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Background: Gefapixant is a P2X3 receptor antagonist for treatment of refractory (RCC) and unexplained chronic cough (UCC). The aim of this study was to evaluate 12 weeks of gefapixant compared with placebo after 12 weeks of treatment for RCC/UCC. Methods: We conducted a 12-week, Phase 2b, randomized, double-blind, placebo-controlled study in RCC or UCC (>1 year) patients (no radiographic chest abnormality; ≥40 mm on the Cough Severity Visual Analog Scale [VAS]) recruited from 44 secondary/tertiary care sites in UK and US (clinicaltrials.gov: NCT02612610, status closed). Patients were randomized to placebo or gefapixant (7·5 mg twice daily [BID], 20 mg BID, or 50 mg BID). The primary endpoint was placebo-adjusted change from baseline in Awake Cough Frequency (coughs/hour) after 12 weeks analysed by intention-to-treat analysis. Adverse events (AE) were monitored and safety was evaluated in all patients receiving ≥1 dose of study drug. Findings: Between December 2015 and July 2016 253 patients were randomized to placebo (n=63), gefapixant 7·5 mg (n=64), 20 mg (n=63), or 50 mg (n=63). Mean (SD) age was 60 (10·0) years and 76% of patients were women. At 12 weeks, Geometric Mean Awake Cough Frequency was 18·2, 14·5, 12·0, 11·3 coughs/hr with placebo and gefapixant 7·5 mg, 20 mg, and 50 mg, respectively; percent change vs. placebo (95% CI) was -37% (-53·3,-14·9) with gefapixant 50 mg (p=0·003), -22·2% (-42,4·3) with 20 mg (p=0·093), and -22·0% (-41·8,4·6) with 7·5 mg (p=0·097). Dysgeusia was the most common AE, occurring in 5%, 10%, 33%, and 48% of placebo and gefapixant 7·5-mg, 20-mg, and 50-mg patients, respectively. Interpretation: Targeting P2X3 with gefapixant at a dose of 50 mg BID significantly reduces cough frequency in patients with RCC and UCC after 12 weeks of treatment compared with placebo. Gefapixant was generally well tolerated with dysgeusia being the most frequent AE.

Shan-Shan Su,1,* Sheng-Nan Zhang,1,* Jun-Ru Ye,1 Ling-Na Xu,1 Peng-Cheng Lin,1 Han-Yan Xu,1 Qing Wu,2 Yu-Ping Li1 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, People’s Republic of China; 2The Center of Laboratory and Diagnosis, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu-Ping LiDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, South Baixiang, Ouhai District, Wenzhou, Zhejiang Province 325015, People’s Republic of ChinaTel/fax +86 577 5557 9273Email wzliyp@163.comBackground: Patients with high-titer anti-IFN-γ autoantibodies present disseminated non-tuberculous mycobacterial (NTM) and other opportunistic infections. Due to its rare occurrence and non-specific symptoms, this syndrome is difficult to diagnose during early disease stages. Here, we report a case with high-concentrations of serum anti-IFN-γ autoantibodies who presented with disseminated Talaromyces marneffei and NTM disease accompanied Sweet’s syndrome.Case presentation: A 62-year-old Chinese woman with no previous history was admitted to our hospital in August 2016 due to intermittent fever for 2 years, left chest wall redness, and swelling for 3 months. During hospitalization, the patient was confirmed with disseminated T. marneffei and successfully treated with antifungal therapy. In July 2017, upon second admission, Mycobacterium avium intracellular (MAC) pulmonary infection was established after positive cultures from the right lung tissue. The patient failed treatment after 1 month of anti-NTM therapy due to side effects. In May 2018, she was confirmed as having disseminated MAC disease accompanied by hand rashes, which was considered as Sweet’s syndrome. High-level anti-IFN-γ antibodies in the patient serum were detected upon comparison with normal controls (2.85-fold increase). Following anti-NTM therapy, both symptoms and pulmonary infiltration gradually improved, and joint destruction and lymphadenitis remained.Conclusions: Patients with anti-interferon-γ autoantibodies should be considered for severe, recurrent infections in adults in the absence of other known risk factors. Sweet’s syndrome is a common skin manifestation of the syndrome.Keywords: Talaromyces marneffei, Mycobacterium avium, Sweet’s syndrome, autoantibodies, interferon-gamma

Simulation training is an inevitable choice for joint operations training. Simulation training platform is considered as the core of military deduction. It combines simulation systems and solid equipment to build the training environment, which provides the necessary conditions for the multi-level multi-area joint training. In this paper, the existing simulation training architecture technologies are reviewed. Considering the characteristics of joint training and functional requirements, an overall structural design of a simulation platform is given, and several challenges technical are discussed.

According to the current status of hull shell plate spraying in dock in China shipyard, the present status of shipyard is discussed, a basic functional design of wall climbing robot for hull plate spraying in dock (WCR-HPSD) is researched, and the international research about the robot is analyzed, the basic function of design strategy is put forward, the design and analysis of index are given, and the basic function of attribute set is established. Finally, the robot operation basic test system is designed.

The aim of this study was to identify the optimal cut-off value of T cell enzyme-linked immunospot assay for tuberculosis (T-SPOT.TB) and evaluate its diagnostic performance alone (in the peripheral blood) or in combination with the adenosine deaminase (ADA) activity test (in peripheral blood and the pleural fluid) in patients with tuberculous pleurisy. Adult patients presenting with pleural effusion were included in this prospective cohort study. Tuberculous pleurisy was diagnosed by T-SPOT.TB in peripheral blood and a combination of T-SPOT.TB and ADA activity test in pleural fluid and peripheral blood. Receiver operating characteristic (ROC) curve in combination with multivariate logistic regression was used to evaluate the diagnostic performance of the assays. Among a total of 189 patients with suspected tuberculous pleurisy who were prospectively enrolled in this study, 177 patients were validated for inclusion in the final analysis. ROC analysis revealed that the area under the ROC curve (AUC) for T-SPOT.TB in pleural fluid and peripheral blood was 0.918 and 0.881, respectively, and for the ADA activity test in pleural fluid was 0.944. In addition, 95.5 spot-forming cells (SFCs)/2.5 × 105 cells were determined as the optimal cut-off value for T-SPOT.TB in pleural fluid. Parallel combination of T-SPOT.TB and ADA activity test in pleural fluid showed increased sensitivity (96.9%) and specificity (87.5%), whereas serial combination showed increased specificity (97.5%). The combination of 3 assays had the highest sensitivity at 97.9%, with an AUC value of 0.964. T-SPOT.TB in pleural fluid performed better than that in peripheral blood and the ADA activity test in pleural fluid for tuberculous pleurisy diagnosis. The optimal cut-off value of T-SPOT.TB in pleural fluid was 95.5 SFCs/2.5 × 105 cells. Combination of 3 assays might be a promising approach for tuberculous pleurisy diagnosis.

In this paper, the influence of radiation asymmetry on radiant heat transfer in the room of plane radiant air-conditioning system is analyzed. The radiation heat transfer model used in the Fanger thermal comfort equation is introduced. Using Airpak simulation analysis, it is concluded that external Windows and external walls should be taken as separate enclosure structures to calculate the PMV value. A new radiation heat transfer model was established, and the radiation heat transfer was solved under the new radiation heat transfer model. As the radiation heat transfer in the PMV equation, the thermal comfort equation was modified.

Aim: To evaluate the efficacy and safety of donepezil plus natural hirudin in patients with mild-to-moderate Alzheimer's Disease. Methods: In the 20-week, randomized, open-label and controlled study, 84 patients received either donepezil (5 mg/day for the first 4 weeks and 10 mg/day thereafter) or donepezil plus natural hirudin (3 g/day) treatment. Efficacy was reflected by the change of the total scores of Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog), Activities of Daily Life (ADL) and Neuropsychiatric Inventory (NPI). Results: The patients with the donepezil plus natural hirudin treatment showed more significant improvement in the daily activities and the decline of the cognition than those with donepezil treatment. Significant difference was present in the groups since the 8th week. No group difference was found in the NPI change. However, within the hirudin treatment group, more powerful efficacy including NPI assessment was found in the patients with vascular risk factors (VRF) as comparing to with those without VRF. The combination of donepezil and natural hirudin was well tolerated. The dropout rate was greater in the donepezil and natural hirudin (50%) treatment group than in the donepezil (39%) treatment group. Similar result was found in the incidence of adverse events (23.8% vs 19.0%), but there was no statistical difference between the two groups. Adverse events were the most common reason for the dropout. Although hemorrhage and hypersensitiveness were more common in donepezil plus Maixuekang treatment (11.9% and 7.1%) group than in donepezil treatment (2.4% and 2.4%) group, no significant difference was present between the two groups. Economic problem was another important reason for the patients' withdrawal. Conclusions: Compared with the donepezil treatment in the patients with mild-to-moderate AD, our results suggest that donepezil combined with natural hirudin may improve the treatment effects in the ADL, BPSD and cognition of the patients. Furthermore, this joint treatment is safe.

Thoracic lymph node (LN) metastasis is the determining factor for NSCLC staging. However, enlargement in thoracic LNs, which can be detected by chest computed tomography (CT), may not be adequate for NSCLC staging. This study aimed to investigate the effectiveness of a new transbronchial needle aspiration (TBNA) procedure to improve the sensitivity and accuracy of lung cancer diagnosis and staging.A standardized TBNA procedure was performed on enlarged and non-enlarged LNs in the order of N3 to N1 station according to Wang's LN map. The status of LN metastasis determined by the standardized TBNA procedure was compared with the results from CT scan.The TBNA biopsy revealed that 21.43% of non-enlarged LNs were malignant. Compared with chest CT, the standardized TBNA procedure improved the accuracy of LN metastasis staging and discovered skip LN metastasis.The standardized TBNA procedure of this study may be recommended to be used as a routine TBNA procedure, in which LNs should be biopsied in the order of N3 to N1 station and both enlarged and non-enlarged LNs should be included to improve the accuracy of lung cancer staging.

The impedance of a capacitively coupled contactless conductivity detector (C 4 D) cell was experimentally examined for different cell parameters by alternative current impedance (ACImp). The effect of the gap between the electrodes and the length of the electrodes on the impedance behavior of the C 4 D cell has been studied. As a result, the impedance of C 4 D cell is largely defined by the length of the gap between the electrodes and the length of the electrodes. The impedance increases with increasing gap between the electrodes and the length of the electrodes. It could be found that tightly coupling of the electrodes to the outer wall of the capillary is needed. The axial contactless conductometric detector can be effectively described by the simplest possible equivalent circuitry consisting of a capacitor, resistor, a second resister and a Warburg impedance. These results are helpful to understand the impedance characteristics of C 4 D cell and improve its detective performance.

An implicit finite-element code is employed to study the internal grinding process of carbon steel Q235 cirque, and its temperature field and thermal deformation are obtained. The method of thermal load calculation is proposed, a 2D finite element model is developed, and analysis steps are introduced. The diameter of the cirque is 150 mm and that of the inner hole is 56.24 mm. By adopting the clamps of surface locating and three-jaw chuck, it is found that, during the grinding process, the workpiece is in an elastic–plastic state, far from thermal-softening state. The thermal deformation of the ground cirque is basically symmetrical in a diamond shape, but the deformations of the inner circle and the outer circle are not uniform, and the inner circle thermal deformation may be negative or positive. Such different thermal displacements will produce shape error and dimension error in the inner hole. Through comparison of the two clamping modes, it is found that the precision of the surface locating is better than the three-jaw chuck. The symmetrical property of the thermal deformation of the cirque and the comparison of two clamping modes indicate that the computation is valid.

A semi-analytical method was proposed to solve the mechanics problem of stamping a sheet on elastic die. The sheet was divided into four parts according to its deformation and contact with the punch and elastic die. Analytical solutions were derived individually for each part by using elastic large deflection and plastic large deformation. Solutions were found out with MATLAB by developing a numerical algorithm. Interface forces were obtained by iteration under the compatibility conditions between the neighboring parts of the sheet. Computation shows the method is efficient.

Xi-Xi Lai, Ren-Ai Xu, Yu-Ping Li, Han Yang Department of Respiratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China Background: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor ligand, has shown survival benefits in the treatment of many types of malignant tumors, including non-small-cell lung cancer (NSCLC). We conducted this systematic review and meta-analysis to investigate the risk of the most clinically relevant adverse events related to bevacizumab in advanced NSCLC.Methods: Databases from PubMed, Web of Science, and Cochrane Library up to August 2015, were searched to identify relevant studies. We included prospective randomized controlled Phase II/III clinical trials that compared therapy with or without bevacizumab for advanced NSCLC. Summary relative risk (RR) and 95% confidence intervals were calculated using random effects or fixed effects according to the heterogeneity among included trials.Results: A total of 3,745 patients from nine clinical trials were included in the meta-analysis. Summary RRs showed a statistically significant bevacizumab-associated increased risk in three of the adverse outcomes studied: proteinuria (RR =7.55), hypertension (RR =5.34), and hemorrhagic events (RR =2.61). No statistically significant differences were found for gastrointestinal perforation (P=0.60), arterial and venous thromboembolic events (P=0.35 and P=0.92, respectively), or fatal events (P=0.29).Conclusion: The addition of bevacizumab to therapy in advanced NSCLC did significantly increase the risk of proteinuria, hypertension, and hemorrhagic events but not arterial/venous thromboembolic events, gastrointestinal perforation, or fatal adverse events. Keywords: toxicities, angiogenesis inhibitors, non-small-cell lung carcinoma, meta-analysis, safety

Quantitative estimation of the ecological footprint in Xingtai City in the years 2003-2009 is carried out by using the Ecological Footprint Model and the Time Series. Result shows that the per capita ecological footprint demand increases in Xingtai City from the year 2003 to 2009; and land use for energy shows a significant increase, accounting for the maximum proportion in per capita ecological footprint demand. Per capita ecological footprint supply gradually decreases. Ecological supply provided by cultivated land occupies the greatest proportion in the supply of per capita ecological carrying capacity, which is the main factor determining the supply of ecological carrying capacity in Xingtai City. In the years 2003-2009, ecological footprint of Xingtai City is at the state of ecological deficit. This indicates that the economic and social development of Xingtai City is based on the over-exploitation of resources, especially the cultivated land and energy land. Thus, the development mode of Xingtai City has already been in a state of unsustainable development. Based on this, corresponding countermeasures are put forward for the sustainable development in future, so as to implement the healthy control of the sustainable development in Xingtai City, China.

Quantitative estimation of the ecological footprint in Xingtai City in the years 2003-2009 is carried out by using the Ecological Footprint Model and the Time Series. Result shows that the per capita ecological footprint demand increases in Xingtai City from the year 2003 to 2009; and land use for energy shows a significant increase, accounting for the maximum proportion in per capita ecological footprint demand. Per capita ecological footprint supply gradually decreases. Ecological supply provided by cultivated land occupies the greatest proportion in the supply of per capita ecological carrying capacity, which is the main factor determining the supply of ecological carrying capacity in Xingtai City. In the years 2003-2009, ecological footprint of Xingtai City is at the state of ecological deficit. This indicates that the economic and social development of Xingtai City is based on the over-exploitation of resources, especially the cultivated land and energy land. Thus, the development mode of Xingtai City has already been in a state of unsustainable development. Based on this, corresponding countermeasures are put forward for the sustainable development in future, so as to implement the healthy control of the sustainable development in Xingtai City, China.

Regional situation of Zhejiang Province and connotation of Logistic Equation are introduced. According to the relevant statistical data from 1978 to 2006, dynamic change and its driving forces of cultivated land area in Zhejiang Province are analyzed. ① Since the year 1978, cultivated land area has shown a significant fluctuant decreasing trend in Zhejiang Province, China. ② Cultivated land at the two stages of 1984-1988 and 1990-1995 decreases sharply. Large area of cultivated land is occupied by non-agricultural construction. ③ Economic development, population growth and agricultural scientific and technological development are the main driving forces. Contradiction between land and human beings becomes more acute; and the load of cultivated land becomes increasingly heavy. ④ Cumulative reduction area of cultivated land changes with time, showing a "S"-shaped curve and according with the Logistic Equation. Change of cultivated land of Jiangsu Province in future is forecasted by Logistic Equation. Result shows that the cumulative reduction area of cultivated land will stop increasing until the year 2020 with the total reduction area of 90.91 thousand hectares. Cultivated area of Zhejiang Province will either be stable at the level of 1498.24 thousand hectares or will fluctuate around it. With the development of industrial structure, encroachment of urbanization and industrialization on cultivated land is not ever-increasing, but will tend to stop at a certain stage. Overall consideration on land use demand for food safety and for urbanization and industrialization may become possible with the advancement of technology and the increase of land inputs.

Regional situation of Zhejiang Province and connotation of Logistic Equation are introduced. According to the relevant statistical data from 1978 to 2006, dynamic change and its driving forces of cultivated land area in Zhejiang Province are analyzed. â‘ Since the year 1978, cultivated land area has shown a significant fluctuant decreasing trend in Zhejiang Province, China. â‘¡ Cultivated land at the two stages of 1984-1988 and 1990-1995 decreases sharply. Large area of cultivated land is occupied by non-agricultural construction. â‘¢ Economic development, population growth and agricultural scientific and technological development are the main driving forces. Contradiction between land and human beings becomes more acute; and the load of cultivated land becomes increasingly heavy. â‘£ Cumulative reduction area of cultivated land changes with time, showing a "S"-shaped curve and according with the Logistic Equation. Change of cultivated land of Jiangsu Province in future is forecasted by Logistic Equation. Result shows that the cumulative reduction area of cultivated land will stop increasing until the year 2020 with the total reduction area of 90.91 thousand hectares. Cultivated area of Zhejiang Province will either be stable at the level of 1498.24 thousand hectares or will fluctuate around it. With the development of industrial structure, encroachment of urbanization and industrialization on cultivated land is not ever-increasing, but will tend to stop at a certain stage. Overall consideration on land use demand for food safety and for urbanization and industrialization may become possible with the advancement of technology and the increase of land inputs.

The present study focuses on the adsorption of a polyelectrolyte, the component of which is a polymer of maleic anhydride sodium salt, on the surface of nanometric zinc oxide particles and the colloidal stability of aqueous dispersions. FTIR spectroscopic data provided evidence in support of hydrogen bonding and chemical interaction in the case of the polyelectrolyte-ZnO system. The adsorption isotherms showed the influences of polyelectrolyte concentration, pH and ionic strength on the adsorption. With the increase of pH the saturated adsorbed amount decreased, while the thickness of adsorption layer increased. The saturated adsorbed amount increased with increasing salt concentration, and decreased with further increasing salt concentration. It should be noted that in the presence of a CaCl2 solution the adsorbed amount and the adsorption layer thickness were greater than those in the NaCl solution of the same concentration. The change of the absorbance of zinc oxide dispersions showed that the absorbance decreased slowly at high pH. There was a maximum point for the absorbance of the zinc oxide dispersions in the presence of various polyelectrolyte concentrations. The change of dispersion stability resulted from the change of macromolecular chains conformation at the interface.

Geogenic Ni exposure via food consumption and soil ingestion was assessed by analyzing Ni concentration and oral bioavailability in soil, wheat, and rice Accumulation and oral bioavailability of nickel (Ni) were rarely assessed for staple crops grown in high geogenic Ni soils. To assess exposure risk of geogenic Ni, soil, wheat, and rice samples were collected from a naturally high background Ni area and measured for Ni oral relative bioavailability (RBA, relative to NiSO4) using a newly developed mouse urinary Ni excretion bioassay. Results showed that soils were enriched with Ni (80.5 ± 23.0 mg kg−1, n = 58), while high Ni contents were observed in rice (2.66 ± 1.46 mg kg−1) and wheat (1.32 ± 0.78 mg kg−1) grains, with rice containing ∼2-fold higher Ni content than wheat. Ni-RBA was low in soil (14.8 ± 7.79%, n = 18), but high in wheat and rice with rice Ni-RBA (85.9 ± 19.1%, n = 9) being ∼2-fold higher than wheat (46.1 ± 21.2%, n = 16). A negative correlation (r = 0.61) was observed between Ni-RBA and iron content in rice and wheat, suggesting the low iron status of rice drives its high Ni bioavailability. The higher Ni accumulation and bioavailability for rice highlights that rice consumption was a more important contributor to daily Ni intake compared to wheat, while Ni intake from direct soil ingestion was negligible. This study suggests a potential health risk of staple crops especially rice when grown in high geogenic Ni areas. Refereed/Peer-reviewed