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Objectives Hydroxychloroquine (HCQ), an anti-malarial drug, is widely used in the treatment of rheumatic diseases. However, the benefits of HCQ in the treatment of Takayasu arteritis (TA) remain unclear, especially in terms of alleviation of vascular progression. Methods This longitudinal observational retrospective study was based on the East China TA cohort. Patients received routine treatment with prednisone and immunosuppressants. Fifty TA patients who underwent magnetic resonance angiography two times within a 1.5-year follow-up period of monitoring vascular changes were divided into HCQ and non-HCQ groups according to whether HCQ was prescribed. Changes in angiographic features were compared. Multivariate Cox regression analysis was employed to further validate the results. Results Of 50 TA patients, 21 were prescribed HCQ. The two groups shared a similar disease course, vascular types, prednisone with immunosuppressants intervention strategy, globin level, and disease remission rate at 6 months. The HCQ group showed greater reduction in the inflammatory indices erythrocyte sedimentation rate and C-reactive protein (CRP) level (p < .05), and a significantly lower incidence of angiographic progression than the non-HCQ group (19.0% vs. 51.7%, p = .035). After adjustment for age and usage of tocilizumab, angiographic progression was found to be independently associated with CRP (hazard ratio [95% confidence interval], HR [95% CI]: 1.102 [1.000–1.024], p = .046), and the usage of HCQ (HR [95% CI]: 0.266 [0.075–0.940], p = .040). Conclusion HCQ enhanced the anti-inflammatory effect of routine treatment strategies with prednisone and immunosuppressants, and alleviated angiographic progression in TA.

Allergic disease is one of the most common chronic diseases, which can affect both children and adults, be often caused by allergen-induced unfavorable immune responses, and initiate various symptoms in different organs, including up-/low-airways and skin, such as asthma, atopic dermatitis, and rhinosinusitis. With increasing prevalence of allergic disease worldwide and their impact on the quality of life, new biological therapeutic approaches for these disorders become hot areas of intensive research. Multiple factors are involved and play important role in the pathogenesis of allergic disease, which can promote or trigger T helper 2 (Th2)-type immune responses, leading to production of the type 2 cytokines and immunoglobulin E (IgE)，the two critical events in the allergic diseases. Using monoclonal antibodies to target these molecules, therefore, might provide possible benefits for the patients suffered from these diseases. Apart of those having approved biologics for allergic diseases, some potential targets such as epithelial-derived alarmins thymic stromal lymphopoietin (TSLP) and interleukin 33 (IL-33) have been also described and proposed to develop monoclonal antibodies against either these cytokines, their receptors, or both. These new and potential targets have substantially enriched the therapeutic opportunities in the field of allergic diseases. The present review aims to briefly outline the role of monoclonal antibodies targeting the cytokines and immunoglobulin involved in the development of allergic diseases, and to discuss the clinical effects of these antibodies.

Background Hypertension occurred in 30–80% of Takayasu arteritis (TAK) patients around the world and the occurrence of hypertension might worsen the disease prognosis. This study aimed to investigate the clinical characteristics and imaging phenotypes, as well as their associations with events free survival (EFS) in Chinese TAK patients with hypertension. Methods This current research was based on a prospectively ongoing observational cohort-the East China Takayasu Arteritis (ECTA) cohort, centered in Zhongshan Hospital, Fudan University. Totally, 204 TAK patients with hypertension were enrolled between January 2013 and December 2019. Clinical characteristics and imaging phenotypes of each case were evaluated and their associations with the EFS by the end of August 30, 2020, were analyzed. Results Severe hypertension accounted for 46.1% of the entire population. Three specific imaging phenotypes were identified: Cluster 1: involvement of the abdominal aorta and/or renal artery (27.5%); Cluster 2: involvement of the ascending aorta, thoracic aorta, the aortic arch, and/or its branches (18.6%); and Cluster 3: combined involvement of Cluster 1 and 2 (53.9%). Clinical characteristics, especially hypertensive severity, differed greatly among the three imaging clusters. In all, 187 patients were followed up for a median of 46 (9–102) months; 72 events were observed in 60 patients (1–3 per person). The overall blood pressure control rate was 50.8%, and the EFS was 67.9% by the end of the follow-up. Multivariate Cox regression indicated that controlled blood pressure (HR = 2.13, 95% CI 1.32–3.74), Cluster 1 (HR = 0.69, 95% CI 0.48–0.92) and Cluster 3 (HR = 0.72, 95% CI 0.43–0.94) imaging phenotype was associated with the EFS. Kaplan–Meier curves showed that patients with controlled blood pressure showed better EFS (p = 0.043). Furthermore, using cases with Cluster 1 imaging phenotype and controlled blood pressure as reference, better EFS was observed in patients with Cluster 2 phenotype and controlled blood pressure (HR = 2.21, 95%CI 1.47–4.32), while the case with Cluster 1 phenotype plus uncontrolled blood pressure (HR = 0.64, 95%CI 0.52–0.89) and those with Cluster 3 phenotype and uncontrolled blood pressure (HR = 0.83, 95%CI 0.76–0.92) suffered worse EFS. Conclusion Blood pressure control status and imaging phenotypes showed significant effects on the EFS for TAK patients with hypertension.

Background Mugwort and house dust mite (HDM) are two of the most common inhalant allergens in Asia, however, whether mugwort affects polysensitized HDM+ allergic rhinitis (AR) patients has not been elucidated. Methods Overall, 15,884 AR outpatients were assessed for clinical status. Amino acid sequences of mugwort were determined by mass spectrometry. Afterward, cross-reactivity between mugwort tropomyosin and Dermatophagoides pteronyssinus 10 (Der p10) was analysed by ELISA inhibition and basophil activation experiments. To compare immunologic responses eliciting by two different tropomyosins, peripheral blood mononuclear cells (PBMCs) of HDM-monosensitized patients were stimulated by mugwort, HDM, Der p10 and synthetic peptides representing mugwort tropomyosin respectively. Results Polysensitized HDM+AR patients were mainly sensitized to cat and mugwort, and the positive rate of monosensitized HDM+AR out-clinic patients was increased during the mugwort pollen season. Tropomyosin protein was able to find in mugwort. Synthetic tropomyosin peptide of mugwort activated basophils which were primed by HDM-specific IgE; ELISA inhibition experiment showed synthetic tropomyosin peptide of mugwort inhibited IgE binding to HDM tropomyosin, Der p10. Unlike HDM and Derp 10, mugwort and mugwort tropomyosin mainly induced IFN-γ and IL-17 release in PBMCs of monosensitized HDM+AR patients, but not IL-5. Conclusions Pan-allergen tropomyosin accounts for the cross-reactivity between mugwort and HDM, which reminds HDM+ patients to reduce mugwort exposure in mugwort pollen season in virtue of the tropomyosin induced mild inflammation.

We investigated how age affected renal function in healthy subjects in Beijing and compared different estimated glomerular filtration rate (eGFR) equations. Kidney function was evaluated by five equations: Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI); Modification of Diet in Renal Disease Study (MDRD); the Chinese version of the MDRD (MDRDc); Full Age Spectrum (FAS); and Berlin Initiative Study (BIS). A total of 46,708 subjects were enrolled and followed-up for 3 years. All showed an increase in sCr and a reduction in eGFR with increasing age. Over the 3 years, the eGFR and serum creatinine (sCr) remained unchanged in most subjects. Different equations showed good consistency; the intraclass correlation coefficients (ICC) was 0.849 for males, and 0.817 for females. The CKD-EPI equation yielded higher GFR values than the other equations (according to sCr levels). For subjects aged over 70 years, the BIS equation produced the lowest eGFR values. In summary, we observed that the renal function of individuals was relatively stable with increasing age, although different eGFR equations yielded data that varied across different populations of subjects and sCr levels.

Aim We investigated whether perioperative urine pH was associated with contrast-associated acute kidney injury (CA-AKI) in patients undergoing emergency percutaneous coronary intervention (PCI). Methods The study enrolled 1109 consecutive patients undergoing emergency PCI. Patients were divided into three groups based on perioperative urine pH (5.0–6.0, 6.5– 7.0, 7.5–8.5). The primary endpoint was the development of CA-AKI, defined as an absolute increase ≥ 0.3 mg/dL or a relative increase ≥ 50% from baseline serum creatinine within 48 h after contrast medium exposure. Results Overall, 181 patients (16.3%) developed contrast-associated acute kidney injury. The incidences of CA-AKI in patients with urine pH 5.0–6.0, 6.5–7.0, and 7.5–8.5 were 19.7%, 9.8%, and 23.3%, respectively. After adjustment for potential confounding factors, perioperative urine pH 5.0–6.0 and 7.5–8.5 remained independently associated with CA-AKI [odds ratio (OR)1.86, 95% confidence interval (CI) 1.25–2.82, P = 0.003; OR 2.70, 95% CI 1.5–4.68, P 2) (HR 5.587, 95% CI 1.178–30.599 vs. HR 2.487, 95% CI 1.331–4.579; overall interaction P Conclusion The urine pH and CA-AKI may underlie the V-shape relationship.

Purpose We hypothesized that increased level of serum β2-microglobulin (β2M) is an independent factor associated with higher mortality in hospitalized patients with exacerbated chronic obstructive pulmonary disease (COPD). Patients and Methods We retrospectively analyzed 488 hospitalized patients with exacerbated COPD as the first diagnosis at Beijing Chao-Yang hospital, P. R. China between December 31st, 2012 and December 28th, 2017. Concentrations of serum β2M and other clinical indexes were measured or collected on admission, and all patients were followed up to 90 days. The relationship between β2M and 30- and 90-day all-cause mortality was explored by Cox regression analysis adjusted for age, C-reactive protein values, N-terminal pro-brain natriuretic peptide/100, respiratory failure [RF, defined as partial arterial oxygen pressure (PaO2)

Background: The number of patients suffering from coronary heart disease with cancer is rising. There is scarce evidence concerning the biomarkers related to prognosis among patients undergoing per...

With the development of smart cities, lots of mobile cooperative sensing based nodes have emerged. However, due to the open nature of wireless transmission, attackers in the networks can use some intelligent radio devices to deteriorate the secure transmission, which imposes a severe issue of information leakage. In this paper, we consider the transmitter has some computational tasks to be computed, under the environments of intelligent attacker. Due to the limited computational capability, the sender needs to offload some tasks to the receiver. To address this problem, we propose a power allocation algorithm based on combining the technology of reinforcement learning and game theory, in order to achieve an optimal secure data rate and meanwhile reduce the whole task latency of the transmission and computation with Q learning and Nash equilibrium. Then, the Nash equilibrium and its existence conditions are derived and proven mathematically. Finally, we perform some simulations under Matlab platform, and the results show that the proposed algorithm can effectively improve the secrecy data rate and reduce the whole system latency.

In the space-ground integrated networks, many tasks come from different access networks, such as cellular network, Wireless Fidelity (WIFI), Satellite network, Unmanned Aerial Vehicle (UAV) and so on. And these tasks have different priorities in general. Therefore, how to couple these tasks in the core network and design a low computational complexity and high-efficiency task processing strategy is a big challenge. In this paper, the concept of virtual queues is introduced to improve the performance of the space-ground integrated networks. The task queue can be split into several virtual queues according to their priorities and the type of access networks. To evaluate the performance of virtual queues, the system performance index is defined. Finally, the system performance of the space-ground integrated networks is analyzed in detail. The result can be applied into the design of the space-ground integrated networks.

ObjectiveTo update a previous individual participant data meta-analysis and determine the accuracy of the Patient Health Questionnaire-9 (PHQ-9), the most commonly used depression screening tool in general practice, for detecting major depression overall and by study or participant subgroups.DesignSystematic review and individual participant data meta-analysis.Data sourcesMedline, Medline In-Process, and Other Non-Indexed Citations via Ovid, PsycINFO, Web of Science searched through 9 May 2018.Review methodsEligible studies administered the PHQ-9 and classified current major depression status using a validated semistructured diagnostic interview (designed for clinician administration), fully structured interview (designed for lay administration), or the Mini International Neuropsychiatric Interview (MINI; a brief interview designed for lay administration). A bivariate random effects meta-analytic model was used to obtain point and interval estimates of pooled PHQ-9 sensitivity and specificity at cut-off values 5-15, separately, among studies that used semistructured diagnostic interviews (eg, Structured Clinical Interview for Diagnostic and Statistical Manual), fully structured interviews (eg, Composite International Diagnostic Interview), and the MINI. Meta-regression was used to investigate whether PHQ-9 accuracy correlated with reference standard categories and participant characteristics.ResultsData from 44 503 total participants (27 146 additional from the update) were obtained from 100 of 127 eligible studies (42 additional studies; 79% eligible studies; 86% eligible participants). Among studies with a semistructured interview reference standard, pooled PHQ-9 sensitivity and specificity (95% confidence interval) at the standard cut-off value of ≥10, which maximised combined sensitivity and specificity, were 0.85 (0.79 to 0.89) and 0.85 (0.82 to 0.87), respectively. Specificity was similar across reference standards, but sensitivity in studies with semistructured interviews was 7-24% (median 21%) higher than with fully structured reference standards and 2-14% (median 11%) higher than with the MINI across cut-off values. Across reference standards and cut-off values, specificity was 0-10% (median 3%) higher for men and 0-12 (median 5%) higher for people aged 60 or older.ConclusionsResearchers and clinicians could use results to determine outcomes, such as total number of positive screens and false positive screens, at different PHQ-9 cut-off values for different clinical settings using the knowledge translation tool atwww.depressionscreening100.com/phq.Study registrationPROSPERO CRD42014010673.

Smart city is to achieve efficient government management, convenient people's livelihood services and sustainable industrial development through the interconnection, comprehensive perception and information utilization ability of things, things and people, and the new generation of information technology such as internet of things, mobile internet and cloud computing. “Smart city” aims to use the new generation of information technology, change the way people interact, improve the real-time processing ability of information and the speed of sensing and response, enhance business flexibility and continuity, improve the efficiency of resource utilization, realize green energy saving, and promote the comprehensive and sustainable development of various social undertakings. From the content of smart city construction in each city, on the one hand, it is to strengthen the construction of urban basic communication network and improve the bandwidth and coverage of communication network. On the other hand, it is to provide smart application services in key areas, such as smart public services, smart social management, smart transportation, smart medical care, smart logistics, smart housing. Smart city is the only way to realize the sustainable development of the city. Smart city is the necessary stage for the development of urban informatization to wisdom. At the same time, in the process of building a smart city, it will also drive the overall development of related industries and become a new engine for economic transformation, industrial upgrading and urban upgrading. If we compare a smart city to a person, the internet of things is the sense organ, the mobile internet is the nerve, cloud computing is a strong body and heart, big data is a smart brain. If smart city leaves data collection, data analysis and data use, smart is empty talk. Big data is the key supporting technology for smart city to realize “intelligence” in all fields, and the construction of smart city can not do without big data. From government decision-making and services, to people's way of life, to the city's industrial layout and planning, to the city's operation and management mode, big data will spread in all aspects of the smart city, which will be “intelligent” under the support of big data. This paper uses conceptual model and multidisciplinary collaborative research methods to integrate innovative thinking led by big data into urban construction to help modernize social governance capacity and governance system.

Background Previous studies suggest that transient receptor potential (TRP) channels and neurogenic inflammation may be involved in idiopathic pulmonary fibrosis (IPF)-related high cough sensitivity, although the details of mechanism are largely unknown. Here, we aimed to further explore the potential mechanism involved in IPF-related high cough sensitivity to capsaicin challenge in a guinea pig model of pulmonary fibrosis induced by bleomycin. Methods Western blotting and real-time quantitative polymerase chain reaction (RT-qPCR) were employed to measure the expression of TRP channel subfamily A, member 1 (TRPA1) and TRP vanilloid 1 (TRPV1), which may be involved in the cough reflex pathway. Immunohistochemical analysis and RT-qPCR were used to detect the expression of neuropeptides substance P (SP), Neurokinin-1 receptor (NK1R), and calcitonin gene-related peptide (CGRP) in lung tissues. Concentrations of nerve growth factor (NGF), SP, neurokinin A (NKA), neurokinin B (NKB), and brain-derived neurotrophic factor (BDNF) in lung tissue homogenates were measured by ELISA. Results Cough sensitivity to capsaicin was significantly higher in the model group than that of the sham group. RT-qPCR and immunohistochemical analysis showed that the expression of TRPA1 and TRPV1 in the jugular ganglion and nodal ganglion, and SP, NK1R, and CGRP in lung tissue was significantly higher in the model group than the control group. In addition, expression of TRP and neurogenic factors was positively correlated with cough sensitivity of the experimental animals. Conclusion Up-regulated expression of TRPA1 and TRPV1 in the cough reflex pathway and neurogenic inflammation might contribute to the IPF-related high cough sensitivity in guinea pig model.

Objective: To compare the clinical outcomes of patients with active immunoglobulin G (IgG) 4 related disease (IgG4-RD) receiving tocilizumab versus those receiving cyclophosphamide (CYC). Methods: This IgG4-RD registry study was a prospective cohort study conducted among patients with active IgG4-RD hospitalized at Zhongshan Hospital, Fudan University. Patients who were treated with tocilizumab or CYC along with glucocorticoids (GCs) were enrolled. All participants were followed up at the hospital clinic at 3 and 6 months after discharge. Primary clinical outcomes were measured via the IgG4-RD responder index (RI), complete response (CR), and partial response (PR), as well as side effects. Results: From January 2015 to June 2020, 29 patients enrolled. Fourteen and 15 patients were treated with tocilizumab and CYC, respectively. At the 6-month follow-up, disease activity parameters including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), IgG4, and IgG4-RD RI, decreased significantly in both groups. At 6 months, tocilizumab demonstrated its superiority, with 50% of patients achieving CR in the Tocilizumab group versus 20% in the CYC group. However, no statistical significance was identified ( p = 0.128). The GC dosage at 6 months was significantly lower in the tocilizumab group than in the CYC group [10 (9.4–15) mg/d versus 15 (15–15) mg/d, p = 0.025]. In the CYC group, two patients experienced lumbar vertebral compression fractures related to GCs. Other patients in both groups showed mild adverse effects. Conclusions: Tocilizumab could be a better steroid-sparing agent, with a comparable curative effect and tolerance, than CYC, in the treatment of IgG4-RD.

Background and objective Isolated blockade of IL-25, IL-33 and thymic stromal lymphopoietin (TSLP) has been shown to reduce airways inflammation and hyperresponsiveness in murine asthma model. The hypothesis that combined blockade of all three cytokines can accomplish this more effectively has never been addressed. Methods We studied a murine asthma model employing sensitization and challenge with ovalbumin (OVA) or saline control. To discern the effects of IL-33 blockade, we compared outcomes in strain identical, wild-type and IL-33 receptor (St2 -/- ) gene-deleted mice. We then examined, in the St2 -/- animals, the effects of additional, single or combined blockade of IL-25 and TSLP with blocking antibodies. Outcomes included airways reactivity, inflammatory cellular infiltration, epithelial cell metaplasia, deposition of fibrosis-related proteins, local Th2-type cytokine expression and total and specific serum IgE concentrations measured by ELISA and quantitative immunohistochemistry. Results St2 -/- gene deletion significantly reduced airways reactivity, inflammatory cellular infiltration, lung tissue expression of Th2 cytokines and fibrosis related proteins and serum total IgE in response to OVA sensitization and challenge. Additional administration of anti-IL-25 and anti-TSLP blocking antibodies to the St2 -/- mice further significantly reduced inflammation, Th2 cytokine expression, airways fibrosis and IgE production, while anti-TSLP alone reduced eosinophil infiltration and local IL-4 expression. The airways inflammatory cellular infiltrate and lung tissue expression of Th2 cytokine, but not fibrosis-related proteins were also reduced in the presence of isotype identical, control antibodies. Conclusion Combined blockade of these three cytokines may better ameliorate airways pathological changes in this murine asthma model, with implications for human asthma.

Advances in fine photoelectric displacement measurement technology have made image angular displacement measurement technology via imaging method a popular research topic; it is now easier than ever to realize small-scale high-resolution angular displacement measurement. This paper proposes a small-sized high-resolution image angular displacement measurement technique based on near-field image acquisition. A measuring mechanism based on the lensless near-field image acquisition is first established. Next, based on the error code problem, a space-value-based code value correction algorithm is proposed. Finally, the proposed device is validated on an experimental system. The proposed technology can achieve 21-bit resolution and 20.14” angle measurement accuracy. The results presented here may provide a workable foundation for further research on image-type fine photoelectric displacement measurement technology.

Objective: This study aimed to conduct an up-to-date systematic review of the literature to evaluate the effects of exercise on fatigue, anxiety, depression, physical activity, and quality of life (QOL) in patients with end-stage renal disease. Data sources: We searched PubMed (October 2018), Embase (from 1966 to October 2018), Web of Science (from 1900 to October 2018), The Cochrane Library (October 2018), and references of papers. Methods: This study includes randomized controlled trials that analyzed the combined effects of exercise intervention on patients with end-stage renal disease. Two reviewers independently screened the retrieved records, extracted data, and assessed the risk of bias for inclusion in the study. The effects of exercise intervention were conducted in the meta-analysis using RevMan 5.3 software. Results: A total of 614 participants were included in 13 randomized controlled studies. The study revealed that exercise can improve fatigue, anxiety, depression, physical activity, and QOL. The effect value results were as follows: (1) fatigue, −0.97 (95% confidence interval (CI) −1.32 to −0.62, P < 0.00001); (2) anxiety, −0.78 (95% CI −1.17 to −0.39, P < 0.0001); (3) depression, −0.85 (95% CI −1.13 to −0.56, P < 0.00001) (4) physical activity, 38.15 (95% CI 21.20 to 55.10, P < 0.0001); (5) QOL, the physical component of the 36-item Short-Form Health Survey (SF-36), 4.73 (95% CI 1.92 to 7.54, P = 0.0010); and (6) the mental component of the SF-36, 3.42 (95% CI 0.27 to 6.56, P = 0.03). Conclusion: Exercise intervention is more effective in fatigue, anxiety, depression, physical activity, and QOL. However, large-scale randomized controlled trials are needed to confirm the appropriate types of exercise and optimal time for patients with end-stage renal disease.

Impact sensors are widely used to detect grain losses in harvesters. Using polyvinylidene fluoride (PVDF) films as sensing elements is a promising way to improve sensor performance due to their high sensitivity, stability, and flexibility. However, the overlap of collision signals significantly reduces the accuracy of a sensor. To solve this problem, a novel impact sensor with two crossed PVDF films was designed and investigated. This sensor has two orthogonal layers of sensing elements that both respond to impacts, which creates positioning information for the impacts. Because of the sensor’s structure, a signal processing method was designed based on multisensor fusion theory. Tests were performed to verify the performance of the proposed impact sensor. The average signal-to-noise ratios (SNRs) for impacted PVDF films were 34.79 and 20.23 dB, respectively, for the upper and lower layers, while the average signal-to-clutter ratios (SCRs) for nonimpacted films were 21.90 and 10.05 dB, respectively. The sensor also has an extremely high detection efficiency of at least 1528 collisions per second and can identify particles that impact at the same time. Keywords: Grain loss detection, Impact sensors, Multisensor fusion, Particle impact tests, PVDF films.

With the development of smart grid construction, the domestic power user consumption information collection system is basically complete. In the current low-voltage meter reading system, most of the downlink channels use power line carrier and RS485 for communication. In the construction process over the years, the power line carrier technology has been updated rapidly, resulting in the coexistence of narrowband carrier, broadband carrier, high-speed carrier, and carrier wireless dual-mode technologies. In order to solve the problem of power line carrier interconnection and intercommunication of different technologies in the same station, this paper designs a low-voltage meter reading interconnection and intercommunication converter, which solves the problem of the communication module upgrade of station electric meters. And the converter can also support data collection after load switching across stations. Verified by field application, the device can effectively solve the problem of power line carrier interconnection in different technical systems.

With the development of new businesses such as electricity spot trading, load dispatching, and marketing user interaction, the metering automation systems have put forward new requirements for data acquisition types and real-time acquisition of large industrial and commercial users. The current metering automation system has certain limitations on data acquisition type expansion, real-time performance and flexibility improvement. This paper introduces a new data acquisition method, which can meet the requirements of rapid response to business data acquisition under complex and changeable business conditions, and can meet the requirements of data type expansion, real-time acquisition, rapid system upgrade and so on.

From the overall strategy to the medical field, it has become a national decision to promote the development of big data in the medical industry. Under the promotion of big data, the construction of medical alliance will form new formats, new ideas and new development. In the past three years, the average growth rate of digital medical users was as high as 30%, and the users' attention to digital medical topics increased more than 11 times than that before the epidemic. However, in terms of remote consultation, there are still few doctors and it is difficult to pay. The penetration rate of scene is only 21%, and the penetration rate of online drug purchase is 31%. At present, the penetration rate of disease management scenarios is only 8%. Patients with chronic diseases and severe diseases have high demand for disease management services, but the penetration rate of the former (about 10%) is much lower than that of the latter (20% - 30%). The construction of Medical Association Based on big data is to fully mobilize the existing resources of specialty, unite with influential discipline institutions, carry out the cooperation of medical teaching and research discipline construction, and improve the basic medical ability. Therefore, we need to promote a series of work, such as the establishment of standardized training system for specialists, the establishment of industry consensus, standardized diagnosis and treatment, and the establishment of promotion standards, as well as the integration of remote consultation, two-way referral, and resource allocation through IT and big data.

The development of Web 2.0 era has driven the online information sharing behavior of consumers. A large amount of evaluation information not only provides reference advice for other consumers, but also provides many valuable information for merchants. In this paper, Python was used to crawling Logitech M110 mouse comment on Jingdong platform, and Latent Dirichlet Allocation theme model analysis and word frequency statistics were carried out. It was found that focus of users on this mouse mainly included customer service, logistics, packaging, appearance, performance, price, brand and after-sales service. Then, the manually labeled text was classified with multiple labels, and the accuracy of the results reached more than 81.82%, indicating the feasibility of classification. Finally, based on the HowNet emotion dictionary, the author calculates the emotion score of the comments in each aspect and puts forward corresponding suggestions to the merchants according to the score results of each aspect.

Through effective measurement and evaluation of the distribution and effect of urban infrastructure, the key tasks of urban work in Liaoning Province can be effectively implemented, weak links are improved, urban functions are optimized and urban comprehensive carrying capacity and radiation ability can be improved. In particular, specific proposals for infrastructure projects in basic cities are put forward. For example, the construction and renovation of urban roads, urban rail transit and urban underground pipeline corridors should be intensified. Strengthen the construction of municipal public facilities, build safe, efficient and convenient life services and municipal utilities network system.

Aims: This study used a large database to develop a reliable and valid shortened form of the Edinburgh Postnatal Depression Scale (EPDS), a self-report questionnaire used for depression screening in pregnancy and postpartum, based on objective criteria. Methods: Item responses from the 10-item EPDS were obtained from 5157 participants (765 major depression cases) from 22 primary screening accuracy studies that compared the EPDS to the Structured Clinical Interview for DSM (SCID). Unidimensionality of the EPDS latent construct was verified using confirmatory factor analysis, and an item response theory model was fit. Optimal test assembly (OTA) methods identified a maximally informative shortened form for each possible scale length between 1 and 9 items. The final shortened form was selected based on prespecified validity and reliability criteria and non-inferiority of screening accuracy of the EPDS as compared to the SCID. Results: A 5-item short form of the EPDS (EPDS-Dep-5) was selected. The EPDSDep-5 had a Cronbach's alpha of 0.82. Sensitivity and specificity of the EPDS-Dep-5 for a cutoff of 4 or greater were 0.83 (95% CI, 0.73, 0.89) and 0.86 (95% CI, 0.80, 0.90) and were statistically non-inferior to the EPDS. The correlation of total scores with the full EPDS was high (r = 0.91). Conclusion: The EPDS-Dep-5 is a valid short form with minimal loss of information when compared to the full-length EPDS. The EPDS-Dep-5 was developed with OTA methods using objective, pre-specified criteria, but the approach is data-driven and exploratory. Thus, there is a need to replicate results of this study in different populations., This study was funded by the Canadian Institutes of Health Research (CIHR, KRS-140994). Dr. Levis was supported by a Fonds de recherche du QuébecSanté (FRQS) Postdoctoral Training Fellowship. Drs. Thombs and Benedetti were supported by FRQS researcher salary awards. Dr. Wu was supported by a FRQS Postdoctoral Training Fellowship. Mr. Bhandari was supported by a studentship from the Research Institute of the McGill University Health Centre. Ms. Neupane was supported by G.R. Caverhill Fellowship from the Faculty of Medicine, McGill University. Ms. Rice was supported by a Vanier Canada Graduate Scholarship. Ms. Azar was supported by a FRQS Masters Training Award. The primary study by Barnes et al was supported by a grant from the Health Foundation (1665/608). The primary study by Beck et al was supported by the Patrick and Catherine Weldon Donaghue Medical Research Foundation and the University of Connecticut Research Foundation. The primary study by Helle et al was supported by the Werner Otto Foundation, the Kroschke Foundation, and the Feindt Foundation. The primary study by de Figueiredo et al was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo. The primary study by Tendais et al was supported under the project POCI/SAU-ESP/56397/2004 by the Operational Program Science and Innovation 2010 (POCI 2010) of the Community Support Board III and by the European Community Fund FEDER. This primary study by Green et al was supported by a grant from the Duke Global Health Institute (453- 0751). The primary study by Kettunen et al was supported with an Annual EVO Financing (Special government subsidies from the Ministry of Health and Welfare, Finland) by North Karelia Central Hospital and Päijät-Häme Central Hospital. The primary study by Phillips et al was supported by a scholarship from the National Health and Medical and Research Council (NHMRC). The primary study by Nakić Radoš et al was supported by the Croatian Ministry of Science, Education, and Sports (134- 0000000-2421). The primary study by Rochat et al was supported by grants from the University of Oxford (HQ5035), the Tuixen Foundation (9940), the Wellcome Trust (082384/Z/07/Z and 071571), and the American Psychological Association. Dr. Rochat receives salary support from a Wellcome Trust Intermediate Fellowship (211374/Z/18/Z). The primary study by Smith-Nielsen et al was supported by a grant from the charitable foundation Tryg Foundation (Grant ID no 107616). The primary study by Prenoveau et al was supported by The Wellcome Trust (grant number 071571). The primary study by Stewart et al was supported by Professor Francis Creed's Journal of Psychosomatic Research Editorship fund (BA00457) administered through University of Manchester. The primary study by Tandon et al was funded by the Thomas Wilson Sanitarium. The primary study by Tran et al was supported by the Myer Foundation who funded the study under its Beyond Australia scheme. Dr. Tran was supported by an early career fellowship from the Australian National Health and Medical Research Council. The primary study by Vega-Dienstmaier et al was supported by Tejada Family Foundation, Inc, and Peruvian-American Endowment, Inc.

Background Anti-glomerular basement membrane disease (GBM) is an autoimmune disease caused by the deposition of circulating anti-GBM antibodies. Non-collagen region of α3 chain of type IV collagen (α3(IV)NC1) is one of the main target antigens, in which EA and EB are the most classical antigen epitopes. It has been reported that anti-GBM antibodies can be detected in HIV patients; however, its immunological characteristics are still unclear. Objectives In this study, the positive rate of the anti-GBM antibodies in HIV and the immunological characteristics of the target antigens were clarified. Methods A total of 93 HIV patients diagnosed in Beijing Youan Hospital from November 2017 to January 2018 were included. Enzyme-linked immunosorbent assay was used to measure the serum IgG autoantibodies specifically against GBM in these patients, as well as their subtypes and antigen spectra. Results It was found that five out of the 93 patients with HIV had low to moderate levels of anti-GBM antibodies. However, these patients presented with no clinical manifestation of any kidney injury or pulmonary hemorrhages. Compared with HIV patients with negative antibodies, there were no significant differences in gender, age, CD4+T cell count and HIV viral load. All sera of five patients recognized non-collagenous domain1 (NC1) of alpha 3 chain of type IV collagen [(α3(IV)NC1] as classic anti-GBM patients, followed by α5(IV)NC1. The antibodies against α3(IV)NC1 were IgG3 predominant, while these antibodies did not react with either of the classic epitopes on α3 (EA and EB). Conclusion These data suggest a distinct immunological profile of anti-GBM antibodies in patients with HIV, and might explain the non-pathogenic features of HIV associated anti-GBM antibodies.

Patients with IgG4-related disease (IgG4-RD) suffer high relapse rates during long-term treatment, but factors that predict relapse outcomes are not well established. In the present study, we aimed to identify predictive factors for treatment resistance and disease relapse in a Chinese IgG4-RD cohort.This study enrolled 102 patients newly diagnosed with IgG4-RD. Disease prognosis was determined by evaluating disease activity and dosage of glucocorticoids. Predictive factors for refractory and relapsed disease were identified by univariate analysis and Cox regression.Among the 102 patients, 78 cases received medical treatment with regular follow-up (21 [6-111] months). During the follow-up period, 55 (70.5%) patients sustained clinical remission, and 23 (29.5%) patients suffered refractory or relapsed disease. The relapse rate of the patients with IgG4-RD was significantly higher among patients who stopped taking medicine than among those who continued treatment with glucocorticoids (GC) + immunosuppressor (IM). Serum TNF-α ≥ 13 pg/mL, sIL-2R ≥ 1010 U/mL, total cholesterol3.55 mmol/L, low-density lipoprotein2.0 mmol/L, IgG ≥ 20.2 g/L, and drug withdrawal were predictive factors for refractory and relapsed IgG4-RD. Multivariate Cox regression revealed that both sIL-2R and TNF-α were independent risk factors for refractory and relapsed disease. The combination of GC and IM treatment was an independent protective factor against refractory and relapsed IgG4-RD.High serum levels of sIL-2R and TNF-α may be informative risk factors for refractory and relapsed IgG4-RD. Our data suggest that a combination treatment of GC along with IM may be protective against refractory and relapsed IgG4-RD. Key Points • High sIL-2R and TNF-α levels are informative risk factors for refractory and relapsed IgG4-related disease. • Combination treatment of GC with IM protects against refractory and relapsed IgG4-related disease.

Chronic rhinosinusitis with nasal polyps (CRSwNP), a type 2-based upper airway disease, is mainly characterized by high asthma comorbidity and recurrence after surgery. It has been shown that type 2 cytokines, including interleukin (IL)-4, IL-5, and IL-13 released from T helper 2 (Th2) cells as well as group 2 innate lymphoid cells (ILC2s), contribute to chronic inflammation of CRSwNP. This review summarizes recent progresses made in our understanding of ILC2 activity, particularly ILC2 accumulation at airway inflammation sites, cooperation with Th2 cells in aggravating the CRSwNP inflammatory process and interactions with regulatory T cells (Tregs) in resisting Tregs-mediated suppressive function in allergic inflammation. A better understanding of the biology of ILC2s should lay a good foundation in elucidating the pathogenesis of CRSwNP, and subsequently may lead to the development of new therapeutic strategies for the management of CRSwNP.

In recent years, big data has been more and more widely and deeply applied, showing great technological advantages and innovative effects. The fundamental reason lies in its ability to hedge various uncertainties inherent in human society, so as to improve economic forecasting, enhance the accuracy and effectiveness of public services, and mitigate policy uncertainty and its negative impact. In the field of public services, big data technology provides strong technical support for optimizing public service supply, meeting people's public service demand, improving government service efficiency and innovating social governance. Mining data, integrating data and applying data will become one of the core tasks of government service departments in the future. Therefore, big data should be better served in public services to maximize the application value of big data technology in the field of public services.

Coronavirus disease 2019 (COVID-19) is a global pandemic infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and abnormal, overactivated innate immunity and "cytokine storms" have been proposed as potential pathological mechanisms for rapid COVID-19 progression. Theoretically, asthmatic patients should have increased susceptibility and severity for SARS-CoV-2 infection due to a deficient antiviral immune response and the tendency for exacerbation elicited by common respiratory viruses. However, existing studies have not shown an expected prevalence of asthmatic individuals among COVID-19 patients. Certain aspects of type 2 immune response, including type 2 cytokines (IL-4, IL-13, etc.) and accumulation of eosinophils, might provide potential protective effects against COVID-19. Furthermore, conventional therapeutics for asthma, including inhaled corticosteroids, allergen immunotherapy (AIT), and anti-IgE monoclonal antibody, might also reduce the risks of asthmatics suffering infection of the virus through alleviating inflammation or enhancing antiviral defense. The interactions between COVID-19 and asthma deserve further attention and clarification.

Background: Leflunomide (LEF) has been considered as an alternative treatment for Takayasu arteritis (TA); however, data on its efficacy are still scanty. Objective: To investigate the efficacy and safety of LEF versus cyclophosphamide (CYC) for initial-onset TA. Methods: Initial-onset TA patients with active disease were enrolled in this research. Patients enrolled from 1 January 2009 to 31 December 2015 were treated with glucocorticoids and CYC, while patients enrolled from 1 January 2016 to 31 October 2018 received glucocorticoids and LEF. Treatment response including complete remission (CR), partial remission (PR), and effectiveness rate (ER) and side effects were evaluated at 6 and 12 months. Results and conclusion: In total, 92 patients were enrolled. A total of 47 patients were treated with LEF, while 45 patients were treated with CYC. The CR and ER rates were 75.55%, and 88.89% at 6 months, and 85.37% and 95.12% at 12 months in the LEF group. The CR and ER rates were 39.02% and 70.73% at 6 months, and 56.41% and 82.05% at 12 months in the CYC group. The CR rate was significantly higher in the LEF group than in the CYC group both at 6 months (75.61% versus 38.24%, p

BackgroundEfficient therapy and potential prophylaxis are confounded by current ignorance of the pathogenesis of airway remodelling and blockade in COPD.ObjectiveTo explore the role of the IL-33/ST2 axis in cigarette smoke (CS) exposure-induced airways remodelling.MethodsC57BL/6, BALB/c and IL-1RL1-/- mice exposed to CS were used to establish an animal surrogate of COPD (air-exposed=5~8, CS-exposed=6~12). Hallmarks of remodelling were measured in mice. Cigarette smoke extract (CSE)-induced proliferation and protein production in vitro by fibroblasts in the presence of anti-interleukin-33 (anti-IL-33) or hST2 antibodies were measured. Expression of IL-33 and ST2 and other remodelling hallmarks were measured, respectively, in bronchoalveolar lavage fluid (BALF) (controls=20, COPD=20), serum (controls=59, COPD=90) and lung tissue sections (controls=11, COPD=7) from patients with COPD and controls.ResultsWild-type mice exposed to CS elevated expression of hallmarks of tissue remodelling in the lungs and also in the heart, spleen and kidneys, which were significantly abrogated in the IL-1RL1-/- mice. Fibroblasts exposed to CSE, compared with control, exhibited early cellular translocation of IL-33, accompanied by proliferation and elevated protein synthesis, all inhabitable by blockade of IL-33/ST2 signalling. Expression of IL-33 and ST2 and hallmarks of tissue remodelling were significantly and proportionally elevated in BALF, serum and tissue samples from patients with COPD.ConclusionsExposure to CS induces remodelling changes in multiple organs. The data support the hypothesis that CS-induced lung collagen deposition is at least partly a result of CS-induced IL-33 translocation and release from local fibroblasts.

Background DD was found to be associated with acute myocardial infarction (AMI) and renal insufficiency. However, it is uncertain whether DD is an independent risk factor of CI-AKI in patients undergoing pPCI. Methods We prospectively enrolled 550 consecutive patients with STEMI undergoing pPCI between January 2012 and December 2016. The predictive value of admission DD for CI-AKI was assessed by receiver operating characteristic (ROC) and multivariable logistic regression analysis. CI-AKI was defined as an absolute serum creatinine increase ≥0.3 mg/dl or a relative increase in serum creatinine ≥50% within 48 h of contrast medium exposure. Results Overall, the incidence of CI-AKI was 13.1%. The ROC analysis showed that the cutoff point of DD was 0.69 μg/ml for predicting CI-AKI with a sensitivity of 77.8% and a specificity of 57.3%. The predictive value of DD was similar to the Mehran score for CI-AKI (AUCDD = 0.729 vs AUCMehran = 0.722; p = 0.8298). Multivariate logistic regression analysis indicated that DD > 0.69 μg/ml was an independent predictor of CI-AKI (odds ratio [OR] = 3.37,95% CI:1.80–6.33, p 0.69 μg/ml was associated with an increased risk of long-term mortality during a mean follow-up period of 16 months (hazard ratio = 3.41, 95%CI:1.4–8.03, p = 0.005). Conclusion Admission DD > 0.69 μg/ml was a significant and independent predictor of CI-AKI and long-term mortality in patients undergoing pPCI.

The alarmin cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) play a critical role in asthma pathogenesis by inducing mucosal Th2-type cytokine production. Although environmental exposure to aeroallergens has been proposed as an alarmin trigger in asthma, there has been no systematic parallel study of the effects of allergen exposure on the expression of these cytokines in the airways of human asthmatics. Using single and sequential double immunohistochemistry, we evaluated the numbers and phenotypes of IL-25–, IL-33–, and TSLP-immunoreactive cells in sections of bronchial biopsies from mild atopic asthmatics (n = 16) before and 24 h after allergen inhalational challenge. Allergen challenge highly increased expression of baseline immunoreactivity for IL-25, IL-33, and TSLP, both in the bronchial epithelium and submucosa (p < 0.001), to a degree that correlated with the extent of the late phase of airway obstruction. Aside from epithelial cells, the principal source of immunoreactivity for all three alarmins, TSLP, and IL-33 immunoreactivity colocalized principally with endothelial cells and mast cells, neutrophils, and fibroblasts, whereas IL-25 immunoreactivity colocalized principally with eosinophils as well as endothelial cells, mast cells, and fibroblasts. The data implicate that allergen challenge directly increases airway alarmin expression in atopic asthmatics to a degree correlating with increase late-phase airway obstruction, affirming these molecules as potential molecular targets for the inhibition of allergen-induced airway inflammation and obstruction.

The effects of rapid thermal annealing (RTA) on the optical properties of GaNAs/GaAs multiple quantum wells (MQWs) grown by chemical beam epitaxy (CBE) are studied by photoluminescence (PL) at 77 K. The results show that the optical quality of the MQWs improves significantly after RTA. With increasing RTA temperature, PL peak energy of the MQWs redshifts below 1023 K, while it blueshifts above 1023 K. Two competitive processes which occur simultaneously during RTA result in redshift at low temperature and blueshift at high temperature. It is also found that PL peak energy shift can be explained neither by nitrogen diffusion out of quantum wells nor by nitrogen reorganization inside quantum wells. PL peak energy shift can be quantitatively explained by a modified recombination coupling model in which redshift nonradiative recombination and blueshift nonradiative recombination coexist. The results obtained have significant implication on the growth and RTA of GaNAs material for high performance optoelectronic device application.

// Zhu Shi-Bai 1 , Liu Rui-Min 2 , Sun Ying-Chuan 2 , Zhai Jie 3 , Jiang Chao 1 , Ye Can-Hua 1 , Chen Xi 1 and Qian Wen-Wei 1 1 Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China 2 Henan University, Kaifeng, China 3 Department of Breast Surgery, Cancer Institute and Hospital, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China Correspondence to: Qian Wen-Wei, email: qianww007@163.com Keywords: rheumatoid arthritis (RA), tumor necrosis factor-α–induced protein 8-like 2 (TIPE2), PEST-containing nuclear protein (PCNP) Received: July 05, 2017 Accepted: September 03, 2017 Published: September 23, 2017 ABSTRACT We investigated the changes in mRNA and protein expression of tumor necrosis factor-α–induced protein 8-like 2 (TIPE2) and PEST-containing nuclear protein (PCNP) in peripheral blood lymphocytes from 54 patients with rheumatoid arthritis (RA) and the spleens of model mice with collagen-induced arthritis (CIA) to generate new ideas for clinical diagnosis and treatment. Expression levels of both TIPE2 and PCNP were higher in RA patients and CIA mice than in their respective controls. They were also higher in the 32 patients with active RA than in the 22 with inactive RA ( P < 0.001 for both). After comprehensively treating patients with active RA with anti-inflammatory and antirheumatic drugs for 6 months, they were stable, and there was no difference in TIPE2 levels between the treated patients and those with inactive RA ( P = 0.85). In addition, TIPE2 mRNA levels in peripheral blood correlated positively with PCNP (R 2 = 0.744, P = 0.001). The DAS28 score correlated positively with peripheral blood TIPE2 levels in the RA patients (R 2 = 0.945, P = 0.001). These findings suggest TIPE2 expression increases with the severity of RA.

Objective To investigate the current situation of sleep status and examine its association with depression among counties in rural areas of Liaoning Province, China. Methods This cross-sectional study was conducted from January 2012 to August 2013 in Northeast China. A total of 11,276 subjects aged ≥35 years were surveyed and completed the Patient Health Questionnaire-9; each participant answered questions about their sleep duration. Results For individuals with a sleep time of ≤6, 6–7, 7–8, 8–9, and ≥9 h, the respective risk of depression was 10.8%, 3.7%, 2.6%, 2.7%, and 5.7% in subjects younger than 65 years old and 15.2%, 5.4%, 3.2%, 6.5%, and 8.6% in those 65 years old or older. Conclusion In the rural population of Liaoning Province, sleep duration and depression are closely related. Both short sleep and long sleep are risk factors for depression. Optimizing sleep status may contribute to good physical and mental health.

In an electric power system with a high penetration of wind power, incoming power ramps pose a serious threat to the power system. To adopt suitable response strategies for wind power ramps, it is important to predict them accurately and in a timely manner. Since power ramps are caused by various factors, their occurrence have irregular characteristics and vary by location, bringing great difficulty in forecasting. To solve this problem, a hybrid forecasting model OT-SVM (Orthogonal Test and Support Vector Machine) was developed in this paper, which combines an orthogonal test with a support vector machine. A novel factor analysis method was established based on the theory of the orthogonal test (OT), and applied to determine the optimal inputs of a support vector machine (SVM). The effectiveness of OT-SVM was tested with three wind farms in China, while comparing the results with other related methods. The results show that the proposed OT-SVM has the highest accuracy covering different input numbers and time resolutions. In addition, a novel evaluation index MAI (Mean Accuracy Index) was proposed, considering both the missed ramps and false ramps, which can be used as a supplementary index for CSI.

In this paper, mathematical characteristics of uplink and downlink interference regions in device-to-device (D2D) communications underlaying cellular networks are analyzed. We consider that one CUE and one pair of D2D user equipments (DUEs) coexist and share uplink and downlink resources of cellular networks. The DUE pair consists of a D2D transmitting user equipment and a D2D receiving user equipment. Therefore, additional interference between the CUE and the DUE pair is introduced. First, uplink and downlink interference regions are defined and described. Next, mathematical characteristics of uplink and downlink interference regions are derived. Finally, blocking probability is formulated based on the mathematical characteristics values. The analysis results show that uplink resources are more suitable to be shared for the CUE and the DUE pair, but the difference between uplink and downlink is not significant. Meanwhile, the simulation results show that theoretical values of blocking probability well match simulation results. The results can provide a theoretical foundation for resource allocation and optimization of D2D communications.

Background: Increased proinflammatory cytokines and chemokines might contribute to infiltration of inflammatory cells and remodeling in airways of asthma. Although these molecules may be associated with asthma, there is lack of systemic evidence showing which and how important these events are in the disease. We aimed to analyze the concentrations of these molecules in the airways and relationships with disease severity and with airway infiltration of inflammatory cells in a large cohort of asthmatics (n = 70, including 37 mild and 33 moderate/severe asthmatics) compared with controls (n = 30). Methods: Meso scale discovery system and commercial ELISA kits were used to measure the concentrations of proinflammatory cytokines interleukin (IL)-1β; tumor necrosis factor-alpha (TNF-α); IL-6; and IL-17 and CC and CXC chemokines CCL2, CCL4, CCL11, CCL13, CCL17, CCL22, and CCL26 and CXCL8, CXCL9, CXCL10, and CXCL11 in bronchoalveolar lavage fluid of asthmatics and controls. Results: The concentrations of IL-1, TNF-α, IL-6, CXCL8 and CXCL10, and CCL4, CCL11, CCL17, and CCL22 were significantly elevated in asthmatics compared with controls (P < 0.05). The concentrations of TNF-α and CXCL8, but not others, were negatively correlated with severity of disease (lung function forced expiratory volume in 1 s) (TNF-α vs. total: r = −0.359, P = 0.002 vs. moderate/severe: r = −0.541, P = 0.001; CXCL8 vs. total: r = −0.327, P = 0.006 vs. moderate/severe: r = −0.625, P = 0.0001, respectively). In addition, concentrations of these two molecules were also correlated with the absolute numbers of infiltrating eosinophils and neutrophils in asthmatic airways. Conclusions: Increased concentrations of TNF-α and CXCL8 are associated with pathogenesis of asthma. Targeting these molecules might provide an alternative therapeutic for this disease.

BackgroundWe previously reported that repeated low-dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late-phase responses, comparable with conventional high-dose subcutaneous and sublingual immunotherapy.ObjectiveTo evaluate the efficacy and mechanism of grass pollen intradermal immunotherapy for treatment of allergic rhinitis.DesignA Phase II, double-blind, randomised controlled parallel-group trial.SettingSingle-centre UK study.ParticipantsAdults aged 18–65 years, with grass pollen-induced allergic rhinoconjunctivitis.InterventionsSeven 2-weekly intradermal injections were given into the forearm, containing eitherPhleum pratensesoluble grass pollen extract (7 ng of the major allergen Phl p 5) or histamine control.Main outcome measuresThe primary outcome was a combined symptom and medication score (CSMS) during the 2013 grass pollen season. Secondary clinical outcomes were overall symptom scores; individual symptoms scores for nose, mouth, eyes and lungs; overall medication scores; CSMSs during the peak season; visual analogue scale (VAS) scores for nose and eye symptoms; Mini Rhinitis Quality of Life Questionnaire scores; health-related quality-of-life scores (European Quality of Life-5 Dimensions, 5-levels); a global evaluation of symptoms, number of symptom-free and medication-free days; number of days when prednisolone was used; and adverse events. Mechanistic studies included measurement of late-phase skin response sizes, allergen-specific antibody titres, analysis of skin biopsies and basophil activation tests.ResultsThere was no significant difference in CSMSs between treatment arms [difference in median area under curve (AUC) 14, 95% confidence interval (CI) –172.5 to 215.1;p = 0.80]. Paradoxically, among the secondary outcomes, nasal symptoms measured with daily scores were higher in the active arm (difference in median AUC 35, 95% CI 4.0 to 67.5;p = 0.03), with a trend for higher nasal symptoms measured by VASs (difference in median AUC 53, 95% CI –11.6 to 125.2;p = 0.05). No differences were seen in other clinical outcomes in the main intention-to-treat analysis. In mechanistic studies, active treatment increasedP. pratense-, Phl p 1- and Phl p 5-specific immunoglobulin E (allp = 0.001) compared with the control. T cells cultured from skin biopsies of active intradermal immunotherapy subjects showed higher T helper type 2 cell (Th2) marker CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) expression (p p p p = 0.03), but not at 10–13 months’ time points.LimitationsGrass pollen doses were not increased during the course, as our proof-of-concept trial showed that repeating the same doses was sufficient to achieve almost complete late-response suppression. Injections were not continued throughout the season, as previous subcutaneous grass pollen immunotherapy trials have demonstrated preseasonal regimen efficacy.ConclusionsIntradermal immunotherapy suppressed late-phase skin responses to allergen, but was not clinically effective. The intervention appeared to have an immunological priming effect and exacerbated certain seasonal symptoms, notably in the nose.Future workFurther studies on low-dose intradermal grass pollen immunotherapy are not recommended because of our demonstrated worsening of allergic rhinitis symptoms and immunological priming. The findings are of great significance for other novel immunotherapies targeting the skin, such as epicutaneous techniques.Trial registrationCurrent Controlled Trials ISRCTN78413121.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

Background: Structural changes such as sub-epithelial fibrosis occur in inflammatory lung disease and as a natural process in the ageing lung. We have previously shown that activation of the CaSR drives inflammation in in vivo models of inflammatory lung disease, and that negative allosteric modulators of the CaSR, termed calcilytics, reduce these effects. Whether CaSR activation also contributes to extracellular matrix (ECM) remodelling and age-related fibrosis is unknown. Aim: To determine the role of the CaSR in ECM remodelling using in vivo models of allergic and non-allergic asthma and of age-related fibrosis. Methods: Ovalbumin-sensitised/challenged and IL33-sensitised mice as well as 15-month-old mice with targeted CaSR deletion from myofibroblasts and smooth muscle cells (achieved using an sm22a Cre promoter) were used as models of allergic asthma, non-allergic asthma and age-related fibrosis, respectively. Masson’s trichrome staining with semi-quantitative histomorphometry was employed to determine collagen expression beneath the airway epithelium of small and large airways. Results: Calcilytic treatment significantly reduced subepithelial collagen deposition in both large and small airways of ovalbumin-challenged mice and in large, but not small airways of IL33-sensitised mice (p Conclusions: CaSR activation drives pulmonary remodelling and fibrosis in animal models of asthma and in ageing mice. In addition to reducing inflammation, calcilytics might prove beneficial at reducing ECM remodelling during inflammatory lung disease.