[Influencing factors of poor treatment adherence in uncontrolled asthma patients in China].

Objective: To evaluate the influencing factors of poor treatment adherence in patients with uncontrolled asthma in China. Methods: From April 2017 to April 2018, all asthma patients with uncontrolled asthma and poor compliance in 32 third-class hospitals in 28 provinces and cities of China mainland included in the "National Mobile Asthma Assessment and Management Project" were selected as the subjects. A total of 923 patients were enrolled in the study including 388 males and 535 females. By analyzing the baseline data of the patients at the initial visit when enrolled, the influencing factors of poor adherence of adult asthma was analyzed by inter-group comparison and χ2 test. Results: Poor compliance in asthma was related to the following factors: age from 59 to 68 years old, course of disease more than 20 years, low education level, non-local follow-up, having obstructive ventilation dysfunction and low awareness of the disease[P values were 0.026(t=1.20), 0.004(t=3.97), 0.001(t=4.92), 0.003(t=3.98), 0.032(t=1.22) and 0.001(t=4.99), respectively]. Totally, 243 patients (26.33%) answered all the questions about asthma correctly. Their medication adherence rating scale (MARS-A) scores were significantly higher than those who answered incompletely correctly (36.23±5.85 vs. 31.77±5.74, P=0.001). Conclusions: The adherence of adult asthma patients was affected by individual and external environment factors. Clinicians should choose individualized methods based on the characteristics of patients. Patient education should be strengthened to improve patients' awareness of the disease at the same time.

[Differential diagnosis of asthma and dysfunctional breathing and vocal cord dysfunction].

The clinical manifestations of bronchial asthma are complex and variable, which can easily be confused with other diseases. So misdiagnosis and missed diagnosis of asthma are common. In the differential diagnosis of asthma, organic diseases such as left ventricular dysfunction, chronic obstructive pulmonary disease, and upper airway obstruction are most often considered, but the understanding of functional disease is insufficient. In fact, GINA guidelines suggested that the differential diagnosis in adult patients with suspected asthma needed to prioritize functional diseases such as dysfunctional breathing (DB)/hyperventilation syndrome (HVS) and vocal cord dysfunction (VCD), rather than organic disease. Here we review the concepts of DB and VCD and their differentiation from asthma.

Achieving thermally stable nanoparticles in chemically complex alloys via controllable sluggish lattice diffusion.

Nanoparticle strengthening provides a crucial basis for developing high-performance structural materials with potentially superb mechanical properties for structural applications. However, the general wisdom often fails to work well due to the poor thermal stability of nanoparticles, and the rapid coarsening of these particles will lead to the accelerated failures of these materials especially at elevated temperatures. Here, we demonstrate a strategy to achieve ultra-stable nanoparticles at 800~1000 °C in a Ni59.9-xCoxFe13Cr15Al6Ti6B0.1 (at.%) chemically complex alloy, resulting from the controllable sluggish lattice diffusion (SLD) effect. Our diffusion kinetic simulations reveal that the Co element leads to a significant reduction in the interdiffusion coefficients of all the main elements, especially for the Al element, with a maximum of up to 5 orders of magnitude. Utilizing first-principles calculations, we further unveil the incompressibility of Al induced by the increased concentration of Co plays a critical role in controlling the SLD effect. These findings are useful for providing advances in the design of novel structural alloys with extraordinary property-microstructure stability combinations for structural applications.

High-entropy induced a glass-to-glass transition in a metallic glass.

Glass-to-glass transitions are useful for us to understand the glass nature, but it remains difficult to tune the metallic glass into significantly different glass states. Here, we have demonstrated that the high-entropy can enhance the degree of disorder in an equiatomic high-entropy metallic glass NbNiZrTiCo and elevate it to a high-energy glass state. An unusual glass-to-glass phase transition is discovered during heating with an enormous heat release even larger than that of the following crystallization at higher temperatures. Dramatic atomic rearrangement with a short- and medium-range ordering is revealed by in-situ synchrotron X-ray diffraction analyses. This glass-to-glass transition leads to a significant improvement in the modulus, hardness, and thermal stability, all of which could promote their applications. Based on the proposed high-entropy effect, two high-entropy metallic glasses are developed and they show similar glass-to-glass transitions. These findings uncover a high-entropy effect in metallic glasses and create a pathway for tuning the glass states and properties.

A highly distorted ultraelastic chemically complex Elinvar alloy.

The development of high-performance ultraelastic metals with superb strength, a large elastic strain limit and temperature-insensitive elastic modulus (Elinvar effect) are important for various industrial applications, from actuators and medical devices to high-precision instruments1,2. The elastic strain limit of bulk crystalline metals is usually less than 1 per cent, owing to dislocation easy gliding. Shape memory alloys3-including gum metals4,5 and strain glass alloys6,7-may attain an elastic strain limit up to several per cent, although this is the result of pseudo-elasticity and is accompanied by large energy dissipation3. Recently, chemically complex alloys, such as 'high-entropy' alloys8, have attracted tremendous research interest owing to their promising properties9-15. In this work we report on a chemically complex alloy with a large atomic size misfit usually unaffordable in conventional alloys. The alloy exhibits a high elastic strain limit (approximately 2 per cent) and a very low internal friction (less than 2 × 10-4) at room temperature. More interestingly, this alloy exhibits an extraordinary Elinvar effect, maintaining near-constant elastic modulus between room temperature and 627 degrees Celsius (900 kelvin), which is, to our knowledge, unmatched by the existing alloys hitherto reported.

Ultrahigh-strength and ductile superlattice alloys with nanoscale disordered interfaces.

Alloys that have high strengths at high temperatures are crucial for a variety of important industries including aerospace. Alloys with ordered superlattice structures are attractive for this purpose but generally suffer from poor ductility and rapid grain coarsening. We discovered that nanoscale disordered interfaces can effectively overcome these problems. Interfacial disordering is driven by multielement cosegregation that creates a distinctive nanolayer between adjacent micrometer-scale superlattice grains. This nanolayer acts as a sustainable ductilizing source, which prevents brittle intergranular fractures by enhancing dislocation mobilities. Our superlattice materials have ultrahigh strengths of 1.6 gigapascals with tensile ductilities of 25% at ambient temperature. Simultaneously, we achieved negligible grain coarsening with exceptional softening resistance at elevated temperatures. Designing similar nanolayers may open a pathway for further optimization of alloy properties.

Dual heterogeneous structures lead to ultrahigh strength and uniform ductility in a Co-Cr-Ni medium-entropy alloy.

Alloys with ultra-high strength and sufficient ductility are highly desired for modern engineering applications but difficult to develop. Here we report that, by a careful controlling alloy composition, thermomechanical process, and microstructural feature, a Co-Cr-Ni-based medium-entropy alloy (MEA) with a dual heterogeneous structure of both matrix and precipitates can be designed to provide an ultra-high tensile strength of 2.2 GPa and uniform elongation of 13% at ambient temperature, properties that are much improved over their counterparts without the heterogeneous structure. Electron microscopy characterizations reveal that the dual heterogeneous structures are composed of a heterogeneous matrix with both coarse grains (10∼30 µm) and ultra-fine grains (0.5∼2 µm), together with heterogeneous L12-structured nanoprecipitates ranging from several to hundreds of nanometers. The heterogeneous L12 nanoprecipitates are fully coherent with the matrix, minimizing the elastic misfit strain of interfaces, relieving the stress concentration during deformation, and playing an active role in enhanced ductility.

[An epidemiological survey on clinical features, self-management and cognitive level of elderly asthmatics in China].

Objective: To investigate the prevalence of asthma among the elderly people in China and to analyze the clinical features, self-management and cognitive level of elderly asthma patients. Methods: According to the multi-stage random cluster sampling methods, a total of 164 215 subjects were visited by a questionnaire in the last epidemiology survey from eight provinces (Beijing, Shanghai, Guangdong, Liaoning, Henan, Shanxi, Jiangsu, Sichuan provinces) and seven regions (north, northeast, southern china, east, south, southwest and northwest) in China from February 2010 to August 2012. 2 034 were diagnosed as asthma. The elderly patients aged ≥65 years were selected from the 2 034 asthma patients. The clinical characteristics, comorbidities, the status of asthma control and self-management and insights of the disease in elderly asthma patients were analyzed. Results: Among the 2 034 asthma patients, 584 (28.7%) were elderly asthmatics aged ≥65 years old and 1 450 (71.3%) were<65 years old. In the elderly asthma group, Early-onset asthma accounted for 439 (75.2%) and 145 (24.8%) were late-onset. The common clinical manifestations of elderly asthma patients were: chest distress 395 (67.6%), wheezing 304 (52.1%), cough 298 (51.0%). Common comorbidities of elderly asthmatics were: chronic obstructive pulmonary disease 144 (24.7%), allergic rhinitis 122(20.9%), gastroesopheal reflux disease (GERD) 114(19.5%), allergic conjunctivitis 86 (14.7%), eczema 82 (14.0%), chronic bronchitis 76 (13.0%). The Asthma Control Test (ACT) scores of elderly asthmatics and non-elderly asthmatics were (18.5±3.2) and (21.7±3.4) respectively. There was a significant difference between the two groups (P=0.042). Of the elderly asthmatics, only 13 (2.2%) patients monitored daily using a peak flow meter. 93 (15.9%) patients aware that asthma was characterized by chronic airway inflammation. 64 (11.0%) asthmatics understood that the treatment goal. Conclusions: The clinical manifestations of elderly asthmatics are atypical, especially paroxysmal wheezing. Asthma in elderly people causes more comorbidities and mortality. The self-management and cognitive level of patients with asthma needs to be improved.

[A survey on clinical characteristics and risk factors of severe asthma in China].

Objective: To investigate the clinical characteristics and risk factors of severe bronchial asthma in Chinese people over 14 years old. Methods: According to the multi-stage random cluster sampling methods, a total of 164 215 subjects were visited by a questionnaire in the epidemiology survey from eight provinces (Beijing, Shanghai, Guangdong, Liaoning, Henan, Shanxi, Jiangsu, Sichuan provinces) located in seven regions (north, northeast, east, central China, south, southwest and northwest) of China from February 2010 to August 2012. A total of 2 034 were diagnosed as asthma. The clinical characteristics and related risk factors of patients with severe asthma in China were analyzed. Results: Among all asthma patients, 560 were newly diagnosed, accounting for 27.5% (560/2 034) and the percentage of previously confirmed patients was 72.5% (1 474/2 034). A total of 145 were eligible for severe asthma, accounting for 9.8% (145/1 474) of previously confirmed asthmatics and 7.1% (145/2 034) of all asthmatics. 83.5% (121/145) severe asthmatics had at least one trigger factor. Correlation analysis showed that the risk factors of severe asthma were: smoking (OR=1.543, 95%CI: 1.250-1.814), obesity (OR=2.186, 95%CI: 1.972-2.354), petting (OR=2.135, 95%CI: 1.904-2.283), combined with allergic rhinitis (OR=3.456, 95%CI: 2.721-4.326), gastroesophageal reflux disease (OR=1.842, 95%CI: 1.682-2.140), bronchiectasis (OR=1.665, 95%CI: 1.347-1.912) or chronic obstructive pulmonary disease (OR=1.312, 95%CI: 1.171-1.694). Conclusions: The most common comorbidities in severe asthmatics in China are allergic rhinitis and gastroesophageal reflux disease. The risk factors of severe asthma include obesity, allergic rhinitis, gastroesophageal reflux disease, chronic obstructive pulmonary disease, bronchiectasis, smoking and petting.

[The efficacy and safety of tiotropium/olodaterol fixed-dose combination in Chinese patients with chronic obstructive pulmonary disease: a pooled subgroup analysis of TONADO 1+2].

Objective: To compare the efficacy and safety profiles of tiotropium/olodaterol with the mono-components in Chinese and total study population from TONADO trial. Methods: In the replicate, double-blind, parallel-group, active-controlled, randomized, 52-week, Phase Ⅲ TONADO studies (TONADO 1+2), patients received tiotropium/olodaterol, tiotropium, or olodaterol via the Respimat(®) Inhaler (Boehringer Ingelheim, Germany). Primary end points were forced expiratory volume in 1 second (FEV(1)) area under the curve from 0 to 3 hours (AUC(0-3h)) response and trough FEV(1) response, and St George's respiratory questionnaire (SGRQ) total score at 24 weeks. Adverse events were also collected. This subgroup analysis only focused on the efficacy and safety of the drug at the approved dose in China. Results: 548 Chinese patients were randomized, aged 41 to 82 years [mean age, (63±8) years] and most were male (526, 96%), 111 received tiotropium/olodaterol 5/5 µg, and 127 received tiotropium 5 µg and 95 received olodaterol 5 µg. The baseline characteristics of these groups were similar. After 24 weeks, treatment with tiotropium/olodaterol 5/5 µg, tiotropium 5 µg and olodaterol 5 µg resulted in an adjusted mean FEV(1) AUC(0-3h) response of 0.240, 0.157 and 0.079 L, and trough FEV(1) response of 0.117, 0.068 and-0.001 L, respectively. Tiotropium/olodaterol 5/5 µg significantly improved SGRQ scores in Chinese patients compared with olodaterol 5 µg (32.729 and 37.202, respectively). Generally, the safety profile of tiotropium/olodaterol was comparable with mono-components in 52 weeks. Conclusion: Compared with tiotropium or olodaterol, tiotropium/olodaterol in Chinese patients provided significant improvement in lung function and quality of life, and the safety profiles were similar.

Multicomponent intermetallic nanoparticles and superb mechanical behaviors of complex alloys.

Alloy design based on single-principal-element systems has approached its limit for performance enhancements. A substantial increase in strength up to gigapascal levels typically causes the premature failure of materials with reduced ductility. Here, we report a strategy to break this trade-off by controllably introducing high-density ductile multicomponent intermetallic nanoparticles (MCINPs) in complex alloy systems. Distinct from the intermetallic-induced embrittlement under conventional wisdom, such MCINP-strengthened alloys exhibit superior strengths of 1.5 gigapascals and ductility as high as 50% in tension at ambient temperature. The plastic instability, a major concern for high-strength materials, can be completely eliminated by generating a distinctive multistage work-hardening behavior, resulting from pronounced dislocation activities and deformation-induced microbands. This MCINP strategy offers a paradigm to develop next-generation materials for structural applications.

Nanoscale Structural Evolution and Anomalous Mechanical Response of Nanoglasses by Cryogenic Thermal Cycling.

One of the central themes in the amorphous materials research is to understand the nanoscale structural responses to mechanical and thermal agitations, the decoding of which is expected to provide new insights into the complex amorphous structural-property relationship. For common metallic glasses, their inherent atomic structural inhomogeneities can be rejuvenated and amplified by cryogenic thermal cycling, thus can be decoded from their responses to mechanical and thermal agitations. Here, we reported an anomalous mechanical response of a new kind of metallic glass (nanoglass) with nanoscale interface structures to cryogenic thermal cycling. As compared to those metallic glasses by liquid quenching, the Sc75Fe25 (at. %) nanoglass exhibits a decrease in the Young's modulus but a significant increase in the yield strength after cryogenic cycling treatments. The abnormal mechanical property change can be attributed to the complex atomic rearrangements at the short- and medium- range orders due to the intrinsic nonuniformity of the nanoglass architecture. The present work gives a new route for designing high-performance metallic glassy materials by manipulating their atomic structures and helps for understanding the complex atomic structure-property relationship in amorphous materials.

UFD1 contributes to MYC-mediated leukemia aggressiveness through suppression of the proapoptotic unfolded protein response.

Despite the pivotal role of MYC in tumorigenesis, the mechanisms by which it promotes cancer aggressiveness remain incompletely understood. Here, we show that MYC transcriptionally upregulates the ubiquitin fusion degradation 1 (UFD1) gene in T-cell acute lymphoblastic leukemia (T-ALL). Allelic loss of ufd1 in zebrafish induces tumor cell apoptosis and impairs MYC-driven T-ALL progression but does not affect general health. As the E2 component of an endoplasmic reticulum (ER)-associated degradation (ERAD) complex, UFD1 facilitates the elimination of misfolded/unfolded proteins from the ER. We found that UFD1 inactivation in human T-ALL cells impairs ERAD, exacerbates ER stress, and induces apoptosis. Moreover, we show that UFD1 inactivation promotes the proapoptotic unfolded protein response (UPR) mediated by protein kinase RNA-like ER kinase (PERK). This effect is demonstrated by an upregulation of PERK and its downstream effector C/EBP homologous protein (CHOP), as well as a downregulation of BCL2 and BCLxL. Indeed, CHOP inactivation or BCL2 overexpression is sufficient to rescue tumor cell apoptosis induced by UFD1 knockdown. Together, our studies identify UFD1 as a critical regulator of the ER stress response and a novel contributor to MYC-mediated leukemia aggressiveness, with implications for targeted therapy in T-ALL and likely other MYC-driven cancers.

[Trends of asthma control, disease management and perception in China].

Objective: To evaluate the changes of asthma control, disease management and perception in recent years in China. Methods: We conducted 2 multi-center, cross-sectional surveys. Outpatient asthmatic patients from 10 cities in mainland China (2007-2008) and 30 central cities from 30 provinces in China (except Tibet)(2015-2016) were recruited respectively. Data of asthma control, disease management and perception from the 2 surveys were compared for 10 cities which took part in both of the 2 surveys. Chi-square test was used for comparison between groups. Results: The asthma control level improved from 28.7%(839/2 928) in 2007-2008 to 39.2%(533/1 361) in 2015-2016(P<0.01). The rate of emergency visits was 18.2%(248/1 362) in 2015-2016, which was lower than that in 2007-2008(33.9%, 1 032/3 044)(P<0.01). The rate of peak flow meter (PFM) usage was 17.9%(244/1 360) in 2015-2016, which was slightly lower than the PFM usage rate in 2007-2008(21.8%, 660/3 030)(P=0.004). 56.0%(763/1 362) of the patients used inhaled corticosteroid (ICS) + formoterol to control asthma when asthma symptoms deteriorated in 2015-2016, which was higher than the result of 2007-2008(31.8%, 803/2 524)(P<0.01). 71.1%(968/1 361) of the patients in 2015-2016 had a right perception on disease nature, while the result in 2007-2008 was 63.3%(1 889/2 986)(P<0.01). 61.6%(839/1 362) of the patients in 2015-2016 had a right perception on medication choice on daily-use first-line medication for chronic asthma, while the result in 2007-2008 was 51.0%(1 500/2 942)(P<0.01). Conclusion: The current level of asthma control and disease perception in China improved significantly in recent years, while the rate of PFM usage showed no significant improvement. Asthma action plan including PFM monitoring and asthma self-management should be further promoted nationwide.

[Evaluation of asthma disease perception from China national asthma control survey].

Objective: In order to evaluate disease perception of asthma patients in urban China and provide evidence for further specific patient education. Methods: A multi-center, cross-sectional, questionnaire-based survey was carried out in 30 general hospitals dispersed in 30 provinces of mainland China (except for Tibet) during Oct 2015 to May 2016. Information of disease perception [Question 1: the disease nature of asthma; Question 2: medication choice of first-line in chronic asthma; Question 3: the occasion of using short-acting aerosols of receptor agonists; Question 4: perception of asthma treatment goal; Question 5: reason for not using peak flow meter (PFM)] were collected from asthma patients of outpatient department. These results were compared with the same type of survey results from 2007-2008. Results: Altogether 3 875 asthmatic outpatients were recruited. 69.0% (2 660/3 857) of the patients had right perception on the disease nature of asthma, 60.2% (2 321/3 857) of the patients considered inhaled corticosteroids (ICS)/inhaled corticosteroids plus long-acting beta2-agonists (ICS+ LABA) as daily-used first-line medication for chronic asthma. 85.7% (3 277/3 823) of the patients had right perception on the condition of using short-acting beta2-agonists (SABA). 75.4% (2 761/3 661) of the patients had right perception on asthma treatment goal. Only 10.1% (388/3 837) of the patients used PFM. Of the reasons for not using PFM, 65.2% (2 518/3 860) of the patients chose doctors never introduced. Among the 10 cities, which were also involved in the asthma control survey in 2007-2008, 71.1% (968/1 361) of the patients had right perception on the disease nature of asthma, 61.6% (839/1 362) of the patients considered ICS/ICS+ LABA as daily-used first-line medication for chronic asthma. 88.7% (1 207/1 361) of the patients had right perception on the condition of using SABA. 74.5% (1 013/1 360) of the patients had right perception on asthma treatment goal. 17.9% (244/1 360) of the patients used PFM. Of the reasons for not using PFM, 76.2% (931/1 221) of the patients chose doctors never introduced. Compared to the survey conducted in 2007-2008, the perception on disease nature and medication choice as daily-used first-line medication for chronic asthma significantly improved, the perception on occasion of using SABA and asthma treatment goal was comparable, while the rate of PFM usage showed no significant improvement. In reasons of not using PFM, doctors never introduced ranked the first. Conclusions: Compared to the similar survey conducted in 2007-2008, the overall status of disease perception of asthma patients has been improved in urban China, while the rate of PFM usage showed no significant improvement. Asthma education on asthma and asthma self-management should be further pushed forward.

[Evaluation of asthma management from the surveys in 30 provinces of China in 2015-2016].

Objective: To evaluate the general level of asthma management in urban areas of China and further promote the national asthma management plan. Methods: A multi-center, cross-sectional survey was carried out in 30 provinces of China (except for Tibet) during Oct 2015 to May 2016. It's a questionnaire-based face-to-face survey which included asthma management using peak flow meter (PFM) and pulmonary function test, medication choice of maintenance therapy and asthma education. Results: A total of 3 875 asthmatic outpatients were recruited including 2 347(60.6%) females and 1 528(39.4%) males. The mean age was (50.7±16.7) years ranging from 14 to 99. Only 10.1%(388/3 837) patients used PFM as monitoring, whereas 62.1%(2 405/3 874) patients underwent pulmonary function test during the past year. There were 57.4%(2 226/3 875) patients treated with inhaled cortical steroid plus long-acting ß(2)-agonist combinations (ICS+LABA) as daily medication. 43.3%(1 661/3 836) patients were followed up by physicians. Among this population, 1 362 asthmatic outpatients were recruited, who also took part in the asthma control survey in 2007-2008 in 10 cities. In this subgroup, 17.9%(244/1 360) were tested by PFM and 66.6%(907/1 362) by pulmonary function test during last year. As to the medication, 63.1%(860/1 362) selected ICS+LABA for daily control. There were 50.4%(685/1 359) patients in the follow-up cohort by physicians. Compared to the similar survey conducted in 2007-2008, the proportion of patients with ICS+LABA regimen and follow-up by physicians were markedly higher, while the rate of PFM use did not have significant improvement. Conclusion: Although the present level of asthma management in China is still far from ideal, asthma management has improved compared to 8 years ago. Yet the use of PFM does not significantly improve. Asthma action plan and application of PFM should be further promoted to improve the level of asthma management.