First-line penpulimab combined with paclitaxel and carboplatin for metastatic squamous non-small-cell lung cancer in China (AK105-302): a multicentre, randomised, double-blind, placebo-controlled phase 3 clinical trial.

BACKGROUND: Penpulimab is a novel programmed death (PD)-1 inhibitor. This study aimed to establish the efficacy and safety of first line penpulimab plus chemotherapy for advanced squamous non-small-cell lung cancer. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 clinical trial enrolled patients with locally advanced or metastatic squamous non-small-cell lung cancer from 74 hospitals in China. Eligible participants were aged 18-75 years, had histologically or cytologically confirmed locally advanced (stage IIIb or IIIc) or metastatic (stage IV) squamous non-small-cell lung cancer, were ineligible to complete surgical resection and concurrent or sequential chemoradiotherapy, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, did not have previous systemic chemotherapy for locally advanced or metastatic non-small-cell lung cancer, and had one or more measurable lesions according to RECIST (version 1.1). Participants were randomly assigned (1:1) to receive intravenous penpulimab 200 mg or placebo (excipient of penpulimab injection), plus paclitaxel 175 mg/m2 and carboplatin AUC of 5 intravenously on day 1 every 3 weeks for four cycles, followed by penpulimab or placebo as maintenance therapy. Stratification was done according to the PD-L1 tumour proportion score (<1% vs 1-49% vs ≥50%) and sex (male vs female). The participants, investigators, and other research staff were masked to group assignment. The primary outcome was progression-free survival assessed by the masked Independent Radiology Review Committee in the intention-to-treat population and patients with a PD-L1 tumour proportion score of 1% or more (PD-L1-positive subgroup). The primary analysis was based on the intention-to-treat analysis set (ie, all randomly assigned participants) and the PD-L1-positive subgroup. The safety analysis included all participants who received at least one dose of study drug after enrolment. This trial was registered with ClinicalTrials.gov (NCT03866993). FINDINGS: Between Dec 20, 2018, and Oct 10, 2020, 485 patients were screened, and 350 participants were randomly assigned (175 in the penpulimab group and 175 in the placebo group). Of 350 participants, 324 (93%) were male and 26 (7%) were female, and 347 (99%) were of Han ethnicity. In the final analysis (June 1, 2022; median follow-up, 24·7 months [IQR 0-41·4]), the penpulimab group showed an improved progression-free survival compared with the placebo group, both in the intention-to-treat population (median 7·6 months, 95% CI 6·8--9·6 vs 4·2 months, 95% CI 4·2-4·3; HR 0·43, 95% CI 0·33-0·56; p<0·0001) and in the PD-L1-positive subgroup (8·1 months, 5·7-9·7 vs 4·2 months, 4·1-4·3; HR 0·37, 0·27-0·52, p<0·0001). Grade 3 or worse treatment-emergent adverse events occurred in 120 (69%) 173 patients in the penpulimab group and 119 (68%) of 175 in the placebo group. INTERPRETATION: Penpulimab plus chemotherapy significantly improved progression-free survival in patients with advanced squamous non-small-cell lung cancer compared with chemotherapy alone. The treatment was safe and tolerable. Penpulimab combined with paclitaxel and carboplatin is a new option for first-line treatment in patients with this advanced disease. FUNDING: The National Natural Science Foundation of China, Shanghai Municipal Health Commission, Chia Tai Tianqing Pharmaceutical, Akeso.

Comparison of extrafine beclomethasone dipropionate/formoterol fumarate dry powder inhaler and pressurized metered-dose inhaler in Chinese patients with asthma: the FORTUNE study.

OBJECTIVE: When selecting inhaled therapies, it is important to consider both the active molecules and the device. Extrafine formulation beclomethasone dipropionate plus formoterol fumarate (BDP/FF) has been available for some years delivered via pressurized metered-dose inhaler (pMDI). More recently, a breath-activated, multi-dose dry-powder inhaler (DPI), the NEXThaler, has been approved. The current study aimed to demonstrate the non-inferiority of BDP/FF delivered via the DPI vs. via the pMDI, in Chinese adults with asthma. METHODS: After a four-week run-in period, when all patients received BDP/FF pMDI 100/6 µg, two inhalations twice daily (BID), patients were randomized equally to BDP/FF pMDI or DPI, both 100/6 µg, two inhalations BID for 12 weeks. The primary objective was to demonstrate non-inferiority of BDP/FF DPI vs. BDP/FF pMDI in terms of average pre-dose morning peak expiratory flow (PEF) over the entire treatment period. RESULTS: Of 252 and 242 patients in the DPI and pMDI groups, respectively, 88.5% and 88.8% completed the study. The primary objective was met, with no statistically significant difference between the treatments in average pre-dose morning PEF, and with the lower limit of the 95% CI above the -15 L/min non-inferiority margin (adjusted mean difference: 5.25 L/min [95% CI: -0.56, 11.06]). Adverse events were reported by 48.4% and 49.6% patients in the DPI and pMDI groups, respectively, most mild or moderate. CONCLUSIONS: The NEXThaler DPI is a similarly effective device to the pMDI for the administration of BDP/FF in adults, so extending the options available for the management of asthma.

High accuracy of recombinant fusion protein early secretory antigenic target protein 6-culture filtrate protein 10 skin test for the detection of tuberculosis infection: a phase III, multi-centered, double-blind, hospital-based, randomized controlled trial.

OBJECTIVES: To verify the diagnostic utility of recombinant fusion protein ESAT6-CPF10 (EC), a novel skin test reagent to detect Mycobacterium tuberculosis infection. METHODS: A multi-centered, double-blind, randomized controlled trial was conducted from December 17, 2015, to March 2, 2018. Participants involved in this study included those with active tuberculosis (TB), suspected pulmonary TB, or non-TB pulmonary disease. Each participant received three tests simultaneously, TB-specific enzyme-linked immunospot assay (T-SPOT.TB), tuberculin skin test (TST), and EC skin test (ECST), and adverse events were reported. RESULTS: Diagnostic accuracy was analyzed using data from 1085 protocol-compliant participants. The sensitivities of the ECST, TST, and T-SPOT.TB were 91.2% (95% CI, 89.0-93.2%), 91.4% (95% CI, 89.1-93.3%), and 92.1% (95% CI, 89.9-93.9%), respectively. The specificities of the ECST (69.7%, 95% CI, 64.5-74.5%) and T-SPOT.TB (76.1%, 95% CI, 71.2-80.5%) were significantly higher than the TST (54.4%, 95% CI, 48.9-59.7%). The agreements between ECST and TST (kappa = 0.632) and between ECST and T-SPOT.TB (kappa = 0.780) were substantial. No severe adverse event was reported. CONCLUSION: The diagnostic performance of the ECST was close to the T-SPOT.TB assay in the detection of TB infection and indicated good potential for clinical application in common scenarios.

Final overall survival data of sintilimab plus pemetrexed and platinum as First-Line treatment for locally advanced or metastatic nonsquamous NSCLC in the Phase 3 ORIENT-11 study.

OBJECTIVES: In ORIENT-11, first-line sintilimab + pemetrexed-platinum significantly improved PFS compared with placebo + pemetrexed-platinum in patients with advanced metastatic nonsquamous non-small-cell lung cancer (AMnsqNSCLC). The study met the primary endpoint of PFS as of 15November2019. Here we report final survival analysis from ORIENT-11 (NCT03607539) using a 15September2021 data cutoff. METHODS: Patients with treatment-naïve locally AMnsqNSCLC without sensitizing EGFR or ALK genomic tumor aberrations were randomly assigned to sintilimab + pemetrexed-platinum (n = 266) or placebo + pemetrexed-platinum (n = 131). Patients were stratified by PD-L1 expression, platinum-chemotherapy, and gender. Treatment continued until PD, unacceptable toxicity, or a maximum of 24 months. Patients in the placebo + pemetrexed-platinum arm could be sequenced to second-line sintilimab monotherapy, contingent upon PD. Response was assessed (RECISTv.1.1) by blinded independent radiographic review committee. Primary endpoint was PFS. OS was a secondary endpoint and defined from date of randomization to date of death due to any cause. Final OS analysis was defined as approximately 2 years after last patient randomized or when approximately 65 % of patients died, whichever first. RESULTS: At data cutoff of final OS analysis, median study follow-up was 30.8 months. Of 397 patients, 243 OS events were observed (sintilimab + pemetrexed-platinum:151[57 %];placebo + pemetrexed-platinum:92 [70 %]). Of the patients in placebo + pemetrexed-platinum arm, 47 % crossed over to sintilimab monotherapy per protocol. Median OS was 24.2 months in sintilimab + pemetrexed-platinum arm and 16.8 months in placebo + pemetrexed-platinum arm (HR:0.65[95 % CI:0.50,0.85]). Estimated 2-year OS rates were 50 %(sintilimab + pemetrexed-platinum) and 32 %(placebo + pemetrexed-platinum). After adjusting for the crossover effect, OS treatment effect was more pronounced with HR 0.52 (95 % CI:0.38,0.69). OS benefit across all prespecified subgroups was largely consistent with that observed in the ITT population. CONCLUSIONS: In the ORIENT-11 final OS analysis, sintilimab + pemetrexed-platinum demonstrated improved OS compared to placebo + pemetrexed-platinum when administered as first-line therapy in AMnsqNSCLC without EGFR or ALK genomic tumor aberrations.

Metagenomic Next-Generation Sequencing Is Highly Efficient in Diagnosing Pneumocystis Jirovecii Pneumonia in the Immunocompromised Patients.

Purposes: To explore the value of metagenomic next-generation sequencing (mNGS) in diagnosing pneumocystis jiroveciipneumonia (PJP) in the immunocompromised patients. Methods: Data of 122 patients with PJP in an immunosuppressed state and 67 non-PJP patients were collected. The diagnostic efficacy of mNGS was compared with the conventional methods, including Gomori methenamine silver (GMS) staining and serum (1,3)-ß-D-glucan (BDG). Changes of anti-microbial therapy for patients with PJP based on mNGS results were also reviewed. Results: The diagnostic sensitivity of mNGS to PJP was higher than that of GMS and BDG (100% vs. 15 and 74.5%, p < 0.001). The diagnostic specificity (91.%) was lower than that of GMS (100%), and similar with BDG (89.6%). In addition to P. jirovecii, mNGS revealed co-pathogens like human ß-herpesvirus 5, human γ-pesvirus 4, and some other opportunistic pathogens. The reads of mNGS were remarkably higher in BALF than in blood samples. Initial antimicrobial treatment was modified in 89.3% patients based on the mNGS results, and 74 cases (60.7%) were treated with anti-P. jirovecii therapy. Conclusion: mNGS is highly efficient in diagnosing PJP and good at identifying pathogens in mixed infections.

Updated Overall Survival Data and Predictive Biomarkers of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC in the Phase 3 ORIENT-11 Study.

INTRODUCTION: Sintilimab plus chemotherapy significantly prolonged progression-free survival (PFS) compared with chemotherapy alone in nonsquamous NSCLC in the ORIENT-11 study. Updated overall survival (OS) and PFS data and corresponding biomarker analyses are reported here. METHODS: In this study, a total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC were assigned to sintilimab plus chemotherapy combination treatment (combo) group or placebo plus chemotherapy treatment group. The patients were stratified by programmed death-ligand 1 (PD-L1) expression levels. Immune signature profiles from tumor RNA sequencing and PD-L1 immunohistochemistry were correlated with clinical outcome to identify predictive biomarkers. RESULTS: As of January 2021, with median follow-up of 22.9 months, median OS was significantly improved in the combo group compared with the placebo plus chemotherapy treatment group (not reached versus 16.8 mo; hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.45-0.79, p = 0.0003). High or medium immune cell infiltration was strongly associated with improved PFS in the combo group, in contrast to absent or low immune cell infiltration, which suggests that chemotherapy could not prime "immune deserts" to obtain benefit from programmed cell death protein-1 inhibition. In particular, high major histocompatibility complex (MHC) class II presentation pathway expression was significantly correlated with prolonged PFS (HR = 0.32, 95% CI: 0.19-0.54, p < 0.0001) and OS (HR = 0.36, 95% CI: 0.20-0.64, p = 0.0005) in the combo group. Importantly, patients with low or absent PD-L1 but high MHC class II expression could still benefit from the combo treatment. In contrast, MHC class I antigen presentation pathway was less relevant in this combination setting. CONCLUSIONS: The addition of sintilimab to chemotherapy resulted to significantly longer OS in nonsquamous NSCLC. Expression of MHC class II antigen presentation pathway could identify patients benefiting most from this combination.

Evaluation of regional transport of PM2.5 during severe atmospheric pollution episodes in the western Yangtze River Delta, China.

During winter 2018, the 16 prefecture-level cities in Anhui Province, Western Yangtze River Delta region, China had very high PM2.5 concentrations and prolonged pollution days. The impact of regional transport in the formation, accumulation, as well as dispersion of fine particulate matter (PM2.5) in Anhui Province was very significant. This study quantified and analyzed the vertical transport of PM2.5 in three major cities (Hefei, Fuyang, and Suzhou) of Anhui Province in January and July 2018 using the Weather Research and Forecasting (WRF) model coupled with the Community Multiscale Air Quality (CMAQ) model. The results of the inter-regional transport of PM2.5 revealed the dominant transport pathways for the three cities. The flux mainly flowed into Fuyang from Henan (2.23 and 1.42 kt/day in January and July, respectively) and Bozhou (1.96 and 1.21 kt/day in January and July, respectively), while the main flux from Fuyang flowed into Henan (-2.15 kt/day) and Lu'an (-1.91 kt/day) in January and Henan (-0.34 kt/day) and Bozhou (-0.29 kt/day) in July. In addition, the dominant transport pathways and the heights at which they occurred were identified: the northwest-southeast and northeast-south pathways in both winter and summer at both lower (˂300 m) and higher (≥300 m) levels for Fuyang; the northwest-south and northeast-southwest pathways in winter (at both lower and upper levels) and northwest-east and northeast-southwest pathways in summer at lower and upper levels for Hefei; and the northwest-southeast and northeast-south pathways in both winter (from 50 m up to the top level) and summer (between 100 and 300 m) for Suzhou. Furthermore, the intensities of daily PM2.5 transport fluxes in Fuyang during the atmospheric pollution episode (APE1) were stronger than the monthly average. These results show that joint emission controls across multiple cities along the identified pathways are urgently needed to reduce winter episodes.

Quantitative estimation of meteorological impacts and the COVID-19 lockdown reductions on NO2 and PM2.5 over the Beijing area using Generalized Additive Models (GAM).

Unprecedented travel restrictions due to the COVID-19 pandemic caused remarkable reductions in anthropogenic emissions, however, the Beijing area still experienced extreme haze pollution even under the strict COVID-19 controls. Generalized Additive Models (GAM) were developed with respect to inter-annual variations, seasonal cycles, holiday effects, diurnal profile, and the non-linear influences of meteorological factors to quantitatively differentiate the lockdown effects and meteorology impacts on concentrations of nitrogen dioxide (NO2) and fine particulate matters (PM2.5) at 34 sites in the Beijing area. The results revealed that lockdown measures caused large reductions while meteorology offset a large fraction of the decrease in surface concentrations. GAM estimates showed that in February, the control measures led to average NO2 reductions of 19 µg/m3 and average PM2.5 reductions of 12 µg/m3. At the same time, meteorology was estimated to contribute about 12 µg/m3 increase in NO2, thereby offsetting most of the reductions as well as an increase of 30 µg/m3 in PM2.5, thereby resulting in concentrations higher than the average PM2.5 concentrations during the lockdown. At the beginning of the lockdown period, the boundary layer height was the dominant factor contributing to a 17% increase in NO2 while humid condition was the dominant factor for PM2.5 concentrations leading to an increase of 65% relative to the baseline level. Estimated NO2 emissions declined by 42% at the start of the lockdown, after which the emissions gradually increased with the increase of traffic volumes. The diurnal patterns from the models showed that the peak of vehicular traffic occurred from about 12pm to 5pm daily during the strictest control periods. This study provides insights for quantifying the changes in air quality due to the lockdowns by accounting for meteorological variability and providing a reference in evaluating the effectiveness of control measures, thereby contributing to air quality mitigation policies.

Persistent high PM2.5 pollution driven by unfavorable meteorological conditions during the COVID-19 lockdown period in the Beijing-Tianjin-Hebei region, China.

Lockdown measures to curtail the COVID-19 pandemic in China halted most non-essential activities on January 23, 2020. Despite significant reductions in anthropogenic emissions, the Beijing-Tianjin-Hebei (BTH) region still experienced high air pollution concentrations. Employing two emissions reduction scenarios, the Community Multiscale Air Quality (CMAQ) model was used to investigate the PM2.5 concentrations change in this region. The model using the scenario (C3) with greater traffic reductions performed better compared to the observed PM2.5. Compared with the no reductions base-case (scenario C1), PM2.5 reductions with scenario C3 were 2.70, 2.53, 2.90, 2.98, 3.30, 2.81, 2.82, 2.98, 2.68, and 2.83 µg/m3 in Beijing, Tianjin, Shijiazhuang, Baoding, Cangzhou, Chengde, Handan, Hengshui, Tangshan, and Xingtai, respectively. During high-pollution days in scenario C3, the percentage reductions in PM2.5 concentrations in Beijing, Tianjin, Shijiazhuang, Baoding, Cangzhou, Chengde, Handan, Hengshui, Tangshan, and Xingtai were 3.76, 3.54, 3.28, 3.22, 3.57, 3.56, 3.47, 6.10, 3.61, and 3.67%, respectively. However, significant increases caused by unfavorable meteorological conditions counteracted the emissions reduction effects resulting in high air pollution in BTH region during the lockdown period. This study shows that effective air pollution control strategies incorporating these results are urgently required in BTH to avoid severe pollution.

Coagulation dysfunction in patients with AECOPD and its relation to infection and hypercapnia.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) often have coagulation abnormalities. However, the factors that lead to coagulation dysfunction in acute exacerbation of COPD (AECOPD) remain insufficiently explored. This study aimed to investigate the factors affecting coagulation status in patients with COPD and their influence on thrombosis. METHODS: Data of COPD patients, including 135 cases in acute exacerbation stage and 44 cases in stable stage from Nov 2016 to Nov 2019 in our hospital, were collected. Healthy people (n = 135) were enrolled as the controls. The coagulation parameters, blood gas indexes and blood routine examination results were collected and analyzed. RESULTS: White blood count (WBC), neutrophil count, neutrophil percentage (N%), platelet (PLT), prothrombin time (PT), international normalized ratio (INR), fibrinogen (FIB), and activated partial thromboplastin time (APTT) increased, plasma thrombin time (TT) decreased in AECOPD group compared with the control group. In AECOPD group, PT, APTT, and FIB were positively correlated with neutrophils and C-reaction protein levels. PT was positively correlated with PCO2 and negatively with pH. Thrombosis was observed in five acute exacerbation and three stable stage COPD patients. CONCLUSIONS: Patients with AECOPD presented abnormal coagulation status, which was correlated to infection and hypercapnia and might be potentially the risk factor of thrombosis.

Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial.

Tocilizumab has been reported to attenuate the "cytokine storm" in COVID-19 patients. We attempted to verify the effectiveness and safety of tocilizumab therapy in COVID-19 and identify patients most likely to benefit from this treatment. We conducted a randomized, controlled, open-label multicenter trial among COVID-19 patients. The patients were randomly assigned in a 1:1 ratio to receive either tocilizumab in addition to standard care or standard care alone. The cure rate, changes of oxygen saturation and interference, and inflammation biomarkers were observed. Thirty-three patients were randomized to the tocilizumab group, and 32 patients to the control group. The cure rate in the tocilizumab group was higher than that in the control group, but the difference was not statistically significant (94.12% vs. 87.10%, rate difference 95% CI-7.19%-21.23%, P = 0.4133). The improvement in hypoxia for the tocilizumab group was higher from day 4 onward and statistically significant from day 12 (P = 0.0359). In moderate disease patients with bilateral pulmonary lesions, the hypoxia ameliorated earlier after tocilizumab treatment, and less patients (1/12, 8.33%) needed an increase of inhaled oxygen concentration compared with the controls (4/6, 66.67%; rate difference 95% CI-99.17% to-17.50%, P = 0.0217). No severe adverse events occurred. More mild temporary adverse events were recorded in tocilizumab recipients (20/34, 58.82%) than the controls (4/31, 12.90%). Tocilizumab can improve hypoxia without unacceptable side effect profile and significant influences on the time virus load becomes negative. For patients with bilateral pulmonary lesions and elevated IL-6 levels, tocilizumab could be recommended to improve outcome.

Efficacy and safety of tratinterol hydrochloride tablets in bronchial asthma: a randomized double-blind and multicenter clinical trial.

PURPOSE: The aim of this study was to investigate the efficacy and safety of tratinterol hydrochloride in bronchial asthma (BA) treatment. METHODS: Patients enrolled in this study were distributed randomly into a treatment group (tratinterol hydrochloride) and an active control group (procaterol hydrochloride) and were treated for 2 weeks after running-in. The end points were changes in pulmonary function and clinical symptoms after administration. Safety indices were physical examinations, laboratory testing and spontaneous reporting. FINDINGS: We enrolled 732 subjects, -365 in the treatment group and 367 in the active control group. Forced expiratory volume (FEV1), significantly increased in both group after treatment (P < 0.05). Least-squares (LS) means were -0.03/in the full-analysis set (FAS) and -0.02 in the per-protocol set (PPS) set, and 95% confidence intervals (CIs) for these sets were -0.09 to 0.03 and -0.08 to 0.04, respectively. Forced expiratory volume (FVC), morning peak expiratory flow (PEF) and asthma scores were significantly different with pretreatment (P < 0.05). There was no difference in asymptomatic days or frequency of relief medicine use (P > 0.05). No serious adverse events occurred. IMPLICATIONS: Tratinterol hydrochloride was effective, safe and not inferior to procaterol hydrochloride in treating BA.

Competing PM2.5 and NO2 holiday effects in the Beijing area vary locally due to differences in residential coal burning and traffic patterns.

The holiday effect is a useful tool to estimate the impact on air pollution due to changes in human activities. In this study, we assessed the variations in concentrations of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) during the holidays in the heating season from 2014 to 2018 based on daily surface air quality monitoring measurements in Beijing. A Generalized Additive Model (GAM) is used to analyze pollutant concentrations for 34 sites by comprehensively accounting for annual, monthly, and weekly cycles as well as the nonlinear impacts of meteorological factors. A Saturday effect was found in the downtown area, with about 4% decrease in PM2.5 and 3% decrease in NO2 relative to weekdays. On Sundays, the PM2.5 concentrations increased by about 5% whereas there were no clear changes for NO2. In contrast to the small effect of the weekend, there was a strong holiday effect throughout the region with average increases of about 22% in PM2.5 and average reductions of about 11% in NO2 concentrations. There was a clear geographical pattern in the strength of the holiday effect. In rural areas the increase in PM2.5 is related to the proportion of coal and biomass consumption for household heating. In the suburban areas between the Fifth Ring Road and Sixth Ring Road there were larger reductions in NO2 than downtown which might be due to decreased traffic as many people return to their hometown for the holidays. This study provides insights into the pattern of changes in air pollution due to human activities. By quantifying the changes, it also provides insights for improvements in air quality due to control policies implemented in Beijing during the heating season.

COVID-19 pandemic in Wuhan: Ambient air quality and the relationships between criteria air pollutants and meteorological variables before, during, and after lockdown.

As a result of the lockdown (LD) control measures enacted to curtail the COVID-19 pandemic in Wuhan, almost all non-essential human activities were halted beginning on January 23, 2020 when the total lockdown was implemented. In this study, changes in the concentrations of the six criteria air pollutants (PM2.5, PM10, SO2, NO2, CO, and O3) in Wuhan were investigated before (January 1 to 23, 2020), during (January 24 to April 5, 2020), and after the COVID-19 lockdown (April 6 to June 20, 2020) periods. Also, the relationships between the air pollutants and meteorological variables during the three periods were investigated. The results showed that there was significant improvement in air quality during the lockdown. Compared to the pre-lockdown period, the concentrations of NO2, PM2.5, PM10, and CO decreased by 50.6, 41.2, 33.1, and 16.6%, respectively, while O3 increased by 149% during the lockdown. After the lockdown, the concentrations of PM2.5, CO and SO2 declined by an additional 19.6, 15.6, and 2.1%, respectively. However, NO2, O3, and PM10 increased by 55.5, 25.3, and 5.9%, respectively, compared to the lockdown period. Except for CO and SO2, WS had negative correlations with the other pollutants during the three periods. RH was inversely related with all pollutants. Positive correlations were observed between temperature and the pollutants during the lockdown. Easterly winds were associated with peak PM2.5 concentrations prior to the lockdown. The highest PM2.5 concentrations were associated with southwesterly wind during the lockdown, and northwesterly winds coincided with the peak PM2.5 concentrations after the lockdown. Although, COVID-19 pandemic had numerous negative effects on human health and the global economy, the reductions in air pollution and significant improvement in ambient air quality likely had substantial short-term health benefits. This study improves the understanding of the mechanisms that lead to air pollution under diverse meteorological conditions and suggest effective ways of reducing air pollution in Wuhan.

Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11).

INTRODUCTION: Sintilimab, an anti-programmed death 1 antibody, plus pemetrexed and platinum had revealed promising efficacy for nonsquamous NSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to compare the efficacy and safety of sintilimab with placebo, both in combination with such chemotherapy (ClinicalTrials.gov: NCT03607539). METHODS: A total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC without sensitizing EGFR or anaplastic lymphoma kinase genomic aberration were randomized (2:1 ratio) to receive either sintilimab 200 mg or placebo plus pemetrexed and platinum once every 3 weeks for four cycles, followed by sintilimab or placebo plus pemetrexed therapy. Crossover or treatment beyond disease progression was allowed. The primary end point was progression-free survival (PFS) as judged by an independent radiographic review committee. RESULTS: As of November 15, 2019, the median follow-up was 8.9 months. The median PFS was significantly longer in the sintilimab-combination group than that in the placebo-combination group (8.9 versus 5.0 mo; hazard ratio, 0.482, 95% confidence interval [CI]: 0.362-0.643; p < 0.00001). The confirmed objective response rate was 51.9% (95% CI: 45.7%-58.0%) in the sintilimab-combination group and 29.8% (95% CI: 22.1%-38.4%) in placebo-combination group. The incidence of grade 3 or higher adverse events was 61.7% in sintilimab-combination group and 58.8% in placebo-combination group. CONCLUSIONS: In Chinese patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC, the addition of sintilimab to chemotherapy with pemetrexed and platinum resulted in considerably longer PFS than with chemotherapy alone with manageable safety profiles.

Efficacy And Safety Of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler (GFF MDI) Formulated Using Co-Suspension Delivery Technology In Chinese Patients With COPD.

Background: Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) is a long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination therapy delivered by MDI, formulated using innovative co-suspension delivery technology. The PINNACLE-4 study evaluated the efficacy and safety of GFF MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) from Asia, Europe, and the USA. This article presents the results from the China subpopulation of PINNACLE-4. Methods: In this randomized, double-blind, placebo-controlled, parallel-group Phase III study (NCT02343458), patients received GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI (all twice daily) for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 second at Week 24. Secondary lung function endpoints and patient-reported outcome measures were also assessed. Safety was monitored throughout the study. Results: Overall, 466 patients from China were included in the intent-to-treat population (mean age 63.6 years, 95.7% male). Treatment with GFF MDI improved the primary endpoint compared to GP MDI, FF MDI, and placebo MDI (least squares mean differences: 98, 104, and 173 mL, respectively; all P≤0.0001). GFF MDI also improved daily total symptom scores and time to first clinically important deterioration versus monocomponents and placebo MDI, and Transition Dyspnea Index focal score versus placebo MDI. Rates of treatment-emergent adverse events were similar across the active treatment groups and slightly higher in the placebo MDI group. Conclusion: GFF MDI improved lung function and daily symptoms versus monocomponents and placebo MDI and improved dyspnea versus placebo MDI. All treatments were well tolerated with no unexpected safety findings. Efficacy and safety results were generally consistent with the global PINNACLE-4 population, supporting the use of GFF MDI in patients with COPD from China.

Elevated FAM83A expression predicts poorer clincal outcome in lung adenocarcinoma.

BACKGROUND: Family with sequence similarity 83 member A (FAM83A) can promote tumor cell proliferation and facilitate epidermal growth factor tyrosine kinase inhibitor resistance in some malignant tumors, but its role in lung cancer has not been directly explored. OBJECTIVE: We investigated FAM83A expression in lung adenocarcinoma (LUAD) and its significance in clinicopathologic characteristics and prognosis of the disease. PATIENTS AND METHODS: We analyzed the mRNA expression of FAM83A in LUAD and normal (or adjacent) lung tissues from Oncomine database firstly. Then, we detected FAM83A protein expression in five paired fresh LUAD and adjacent lung tissue specimens from patients in our hospital by Western blotting. In addtion, FAM83A expression in 86 paraffin-embedded archived LUAD samples was evaluated by Immunohistochemistry, and the correlations between FAM83A expression and clinicopathologic characteristics and prognosis of the patients were analyzed. RESULTS: Oncomine data analysis manifested that FAM83A mRNA expression was increased in LUAD. Western blotting revealed higher FAM83A expression in fresh LUAD tissues than in the adjacent lung tissues (P= 0.036). Immunohistochemistry analysis on 86 paraffin samples further demonstrated that the LUAD tissue had higher FAM83A expression than adjacent lung tissue (P< 0.001). The correlation analysis revealed that advanced stage tumors (stage III-IV) had higher FAM83A expression than early stage tumors (stage I-II) (P= 0.004). High FAM83A expression was significantly associated with lymphnode involvement and clinical staging (P= 0.008 and 0.008 respectively). Univariate and multivariate Cox regression analysis manifested that FAM83A expression was an independent predictive factor for poor survival. Kaplan-Meier survival curves showed that patients with higher FAM83A expression had shorter overall survival than those with lower FAM83A expressions (P= 0.002). CONCLUSION: FAM83A is upregulated in advanced LUAD and is related to unfavorible prognosis. FAM83A might be a novel diagnostic and prognositic biomarker for LUAD.

A high-throughput drug screen identifies auranofin as a potential sensitizer of cisplatin in small cell lung cancer.

Small cell lung cancer (SCLC) is a highly lethal malignancy with the 5-year survival rate of less than 7%. Chemotherapy-resistance is a major challenge for SCLC treatment in clinic. In the study, we developed a high-throughput drug screen strategy to identify new drugs that can enhance the sensitivity of chemo-drug cisplatin in SCLC. This screen identified auranofin, a US Food and Drug Administration (FDA)-approved drug used therapeutically for rheumatoid arthritis, as a sensitizer of cisplatin. Further study validated that auranofin synergistically enhanced the anti-tumor activity of cisplatin in chemo-resistant SCLC cells, which was accompanied by the enhanced induction of cell cycle arrest and apoptosis. The synergistic action of auranofin and cisplatin was through ROS overproduction, thereby leading to mitochondrial dysfunction and DNA damage. Furthermore, in vivo study demonstrated that the combination treatment of auranofin and cisplatin dramatically inhibited tumor growth in SCLC. Therefore, our study provides a rational basis for further clinical study to test whether auranofin could enhance the sensitivity of cisplatin-based therapy in SCLC patients.

Pravastatin sodium attenuated TREM-1-mediated inflammation in human peripheral blood mononuclear cells.

Pravastatin sodium on triggering receptor expressed on myeloid cell-1 (TREM-1)-mediated inflammation in human peripheral blood mononuclear cells (PBMCs) has been poorly investigated. In this study, we isolated PBMCs from the peripheral blood samples of patients with chronic obstructive pulmonary disease, treated the cells with pravastatin sodium, and determined a concentration at which more than 90% cells could survive. Then we treated cells with 10 ng/ml of lipopolysaccharide, added with 10, 50, 100 µM of pravastatin sodium combined with or without LR-12, a known TREM-1 inhibitor. The expression of TREM-1 was determined by quantitative RT-PCR. The levels of TREM-1, IL-6, and TNF-α in cell culture supernatant were measured with ELISA. Simultaneously, NF-κB signaling pathway-related protein p-p65 and p-IκBα were detected by Western blot assay. Results demonstrated that pravastatin sodium significantly mitigated lipopolysaccharide-stimulated TREM-1 over-expression at mRNA and protein levels dose-dependently. Elevated IL-6 and TNF-α levels changed synchronously. LR-12 inhibited the TREM-1 over-expression and inflammatory factor production but did not show extra synergistic effect to pravastatin. Lipopolysaccharide induced phospho-p65 and -IκBα over-expression was weakened significantly when cells were treated with pravastatin sodium. In conclusion, pravastatin could inhibit TREM-1-medieted inflammation and NF-κB signaling pathway was involved.

Biosimilar candidate IBI305 plus paclitaxel/carboplatin for the treatment of non-squamous non-small cell lung cancer.

BACKGROUND: Bevacizumab is a monoclonal antibody (mAb) against vascular endothelial growth factor (VEGF) and used for treatments of various cancers. Due to the high costs of bevacizumab treatments, a biosimilar provides an affordable alternative therapy for cancer patients. METHODS: In this randomized, double-blind, multicenter, phase 3 study, locally advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor were enrolled and randomized (1:1) into IBI305 or bevacizumab groups. Patients received 6 cycles of paclitaxel/carboplatin plus IBI305 or bevacizumab 15 mg/kg intravenously followed by IBI305 or bevacizumab 7.5 mg/kg maintenance until disease progression, unacceptable toxicity or death. The primary endpoint was confirmed objective response rate (ORR) by an independent radiological review committee (IRRC) and secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. RESULTS: A total of 450 NSCLC patients were enrolled (224 in IBI305 group and 226 in bevacizumab group). ORRs were 44.3% for IBI305 and 46.4% for bevacizumab, and the ORR ratio was 0.95 (90% CI: 0.803 to 1.135), within the predefined equivalence margin of 0.75 to 1.33. No significant difference in PFS (7.64 vs. 7.77 m, P=0.9987) was observed between the 2 groups. Serious adverse events (AEs) occurred in 33.5% (75/224) of patients in the IBI305 group and 37.6% (85/226) in the bevacizumab group. AEs ≥ grade 3 were similar in the IBI305 and bevacizumab groups [84.4% (189/224) vs. 89.8% (203/226), P=0.085]. CONCLUSIONS: IBI305 is similar to bevacizumab in terms of efficacy and safety. TRIAL REGISTRATION: Clinicaltrials.org Identifier: NCT02954172. Registered on 3 November 2016. Https://clinicaltrials.gov/.