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Background: The effect of inhaled corticosteroid (ICS) on the risk of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection is unclear. Methods: We performed a systematic review and meta-analysis of clinical studies that assessed the association between the use of ICS and the risk of SARS-COV-2 infection. PubMed, Web of Science, Scopus, Cochrane Library and Google Scholar were searched to January 1st, 2023. ROBINS-I was used to assess risk of bias of included studies. The outcome of interest was the risk of SARS-COV-2 infection in patients and odds ratio (OR) with 95% confidence interval (95% CI) were calculated using Comprehensive Meta-analysis software version 3. Results: Twelve studies involving seven observational cohort studies, three case-control studies, and two cross-sectional studies were included in this meta-analysis. Overall, compared to non-ICS use, the pooled odds ratio (OR) of the risk of SARS-COV-2 infection was 0.997 (95% confidence interval [CI] 0.664–1.499; p = 0.987) for patients with ICS use. Subgroup analyses demonstrated no statistical significance in the increased risk of SARS-COV-2 infection in patients with ICS monotherapy or in combination with bronchodilators (pooled OR=1.408; 95% CI=0.693–2.858; p = 0.344 in ICS monotherapy, and pooled OR=1.225; 95% CI=0.533–2.815; p = 0.633 in ICS combination, respectively). In addition, no significant association was observed between ICS use and the risk of SARS-COV-2 infection for patients with COPD (pooled OR=0.715; 95% CI=0.415–1.230; p = 0.225) and asthma (pooled OR=1.081; 95% CI=0.970–1.206; p = 0.160). Conclusions: The use of ICS, either monotherapy or in combination with bronchodilators, does not have impact on the risk of SARS-COV-2 infection.

The influence of inhaled corticosteroids (ICS) on COVID-19 outcomes remains uncertain. To address this, we conducted a systematic review and meta-analysis, analyzing 30 studies, to investigate the impact of ICS on patients with COVID-19. Our study focused on various outcomes, including mortality risk, hospitalization, admission to the intensive care unit (ICU), mechanical ventilation (MV) utilization, and length of hospital stay. Additionally, we conducted a subgroup analysis to assess the effect of ICS on patients with chronic obstructive pulmonary disease (COPD) and asthma. Our findings suggest that the prior use of ICS did not lead to significant differences in mortality risk, ICU admission, hospitalization, or MV utilization between individuals who had used ICS previously and those who had not. However, in the subgroup analysis of patients with COPD, prior ICS use was associated with a lower risk of mortality compared to non-users (OR, 0.95; 95% CI, 0.90-1.00). Overall, while the use of ICS did not significantly affect COVID-19 outcomes in general, it may have beneficial effects specifically for patients with COPD. Nevertheless, more research is needed to establish a definitive conclusion on the role of ICS in COVID-19 treatment. PROSPERO registration number: CRD42021279429.

Abstract Background Allergic asthma occurs worldwide and is particularly prevalent in westernized countries characterized by chronic airway inflammation resulting in airway hyperresponsiveness. The house dust mites (HDM) including Dermatophagoides pteronyssinus are major sources of sensitization and triggering allergic symptoms in asthmatic patients. The Der p 2 is a major allergen and the predominant source of causative respiratory disorders which induce airway inflammation and bronchial constriction in mite-allergic patients. Few studies evaluate the ameliorating effects of modified Liu-Wei-Di-Huang-Wan (modified LWDHW) on allergic asthma. Methods This study aimed to investigate the immunological mechanisms of modified LWDHW on the reductions of airway inflammation, signal transduction, inflammatory cytokine production, Th2 cell proliferation, and bronchial obstruction in Der p 2-induced asthmatic mice. Results At least ten active ingredients were contained in the formula of modified LWDHW- 1217A and 1217B. Results showed that the immunoglobulin generations (Der p 2 specific- IgE and IgG1), inflammatory cytokine productions (IL-5 and IL-13) in the Sera and BALF could be down-regulated, and the Th1-cytokine productions (IL-12 and IFN-γ) be increased after immunotherapy with modified LWDHW of 1217A or 1217B. The inflammatory cell infiltrations (macrophages, eosinophils, and neutrophils) in the airway and the expressions of TH2-related genes (IL-4, IL-5, and IL-13), TH2-related transcription factor (GATA-3), and neutrophil chemotactic chemokine (IL-8) in the lung tissue of asthmatic mice were significantly decreased after the immunotherapy. The Th1/Th2 polarization had been identified that the IL-4+/CD4+ T cells were downregulated and IFN-γ+/CD4+ T cells were increased. The airway hyperresponsiveness to methacholine inhalation of Penh values was significantly decreased in the treated groups. There were significant improvements in the bronchus histopathology after immunotherapy with 1217A or 1217B which were evaluated by tracheal thickness, inflammatory cell count, and tracheal rupture of mouse lung. Conclusion It revealed that 1217A or 1217B could regulate the immune responses and improve pulmonary function. Data suggests that modified LWDHW of 1217A or 1217B have the potential for use as a therapeutic intervention for the treatment of mite allergen Der p 2-induced allergic asthma.

Abstract Background The successful management of patients infected with coronavirus disease 2019 (COVID-19) with inhaled ciclesonide has been reported, however few studies have investigated its application among hospitalized patients. Methods This retrospective cohort study enrolled all adult patients admitted to our hospital with confirmed COVID-19 infection from May to June 2021. Critical patients who received mechanical ventilation within 24 h after admission and those who started ciclesonide more than 14 days after symptom onset were excluded. The in-hospital mortality rate was compared between those who did and did not receive inhaled ciclesonide. Results A total of 269 patients were enrolled, of whom 184 received inhaled ciclesonide and 85 did not. The use of ciclesonide was associated with lower in-hospital mortality (7.6% vs. 23.5%, p = 0.0003) and a trend of shorter hospital stay (12.0 (10.0–18.0) days vs. 13.0 (10.0–25.3) days, p = 0.0577). In subgroup analysis, the use of inhaled ciclesonide significantly reduced mortality in the patients with severe COVID-19 infection (6.8% vs. 50.0%, p

IntroductionBeta-blockers are widely prescribed to manage hypertension and cardiovascular diseases and have been suggested as an attractive therapy to improve the prognosis of sepsis. Herein, we investigated the potential benefits of premorbid selective beta-blocker use in sepsis with a real-world database and explored the underlying mechanism by in vivo and in vitro experiments.MethodsA total of 64,070 sepsis patients and 64,070 matched controls who were prescribed at least one anti-hypertensive drug for more than 300 days within 1 year were selected for the nested case–control study. Female C57BL/6 J mice and THP-1 cells stimulated with lipopolysaccharide (LPS) were used for studying systemic responses during sepsis to validate our clinical findings.ResultsThe risk of sepsis was lower in current selective beta-blocker users than in non-users (adjusted OR (aOR), 0.842; 95% CI, 0.755–0.939), and in recent users than in non-users (aOR, 0.773; 95% CI, 0.737–0.810). A mean daily dose of ≥0.5 DDD was associated with a lower risk of sepsis (aOR, 0.7; 95% CI, 0.676–0.725). Metoprolol, atenolol, and bisoprolol users had lower risk of sepsis than non-users. In a LPS-induced sepsis mouse model, mice pre-fed with atenolol had significantly reduced mortality. While atenolol had some mild effects on LPS-induced release of inflammatory cytokines in septic mice, it significantly reduced serum soluble PD-L1 levels. Notably, atenolol treatment reversed the negative correlation of sPD-L1 with inflammatory cytokines in septic mice. Moreover, atenolol markedly downregulated the PD-L1 expression on LPS-stimulated THP-1 monocytes/macrophages via targeting ROS-induced NF-κB and STAT3 activation.ConclusionAtenolol pretreatment can reduce sepsis mortality in mice, and in vivo and in vitro studies of PD-L1 expression suggest a role for atenolol in the modulation of immune homeostasis. These findings may contribute to the reduced incidence of sepsis in hypertensive patients with premorbid treatment with selective beta-blockers, especially atenolol.

BackgroundThe aim of our study was to externally validate the predictive capability of five developed coronavirus disease 2019 (COVID-19)-specific prognostic tools, including the COVID-19 Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), Shang COVID severity score, COVID-intubation risk score-neutrophil/lymphocyte ratio (IRS-NLR), inflammation-based score, and ventilation in COVID estimator (VICE) score.MethodsThe medical records of all patients hospitalized for a laboratory-confirmed COVID-19 diagnosis between May 2021 and June 2021 were retrospectively analyzed. Data were extracted within the first 24 h of admission, and five different scores were calculated. The primary and secondary outcomes were 30-day mortality and mechanical ventilation, respectively.ResultsA total of 285 patients were enrolled in our cohort. Sixty-five patients (22.8%) were intubated with ventilator support, and the 30-day mortality rate was 8.8%. The Shang COVID severity score had the highest numerical area under the receiver operator characteristic (AUC-ROC) (AUC 0.836) curve to predict 30-day mortality, followed by the SEIMC score (AUC 0.807) and VICE score (AUC 0.804). For intubation, both the VICE and COVID-IRS-NLR scores had the highest AUC (AUC 0.82) compared to the inflammation-based score (AUC 0.69). The 30-day mortality increased steadily according to higher Shang COVID severity scores and SEIMC scores. The intubation rate exceeded 50% in the patients stratified by higher VICE scores and COVID-IRS-NLR score quintiles.ConclusionThe discriminative performances of the SEIMC score and Shang COVID severity score are good for predicting the 30-day mortality of hospitalized COVID-19 patients. The COVID-IRS-NLR and VICE showed good performance for predicting invasive mechanical ventilation (IMV).

OBJECTIVES/GOALS: Glioblastoma (GBM) is the most common and aggressive adult primary brain malignancy. Clinically, GBM is refractory to T cell immune checkpoint blockade (ICB), in part due to its dense immune suppressive myeloid stroma. Here we show that myeloid-targeting STING agonists can repolarize the GBM microenvironment to cure ICB-refractory GBM models. METHODS/STUDY POPULATION: Using the synthetic cyclic di-nucleotide STING agonist IACS-8803 (8803) we treated orthotopic ICB-refractory QPP8 orthotopic murine GBM tumors intratumorally. We then analyzed survival and performed high parameter flow cytometry profiling of the tumor immune microenvironment following STING agonist treatment. To assess the contribution of adaptive immunity to STING agonist therapeutic efficacy, we treated orthotopic QPP8 tumors implanted in RAG1 KO mice and monitored survival. RESULTS/ANTICIPATED RESULTS: We found that STING agonist therapy cured murine orthotopic QPP8 tumors, in contrast to ICB that showed no survival benefit. In RAG1-/- mice bearing QPP8 tumors STING agonist therapy extended survival, however, the curative effect observed in wild-type mice was lost in the absence of adaptive immunity. STING agonist-treated QPP8 tumors displayed increased counts of CD8 T cells and NK cells, and decreased CD8 T cell PD1 expression. Infiltration of STING-treated gliomas by Ly6C+ F4/80+ Mono-MDSC substantially increased; however, these cells expressed reduced CD206 and CD163, suggestive of reduced immuno-suppression. Finally, in the cervical LN of QPP8-treated mice the frequency and CD80/CD86 expression of cDC1 cells increased.​ DISCUSSION/SIGNIFICANCE: ICB has failed in GBM, and the suppressive myeloid stroma remains a major barrier to generating anti-GBM T cell responses. Our work shows that STING activation, which primarily targets innate immunity myeloid cells 'upstream' of T cells in the antitumor immunity cycle, can cure ICB-refractory GBM tumors in an adaptive immunity-dependent manner.

Purpose: The aim of this meta-analysis is to compare the clinical efficacy and safety of baloxavir with other anti-influenza agents or placebo in the treatment of influenza. Methods: PubMed, Embase, Web of Science, Google Scholar, Scopus, CINAHL, Cochrane databases and clinical registration were searched from inception until February 15 2021 for relevant randomized controlled trials (RCTs). Only phase 3 RCTs evaluating the usefulness of baloxavir in the treatment of influenza were included. Results: Three RCTs enrolling 3771 patients (baloxavir group, n = 1451; oseltamivir group, n = 1288; placebo group, n = 1032) were included. Compared with oseltamivir, baloxavir had an insignificantly shorter time to the alleviation of symptoms (mean difference [MD], −1.29 h; 95% CI, −6.80 to 4.21; I2 = 0%). In contrast, baloxavir had a significantly shorter time to the alleviation of symptoms than placebo (MD, −26.32 h; 95% CI, −33.78 to −18.86; I2 = 0%). Baloxavir was associated with a significant decline in influenza virus titers and viral RNA load compared to oseltamivir and placebo. Baloxavir was associated with a lower risk of any adverse events than oseltamivir (OR, 0.82; 95% CI, 0.69–0.98; I2 = 0%) and placebo (OR, 0.79; 95% CI, 0.66–0.96; I2 = 0%). Conclusions: The findings of this meta-analysis suggested that baloxavir is superior to placebo in the treatment of influenza in both clinical outcome and virological response. Moreover, baloxavir was found to have a better virological response than oseltamivir and to be as effective as oseltamivir clinically. Compared with oseltamivir and placebo, baloxavir appears to be a relatively safe anti-influenza agent.

Abstract Background The effect of additional antimicrobial agents on the clinical outcomes of patients with idiopathic pulmonary fibrosis (IPF) is unclear. Methods We performed comprehensive searches of randomized control trials (RCTs) that compared the clinical efficacy of additional antimicrobial agents to those of placebo or usual care in the treatment of IPF patients. The primary outcome was all-cause mortality, and the secondary outcomes were changes in forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLCO), and the risk of adverse events (AEs). Results Four RCTs including a total of 1055 patients (528 receiving additional antibiotics and 527 receiving placebo or usual care) were included in this meta-analysis. Among the study group, 402 and 126 patients received co-trimoxazole and doxycycline, respectively. The all-cause mortality rates were 15.0% (79/528) and 14.0% (74/527) in the patients who did and did not receive additional antibiotics, respectively (odds ratio [OR] 1.07; 95% confidence interval [CI] 0.76 to 1.51; p = 0.71). No significant difference was observed in the changes in FVC (mean difference [MD], 0.01; 95% CI − 0.03 to 0.05; p = 0.56) and DLCO (MD, 0.05; 95% CI − 0.17 to 0.28; p = 0.65). Additional use of antimicrobial agents was also associated with an increased risk of AEs (OR 1.65; 95% CI 1.19 to 2.27; p = 0.002), especially gastrointestinal disorders (OR 1.54; 95% CI 1.10 to 2.15; p = 0.001). Conclusions In patients with IPF, adding antimicrobial therapy to usual care did not improve mortality or lung function decline but increased gastrointestinal toxicity.

Objectives: The aim of this study was to investigate the clinical efficacy and safety of cefiderocol in the treatment of acute bacterial infections. Methods: The PubMed, Embase and Cochrane Library databases as well as the clinical trials registries of ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched up to 8 November 2020. Only randomised controlled trials (RCTs) that compared the treatment efficacy of cefiderocol with that of other antibiotics for adult patients with acute bacterial infections were included in this meta-analysis. The primary outcome was clinical response at test of cure (TOC). Results: Three RCTs, including one phase 2 and two phase 3 trials, were included. No significant difference in clinical response rate was observed between cefiderocol and comparators [odds ratio (OR) = 1.04]. In a subgroup analysis, no significant difference was observed in the clinical response at TOC between cefiderocol and comparators in patients with nosocomial pneumonia (OR = 0.92) or complicated urinary tract infection (OR = 1.28). In addition, all-cause mortality at Days 14 and 28 did not differ between the cefiderocol and control groups (14-day mortality, OR = 1.25; 28-day mortality, OR = 1.12). Furthermore, cefiderocol was associated with similar microbiological response to comparators at the TOC assessment (OR = 1.44). Finally, cefiderocol was associated with a similar risk of adverse events as comparators. Conclusion: Cefiderocol can achieve similar clinical and microbiological responses as comparators for patients with serious bacterial infections. In addition, cefiderocol shares a safety profile similar to that of comparators.

Targeted temperature management (TTM) is often considered to improve post-cardiac arrest patients’ outcomes. However, the optimal timing to initiate cooling remained uncertain. This retrospective analysis enrolled all non-traumatic post-cardiac arrest adult patients with either out-of-hospital cardiac arrest (OHCA) or in-hospital cardiac arrest (IHCA) who received TTM from July 2015 to July 2021 at our hospital. The values of time delay before TTM and time to target temperature were divided into three periods according to optimal cut-off values identified using receiver operating characteristic curve analysis. A total of 177 patients were enrolled. A shorter time delay before TTM (pre-induction time) was associated with a lower survival chance at 28 days (32.00% vs. 54.00%, p = 0.0279). Patients with a longer cooling induction time (>440 minis) had better neurological outcomes (1.58% vs. 1.05%; p = 0.001) and survival at 28 days (58.06% vs. 29.25%; p = 0.006). After COX regression analysis, the influence of pre-induction time on survival became insignificant, but patients who cooled slowest still had a better chance of survival at 28 days. In conclusion, a shorter delay before TTM was not associated with better clinical outcomes. However, patients who took longer to reach the target temperature had better hospital survival and neurological outcomes than those who were cooled more rapidly. A further prospective study was warranted to evaluate the appropriate time window of TTM.

The revised post-Cardiac Arrest Syndrome for Therapeutic hypothermia (rCAST) score was proposed to predict neurologic outcomes and mortality among out-of-hospital cardiac arrest (OHCA) patients. However, it has rarely been validated outside Japan. Therefore, this study aimed to investigate this issue. All adult patients admitted to our medical intensive care unit for targeted temperature management (TTM) between July 2015 and July 2021 were enrolled. Their medical records were retrieved, and rCAST scores were calculated. A total of 108 post-cardiac arrest syndrome (PCAS) patients who received TTM were analyzed. According to the rCAST score, 49.1%, 50.0%, and 0.9% of the patients were classified as low, moderate, and high severity, respectively. The areas under the curves for the rCAST score were 0.806 (95% confidence interval [CI]: 0.719–0.876) and 0.794 (95% CI: 0.706–0.866) to predict poor neurologic outcomes and mortality at day 28, respectively. In contrast to the original report, only low-severity patients had favorable neurologic outcomes. The rCAST score showed moderate accuracy in our OHCA patients with PCAS who received TTM to predict poor neurologic outcomes and mortality at day 28.

This network meta-analysis compared the clinical efficacy and safety of anti-viral agents for the prevention of disease progression among non-hospitalized patients with COVID-19. PubMed, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched from their inception to 28 May 2022. Only randomized controlled trials (RCTs) that investigated the clinical efficacy of anti-viral agents for non-hospitalized patients with COVID-19 were included. Three RCTs involving 4241 patients were included. Overall, anti-viral agents were associated with a significantly lower risk of COVID-19 related hospitalization or death compared with the placebo (OR, 0.23; 95% CI: 0.06–0.96; p = 0.04). Compared with the placebo, patients receiving nirmatrelvir plus ritonavir had the lowest risk of hospitalization or death (OR, 0.12; 95% CI: 0.06–0.24), followed by remdesivir (OR, 0.13; 95% CI: 0.03–0.57) and then molnupiravir (OR, 0.67; 95% CI: 0.46–0.99). The rank probability for each treatment calculated using the P-score revealed that nirmatrelvir plus ritonavir was the best anti-viral treatment, followed by remdesivir and then molnupiravir. Finally, anti-viral agents were not associated with an increased risk of adverse events compared with the placebo. For non-hospitalized patients with COVID-19 who are at risk of disease progression, the currently recommended three anti-viral agents, nirmatrelvir plus ritonavir, molnupiravir and remdesivir, should continue to be recommended for the prevention of disease progression. Among them, oral nirmatrelvir plus ritonavir and intravenous remdesivir seem to be the better choice, followed by molnupiravir, as determined by this network meta-analysis. Additionally, these three anti-viral agents were shown to be as tolerable as the placebo in this clinical setting.

Objective(s): The aim of this study was to conduct a meta-analysis to assess the clinical safety of ceftolozane-tazobactam for the treatment of acute bacterial infections in adult patients. Methods: The PubMed, Embase, and Cochrane databases were searched from their inception until May 2020 for relevant randomized controlled trials (RCTs). Only RCTs evaluating the risk of adverse events (AEs) for ceftolozane-tazobactam and comparative treatments for acute bacterial infections in adult patients were included. Results: Overall, four RCTs including a total of 2924 patients (1475 in the ceftolozane-tazobactam group and 1449 in the control group) were included in the meta-analysis. The rate of treatment-emergent AEs was 51.3% (748/1458) in the ceftolozane-tazobactam group, which was comparable to the control group, 49.9% [714/1430; odd’s ratio (OR), 1.06; 95% confidence interval (CI), 0.91–1.25; I 2 = 0%]. In addition, no difference was observed between the ceftolozane-tazobactam and control groups in terms of the risk of serious AEs (OR, 1.22; 95% CI, 0.93–1.61; I 2 = 15.5%) and the risk of discontinuing the study drug due to AEs (OR, 0.85; 95% CI, 0.55–1.33; I 2 = 0%). The rate of all-cause mortality did not significantly differ between the ceftolozane-tazobactam and control groups (OR, 1.11; 95% CI, 0.82–1.50; I 2 = 0%). The only exception was the risk of Clostridiodes difficile ( C. difficile ) colitis, where ceftolozane-tazobactam treatment was associated with a significantly higher risk compared with the control group [0.72% (10/1376) versus 0.14% (2/1391), OR, 3.84; 95% CI, 1.23–11.97; I 2 = 0%]. Conclusion: Ceftolozane-tazobactam treatment is as tolerable as comparative treatment options for acute bacterial infections in adult patients, however it has an increased risk of C. difficile infection. As a novel broad-spectrum antibiotic, ceftolozane-tazobactam could be a safe therapeutic option for use in common clinical practice. Plain language summary The safety of ceftolozane-tazobactam (an antibiotics) for the treatment of acute bacterial infections Objective(s): Ceftolozane-tazobactam is an effective antibiotic for the treatment of acute bacterial infections. This study conducts a meta-analysis to assess the clinical safety (side effects) of ceftolozane-tazobactam for the treatment of acute bacterial infections in adult patients compared with other drugs. Methods: We extracted data from four randomized controlled trials, including a total of 2924 patients (1475 in the ceftolozane-tazobactam group and 1449 in the control group). Results: The rate of treatment related adverse events (AEs) was similar in the ceftolozane-tazobactam group (51.3%) and control group (49.9%). There was also no difference in risk of serious adverse events, the risk of discontinuing the study drug due to AEs, and all-cause mortality. The only exception was the risk of Clostridiodes difficile colitis (a cause of antibiotic-associated diarrhea), where ceftolozane-tazobactam treatment was associated with a significantly higher risk compared with the control group. Conclusion: In conclusion, as a novel broad-spectrum antibiotic, ceftolozane-tazobactam could be a safe therapeutic option for use in clinical practice.

Abstract Background Low availability of oxygen in tumors contributes to the hostility of the tumor microenvironment toward the immune system. However, the dynamic relationship between local oxygen levels and the immune surveillance of tumors by tumor infiltrating T-lymphocytes (TIL) remains unclear. This situation reflects a methodological difficulty in visualizing oxygen gradients in living tissue in a manner that is suitable for spatiotemporal quantification and contextual correlation with individual cell dynamics tracked by typical fluorescence reporter systems. Methods Here, we devise a regimen for intravital oxygen and cell dynamics co-imaging, termed ‘Fast’ Scanning Two-photon Phosphorescence Lifetime Imaging Microscopy (FaST-PLIM). Using FaST-PLIM, we image the cellular motility of T-lymphocytes in relation to the microscopic distribution of oxygen in mouse models of hematological and solid tumors, namely in bone marrow with or without B-cell acute lymphocytic leukemia (ALL), and in lungs with sarcoma tumors. Results Both in bone marrow leukemia and solid tumor models, TILs encountered regions of varying oxygen concentrations, including regions of hypoxia (defined as pO2 below 5 mmHg), especially in advanced-stage ALL and within solid tumor cores. T cell motility was sustained and weakly correlated with local pO2 above 5 mmHg but it was very slow in pO2 below this level. In solid tumors, this relationship was reflected in slow migration of TIL in tumor cores compared to that in tumor margins. Remarkably, breathing 100% oxygen alleviated tumor core hypoxia and rapidly invigorated the motility of otherwise stalled tumor core TILs. Conclusions This study demonstrates a versatile and highly contextual FaST-PLIM method for phosphorescence lifetime-based oxygen imaging in living animal tumor immunology models. The initial results of this method application to ALL and solid lung tumor models highlight the importance of oxygen supply for the maintenance of intratumoral T cell migration, define a 5 mmHg local oxygen concentration threshold for TIL motility, and demonstrate efficacy of supplementary oxygen breathing in TIL motility enhancement coincident with reduction of tumor hypoxia.

IntroductionNintedanib can inhibit processes involved in the progression of fibrosis and can reduce the decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF) and fibrotic-interstitial lung disease (fibrotic-ILDs). Although the adverse events associated with nintedanib in IPF patients are well known, its safety in other fibrotic-ILD patients remained unclear.MethodsWe searched PubMed, EMBASE, Cochrane CENTRAL and Cochrane CDSR for randomized controlled studies which compared nintedanib with a placebo in ILD patients. We estimated pooled odds ratios (ORs) and 95% confidence intervals (CIs) for adverse events using the DerSimonian-Laird random-effects model.ResultsSix studies with a total of 2,583 patients were included in the meta-analysis. The pooled estimates showed that patients treated with nintedanib had a significantly higher likelihood of having any adverse events (OR = 2.39; 95% CI = 1.71-3.36) or adverse events leading to treatment discontinuation (OR = 1.73; 95% CI = 1.34-2.25). However, they had trend to lower likelihood of having fatal adverse events (OR = 0.69; 95% CI = 0.41-1.14) compared with the placebo group. Use of nintedanib was positively associated with diarrhea (OR = 5.96; 95% CI = 4.35-8.16), nausea (OR = 3.00; 95% CI = 1.93-4.66), vomiting (OR = 3.22; 95% CI = 2.17-4.76) and weight loss (OR = 3.38; 95% CI = 1.1.76-6.47). Whereas, patients treated with nintedanib were less likely to have a cough (OR = 0.73; 95% CI = 0.56-0.96) and dyspnea (OR = 0.70; 95% CI = 0.53-0.94).ConclusionsCompared to a placebo, nintedanib was associated with a higher risk of adverse events, especially for diarrhea, nausea, vomiting and weight loss, but it was also associated with a lower risk of cough and dyspnea in IPF and fibrotic-ILD patients.

To enhance driving safety at night, a new freeform-surface street light luminaire was proposed and evaluated in this study that meets the requirements of the International Commission on Illumination (CIE) M3 class standard for road lighting. The luminaire was designed using simulations to optimize the location of the bulb according to the requirements of the standard. The light source IES file was experimentally obtained for the optimized luminaire prototype with a 150 W ceramic metal halide lamp using an imaging goniophotometer. The trial road lighting simulation results computed by the lighting software DIALux indicated that the proposed luminaire provided an average road surface brightness of 1.1 cd/m2 (compared to a minimum requirement of 1.0 cd/m2), a brightness uniformity of 0.41 (compared to a minimum requirement of 0.4), a longitudinal brightness uniformity of 0.64 (compared to a minimum requirement of 0.6), and a glare factor of 7.6% (compared to a maximum limit of 15%). The findings of the image goniophotometer tests were then confirmed by the results of a certified mirror goniophotometer test conducted by the Taiwan Accreditation Foundation (TAF). The results of this study can be used to provide improved street lighting designs to meet enhanced international standards.

There are more single inhaler device triple therapy available for COPD patients now. However, the effect of long-term triple therapy fixed dose combination (FDC) on mortality remains unclear. This study aimed to evaluate the impact of one-year single inhaler device triple therapy, including long-acting β2-agonists (LABAs), long-acting muscarinic receptor antagonists (LAMAs), and inhaled corticosteroids (ICSs), with dual therapies, comprised of either LABA/LAMA or ICS/LABA, on the mortality of patients with COPD. We searched the PubMed, Cochrane library, Web of Science, Embase databases, and clinical trial registry of clinicaltrials.gov and WHO ICTRP. Randomized controlled trials (RCTs) compared single inhaler device triple and dual therapies for 52 weeks were selected for the meta-analysis. The primary endpoint was all-cause mortality. A total of 6 RCTs were selected for the meta-analysis, including 10,274 patients who received single inhaler device triple therapy (ICS/LABA/LAMA FDC) and 12,395 patients who received ICS/LABA or LABA/LAMA dual therapy. Risk of death was significantly lower in the ICS/LABA/LAMA FDC group compared to the LABA/LAMA group (RR = 0.69, 95% CI = 0.53–0.90, p = 0.007). There was no significant difference in mortality between the ICS/LABA/LAMA FDC and ICS/LABA therapy groups (RR = 0.94, 95% CI = 0.72–1.24, p = 0.66). In addition, patients receiving ICS/LABA/LAMA FDC therapy had less moderate or severe exacerbations compared with the dual therapy groups (RR = 0.76, 95% CI = 0.73–0.80, p < 0.001 for LABA/LAMA; RR = 0.84, 95% CI = 0.78–0.90, p < 0.001 for ICS/LABA). By contrast, the risk of pneumonia in the ICS/LABA/LAMA FDC group was higher than in the LABA/LAMA group (RR = 1.43, 95% CI = 1.21–1.68, p < 0.001). In conclusion, ICS/LABA/LAMA FDC therapy could help improve the clinical outcomes of patients with COPD. However, triple therapy could increase the risk of pneumonia in comparison with LABA/LAMA dual therapy.

Background: Japanese encephalitis virus (JEV) non-structural protein 5 (NS5) exhibits type I interferon (IFN) antagonists, contributing to immune escape, and even inducing viral anti-apoptosis. This study investigated the anti-apoptotic mechanism of JEV NS5 protein on type I IFN-induced apoptosis of human medulloblastoma cells. Methods: Vector control and NS5-expressing cells were treated with IFN-β, and then harvested for analyzing apoptotic pathways with flow cytometry, Western blotting, subcellular localization, etc. Results: Annexin V-FITC/PI staining indicated that IFN-β triggered apoptosis of human medulloblastoma cells, but JEV NS5 protein significantly inhibited IFN-β-induced apoptosis. Phage display technology and co-immunoprecipitation assay identified the anti-apoptotic protein Hsp70 as a NS5-interacting protein. In addition, Western blotting demonstrated that NS5 protein up-regulated the Hsp70 expression, and reduced IFN-β-induced phosphorylation of ERK2, p38 MAPK and STAT1. Hsp70 down-regulation by quercetin significantly recovered IFN-β-induced apoptosis of NS5-expressing cells, correlating with the increase in the phosphorylation of ERK2, p38 MAPK, and STAT1. Inhibiting the ATPase activity of Hsp70 by VER-155008 resulted in the elevated IFN-β-induced apoptosis in vector control and NS5-expressing cells. Conclusions: The results indicated Hsp70 up-regulation by JEV NS5 not only involved in type I IFN antagonism, but also responded to the anti-apoptotic action of JEV NS5 protein through the blocking IFN-β-induced p38 MAPK/STAT1-mediated apoptosis. Keywords: Japanese encephalitis virus, NS5, Interferon, Anti-apoptosis, Hsp70

Background/Purpose: Human coronavirus (HCoV) NL63 is recognized in association with upper or lower respiratory tract illnesses in children. This study surveyed the prevalence of HCoV-NL63 and influenza viruses in patients with influenza-like illness in Taiwan during 2010â2011. Methods: Throat samples from 107 hospitalized patients with pneumonia and 175 outpatients with influenza-like illness were examined using real-time polymerase chain reaction assays with virus-specific primers, and then virus-positive specimens were confirmed by sequencing the polymerase chain reaction products. Results: HCoV-NL63 infection was identified in 8.4% (9/107) of hospitalized patients with pneumonia, but not found in outpatients with influenza-like illness. Age distribution of HCoV-NL63 infection in hospitalized patients with pneumonia indicated that the group aged 16â25Â years (20%) had the highest positive rate compared with the other groups, and exhibited a similar age-specific pattern to influenza A/H1N1 infection, but not influenza A/H3N2 and B infections in hospitalized patients. Seasonal prevalence of HCoV-NL63 infection was late winter, overlapping the highest peak of the influenza A/H1N1 epidemic during December 2010 to March 2011 in Taiwan. Co-infection of HCoV-NL63 and influenza A/H1N1 was detected in three hospitalized patients. Clinical manifestation analysis indicated that the main symptoms for HCoV-NL63 infection included fever (88.9%), cough (77.8%), and pneumonia (100%). Co-infection caused significantly higher rates of breathing difficulties, cough, and sore throat than those of single infection with HCoV-NL63 and influenza A/H1N1. Phylogenetic analysis indicated a low level of heterogeneity between Taiwan and global HCoV-NL63 strains. Conclusion: Understanding epidemiology of HCoV-NL63 in Taiwan provides an insight for worldwide surveillance of HCoV-NL63 infection. Keywords: age distribution, human coronavirus NL63, phylogenetic analysis, pneumonia, seasonality

In fields such as biology, archeology, and industry, underwater photogrammetry can be achieved using consumer-grade equipment. However, camera operations underwater differ considerably from those on land because underwater photogrammetry involves different optical phenomena. On the basis of the requirements and specifications of the marine vessel Polaris, we developed a novel underwater camera with prime and zoom lenses and a high resolving power. The camera can be used in the spectrum in shallow water and the blue–green spectrum in deep water. In the past, ordinary cameras would be placed in waterproof airtight boxes for underwater photography. These cameras were not optimized to the underwater spectrum and environment, resulting in no breakthroughs in resolving power. Furthermore, the use of the blue spectrum greatly increases during underwater and particularly deep-water surveying. Chromatic aberration and focus-point displacement generated by the shift from the shallow-water spectrum to the blue–green spectrum in deep water makes universal underwater photography even more difficult. Our proposed optical design aimed to overcome such challenges for the development of a high-resolution underwater surveying camera. We designed a prime lens and a zoom lens. We adopted a waterproof dome window on the outer surface as the basic structure and optimized it in accordance with the conditions of different water depths and spectra to obtain distortion within ±2% and high-resolution underwater imaging quality. For the zoom lens design, we employed a genetic algorithm in Zemax to attenuate chromatic aberration as a kind of extended optimization. This novel optical design that can be used in all waters is expected to greatly reduce the volume and weight of conventional underwater cameras by more than 50% and 60%, respectively, and increase their resolving power by 30–40%.

This study aimed to investigate the association between the risk of aortic aneurysm (AA)/aortic dissection (AD) and the use of fluoroquinolones (FQs). PubMed, Embase, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, Web of Science and Scopus were searched for relevant articles to 21st February 2021. Studies that compared the risk of AA/AD in patients who did and did not receive FQs or other comparators were included. The pooled results of nine studies with 11 study cohorts showed that the use of FQs increased the risk of AA/AD by 69% (pooled risk ratio (RR) = 1.69 (95% CI = 1.08, 2.64)). This significant association remained unchanged using leave-one-out sensitivity test analysis. Similar results were found for AA (pooled RR = 1.58 (1.21, 2.07)) but no significant association was observed for AD (pooled RR = 1.23 (0.93, 1.62)). Stratified by the comparators, the use of FQs was associated with a significantly higher risk of AA/AD compared to azithromycin (pooled RR = 2.31 (1.54, 3.47)) and amoxicillin (pooled RR = 1.57 (1.39, 1.78)). In contrast, FQ was not associated with a higher risk of AA/AD, when compared with amoxicillin/clavulanic acid or ampicillin/sulbactam (pooled RR = 1.18 (0.81, 1.73)), sulfamethoxazole–trimethoprim (pooled RR = 0.89 (0.65, 1.22)) and other antibiotics (pooled RR = 1.14 (0.90, 1.46)). In conclusion, FQs were associated with an increased risk of AA or AD, although the level of evidence was not robust. However, FQs did not exhibit a higher risk of AA or AD compared with other broad-spectrum antibiotics. Further studies are warranted to clarify the role of FQs in the development of AA or AD.

An LED Counter Beam Light (CBL) with a free surface secondary lens is proposed to enhance the safety and efficiency of tunnels. The secondary lens was designed and produced to be mounted on a 50 W white-light LED array to generate the targeted counter beam pattern, in order to meet the standards for enhanced tunnel road lighting of the CIE (Commission Internationale de l’Eclairage)—CIE 88:2004—in a trial tunnel lighting scheme. Through the simulation of a road tunnel in Northern Taiwan using the LiteStar four-dimensional software, it was shown that the proposed LED light can serve as a qualifying CBL to generate an average road tunnel surface luminance (Lav) of 182.76 cd/m2, which is better than the 138 cd/m2 that commercial High-Pressure Sodium (HPS) tunnel lights can provide and the 181 cd/m2 minimum stipulated in the CIE 88:2004 regulations. The results also show that the proposed LED light accomplishes a contrast revealing coefficient qc of 1.03, which is above the minimum regulatory level of 0.6 for a qualified CBL, as well as a luminance uniformity Uo of 0.89 (regulatory minimum, 0.4), longitudinal luminance uniformity UL of 0.99 (regulatory minimum, 0.6), and glare factor TI (threshold increment) of 7.24% (regulatory minimum, 15%). In order to test the feasibility of the LED CBL for future commercialization, the proposed LED CBL was prototyped and measured; the results demonstrate that an average road surface luminance (Lav) of 184.5 cd/m2, intensity of the luminance uniformity Uo of 0.7, intensity of the longitudinal luminance uniformity UL of 0.94, glare factor of 7.04%, and contrast revealing coefficient qc of 1.38 can be achieved, which are all above the levels required by the CIE 88:2004 regulations.

In the field of vehicle lighting, due to the diode laser, its small size and high energy conversion efficiency, it can be effectively used as the headlight source of high beam. In recent years, it was adopted by European advanced car manufacturers as a new generation of automotive headlight lighting products. The current mature technology on the market is to extend the laser beam by means of reflection and to use a single high-power laser as the light source to meet the needs of surface lighting. In this research, we propose a new integrated optical design for an automotive headlight system with the rod lens, gradient-index lens (GRIN lens) and freeform lens to expand the laser beam. With regard to the diffusion of the beam by reflection and refraction, the liquid lens is used as a switch for the high beam and low beam lights to meet the needs of vehicle lighting functions and to use low-power diode lasers to synthesize the array light source. Compared with the 24-W LED headlight module available in the current market, the energy saved by this proposed optical design can increase efficiency by an average of 33%. The maximum illuminance is 56.6 lux in the high-beam mode, which is 18% higher than the standard value. Let the laser light meet the lighting requirements of regulatory standard values even beyond.

In this article, we review how acupuncture regulates oxidative stress to prevent ischemia−reperfusion injury. We electronically searched databases, including PubMed, Clinical Key and the Cochrane Library, from their inception to November 2019 by using the following medical subject headings and keywords: acupuncture, ischemia-reperfusion injury, oxidative stress, reactive oxygen species, and antioxidants. We concluded that acupuncture is effective in treating oxidation after ischemia-reperfusion injury. In addition to increasing the activity of antioxidant enzymes and downregulating the generation of reactive oxygen species (ROS), acupuncture also repairs the DNA, lipids, and proteins attacked by ROS and mediates downstream of the ROS pathway to apoptosis.

Enterovirus A71 (EV-A71) in the Picornaviridae family causes hand-foot-and-mouth disease, aseptic meningitis, severe central nervous system disease, even death. EV-A71 2A protease cleaves Type I interferon (IFN)-α/β receptor 1 (IFNAR1) to block IFN-induced Jak/STAT signaling. This study investigated anti-EV-A7l activity and synergistic mechanism(s) of a novel furoquinoline alkaloid compound CW-33 alone and in combination with IFN-β Anti-EV-A71 activities of CW-33 alone and in combination with IFN-β were evaluated by inhibitory assays of virus-induced apoptosis, plaque formation, and virus yield. CW-33 showed antiviral activities with an IC50 of near 200 µM in EV-A71 plaque reduction and virus yield inhibition assays. While, anti-EV-A71 activities of CW-33 combined with 100 U/mL IFN-β exhibited a synergistic potency with an IC50 of approximate 1 µM in plaque reduction and virus yield inhibition assays. Molecular docking revealed CW-33 binding to EV-A71 2A protease active sites, correlating with an inhibitory effect of CW33 on in vitro enzymatic activity of recombinant 2A protease IC50 = 53.1 µM). Western blotting demonstrated CW-33 specifically inhibiting 2A protease-mediated cleavage of IFNAR1. CW-33 also recovered Type I IFN-induced Tyk2 and STAT1 phosphorylation as well as 2',5'-OAS upregulation in EV-A71 infected cells. The results demonstrated CW-33 inhibiting viral 2A protease activity to reduce Type I IFN antagonism of EV-A71. Therefore, CW-33 combined with a low-dose of Type I IFN could be applied in developing alternative approaches to treat EV-A71 infection.

Studies on the association between aortic aneurysm (AA) and the subsequent risk of venous thromboembolism (VTE) are limited to a few case reports and investigations which only focused on surgical effects. Therefore, we used the National Health Insurance Research Database to clarify whether patients with AAs have a heightened risk of subsequent VTEs, including deep vein thrombosis (DVT) and pulmonary embolism (PE). Our retrospective cohort study comprised patients aged ≥ 18 years who received a diagnosis of an AA and were hospitalized at any point during 2000-2010 (n = 16,630). Each AA patient was frequency-matched to 4 non-AA hospitalized patients based on age, sex, and index year (n = 66,453). The Cox proportional hazard regressions model was used to estimate the adjusted effect of AAs on VTE risk. The overall incidence of DVT and PE was higher in the patients with AA than in the non-AA group patients (23.5 versus 13.2 and 13.5 versus 7.98/1,000 person-years). After adjustment for age, sex, duration of hospitalization in the study period, and comorbidities, patients with AAs were associated with a 1.88-fold higher risk of DVT and 1.90-fold higher risk of PE compared to the non-AA cohort. Patients with abdominal AAs were more likely to develop DVT, whereas thoracic AA patients were more likely to develop PE. A diagnosis of a ruptured AA was associated with a substantially increased risk of DVT. Surgical treatment of AAs was associated with a heightened risk of VTE within 6-months post-operation. Our study demonstrates that AAs are associated with an increased risk of subsequent VTE. Future investigations are encouraged to delineate the mechanisms underlying this association and to evaluate the cost-effectiveness of screening for VTEs in patients with AAs.

PURPOSE:Previous studies have reported conflicting results on the association between Helicobacter pylori infection and osteoporosis. A few studies have discussed the influence of H. pylori eradication therapy on bone mineral density. METHODS:We assessed the prevalence of osteoporosis among the H. pylori-infected population in Taiwan and the influence of early and late H. pylori eradication therapy on bone mineral density. RESULTS:Using data from Taiwan's National Health Insurance Research Database, we identified 5,447 patients who received H. pylori eradication therapy from 2000 to 2010 and 21,788 controls, frequency-matched according to age, sex, and year of receiving H. pylori eradication therapy. Those who received H. pylori eradication therapy were divided into two groups based on the time interval between the diagnosis of a peptic ulcer and commencement of eradication therapy. The risk of developing osteoporosis was higher in the early H. pylori treatment cohort (hazard ratio [HR] = 1.52, 95% confidence interval [CI] = 1.23-1.89) and late H. pylori treatment cohort (HR = 1.69, 95% CI = 1.39-2.05), compared with the risk in the control cohort. When followed for less than 5 years, both the early and late cohorts had a higher risk of developing osteoporosis (HR = 1.69, 95% CI = 1.32-2.16 and HR = 1.72, 95% CI = 1.38-2.14). However, when the follow-up period was over 5 years, only the late eradication group exhibited a higher incidence of osteoporosis (HR = 1.62, 95% CI = 1.06-2.47). CONCLUSION:The development of osteoporosis is complex and multi-factorial. Via this population-based cohort study and adjustment of possible confounding variables, we found H. pylori infection may be associated with an increased risk of developing osteoporosis in Taiwan. Early eradication could reduce the influence of H. pylori infection on osteoporosis when the follow-up period is greater than 5 years. Further prospective studies are necessary to discover the connection of H. pylori and osteoporosis.

This study investigated whether alcoholic intoxication (AI) increases the risk of inflammatory bowel disease (IBD) by using a population-based database in Taiwan.This retrospective matched-cohort study included 57 611 inpatients with new-onset AI (AI cohort) and 230 444 randomly selected controls (non-AI cohort). Each patient was monitored for 10 years to individually identify those who were subsequently diagnosed with Crohn disease (CD) and ulcerative colitis (UC) during the follow-up period. Cox proportional hazard regression analysis was conducted to determine the risk of IBD in patients with AI compared with controls without AI.The incidence rate of IBD during the 10-year follow-up period was 2.69 per 1 000 person-years and 0.49 per 1 000 person-years in the AI and non-AI cohorts, respectively. After adjustment for age, sex, and comorbidity, the AI cohort exhibited a 3.17-fold increased risk of IBD compared with the non-AI cohort (hazard ratio [HR] = 3.17, 95% confidence interval [CI] = 2.19-4.58). Compared with the non-AI cohort, the HRs of CD and UC were 4.40 and 2.33 for the AI cohort, respectively. After stratification for the severity of AI according to the duration of hospital stay, the adjusted HRs exhibited a significant correlation with the severity; the HRs of IBD were 1.76, 6.83, and 19.9 for patients with mild, moderate, and severe AI, respectively (p for the trend < .0001).The risk of IBD was higher in patients with AI and increased with the length of hospital stay.