data, in-hospital mortality, aortic aneurysms, or congenital connective tissue disorders, such as Marfan syndrome, were excluded. Prescription patterns of antihypertensive drugs were identified from medical records of outpatient visits within 90 days after discharge. Antihypertensive drugs were classified into four classes: 1) ß-blockers, 2) calcium channel blockers (CCBs), 3) renin-angiotensin system, and 4) other antihypertensive drugs. Patients were classified according to the number of classes of antihypertensive drugs as follows: 1) class 0, no exposure to antihypertensive drugs; 2) class 1, antihypertensive drugs of the same class; 3) class 2, antihypertensive drugs of two classes; 4) class 3, antihypertensive drugs of three classes; or 5) class 4, antihypertensive drugs of four classes. The primary composite outcomes included rehospitalization associated with aortic dissection, death due to aortic dissection, and all-cause mortality. Results: Most patients were prescribed two (28.87%) or three classes (28.01%) of antihypertensive drugs. In class 1, ß-blockers were most commonly used (8.79%), followed by CCBs (5.95%). In class 2, ß-blockers+CCB (10.66%) and CCB+RAS (5.18%) were the most common drug combinations. In class 3, ß-blockers + CCB+RAS (14.84%) was the most prescribed combination. Class 0 had a significantly higher hazard of the composite outcome (HR, 2.1; CI, 1.46-3.02; p < 0.001) and all-cause mortality (HR, 2.34; CI, 1.56-3.51; p < 0.001) than class 1. There were no significant differences in hazards for rehospitalization associated with aortic dissection among classes. Conclusion: Among operated patients with type A aortic dissection, no specific type of antihypertensive drug was associated with a better outcome, whereas among those with type B aortic dissection, the use of ß-blockers and CCBs was related to a significantly lower risk of the composite outcome.

Real world experience on the effectiveness and safety of pirfenidone in patients with idiopathic pulmonary fibrosis in Taiwan.

Introduction: Randomized controlled trials have demonstrated a reduction in the decline of lung function and a reduced risk of acute exacerbation in patients with idiopathic pulmonary fibrosis treated with the antifibrotic prifenidone. The present study aimed to investigate the real-world effectiveness and safety profile of pirfenidone treatment for patients with IPF in Taiwan. Methods: Between January 1, 2019 and December 31, 2020, we enrolled 50 patients who were newly diagnosed with IPF and had at least 12 months follow-up period after pirfenidone administration. Result: The primary outcome of pharmacologic effect showed that the mean differences in the absolute values of forced vital capacity from baseline were 0.2 liter (n = 36), 0.13 liter (n = 32), 0.04 liter (n = 26), and - 0.004 liter (n = 26) after 3, 6, 9, and 12 months of administration, respectively. A slight improvement in quality of life, including scores of chronic obstructive pulmonary disease assessment test and St. George's respiratory questionnaire scores. The most common adverse effects were gastrointestinal upset and dermatological problems. No new safety concerns were observed in the present study. Conclusion: Our real-world study describe for the first time in Taiwan, the use of pirfenidone over a 12 months period. This drug preserves the lung function and improves quality of life with tolerable side effects.

The Effects of Biologics on Hematologic Malignancy Development in Patients with Ankylosing Spondylitis, Psoriasis, or Psoriatic Arthritis: A National Cohort Study.

Biologics are used for ankylosing spondylitis (AS), psoriasis, and psoriatic arthritis (PsA) treatment. The association between biologics and the development of hematologic malignancies is controversial, and data on patients with AS, psoriasis, and PsA are scarce. This retrospective cohort study used data from 2010 to 2020 from Taiwan's National Health Insurance Research Database (NHIRD). Patients with AS, psoriasis, and PsA were divided into a biologics and non biologics group after 1:10 propensity score matching. The hematologic malignancy incidences and the time-/dose-dependent effects on biologics were analyzed by Poisson regression to evaluate the incidence rate ratio (IRR). Of the 4157 biologics users and 38,399 non biologics users included in the study, 10 and 72 persons developed hematologic malignancies, respectively. Biologics only significantly increased the risk of hematologic malignancies in non-Hodgkin's lymphoma (IRR: 2.48, 95% confidence interval (CI): 1.28-4.80). Different treatment patterns, types of biologics prescribed, cumulative defined daily doses, comorbidities, and comedications did not significantly affect hematologic malignancy development. A significantly increased risk was observed when biologics had been prescribed for 1-2 years (IRR: 2.95, 95% CI: 1.14-7.67). Clinical professionals should be aware of a patients' risk of hematologic malignancies during the second year of biologic treatment.

T790M detection rate after first-line combination therapy with bevacizumab and EGFR-TKIs in advanced NSCLC (TERRA Study).

Real-world data regarding the T790M mutation rate after acquiring resistance to first-line combination therapy with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and bevacizumab in patients with advanced non-small-cell lung cancer (NSCLC) are limited. The present study was aimed at analyzing predictors of acquired T790M mutations in this patient group. A total of 107 patients who received first-line combination therapy with EGFR-TKIs and bevacizumab at 11 tertiary referral centers in Taiwan were enrolled in this multicenter retrospective study. Survival data and genomic test results after acquiring resistance were analyzed. We discovered that patients who received a combination of afatinib, a second generation EGFR-TKI, and bevacizumab showed better progression-free survival (PFS). After disease progression, 59 patients (55.1%) were confirmed to test positive for EGFR T790M. A longer duration of first-line therapy could be a predictor of subsequent T790M mutations. To our knowledge, this is one of the few and early studies to demonstrate the T790M mutation rate after first-line combination therapy with an EGFR-TKI and bevacizumab. Whether the longer PFS afforded by the addition of bevacizumab could lead to subsequent T790M mutations needs further investigation.

Acute effect of combined exercise with aerobic and resistance exercises on executive function.

Objective: Recent studies indicate that acute exercise, whether aerobic exercise (AE) or resistance exercise (RE), improves cognitive function. However, the effects on cognitive function of combined exercise (CE), involving both AE and RE in an exercise session, remain unknown. The aim of this study was to investigate the effects of acute CE on cognitive function. Design: Within-subject design with counterbalancing. Methods: Fifteen healthy men with a sedentary lifestyle in the previous three months were recruited. The participants were assessed for muscular fitness after performing four upper body exercises for a 10-repetition maximum and underwent a submaximal aerobic fitness assessment for V̇O2peak and corresponding workload (watts). They were then assigned to a CE, RE, or sitting control (SC) session in counterbalanced order and were assessed with the Stroop Color and Word Test (SCWT) after each session. Results: Acute CE led to a significantly shorter response time compared to SC (p < .05) in the SCWT, wherein there were no significant differences between acute CE and RE (p = 1.00). Additionally, no significant differences in the accuracy rate were observed across the different sessions (ps > .05). Conclusion: A single session of moderate-intensity CE improved response time in the SCWT, comparable to RE. CE shows promise for enhancing cognitive function, warranting further research on its benefits and other exercise modalities.

Factors associated with outcomes of second-line treatment for EGFR-mutant non-small-cell lung cancer patients after progression on first- or second-generation EGFR-tyrosine kinase inhibitor treatment.

Purpose: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard first-line treatments for advanced EGFR-mutant non-small-cell lung cancer (NSCLC) patients. However, factors associated with outcomes after progression on first-line therapy are seldom investigated. Materials and methods: From January 2016 to December 2020, we enrolled 242 EGFR-mutant stage IIIB-IV NSCLC patients who progressed on first- or second-generation EGFR-TKI treatments, and 206 of them receive second-line treatments after disease progression. The factors that predict the survival outcomes of different second-line treatments after disease progression were evaluated. Clinical and demographic characteristics, including metastatic sites, neutrophil-to-lymphocyte ratio (NLR) at first-line progression, and second-line treatment regimens, and whether re-biopsied after disease progression or not, were reviewed for outcome analysis. Results: The univariate analysis showed that the PFS was shorted in male patients (p =0.049), patients with ECOG performance state ≥ 2 (p =0.014), former smokers (p =0.003), patients with brain metastasis (p =0.04), second-line chemotherapy or EGFR-TKIs other than osimertinib (p =0.002), and NLR ≥5.0 (p=0.024). In addition, second-line osimertinib was associated with longer OS compared to chemotherapy and other EGFR-TKI treatment (p =0.001). In the multivariate analysis, only second-line osimertinib was an independent predictor of PFS (p =0.023). Re-biopsy after first-line treatment was associated with a trend of better OS. Patients with NLR ≥5.0 at disease progression had shorter OS than patients with NLR <5.0 (p = 0.008). Conclusion: The benefits of osimertinib necessitate that aggressive re-biopsy after progression on first- or second-generation EGFR-TKI treatment is merited for appropriate second-line treatments to provide better outcomes for these patients.

Treatment patterns of targeted and nontargeted therapies and survival effects in patients with locally advanced head and neck cancer in Taiwan.

BACKGROUND: Taiwan's National Health Insurance has covered targeted therapy, namely cetuximab, for locally advanced head and neck cancers (LAHNC) since July 2009. This study examines treatment trends and survival effects of locally advanced head and neck cancer patients before and after Taiwan's National Health Insurance covered cetuximab. METHODS: We examined treatment trends and survival effects for patients with LAHNC using Taiwan's National Health Insurance Research Database. Patients who received treatment within 6 months were categorized as either nontargeted or targeted therapy groups. We analyzed treatment trends with the Cochran-Armitage trend test and explored factors associated with treatment selection and survival effects using multivariable logistic regression and Cox proportional hazards models. RESULTS: Of the 20,900 LAHNC patients included in the study, 19,696 received nontargeted therapy, while 1,204 received targeted therapy. Older patients with more comorbid conditions, advanced stages and patients with hypopharynx and oropharynx cancers were more likely to receive targeted therapy with concomitant cetuximab treatment. Patients who received targeted therapy in addition to other treatment modalities had a greater risk of one-year and long-term all-cause mortality or cancer-specific mortality than those without receiving targeted therapy (P < 0.001). CONCLUSIONS: Our study found an increasing trend in cetuximab utilization among LAHNC after reimbursement in Taiwan, but overall usage rates were low. LAHNC patients receiving cetuximab with other treatments had higher mortality risk than those receiving cisplatin, suggesting cisplatin may be preferred. Further research is needed to identify subgroups that could benefit from concomitant cetuximab treatment.

Evaluating Prescription Pattern and Effectiveness of Antihypertensive Drugs in Non-Operated Aortic Dissection Patients.

INTRODUCTION: Aortic dissection (AD) is a life-threatening disease. However, the effectiveness of different strategies of antihypertensive therapies in non-operated AD patients is still unclear. MATERIALS AND METHODS: Patients were classified into five groups (groups 0-4) based on the number of classes of antihypertensive drugs, including ß-blockers, renin-angiotensin system (RAS) agents (angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and the renin-inhibitors), calcium channel blockers (CCBs), and other antihypertensive drugs, were prescribed within 90 days after discharge. The primary endpoint was a composite outcome of re-hospitalization associated with AD, referral for aortic surgery, and all-cause death. RESULTS: A total of 3932 non-operated AD patients were included in our study. The most prescribed antihypertensive drugs were CCBs, followed by ß-blockers and ARBs. Within group 1, compared to other antihypertensive drugs, patients using RAS agents (aHR, 0.58; p = 0.005) had a significantly lower risk of occurrence of the outcome. Within group 2, the risk of composite outcomes was lower in patients using ß-blockers + CCBs (aHR, 0.60; p = 0.004) or CCBs + RAS agents (aHR, 0.60; p = 0.006) than in those using RAS agents + others. CONCLUSION: For non-operated AD patients, RAS agents, ß-blockers, or CCBs should be given in a different strategy of combinations to reduce the hazard of AD-related complications compared to other agents.

Gas-phase and PM2.5-bound phthalates in nail salons: characteristics, exposure via inhalation, and influencing factors.

This study aimed to investigate the characteristics of, exposure to, and factors influencing gas-phase and PM2.5-bound phthalates (PAEs) in nail salons. Data on both indoor and outdoor gas-phase and PM2.5-bound PAEs, carbon dioxide (CO2), temperature, and relative humidity were collected in nail salons. We also used questionnaires to survey building characteristics and occupants' behaviors. The average total gas-phase and PM2.5-bound PAE concentrations indoors were higher than those outdoors by 6 and 3 times, respectively. Diethyl phthalate, diisobutyl phthalate (DiBP), di-n-butyl phthalate (DnBP), and di-(2-ethylhexyl) phthalate (DEHP) were the predominant compounds among both the gas-phase and PM2.5-bound PAEs in indoor air. The volume of the salon's space or the difference of indoor and outdoor CO2 concentrations (dCO2) was significantly associated with indoor PAE concentrations. The ratios of PM2.5-bound to gas-phase PAEs, especially high-molecular-weight PAEs, were positively associated with the dCO2 concentrations. Higher ratios of indoor to outdoor PM2.5-bound DiBP, DnBP, and DEHP concentrations were discovered when more clients visited each day. Building characteristics, ventilation conditions, and occupants' activities have influences on the gas-phase and particle-phase PAEs. The study identifies the characteristics of gas-phase and PM2.5-bound PAEs in nail salons and their influencing factors.

Comparative effectiveness of tenofovir versus entecavir in patients with hepatitis B virus-related cirrhosis in Taiwan: a retrospective cohort study.

Background: Tenofovir and entecavir demonstrated substantial effectiveness in the reversion of fibrosis and reversed cirrhosis in patients with hepatitis B virus (HBV)-related cirrhosis. However, there has not been a definitive conclusion regarding the association between entecavir and tenofovir on the risk of cirrhosis-related complications. Therefore, this study aimed to investigate the comparative effectiveness between tenofovir and entecavir in HBV-related cirrhosis patients. Methods: This was a retrospective study using Taiwan's Health Insurance Research Database. We enrolled newly diagnosed HBV-related cirrhosis patients who initiated entecavir and tenofovir between 2011 and 2019. Treatment groups were determined by the initial HBV antiviral medication prescribed. The primary composite outcome was the development of hepatocellular carcinoma (HCC), death from any causes, and liver transplantation. The secondary outcomes included all the individual components of the primary outcome. The incidence rate was calculated for each outcome for both treatment groups using the Fine-Gray subdistribution hazard models. Propensity score adjustment was used to balance treatment groups. Results: A total of 7,316 propensity score-matched treatment-naïve patients and 3,524 propensity score-matched treatment-experienced patients were included. Within treatment-naïve patients, those receiving tenofovir showed significantly lower hazards of developing the composite outcome (HR, 0.79; p < 0.0001), hepatocellular carcinoma (HR, 0.86; p = 0.027), mortality (HR, 0.75; p < 0.0001), and liver transplantation (HR, 0.70; p = 0.0189) than those receiving entecavir. As for treatment-experienced patients, tenofovir was associated with a significantly lower risk of the composite outcome (HR, 0.82; p = 0.0033) and hepatocellular carcinoma (HR, 0.60; p < 0.0001), but it did not show a significantly different risk of all-cause mortality (HR, 0.93; p = 0.3374) or liver transplantation (HR, 1.17; p = 0.5112) compared to entecavir. Conclusion: Tenofovir presented a significantly lower incidence of cirrhosis-related complications than entecavir in patients with hepatitis B virus-related cirrhosis. However, no statistically significant difference in death and liver transplantation was seen in treatment-experienced patients.

The Influence of Influenza Virus Infections in Patients with Chronic Obstructive Pulmonary Disease.

Introduction: Chronic obstructive pulmonary disease (COPD) is a common disease and is preventable and treatable. A previous study showed that influenza virus infections were also associated with the risk of acute exacerbation in patients with COPD, and other studies showed that the influenza virus might increase the risk of stroke. However, studies on the influence of influenza infection among COPD patients are limited. In this study, we review the role of influenza infection in contributing to mortality, pneumonia, respiratory failure, COPD acute exacerbation, and ischemic stroke among COPD patients. Materials and Methods: We performed a population-based cohort study of COPD patients using data from Taiwan between January 1, 2011, and December 31, 2019. We excluded patients with lung cancer, lung transplantation and asthma. We also excluded patients who lacked COPD medication prescriptions and those treated with anti-influenza drugs without flu diagnosis records. Patients with missing or incomplete data were also excluded from the study cohort. Results: After 1:1 matching by age, sex, COPD duration, diagnosed years and comorbidities, we enrolled 10,855 cases and controls for further analysis. The risks of pneumonia, respiratory failure, COPD acute exacerbation, and ischemic stroke were 1.770 (95% CI=1.638-1.860; P<0.0001), 1.097 (95% CI=1.008-1.194; P=0.0319), 1.338 (95% CI=1.248-1.435; P<0.0001), and 1.134 (95% CI=1.039-1.239, P=0.0051), respectively, in the influenza infection group compared with COPD patients without influenza infection. Conclusion: Influenza infections are linked to an increased risk of ischemic stroke, pneumonia, respiratory failure, and COPD acute exacerbation among COPD patients. In conclusion, patients with COPD need to be closely monitored after having an influenza infection.

Recalibrating Risk Prediction Models by Synthesizing Data Sources: Adapting the Lung Cancer PLCO Model for Taiwan.

BACKGROUND: Methods synthesizing multiple data sources without prospective datasets have been proposed for absolute risk model development. This study proposed methods for adapting risk models for another population without prospective cohorts, which would help alleviate the health disparities caused by advances in absolute risk models. To exemplify, we adapted the lung cancer risk model PLCOM2012, well studied in the west, for Taiwan. METHODS: Using Taiwanese multiple data sources, we formed an age-matched case-control study of ever-smokers (AMCCSE), estimated the number of ever-smoking lung cancer patients in 2011-2016 (NESLP2011), and synthesized a dataset resembling the population of cancer-free ever-smokers in 2010 regarding the PLCOM2012 risk factors (SPES2010). The AMCCSE was used to estimate the overall calibration slope, and the requirement that NESLP2011 equals the estimated total risk of individuals in SPES2010 was used to handle the calibration-in-the-large problem. RESULTS: The adapted model PLCOT-1 (PLCOT-2) had an AUC of 0.78 (0.75). They had high performance in calibration and clinical usefulness on subgroups of SPES2010 defined by age and smoking experience. Selecting the same number of individuals for low-dose computed tomography screening using PLCOT-1 (PLCOT-2) would have identified approximately 6% (8%) more lung cancers than the US Preventive Services Task Forces 2021 criteria. Smokers having 40+ pack-years had an average PLCOT-1 (PLCOT-2) risk of 3.8% (2.6%). CONCLUSIONS: The adapted PLCOT models had high predictive performance. IMPACT: The PLCOT models could be used to design lung cancer screening programs in Taiwan. The methods could be applicable to other cancer models.

Verbascoside and isoverbascoside ameliorate transforming growth factor ß1-induced collagen expression by lung fibroblasts through Smad/non-Smad signaling pathways.

AIMS: Pulmonary fibrosis (PF) is a chronic, irreversible, and debilitating lung disease that typically leads to respiratory failure, and is a major cause of morbidity and mortality. Few drugs are effective for the treatment of patients with PF or for reducing the rate of disease progression. MAIN METHODS: Transforming growth factor-ß1 (TGF-ß1) is a profibrotic cytokine that signals through Smad and non-Smad pathways. Verbascoside (VB) and isoverbascoside (isoVB) exhibit anti-oxidative and anti-inflammatory activities, however, their anti-fibrotic effects remain unclear. This study evaluated the effects of VB and isoVB on TGF-ß1-stimulated murine lung fibroblasts (MLg 2908) and also human lung fibroblasts (confirmed by immunostaining). KEY FINDINGS: Neither VB nor isoVB had a cytotoxic effect on MLg 2908 fibroblasts. Both compounds (10 µM) reduced intracellular reactive oxygen species and markedly attenuated collagen I expression in TGF-ß1 (5 ng/ml)-induced MLg 2908 cells compared to TGF-ß1 alone. Both compounds suppressed the TGF-ß1-induced phosphorylation of Smad2/3 and ERK/p38 mitogen-activated protein kinases (MAPKs). VB and isoVB, but not pirfenidone and nintedanib, inhibited TGF-ß1-induced pSmad2/3, ERK/p38 MAPK, and collagen I expression. VB and isoVB also decreased collagen I deposition in TGF-ß1-induced MLg 2908 cells. Only isoVB significantly suppressed collagen I deposition in TGF-ß1-induced human pulmonary cells. Our results indicated that VB and isoVB may exert antifibrotic effects by inhibiting TGF-ß1-induced collagen I expression via inhibition of oxidative stress and downregulation of the Smad/non-Smad pathway. SIGNIFICANCE: The present findings suggest that VB or isoVB may be used as a supplement to alleviate PF.

Comparative Effectiveness of Abiraterone and Enzalutamide in Patients With Metastatic Castration-Resistant Prostate Cancer in Taiwan.

Background: Abiraterone and enzalutamide are widely used as first-line treatment for metastatic castration-resistant prostate cancer (mCRPC); however, their efficacy in mCRPC has been inconsistently demonstrated in other outcome studies from real-world databases. The aim of our study was to assess the comparative effectiveness of abiraterone and enzalutamide in patients with mCRPC using real-world data from Taiwan. Methods: This retrospective cohort population-based study included patients identified in the Taiwan National Health Insurance Research Database who had been diagnosed with mCRPC and who had taken abiraterone or enzalutamide between December 2014 and August 2017. The study's outcome evaluated the differences in overall survival (OS) and time to treatment failure (TTF) between abiraterone and enzalutamide over a 15-month follow-up period. The patients were followed from the index date to when the outcome occurred, to December 31, 2018, or to the patients' withdrawal from the National Health Insurance program. The estimated relative treatment effects of abiraterone and enzalutamide on OS and TTF were adjusted by the inverse probability of treatment weighting (IPTW) using the Kaplan-Meier method and a Cox proportional hazards model. Results: The abiraterone and enzalutamide groups consisted of 1,046 and 118 patients, respectively. After IPTW adjustment, 1,164 patients in the abiraterone group and 1,158 in the enzalutamide group underwent an outcome evaluation. Enzalutamide showed a similar OS rate to that of abiraterone (57.58% vs. 49.51%, p = 0.095 by log-rank test). Enzalutamide significantly reduced the risk of death for mCRPC when compared with abiraterone [adjusted hazard ratio (aHR), 0.828; 95% CI 0.731-0.938]. However, similar results were not observed in the TTF outcomes (63.84% vs. 67.79%, p = 0.2651 by log-rank test; aHR, 0.902; 95% CI 0.812-1.002). Conclusion: In conclusion, enzalutamide was associated with better OS for mCRPC than abiraterone in the Taiwan population. Our study showed that there was no statistically significant difference in TTF between enzalutamide and abiraterone. Studies with longer surveillance of enzalutamide and abiraterone using real-world databases are needed.

Sexual Crossing, Chromosome-Level Genome Sequences, and Comparative Genomic Analyses for the Medicinal Mushroom Taiwanofungus Camphoratus (Syn. Antrodia Cinnamomea, Antrodia Camphorata).

Taiwanofungus camphoratus mushrooms are a complementary and alternative medicine for hangovers, cancer, hypertension, obesity, diabetes, and inflammation. Though Taiwanofungus camphoratus has attracted considerable biotechnological and pharmacological attention, neither classical genetic nor genomic approaches have been properly established for it. We isolated four sexually competent monokaryons from two T. camphoratus dikaryons used for the commercial cultivation of orange-red (HC1) and milky-white (SN1) mushrooms, respectively. We also sequenced, annotated, and comparatively analyzed high-quality and chromosome-level genome sequences of these four monokaryons. These genomic resources represent a valuable basis for understanding the biology, evolution, and secondary metabolite biosynthesis of this economically important mushrooms. We demonstrate that T. camphoratus has a tetrapolar mating system and that HC1 and SN1 represent two intraspecies isolates displaying karyotypic variation. Compared with several edible mushroom model organisms, T. camphoratus underwent a significant contraction in the gene family and individual gene numbers, most notably for plant, fungal, and bacterial cell-wall-degrading enzymes, explaining why T. camphoratus mushrooms are rare in natural environments, are difficult and time-consuming to artificially cultivate, and are susceptible to fungal and bacterial infections. Our results lay the foundation for an in-depth T. camphoratus study, including precise genetic manipulation, improvements to mushroom fruiting, and synthetic biology applications for producing natural medicinal products. IMPORTANCETaiwanofungus camphoratus (Tc) is a basidiomycete fungus that causes brown heart rot of the aromatic tree Cinnamomum kanehirae. The Tc fruiting bodies have been used to treat hangovers, abdominal pain, diarrhea, hypertension, and other diseases first by aboriginal Taiwanese and later by people in many countries. To establish classical genetic and genomic approaches for this economically important medicinal mushroom, we first isolated and characterized four sexually competent monokaryons from two dikaryons wildly used for commercial production of Tc mushrooms. We applied PacBio single molecule, real-time sequencing technology to determine the near-completed genome sequences of four monokaryons. These telomere-to-telomere and gapless haploid genome sequences reveal all genomic variants needed to be studied and discovered, including centromeres, telomeres, retrotransposons, mating type loci, biosynthetic, and metabolic gene clusters. Substantial interspecies diversities are also discovered between Tc and several other mushroom model organisms, including Agrocybe aegerita, Coprinopsis cinerea, and Schizophyllum commune, and Ganoderma lucidum.