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In April 2024, the World Health Organization/International Agency for Research on Cancer (IARC) published the global cancer statistics 2022 in the CA : Cancer Journal for Clinicians . This report focuses on the incidence and mortality of 36 cancers in 185 countries or territories worldwide, analyzing the differences of gender, geographic region, and the Human Development Index (HDI) level. It is estimated that in the year 2022, there were 19.96 million new cancer cases and 9.74 million cancer deaths worldwide. Lung cancer (2 480 301, 12.4%) was the most frequently diagnosed cancer in 2022, followed by female breast cancer (2 295 686, 11.5%), colorectal cancer (1 926 118, 9.6%), prostate cancer (1 466 680, 7.3%), and gastric cancer (968 350, 4.9%). Lung cancer (1 817 172, 18.7%) was also the leading cause of cancer death, followed by colorectal cancer (903 859, 9.3%), liver cancer (757 948, 7.8%), female breast cancer (665 684, 6.9%), and gastric cancer (659 853, 6.8%). With demographics-based predictions indicating that the number of new cases of cancer will reach over 35 million by 2050. The Beijing Office for Cancer Prevention and Control team has collated this report and briefly interpreted it in combination with the current situation of cancer incidence and mortality in China.

Acute respiratory distress syndrome (ARDS) is a collection of clinical syndromes characterized by a variety of heterogeneous causes. It includes diffuse lung diseases of various etiologies that ultimately lead to refractory hypoxia and severe acute respiratory failure. Despite advances in research and treatment of ARDS, its incidence and mortality continue to pose significant challenges in clinical practice. Since its inception in 1967, the definition of ARDS has undergone several revisions that have generated controversy and influenced the implementation of diagnostic and treatment strategies. At present, ARDS remains a formidable obstacle to both diagnosis and treatment. This article undertakes a comprehensive review of the evolution of ARDS definitions, examines the current diagnostic paradigm, and explores its far-reaching consequences. Our aim is to identify research directions, both in the realm of basic science and clinical practice, that are consistent with the nature of this complex disorder.

Pneumocystis pneumonia (PCP) is an opportunistic infection caused by Pneumocystis carinii and is the most common fungal infection in HIV/AIDS patients. With the routine use of antiretroviral therapy (ART), the incidence of PCP infection in HIV/AIDS patients has decreased and the prognosis has improved significantly. On the other hand, the use of chemoradiotherapy and immunotherapy in patients with cancer, post-transplantation and autoimmune diseases are increasing dramatically, which has led to a similar increase in the incidence of PCP in these non-HIV/AIDS patients. There is a global shift in research on PCP from HIV-infected co-infected PCP (HIV-PCP) to non-HIV-infected co-infected PCP. The clinical course of non-HIV-PCP is rapid and severe, and the morbidity and mortality rates are higher than those of HIV-PCP. Studies have shown that 90% of non-HIV-PCP patients have a history of glucocorticoid use prior to infection, such as in patients with hematologic malignancies, solid organ transplants, and rheumatic diseases, and that long-term high-dose glucocorticoid use is an important risk for PCP susceptibility. Clinical practice has shown that PCP often occurs during the tapering of glucocorticoids, and a higher proportion of patients develop diffuse pulmonary lesions and, in more severe cases suffer from life-threatening acute respiratory failure. The pathogenesis of non-HIV infections associated with PCP is not yet clarified, and there is a lack of effective therapeutic practices that require further investigation.

Chronic obstructive pulmonary disease (COPD) is a common respiratory system disease that seriously affects the quality of life and has a high mortality rate. Exertional dyspnea is the most common symptom in COPD patients with complexed pathogenesis and limited therapeutic drug effects. In this paper, we reviewed the relevant mechanisms and assessment, in order to improve understanding of the pathogenesis of exertional dyspnea in COPD, to emphasize the importance of accurate assessment, and to explore effective interventions that can effectively improve the degree of dyspnea and even delay or reverse the decline in lung function.

This study investigated the neuroprotective effects and underlying mechanism of Liujing Toutong Tablets(LJTT) on a rat model of permanent middle cerebral artery occlusion(pMCAO). The pMCAO model was established using the suture method. Eighty-four male SPF-grade SD rats were randomly divided into a sham operation group, a model group, a nimodipine group(0.020 g·kg~(-1)), and high-, medium-, and low-dose LJTT groups(2.8, 1.4, and 0.7 g·kg~(-1)). The Longa score, adhesive removal test and laser speckle contrast imaging technique were used to evaluate the degree of neurological functional impairment and changes in local cerebral blood flow. The survival and mortality of rats in each group were recorded daily. After seven days of continuous administration following the model induction, the rats in each group were euthanized, and brain tissue and blood samples were collected for corresponding parameter measurements. Nissl staining was used to examine pathological changes in brain tissue neurons. The levels of tumor necrosis factor-alpha(TNF-α), interleukin-6(IL-6), IL-1β, vascular endothelial growth factor(VEGF), calcitonin gene-related peptide(CGRP), beta-endorphin(β-EP), and endogenous nitric oxide(NO) in rat serum were measured using specific assay kits. The entropy weight method was used to analyze the weights of various indicators. The protein expression levels of nuclear factor kappa-B(NF-κB), inhibitor kappaB alpha(IκBα), phosphorylated IκBα(p-IκBα), and phosphorylated inhibitor of NF-κB kinase alpha(p-IKKα) in brain tissue were determined using Western blot. Immunohistochemistry was used to detect the protein expression of chemokine-like factor 1(CKLF1) and C-C chemokine receptor 5(CCR5) in rat brain tissue. Compared with the sham operation group, the model group showed significantly higher neurological functional impairment scores, prolonged adhesive removal time, decreased cerebral blood flow, increased neuronal damage, reduced survival rate, significantly increased levels of TNF-α, IL-1β, IL-6, CGRP, and NO in serum, significantly decreased levels of VEGF and β-EP, significantly increased expression levels of NF-κB p65, p-IκBα/IκBα, and p-IKKα in rat brain tissue, and significantly upregulated protein expression of CKLF1 and CCR5. Compared with the model group, the high-dose LJTT group significantly improved the neurological functional score of pMCAO rats after oral administration for 7 days. LJTT at all doses significantly reduced adhesive removal time and restored cerebral blood flow. The high-and medium-dose LJTT groups significantly improved neuronal damage. The LJTT groups at all doses showed reduced levels of TNF-α, IL-1β, IL-6, CGRP, and NO in rat serum, increased VEGF and β-EP levels, and significantly decreased expression levels of NF-κB p65, p-IκBα/IκBα, p-IKKα, and CCR5 protein in rat brain tissue. The entropy weight analysis revealed that CGRP and β-EP were significantly affected during the model induction, and LJTT exhibited a strong effect in reducing the release of inflammatory factors such as TNF-α and IL-1β. LJTT may exert a neuroprotective effect on rats with permanent cerebral ischemia by reducing neuroinflammatory damage, and its mechanism may be related to the inhibition of the NF-κB signaling pathway and the regulation of the CKLF1/CCR5 axis. Additionally, LJTT may exert certain analgesic effects by reducing CGRP and NO levels and increasing β-EP levels.

Territorial ecological restoration planning is a carrier process for carrying out territorial space regulation and ecological restoration. However, current urban planning efforts only focus on ecological processes, and fail to coordinate the development of both ecology and society. Taking Shantou, a city in Guangdong Province, as an example, we focused on the identification of ecological restoration nodes and the development of differentiated planning strategies from a comprehensive ecological-social perspective. By considering ecosystem integrity, we extracted the ecological corridors and key points by identifying ecological sources and constructing resistance surfaces, constructed an ecological recreation service evaluation system from the social perspective in terms of recreational allocation and recreational value to identify key areas for recreation services, and obtained different types of ecological restoration strategies by synthesizing the results of ecology and recreation. The results showed that there were 136 ecological corridors and 77 ecological nodes in Shantou, with a total length of 380.58 km. The most important recreation areas were the coastline, several inland bays, and wetland tidal flats, with an area of 33.78 km 2 and accounting for 1.6% of the total area. Low-level recreation areas was the largest, accounting for 57.3% of the total area. We proposed the composite strategy of "recreation expansion & fishery development", the connectivity strategy of "ecological construction & corridor connection", and the protection strategy of "vegetation restoration & development restriction". This study would provide a comprehensive analysis path for the ecological protection and restoration planning of coastal cities, and would help promote the practicality and maximizing the comprehensive benefits of territorial ecological restoration planning.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder characterized by chronic bronchitis, emphysema, or both. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has had a tremendous impact on the diagnosis and treatment of COPD. This article reviewed the evolution of the definition of COPD in GOLD and the change of its treatment strategy. In addition, in light of relevant clinical studies, the paper attempted to illustrate the importance of understanding the heterogeneous nature of COPD, and analyzed the possible consequences of ignoring this nature, including confusion with bronchial asthma caused by lung function as the "gold standard" and excessive use of inhaled glucocorticoids (ICS). It is suggested that in clinical practice, the essential characteristics of COPD patients should be clarified by collecting a variety of information in order to provide personalized treatment for patients' assessment, therapy and rehabilitation. At the same time, more basic and clinical research on COPD should be conducted, based on the nature of the disease, to explore new treatment methods.

Objective: To evaluate with 7T cardiac magnetic resonance tissue tracking imaging (CMR-TT) the ameliorative effect of Cang-ai volatile oil (CAVO) on left ventricular remodeling (LVR) in rats induced by isoproterenol (ISO), and to make preliminary investigation into CAVO's effects on endothelial dysfunction in LVR., Methods: A total of 35 healthy male Sprague-Dawley (SD) rats were randomly assigned to two groups, the experimental group ( n =27) and the normal control group ( n =8). The rat model of LVR was established by subcutaneous injection of ISO solution at 10 mg·kg -1 ·d -1 at multiple sites for 10 consecutive days. After modeling was completed, the surviving rats ( n =24) in the experimental group were then randomly assigned to the blank experimental group, CAVO group, and Shexiang Baoxin pill (SXBXP) group ( n =8 in each group). Rats in each group were given via gavage the corresponding intervention medicine or an equivalent amount of normal saline solution for 28 consecutive days. At the end of modeling and intragastric intervention, 7T CMR cine sequence scanning was conducted to collect data. Then, post-processing software CVI42 was used to analyze the images and to compare and contrast the changes in the parameters of left ventricular cardiac function and myocardial strain in each group before and after the administration of the medication. The rats were sacrificed after MRI scanning, and their hearts were harvested for pathological examination. The levels of serum biochemical indicators were measured by enzyme-linked immunosorbent assay (ELISA)., Results: CAVO significantly increased LV ejection fraction and overall myocardial strain parameters in LVR rats, while it decreased LV volume, mass, and serum levels of endothelial function indicators in LVR rats. In addition, pathological staining showed marked improvements in the hypertrophy, necrosis and interstitial fibrosis of cardiomyocytes., Conclusion: Through the regulation of myocardial vascular endothelial function, CAVO can significantly improve cardiac functions in LVR rats, delay the process of ventricular remodeling, and have a certain amount of protective effect on cardiac structure and function in rats., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

Objective: To observe the effect of electroacupuncture (EA) on pain behavior, synovial inflammatory response and demyelination of saphenous nerve in the rats modeled with knee osteoarthritis (KOA) and explore the effect mechanism of EA for reliving allodynia., Methods: Eighty-four male SD rats were randomly divided into a control group, a model group and an EA group, 28 rats in each one. Intra-articular injection of sodium monoiodoacetate (MIA) was administered in right knee joint of each rat in the model group and the EA group to establish the KOA model. In the EA group, separately, on day 5, 7 and 9 after modeling, EA was applied at "Zusanli" (ST 36) and "Yanglingquan" (GB 34) on the right side, with disperse-dense wave (2 Hz/15 Hz), 1 mA in current intensity, for 30 min in one intervention, once a day, and 3 interventions were required. On the 9th day after modeling, the weight-bearing rate was calculated for the affected limbs of the rats in each group, the synovial morphological changes were observed using HE and Masson staining, flow cytometry was adopted to detect the synovial immunocyte counts, and MSD multi-spot assay was used to detected the synovial inflammatory cytokine content. On the 14th day after modeling, the hind-paw mechanical withdrawal threshold was observed in each group and the ultrastructure of the saphenous nerve was observed under transmission electron microscopy., Results: On the 9th day after modeling, compared with the control group, the weight-bearing rate of the affected limb was reduced ( P <0.01), the synovial hyperplasia, inflammatory cell infiltration and synovial fibrosis occurred in the affected limb; the counts of synovial CD11b + cells and M1 macrophages (CD11b + CD86 + ) were increased ( P <0.01), the contents of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β, IL-10 and IL-13 in the synovial tissue were elevated ( P <0.01, P <0.05) for the rats of the model group. Compared with the model group, the weight-bearing rate of the affected limb was increased ( P <0.05), the synovial hyperplasia, inflammatory cell infiltration and synovial fibrosis were mitigated, the counts of CD11b + cells and M1 macrophages (CD11b + CD86 + ) in the synovial tissue, and the contents of TNF-α and IL-6 were reduced ( P <0.01, P <0.05) in the EA group. On the 14th day after modeling, the hind-paw mechanical withdrawal threshold was reduced in the model group when compared with the control group ( P <0.01), and it was increased in the EA group when compared with the model group ( P <0.05). Besides, in the model group, obviously, the myelin sheath structure was destroyed, the myelin layer was disintegrated and loosened, the axon was extruded or the layer thicken and cracked. Compared with the model group, the injury of saphenous nerve was alleviated remarkably in the EA group., Conclusion: The intervention with EA may attenuate the synovial inflammatory response and the injury of saphenous nerve in the affected limb of the rat with KOA, so that the spontaneous pain during the synovial inflammatory response stage and allodynia at the later stage are relieved.

Objective: To investigate the changes of skin temperature, blood infusion and inflammatory cytokines of cutaneous tissue in the sensitized area of colitis model rats, as well as the relationship between sensory and sympathetic nerves and the formation of sensitized area, and to initially reveal the partial physical - chemical characteristics of the sensitized area in the colitis model rats., Methods: Thirty-five male SD rats were randomly divided into a control group ( n =10), a model group ( n =18) and a guanethidine group ( n =7). 5% dextran sulfate sodium (DSS) was adopted for 6-day free drinking to establish colitis model in the model group and the guanethidine group. On day 6 and 7, in the guanethidine group, guanethidine solution (30 mg/kg) was injected intraperitoneally for sympathetic block. On day 7, after injection of evans blue (EB) solution, the EB extravasation areas on the body surface were observed to investigate the distribution and physical-chemical characteristics of the sensitized area. The control area was set up, 0.5 cm away from the sensitized area, and with the same nerve segment innervation. Disease activity index (DAI) score of rats was compared between the normal group and the model group, and the morphological changes in the colon tissue were investigated with HE method. Using infrared thermal imaging technology and laser speckle flow imaging technology, skin temperature and blood infusion were determined in the sensitized area and the control area of the rats in the model group. Immunofluorescence technique was adopted to observe the expression levels of the positive nerve fibers of substance P (SP), calcitonin gene-related peptide (CGRP) and tyrosine hydroxylase (TH), and the correlation with blood vessels; as well as the expression levels of SP positive nerve fibers/tryptase + mast cells, and tryptase + mast cells/5-hydroxytryptamine (5-HT) in skin tissue in the sensitized area and the control area of the rats in the model group. MSD multi-level factorial method and ELISA were applied to determine the contents of pro-inflammatory and anti-inflammatory cytokines (e.g. TNF-α, IL-1β, IL-6, IL-4 and IL-10) and anti-inflammatory substance corticosterone (CORT)., Results: Sensitization occurred at the T 12 -S 1 segments of the colitis model rats, especially at L 2 -L 5 segments. Compared with the normal group, DAI score was increased in the rats of the model group ( P <0.05), and the colonic mucosal damage was obvious, with the epithelial cells disordered, even disappeared, crypt destructed, submucosal edema and a large number of inflammatory cells infiltrated. In comparison with the control area, the skin temperature and blood infusion were increased in the sensitized area of the model group ( P <0.05, P <0.01); as well as the expression levels of the positive nerve fibers of SP, CGRP and TH of skin tissue ( P <0.05), which was specially distributed in peripheral vessels, the expression levels of SP positive nerve fibers/tryptase + mast cells, and tryptase + mast cells/5-HT of the skin tissue were all expanded ( P <0.05) in the sensitized area of the model group. Compared with the model group, the number of sensitized areas was reduced in the guanethidine group ( P <0.05). In comparison with the control area of the model group, in the sensitized area, the contents of pro-inflammatory cytokines, e.g. TNF-α, IL-1β and IL-6, and the anti-inflammatory substance CORT of skin tissue were all increased ( P <0.05); and the contents of IL-6 and TNF-α were negatively correlated with CORT ( P <0.05)., Conclusion: The sensitized areas on the body surface of colitis rats are mainly distributed in the L 2 -L 5 segments. Sensory and sympathetic nerves are involved in the acupoint sensitization, and the sensitized areas may have the dynamic changes in pro-inflammatory and anti-inflammatory substances.

As a new technology of drug-free treatment, virtual reality technique has been used in various medical fields, and is being increasingly applied in the field of wound repair. Virtual reality technology can alleviate the pain caused by acute and chronic wounds, relieve the psychological anxiety of patients with wounds, and then facilitate the recovery of patients. This paper reviews the research progress of virtual reality technique's application as a clinical adjuvant therapy in wound repair in three aspects: pain treatment, psychological treatment, and functional rehabilitation, analyzes the advantages and disadvantages of this technique, and discusses the prospects of its further application in the field of wound repair.

Objective: To investigate the clinical effect of biofeedback and electrical stimulation therapy (BFES) combined with Sabale capsules (SC) on chronic prostatitis / chronic pelvic pain syndrome (CP/CPPS)., Methods: A total of 140 outpatients meeting CP/CPPS diagnostic and research criteria in the Second Affiliated Hospital of Xi'an Jiaotong University were randomly divided into groups A (blank control), B (BFES intervention), C (SC intervention) and D (BFES+SC intervention), 35 cases in each group. The patients in group A were left untreated, while those in groups B, C and D received BFES, SC and BFES+SC, respectively, all for 12 weeks. Then the patients were followed up at 30 days after treatment and the urinary flow rate and NIH-CPSI scores were obtained and compared with the baseline., Results: In comparison with the baseline, the total NIH-CPSI scores after intervention were significantly decreased in groups B, (［27.30 ± 2.44］ vs ［19.43 ± 2.33］), C (［26.77 ± 2.54］ vs ［19.40 ± 2.75］) and D (［27.67 ± 3.69］ vs ［15.57 ± 1.94］) (all P < 0.05), and so were the individual item scores in pain or discomfort (［12.50 ± 1.94］ vs ［9.40 ± 2.01］, ［11.93 ± 1.64］ vs ［9.23 ± 1.96］, and ［12.33 ± 2.20］ vs ［7.50 ± 1.55］), urination symptoms (［6.07 ± 1.57］ vs ［3.83 ± 1.05］, ［5.97 ± 1.33］ vs ［3.77 ± 1.14］, and ［6.20 ± 1.88］ vs ［2.87 ± 0.94］), quality of life (QOL) (［8.73 ± 1.62］ vs ［6.20 ± 1.42］, ［8.87 ± 1.25］ vs ［6.40 ± 1.59］, and ［9.13 ± 1.70］ vs ［5.20 ± 1.40］) (all P < 0.05), while the maximum urinary flow rate (Qmax) was remarkably increased (［15.72 ± 2.38］ vs ［19.73 ± 2.85］, ［16.20 ± 2.44］ vs ［19.46 ± 2.48］, and ［15.83 ± 2.52］ vs ［22.49 ± 2.76］) (all P < 0.05), and so was the average urinary flow rate (Qavg) (［9. 282 ± 1.52］ vs ［11.27 ± 1.95］, ［8.97 ± 1.25］ vs ［11.16 ± 1.74］, and ［9.20 ± 1.36］ vs ［13.50 ± 2.30］) (all P < 0.05). The decrease in NIH-CPSI total and item scores and increase in Qmax and Qavg after treatment were more significant in group D than in B and C (P < 0.05), but showed no statistically significant difference between groups B and C (P > 0.05). Nor was any significant change observed in the above parameters in group A after treatment ( P > 0.05)., Conclusions: Biofeedback and electrical stimulation therapy combined with Sabale capsules can alleviate urination dysfunction, pelvic floor tension myalgia and other symptoms and significantly improve the QOL of CP/CPPS patients.

Objective: To understand the current status of foreign dual-degree programs of Medical Doctor (MD) and Master of Public Health (MPH) and provide evidence-based decision-making reference for promoting the education of high-level applied public health talents in China. Methods: The list of involved institutions and information of foreign MD-MPH dual-degree programs was collected through literature retrieval, online information searching, and additional survey of key figures. We extracted the details of each project regarding professional fields, core competence, length of schooling, teaching and learning arrangement, internship eligibility, and graduation assessment. Python 3.8.0 was used for data cleaning, and the occurrence frequency of related items in each dimension was calculated. Results: A total of 99 MD-MPH programs from 104 foreign institutions were included, among which 97.1% of them were implemented in universities from the United States. The School of Public Health provided 42.4% (42/99) of the programs. Epidemiology was the major discipline set up among most programs, accounting for 12.0% (29/241) of all the specialties involved. Epidemiological research methods, health policy management and practice, and public health practice were the top 3 core competencies to be mastered. Of the 99 programs, 87 gave information on the length of the program, of which 74.7% (65/87) were five years, 6.9% (6/87) were four years, and 18.4% (16/87) included both 4-year and 5-year programs. Conclusions: The international MD-MPH programs were sophisticated and mainly organized by the School of Public Health alone or in conjunction with the School of Medicine. Epidemiology is the core course and competence objective, with a length of 4-5 years. Through learning experience from international MD-MPH programs and the Chinese unique medical development background, China should optimize its medical education system to develop a suitable talent training strategy for MD-MPH dual-degree programs in the new era.

The application of day surgery on thoracic surgery is just started, and the innovation of surgical robots and their application on thoracic surgery bring new opportunities to the development of thoracic day surgery. However, the clinical practice of robot-assisted thoracic day surgery (RTDS) in China still has challenges and disagreements. Based on the experience of domestic experts in the field of RTDS clinical practice, this review discussed several key points of RTDS, including the future direction of RTDS, adjusting the indications according to their own conditions for the institutions carrying out RTDS, the robot-assisted advantage of RTDS being brought into play during the operation, and the perfect post-discharge follow-up mechanism being an important guarantee for the safe development of RTDS, to promote the application progress of RTDS in China.

Objective: To analyze the level of the knowledge and related factors of cancer prevention and treatment among residents of Beijing in 2020. Methods: From April 14 to 21,a total of 11 721 residents were recruited in the study by using anonymous network sampling method. A WeChat online electronic questionnaires was conducted to collect basic demographic characteristics and the knowledge of cancer prevention and treatment. The Chi-square test was used to compare the difference of the level of the cancer prevention and treatment knowledge among different groups. A multivariate linear regression model was used to analyze the related factors. Results: Among the subjects, 72.9% (8 542) were male and 93.7% (10 983) were urban residents. The total number of questions answered by the subjects was 117 210 of which 89 093 were known, and the overall awareness rate among the residents was 76.0%. The female, aural residents, with junior college education, and worked in government institutions had a good performance of the knowledge ( P< 0.05), about 83.4%, 79.7%, 82.3% and 82.0% respectively. The results of multivariate linear regression model showed that female[β=0.798(95 %CI :0.702,0.894)] and junior college education[β=3.271(95 %CI :2.993,3.609)] could know more questions compared to male and primary school education ( P< 0.05); compared with working in the government institutions, agricultural laborer[β=-0.911(95 %CI :-1.057,-0.766)], retired personnel[β=-2.273(95 %CI :-2.532,-2.014)], school students[β=-0.629(95 %CI :-0.796,-0.462)] and other occupation people[β=-0.376(95 %CI :-0.634,-0.119)] could know fewer questions ( P< 0.05). Conclusion: The level of the cancer prevention and treatment knowledge among residents in Beijing was relatively high. Gender, education level and occupation were relevant factors.

Objective: To analyze the current status of lung cancer screening among residents in Urban Beijing Cancer Screening Program, 2014-2019. Methods: Based on an on-going cancer screening program launched by the National Urban Cancer Screening Program, residents aged 40 to 69 were recruited from 80 streets in six districts of Beijing (Dongcheng, Xicheng, Chaoyang, Haidian, Fengtai, and Shijingshan District) by using a cluster sampling method. Subjects who were evaluated as high-risk individuals by using the questionnaire received Low-Dose spiral Computed Tomography (LDCT) screening in designated hospitals. All participants were followed up annually using active and passive follow-up methods to obtain their health outcomes (diagnosed with lung cancer or not). The proportion of high-risk cases evaluated by using the questionnaire, clinical recall rate for receiving LDCT screening, the proportion of cases with positive pulmonary node, incidence rate, cumulative incidence rate, and the proportion of patients with stage 0 or Ⅰ were calculated. Cox proportional hazard regression model was used to estimate the hazard ratio ( HR ) and 95% confidence interval (95% CI ) among individuals who experienced different screening scenarios. Results: A total of 88 044 residents with the age of (57.4±7.4) with completed high-risk assessment were included in the analysis. 23.14% of participants were evaluated as high-risk individuals by using the questionnaire. The clinical recall rate was 52.26% among the high-risk individuals. The positive rate of pulmonary node detected by LDCT was 10.99%. The incidence rate of lung cancer among males and females aged 40-69 years were 172.82/100 000 person-years and 133.52/100 000 person-years, respectively after 3 years follow-up. The incidence rates increased with age ( P trend <0.001). The incidence rate of lung cancer among high-risk individuals was 259.22/100 000 person-years, with the HR ( 95%CI ) about 2.27 (1.83-2.81) when compared with that among low-risk individuals. The incidence rate and cumulative incidence rate of lung cancer among individuals with positive pulmonary node detected by LDCT were 1 825.03/100 000 person-years and 4 615.38/100 000, respectively, with the HR (95% CI) about 13.80 (8.91-21.36) when compared with that among individuals with no or negative pulmonary node. The early diagnosis rate among individuals who received LDCT screening was 70.21%, which was higher than that among individuals with no LDCT screening (45.45%). Conclusion: Individuals with a high risk of lung cancer in Beijing have a better recall rate of receiving LDCT screening. Using LDCT screening among high-risk individuals is an effective strategy to detect lung cancer cases and improve the early detection rates of lung cancer in Beijing, China.

Objective: To evaluate 5-years breast cancer-specific survival (CCS) by age, and the relationship of age at diagnosis and the risk of breast cancer mortality. Methods: Medical records of 3 470 resident patients diagnosed with primary, invasive female breast cancer between January 1, 2006 and December 31, 2010 in four hospitals in Beijing were reviewed and collected. All patients were followed up until December 31, 2018 to acquire survival outcome. Five-years breast CCS of the five subgroups was estimated by the life-table method. Cox proportional hazard regression models were used to estimate hazard ratios ( HR s) and 95% confidence intervals (CIs) of different levels of age stratification and breast cancer mortality, and restricted cubic spline (RCS) model was used to detect the dose-response relationship. Results: The median diagnosis age among 3 470 female breast cancer patients was 53.2 years. There were 1 289 patients in the age-group of 45~54 years, with the highest proportion of 37.15%. However, only 126 patients occurred in the age-group of less than 35 years, with the lowest proportion of 3.63%. A total of 528 (15.22%) patients died of breast cancer during the study period. Overall 5-year CCS was 90.72% (95% CI: 89.74%~91.70%), 88.68% (95% CI: 83.09%~94.27%) and 87.05% (95% CI: 84.27%~89.82%) for all of the patients, aged less than 35 years and those aged 65 years and older. Compared with patients with diagnosis age of 45~54 years, the multivariate-adjusted HR s for breast cancer mortality associated with patients in age-group of <35 years and those in the age-group of ≥65 years were 1.72 (95% CI: 1.06~2.81) and 1.89 (95% CI: 1.43~2.49), respectively. In addition, patients aged ≥65 years had significantly higher risk of breast cancer mortality in Luminal subtypes, with HR of 1.70 (95% CI: 1.17~2.46) for Luminal A breast cancer and HR of 3.84 (95% CI: 1.74~8.49) for Luminal B breast cancer. RCS analysis exhibited a non-linear ( "J-shaped" ) relationship between diagnosis age of female breast cancer and the risk of breast cancer mortality (nonlinear P <0.000 1). In addition, patients aged ≥65 years had significantly higher risk of breast cancer mortality in Luminal subtypes, with HR of 1.70 (95% CI: 1.17~2.46) for Luminal A breast cancer and HR of 3.84 (95% CI: 1.74~8.49) for Luminal B breast cancer. RCS analysis exhibited a non-linear ( "J-shaped" ) relationship between diagnosis age of female breast cancer and the risk of breast cancer mortality (nonlinear P <0.000 1). Conclusion: Age at diagnosis is an important prognostic factor for female breast cancer, with worse outcome for both young and old patients.

In this study, a continuous rape-rice rotation plot experiment was conducted over three years. Repair materials were continuously applied in the first two years, and no repair materials were applied in the second year. The repair effects of hydroxyapatite, lime, biochar, bio-organic fertilizer, and nano-materials on copper contaminated soil and the enrichment of copper in different parts of rape and rice were investigated. The results show that hydroxyapatite, lime, and nanomaterials can significantly increase soil pH, and different restoration materials can effectively inhibit the movement of soil copper. The effective copper treatment with lime restoration soil had the largest decrease. The four seasons of continuous application of restoration materials were 38.9%, 34.9%, 27.88%, and 29.04%, respectively, and the subsequent effect of lime passivation of effective copper was better than other restoration materials. The application of the repair material significantly reduced the copper content in edible parts of rape and rice. In the four seasons of application of the repair material, the maximum copper content in edible parts of different crops decreased by 46.03%, 22.2%, 29.44%, and 31.71%, respectively. Due to the application effect of the repair material, the copper content in the edible part of the two season crops, without the repair material, did not exceed the national food safety limit. With the use of different repair materials, the yields of rapeseed and rice were improved. This test can provide some theoretical basis and technical support for soil improvement in copper-contaminated areas.

Objective: To investigate the application of severity classification according to the protocol on the Diagnosis and Treatment of coronavirus disease 2019(COVID-19)by the National Health Commission of China, pneumonia severity index(PSI) and CURB-65　in risk stratification and prognostic assessment of COVID-19. Methods: Clinical data of 234 in-hospital patients with COVID-19 were collected and retrospectively reviewed in Wuhan Tongji Hospital. Patients were divided into 3 groups (common, severe, and critical type) at admission according to the sixth version of the protocol issued by the National Health Commission of China on Diagnosis and Treatment of COVID-19. At the same time, the severity of pneumonia was calculated by PSI and CURB-65, and the patients were stratified into 3 risk groups, namely mild, moderate, and severe groups. The hospital mortality rate was evaluated in each group. Sensitivity, specificity, positive predictive values, negative predictive values, and the area under the receiver operating characteristic(ROC) curve(AUC) for predicting hospital mortality in each rule were assessed. Results: According to the severity classification of Chinese protocol, the proportion of patients with common type, severe type, and the critical type was 15.8%, 75.6%, and 8.5%, respectively. No in-hospital death occurred in the common type. As for PSI and CURB-65, greater proportions of patients were classified as low risk(79.1% and 75.6%, respectively), while smaller proportions of patients were classified as moderate and high risk(16.2%, 15.0%; 4.7%, 9.4%, respectively). In-hospital death occurred in low and moderate risk patients identified by these 2 scoring systems. The mortality of the critical group of the Chinese protocol was 65%, and the sensitivity and specificity of predicting in-hospital mortality were 36.4% and 97.0%, respectively. The mortality in the high risk group of PSI and CURB-65 was 100% and 77.3%. The risk class V of PSI and CURB-65 score 3-5 had high specificity(100% and 97.4%, respectively)but low sensitivity(33.3% and 51.5%, respectively)in predicting in-hospital mortality. The AUC of the Chinese protocol severity classification, PSI, and CURB-65 was 0.735, 0.951, and 0.912. The optimal cut-off point of PSI was risk class Ⅳ, and the sensitivity and specificity for predicting mortality were 90.9% and 90.5%. The optimal cut-off point of CURB-65 was score 2, and the corresponding sensitivity and specificity were 84.8% and 85.6%. Conclusions: PSI and CURB-65 can be used for risk stratification and prognostic assessment in patients with COVID-19.

Objective: To analyze the current status of breast cancer screening among females in Urban Beijing Cancer Screening Program, 2014-2019. Methods: Based on an on-going cancer screening program launched by the National Urban Cancer Screening Program, women residences aged 40 to 69 were recruited from 80 streets in six districts of Beijing (Dongcheng, Xicheng, Chaoyang, Haidian, Fengtai and Shijingshan District) using cluster sampling method. General demographic information and potential risk factors, results of clinical examination and follow-up outcomes of the target population (diagnosed breast cancer or not) were collected using epidemiological questionnaire, risk evaluation, clinical examination using ultrasound and (or) joint screening with mammography and follow-up, respectively. Proportion of high-risk cases evaluated by the questionnaire, recall rate, proportion of cases with BI-RADS grade 3 and BI-RADS grade 4/5, proportion of the cases with stage 0 or I, incidence rate and cumulative incidence rate were calculated. Cox proportional hazard regression model was used to estimate the hazard ratio ( HR ) and 95% confidence interval (95% CI ) among females who experienced different screening scenario. Results: A total of 53 916 women with the age of (57.2±7.3) completed high-risk assessment were included into analysis. The proportion of overweigh and obesity were 40.90% (22 053 cases) and 15.34% (8 270 cases), respectively. A total of 17 535 cases (32.52%) were evaluated as positive case detected by the questionnaire. The clinical recall rate was 47.64% (8 353 cases) among the high-risk females. The positive rate detected by ultrasound or mammography alone was 1.84% and 4.00%, while the suspicious positive detection rates were 14.50% and 17.83%, respectively. The positive rate and suspicious positive rate detected by joint screening using ultrasound and mammography were 5.44% and 27.74% respectively. In total, 252 cases were diagnosed with breast cancer after an average of 2.68 years follow-up. The incidence rate and cumulative incidence rate of breast cancer were 174.34/100 000 person years and 470/100 000, respectively. The early detection rate was 68.6% among the residences who received clinical examination. Compared with the negative residence evaluated by the questionnaire, the positive cases has a 55% higher risk of diagnosed with breast cancer ( HR =1.55, 95% CI :1.20-2.00); Cases that recognized by baseline ultrasound and mammography joint screening as BI-RADS 4/5 and BI-RADS 3 have higher risk of diagnosed with breast cancer than that of with the results of BI-RADS 1-2, with the HR of 12.60 (95% CI :6.49-24.47) and 1.89 (0.93-3.83), respectively. Conclusion: Females with high risk of breast cancer in Beijing have a better recall rate of receiving the clinical screening examination. Joint using ultrasonography and mammography in breast cancer screening can improve the positive detection rate among high risk females.

Objective: To analyze the characteristics of allelic and haplotypic polymorphisms of human leukocyte antigens at HLA-A, -B, -C, DRB1 and DQB1 loci in Guangxi Zhuang population., Methods: Polymerase chain reaction-sequence based typing (PCR-SBT) was used to detect. The five loci (HLA-A, -B, -C, -DRB1, -DQB1) in 350 unrelated Zhuang ethnic individual from Guangxi region. Allelic and haplotypic frequencies were calculated by using Arlequin software 3.5.2.2. Phylogeny tree were constructed by using MEGA software 6.0, and SPSS software was used for principal component analysis., Results: Among the five loci in the population, only HLA-A and DRB1 loci were observed as departures from Hardy-Weinberg expectations. A total of 19 HLA-A, 42 HLA-B, 22 HLA-C, 25 HLA-DRB1 and 15 HLA-DQB1 alleles were found in 350 samples. The most highest frequent alleles were A*11: 01(28.57%), B*46: 01(14.00%), C*01: 02(18.43%), DRB1*16: 02 (15.71%）and DQB1*05: 02 (35.00%) . The most common five loci haplotype was A*33: 03-C*03: 02-B*58: 01-DRB1*03: 01-DQB1*02: 01（6.86%）. The phylogenetic tree analysis showed that Guangxi Zhuang population had a relative close genetic relationship with southern Han Chinese populations., Conclusion: This reaserch found that the HLA-A, B, C, DRB1 and DQB1 loci are highly polymorphic in Guangxi Zhuang population.

Severe and critical coronavirus pneumonia 2019 (COVID-19) often occurs in elder patients with multiple comorbidities, and severe hypoxemia events constitute a key factor for the deterioration of some cases. The critical type of COVID-19 could progress into acute respiratory distress syndrome and multi-organ dysfunction, which are the major causes of death. Early non-invasive ventilation (NIV) treatment of possible pathophysiological abnormalities is helpful to improve prognosis. Close monitoring of oxygenation, reducing patients' oxygen consumption, active psychological intervention, and rapid handling of severe hypoxemia events are the key factors for successful NIV treatment. In addition, active adjuvant therapies such as correcting coagulation dysfunction, providing proper nutritional support, accurate volume control, and safe individualized blood glucose monitoring are of great significance.

Objective: To understand the consciousness of the cancer early treatment and its demographic and socioeconomic factors. Methods: A cross-sectional survey was conducted in 16 provinces covered by the Cancer Screening Program in Urban China (CanSPUC) from 2015 to 2017. A total of 32 257 local residents aged ≥18 years old who could understand the investigation procedure were included in the study by using the cluster sampling method and convenient sampling method. All local residents were categorized into four groups, which contained 15 524 community residents, 8 016 cancer risk assessment/screening population, 2 289 cancer patients and 6 428 occupational population, respectively. The questionnaire collected personal information, the consciousness of the cancer early treatment and relevant factors. The Chi square test was used to compare the difference between the consciousness of the cancer early treatment and relevant factors among the four groups. The logistic regression model was used to analyze the influencing factors related to the consciousness of the cancer early treatment. Results: With the assumption of being diagnosed as precancer or cancer, 89.97% of community residents, 91.84% of cancer risk assessment/screening population, 93.00% of cancer patients and 91.52% of occupational population would accept active treatments ( P< 0.001). If the immediate family members were diagnosed as precancer or cancer, people who would encourage their family members to receive early treatment in the four groups accounted for 91.96%, 91.94%, 92.44% and 91.55%, respectively ( P< 0.001). The company employees, annual household income with 40 000 yuan and more and other three groups had a relatively better consciousness of the cancer early treatment ( P< 0.05). Male, widowed, unemployed and from the central and western regions had a relatively worse consciousness of the cancer early treatment ( P< 0.05). Conclusion: Residents in urban China participants had a good consciousness of the cancer early treatment. The marital status, occupation, annual household income and residential regions were major factors related to the consciousness of the cancer early treatment.

Two different mixed sludges (aerobic nitrifying sludge and ANAMMOX-denitrification sludge:R1, and anaerobic digestion flocculent sludge and ANAMMOX-denitrification sludge:R2), were used as inocula in two UBF reactors to enrich Anammox bacteria. Both kinds of mixed sludge set up the Anammox process successfully. It took 36 days for R1, while R2 required 53 days. Nitrogen removal rates of R1 and R2 were high during the whole operation. During the stable operation stage, the removal rates of NH 4 + -N, NO 2 - -N, and TN were about 99.92%, 96.64%, and 81.87% for R1; and 97.54%, 94.91%, and 80.98% for R2. Illumina High-throughput Sequencing revealed Candidatus Kuenenia was in the top six taxa in the two reactors with 3.22% relative abundance in R1 and 2.35% in R2 after the successful start-up. Simulation results indicated that the Modified Stover-Kincannon model and the second-order model were appropriate models. It was deduced that the N-removal potential of R1 was a little greater than that of R2 after comparing the projected maximum substrate removal rate U max of the two reactors.

Analyzing the interspecific association of major tree populations of Cyclobalanopsis glauca community and revealing the coexistence among the populations would provide theoretical basis for the restoration and reconstruction, management and biodiversity conservation of Karst hills in Gui-lin. Based on field survey, the &chi; 2 test, association coefficient (AC), co-occurrence percentage (PC), Ochiai index (OI), Dice index (DI), and principal component analysis (PCA) were used to investigate the interspecific association and eco-taxonomic classification of the top 22 tree species in Cyclobalanopsis glauca community in Guilin Karst Rocky Mountains. The results showed that there was a significant positive correlation between the interspecific associations of the 22 main tree populations, indicating that this community was in a stable climax stage. The results of &chi; 2 test showed that 108 pairs of 231 species pairs had positive associations, 115 species pairs had negative associations, 8 species pairs were unrelated, with the positive and negative linkage ratio being 93.9%. The vast majority of species pairs showed no significant association. The strong indepen-dence between species might be mainly caused by the higher habitat heterogeneity of the Karst hills in Guilin which led to the differentiation of niches between species. The results of AC, PC, OI and DI were basically consistent with that of &chi; 2 test, indicating that the analysis of interspecific association should be based on the &chi; 2 test and supplemented by AC, PC, OI and DI indices. According to the PCA and evaluation of interspecific relationships, the 22 main tree species were divided into three ecological groups. The species within each group had the same adaptability to habitat but different ecological requirements.

Objective: To establish a method for in vitro culture of the fetal rat testis tissue., Methods: Nine sexually mature specific-pathogen-free rats, 3 males and 6 females, weighing 200－250 g, were used for this study. The estrus of the female rats was determined according to the results of the vaginal smear test. The female rats were mated with the male ones in proestrus and estrus at night in the ratio of 2∶1 and observed the following day for conception (0.5 day post-conception ［dpc］) based on the presence of sperm in the vaginal smear. At 15.5 dpc, the fetal testes were isolated under the anatomical microscope, some for HE staining and the rest divided into a control and an hCG group to be cultured in a soft agar culture system at 37 ℃ in a humidified atmosphere containing 5% CO2. From the first day of culture (d 0), the development of the testes was observed under the inverted microscope, the culture medium collected and replaced on d 1, d 2, d 3 and d 4, and the testis tissue obtained on d 4. The concentration of testosterone in the culture medium was determined and the testis tissues were fixed, dehydrated and embedded for histological examination., Results: Fetal rats were successfully obtained with the vaginal smear at 15.5 dpc, and the fetal testes effectively isolated, which were well developed, with gradual increase of their volume and enlargement of convoluted seminiferous tubules under the inverted microscope. Testosterone was observed in the culture medium, its concentration gradually increasing and reaching the peak on d 3, and its secretion stimulated by hCG. At 15.5 dpc. The fetal testes showed a histomorphological integrity, with typical seminiferous tubules, gonocytes, Sertoli cells and Leydig cells, but no central necrosis. Transmission electron microscopy revealed gonocytes and Sertoli cells within and Leydig cells between the seminiferous tubules, without obvious swelling of the mitochondria and endoplasmic reticula in the cells., Conclusions: The fetal rat testis tissue cultured in the soft agar culture system can develop well, retain its normal activity, and excrete testosterone into the culture medium.

Objective: To analyze the causes of preoperative miscarriage of pancreatic serous cystadenoma (SCN) and find the ways to improve it. Methods: Clinical data of 425 pancreatic cystic neoplasm patients who underwent surgical resection from January 2006 to December 2016 in Department of Pancreatic Surgery in Huashan Hospital were retrospectively analyzed.Excel database was created which covered 128 fields of 7 fields: general information of patients, preoperative blood biochemical indexes, tumor markers, surgical related data, postoperative complications, imaging findings and pathology.One hundred and sixty-one cases of SCN were analyzed in depth, mainly in three aspects: surgical benefit, preoperative imaging diagnostic value and interference factors in preoperative judgement.The classification data were analyzed by χ(2) test and the quantitative data were analyzed by t test.The Logistic regression model was used for multiple factor analysis. Results: Of the 425 PCN cases surgically removed, 161 cases (37.9%) were SCN, the incidence of operative complications was 40.4%(65/161), the hospitalization days was (20.7±12.1)days and the medical cost was (75 267±37 866) yuan.Only 3 of 161 cases of SCN were accurately diagnosed by preoperative imaging methods, 61 cases were diagnosed as "cystic lesions of pancreas" (37.9%) and 52 cases were diagnosed as "pancreatic cystadenoma" (32.3%). SCN was misdiagnosed as MCN(32.3%) and IPMN(28%) before operation.25.5% of them were diagnosed as SCN before operation, but still underwent radical operation.The rate of preoperative imaging diagnosis for identifying SCN was 62.8%.The lack of preoperative endoscopy and the lack of understanding of the image characteristics and biological behavior of SCN were the most important factors affecting the accuracy of preoperative judgment.Statistics found that gender, age, CA125 and tumor location can be used as independent factors contribute to the clinical identification(χ(2)=8.995, P =0.003; χ(2)=10.019, P =0.007; t =3.157, P =0.002; χ(2)=6.790, P =0.009). Logistic analysis showed that women, older than 60 years old, the tumors located in the pancreatic body and tail were the independent factors of SCN classification and diagnosis ( OR =0.481, 0.376, 0.577, 0.666, 95% CI : 0.305-0.759, 0.199-0.710, 0.361-0.924, 0.433-1.024, P =0.002, 0.003, 0.022, 0.064). Conclusions: SCN has more benign biological behavior.Although surgical excision is acceptable for clinical safety, the corresponding benefit is very limited.It is possible to improve the rationality of SCN clinical operation decisions to some extent by performing endoscopic examination, imaging doctors to improve the SCN feature recognition and surgeons to enhance the awareness of SCN.

Objective: To analyze the temporal trends of lung cancer incidence between age, gender (male and female) and areas (urban and rural) in Beijing during 2000-2012. Methods: The lung cancer cases were collected by Beijing cancer registry between 2000 and 2012. We calculated the incidence and world age-standardized incidence rates (ASR) which standardized by World Segi's population. Also, the average age and median age of lung cancer incidence were calculated. The annual percent changes (APC) for the whole period, for the gender ratio and for the area ratio were evaluated with Joinpoint analysis. Result: Totally, 81 378 new cases of lung cancer were diagnosed in 2000-2012 with the average incidence rate of 52.67/100 000. The incidence rate increased by 4.84% per year from 38.99/100 000 to 65.33/100 000, but the APC of ASR was 1.69% ( P< 0.001) . The ASR increased 0.54% ( P= 0.029) per year in urban from 29.71/100 000 to 30.55/100 000 and 3.93% ( P< 0.001) in rural areas from 24.02/100 000 to 35.79/100 000. The incidence ratio of urban to rural decreased from 1.24 to 0.85 (APC=-3.29%, P< 0.001). The incidence ratio of male to female decreased from 1.84 to 1.69 (APC=-0.45%, P= 0.019).The average age of lung cancer incidence of male and female increased from 66.27 and 66.00 to 68.97 and 69.11 ( P< 0.001), respectively. Conclusion: The incidence rate of lung cancer increased slightly in urban areas but increased significantly in rural areas during 2000-2012, the area ratio trend was declined. The average age of lung cancer occurrence gradually increased, but the temporal trends varied with age group. The gender ratio decreased from 2000 to 2012.

An in-situ paddy field experiment was carried out to study the influence of a tribasic amendment (QFJ, hydroxyapatite+zeolite+biochar) on Cd and As accumulation and translocation in rice grown in soil contaminated with cadmium and arsenic, with the concentrations of soil Cd and As being 3.58 mg·kg -1 and 124.79 mg·kg -1 , respectively. The results showed that, after application of QFJ, the pH, CEC, and OM contents of the rice rhizosphere soil tended to increase. The exchangeable concentrations of Cd and As were reduced from 0.37 mg·kg -1 and 0.07 mg·kg -1 to 0.12 mg·kg -1 and 0.04 mg·kg -1 , respectively. The concentrations of Cd and As in rice tissues decreased after in-situ restoration. When 9.00 t·hm -2 of QFJ was applied, the Cd concentration in brown rice was reduced from 0.46 to 0.18 mg·kg -1 , and that of inorganic As was reduced from 0.25 to 0.16 mg·kg -1 , both lower than 0.2 mg·kg -1 , meeting the requirement set by the National Food Standards (GB 2762-2012). QFJ application decreased the Cd and As bioaccumulation capacity of the roots and decreased the rice plant's capacity of Cd translocation quantity from the underground parts to the aerial parts; at same time, the Cd transferring capacity of the roots and the As transferring capacity in straw and husk were also decreased.

Objective: To study the effects of surgical reconstruction of the lateral ligament complex for posterolateral rotatory instability (PLRI) of the elbow joint., Methods: From January 2013 to January 2015, 20 patients with posterolateral rotatory instability of elbow joint were treated in our department. There were 12 males and 8 females whose age ranged from 30 to 60 years old, with an average age of 45.5 years old. Sixteen patients had injuries on the right side and 4 patients had injuries on the left side. Nine patients were caused by elbow dislocation and 6 cases were caused by elbow fracture. Five patients had no history of trauma. All the patients had closed injuries. According to the patient's history, physical examination and preoperative X-ray and MRI examination, a definite diagnosis was made. All the patients were treated conservatively for more than 2 months without efficacy, and they were treated with reconstruction of the lateral collateral ligament complex using palmaris longus tendon as a reconstruction graft under general anesthesia. Individual rehabilitation exercises were carried out according to the patient's condition., Results: All the patients were followed up, and the duration ranged from 12 to 23 months(mean, 16 months). There were no complications such as infection and obvious limitation of elbow joint. The HSS score of all the patients was improved from preoperative 75.2±8.3 to postoperative 94.1±5.4; and the VAS score was improved from preoperative 6.7±3.2 to postoperative 2.3±1.5., Conclusions: The lateral cubital ligament complex is the most important limiting structure for the posterolateral rotatory instability of the elbow joint. Reconstruction of the lateral ligament complex is an effective method for the treatment of posterolateral rotatory instability of the elbow joint., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.

Objective: To evaluate the incidence and mortality status of thyroid cancer in China, 2013. Methods: Incidence and mortality data of thyroid cancer were derived from 255 population-based cancer registries in China. Age-specific and age standardized incidence and mortality rates of thyroid cancer in different areas (urban and rural) with different gender were calculated based on the stratification of area (urban and rural), gender, age and tumor position. Chinese census in 2000 and the world Segi's population were used for age-standardized incidence/mortality rates. The incident cases and deaths were estimated using age-specific rates and national population data in 2013. Results: The estimates of new cancer incident cases and deaths were 143.9 thousand and 6 500, respectively. The crude incidence rate was 10.58/100 000 (Male 5.12/100 000, Female 16.32/100 000). Age-standardized incidence rates by Chinese standard population (ASIRC, 2000) and by world standard population (ASIRW) were 8.82/100 000 and 7.67/100 000, respectively. Male to female ratio was 1∶3.2. The crude incidence rate in urban and rural areas were 15.03/100 000 and 5.41/100 000, respectively. After adjustment by China standard population, the rate in urban areas was 2.57 times higher than that of rural areas. The crude mortality rate of thyroid cancer was 0.48/100 000 (Male 0.33/100 000, Female 0.63/100 000). Age-standardized mortality rates by Chinese standard population (ASIRC, 2000) and by world standard population (ASIRW) were 0.33/100 000 and 0.32/100 000, respectively. The crude mortality rate in urban and rural areas were 0.57/100 000 and 0.38/100 000, respectively. After adjustment by China standard population, the rate in urban areas was 1.41 times higher than that of rural areas. The cumulative incidence and mortality rates (0-74 years old) were 0.74% and 0.03%, respectively. According to the data from 255 cancer registries, papillary carcinoma is the main pathology type, which accounted for 89.9% of all malignant tumors. Conclusions: The disease burden of thyroid cancer in urban areas is higher than that in rural areas. Females have the higher incidence rate than that of males. The reasons related to the higher incidence rate of thyroid cancer should be further investigated to provide evidence for appropriate cancer control strategies and policies to be made in China.

Objective: To analyze the incidence trends and to describe the characteristics of soft tissue sarcoma (STS) among residents in Beijing from 1999 to 2013. Methods: Medical information of the cases diagnosed as STS(ICD10: C47&C49) from 1999 to 2013 in Beijing was extracted from the population-based database of Beijing Cancer Registry.Crude incidence rate, age-standardized incidence rates to Chinese population (ASRC)and the world population(ASRW) were calculated. The characteristics of the STS cases in different gender and age groups from urban and rural areas were respectively analyzed.The incidence trends and annual percentage changes (APC) during last 15 years were analyzed by using JoinPoint 3.4.3 software. Results: A total of 2 048 cases were diagnosed as STS during the study period and the incidence rate of STS was 1.15 per 100 000 person-years. The ASRC was 0.74 per 100 000 person-years and ASRW was 0.86 per 100 000 person-years, respectively. Except for the impact of changes in the age composition, the APC of ASRW from 1999 to 2013 was 3.95%. For males, the incidence rate was increased from 0.65 per 100 000 in 1999 to 1.51 per 100 000 in 2013, and the APC was 4.27% ( P <0.05); For females, the incidence rate was increased from 0.61 per 100 000 in 1999 to 0.91 per 100 000 in 2013, and the APC was 3.38% ( P <0.05). In urban area, the incidence rate increased from 1.14 per 100 000 in 2000 to 1.35 per 100 000 in 2013, and the APC was 2.70% ( P =0.05); In rural area, the incidence rate increased from 0.57 per 100 000 in 2000 to 0.98 per 100 000 in 2013, and the APC was 4.66% ( P =0.04). 85.89%cases were pathologically diagnosed.Among them, undifferentiated pleomorphic sarcoma was the most common subtype, which accounting for 19.22%, followed by liposarcoma (19.04%), malignantnerve sheath tumor (10.18%), fibrosarcoma (10.06%)and sarcoma without definite type(7.22%). Conclusions: The incidence rate of STS is still increasing, especially in the rural area of Beijing. The most common subtypes of STS in different age-groups were different. Further study is needed to explore the high risks of STS in the population with specific characteristics.

Objective: To understand the characteristics of Mycobacterium tuberculosis (MTB) in epidemiology and distribution from Guangdong Province, and to explore the risk factors associated with drug resistance. Methods: A total of 225 clinical strains of MTB collected from 5 drug resistance monitoring sites of Guangdong Province in 2015 were tested by Regions of Difference 105 (RD105) deletion test and 15 loci mycobacterial interspersed repetitive units (MIRU) were used for genotyping. Gene clustering was analyzed using BioNumerics7.6. Drug susceptibility test was tested by proportion method. The statistical analysis used chi-square test and multivariate logistic regression. Results: There were 158 (70.2%) Beijing family strains from the 225 cases. Hunter-gaston index of MIRU loci varied from each other. The MTBs from Guangdong Province were categorized into 2 gene clusters by clustering analysis in which the rate of cluster of complexⅠwas significantly higher than complexⅡ(χ(2) values were 9.331, P values were 0.020). It was found by multivariate logistic regression that Qub11b was associated with resistance to rifampicin and isoniazid ( P values were 0.013, 0.012 respectively.), ETR F with resistance to isoniazid, streptomycin, ethambutol and ofloxacin ( P values were 0.039, 0.040, 0.023 and 0.003 respectively), Mtub21 with resistance to capreomycin ( P values were 0.040), and QUB26 with resistance to ethionamide ( P values were 0.047). Conclusions: The genes of MTB from Guangdong Province were of polymorphisms and the distribution of strains were stable. QUB11b, ETR F, Mtub21 and QUB26 could be related to biomarkers for predicting drug resistance.

Objective: To analyze the associations between molecular subtypes and overall breast cancer survival among premenopausal and postmenopausal breast cancer in Beijing, and to provide basic information for breast cancer clinical researches and control. Methods: All the resident patients diagnosed with breast cancer in four well-established hospitals were retrieved from Beijing cancer registry, related information, such as TNM stages, receptor status, histological grade, height, weight, were collected by case extraction. Cancer registration information and population-based follow-up information were used to acquire survival outcome. All the patients were followed up until 31 December 2015, 4 531 cases with invasive, primary breast were included in the final analysis. All the cases were classified into Luminal and non-Luminal according to receptor status. Five-year survival rates of the two subtypes were estimated by the life-table method. Multivariable Cox proportional hazards models were employed to evaluate the associations between molecular subtypes and breast cancer survival. Results: Of all the 4 531 patients, premenopausal patients accounted for 44.5% (2 017 cases) and postmenopausal patients accounted for 55.5% (2 514 cases). 643 cases died during the study period. Overall five-year survival was 89.5% (95 %CI: 88.6%-90.4%), for premenopausal and postmenopausal patients, they were 92.1% (95 %CI: 90.9%-93.3%), and 87.5% (95 %CI: 86.2%-88.8%), respectively. Among all the patients, 3 730 patients had molecular subtype, 76.7% (2 861 cases) were Luminal breast cancer, and 23.3% (869 cases) were non-Luminal breast cancer. Five-year survival rates for Luminal and non-Luminal were 91.8% (95 %CI: 90.8%-92.8%), and 83.2% (95 %CI: 80.7%-85.7%), respectively. No matter in premenopausal or postmenopausal patients, non-Luminal breast cancer had significantly higher risk of death compared to Luminal breast cancer (premenopausal: HR= 1.85, 95 %CI: 1.26-2.73; premenopausal: HR= 1.42, 95 %CI: 1.07-1.88). Conclusion: For both premenopausal and postmenopausal breast cancer patients, non-Luminal breast cancer had lower five-year survival rates than Luminal breast cancer, which was a risk factor on breast cancer survival.

Objective: To analyze the pathogenesis, clinical features, diagnosis and differential diagnosis of primary perivascular epithelioid cell tumor(PEComa). Methods: The clinical features, auxiliary examinations and diagnosis of a case with rapidly progressive pulmonary malignant PEComa were reported and the related literatures were reviewed.The literature review was carried out respectively in Wanfang Data, CNKI and PubMed from Jan. 1975 to Jul. 2015 with "pulmonary malignant perivascular epithelioid cell tumor" and "PEComa" being the search terms. Results: A 50 year-old female patient was admitted to the hospital on September 4, 2014 because of cough and dyspnea for 60 days, hemoptysis for 40 days and fever for 7 days.Chest CT scan showed diffuse small nodules with infiltrative border and multiple pure and mixed ground-glass opacity. Transbronchial lung biopsy (TBLB) was performed and the pathological study confirmed the diagnosis of primary pulmonary malignant PEComa. The patient declined further specific therapy, but followed by rapidly progressive respiratory failure, and died two weeks after the diagnosis. A total of 8 literatures were retrieved from Wanfang Data, CNKI and PubMed and all of them were case reports.There were 3 male and 5 female patients, aging from 50 to 79 years.Radiographically, the previously reported cases presented as round and well-circumscribed masses with or without multiple nodules in both lungs. The symptoms had no specificity. Conclusions: Pulmonary malignant PEComa is a rare disease.It is easily misdiagnosed because of non-specific clinical and imaging manifestations.The final diagnosis depends on pathological biopsy.TBLB is an effective diagnostic method.

Objective: To identify a novel human leukocyte antigen (HLA) allele HLA-B*13:92 and analyze 3D model of HLA molecule., Methods: Polymerase chain reaction sequencing-based (PCR-SBT) was used in routine HLA typing, the B locus typing results of one sample was one base mismatch with B*13:01:01, B*58:01:01 at locus 189, The Group Specific Sequencing Products (GSSP) which target at B*13 and B*58 were used to confirm difference between the new allele and highest homologous allele, then the new allele was modeled by Swiss-model to its 3D structure., Results: The sequencing results showed that the new allele with highest homologous allele B*13:01:01 was the difference in the second exon at position 189 C>A (codon 39 GAC>GAA), 39 Asp (D) was changed to Glu (E). The amino acid substitution at residue 39 of the HLA polypeptide was located in α-helices of antigenic peptide-biding region., Conclusion: This allele is a new HLA-B allele found in Chinese Guangxi Zhang population and has been designated as HLA-B*13:92 by the World Health Organization (WHO) HLA Nomenclature Committee.

Objective: To summarize the experience in the diagnosis and treatment of refractory hematospermia and ejaculatory duct obstruction by seminal vesiculoscopy., Methods: We retrospectively analyzed the clinical data about 42 cases of refractory hematospermia and 6 cases of ejaculatory duct obstruction with azoospermia. We investigated the diagnosis, treatment, and prognosis of the diseases., Results: All the patients underwent pelvic MRI and seminal vesiculoscopy. MRI for the 42 refractory hematospermia patients showed that 21 (50.0%) had cystic dilatation in the uni- or bilateral seminal vesicles, 25 (59.5%) had abnormal internal signal intensity in the uni- or bilateral seminal vesicles, 12 (28.6%) had both the problems above, and 4 (9.52%) had no obvious abnormality in the seminal vesicle area. The bilateral seminal vesicles were <1 cm in width in 3 of the 6 cases of ejaculatory duct obstruction, and obviously enlarged in the other 3, but without abnormal internal signals. No recurrence was found during the 3－36 months follow-up., Conclusions: The history and physical examination play important roles in the diagnosis of refractory hemospermia, and MRI is more valuable than TRUS in the diagnosis of seminal vesicle diseases. Seminal vesiculoscopy is an effective option for the management of persistent hematospermia and ejaculatory duct obstruction.

The aim of the present study was to investigate the effects of minocycline on cognitive functions in neonatal rat after hypoxia exposure and the underlying mechanism. A model of hypoxic brain damage (HBD) was developed by exposing postnatal 1 day (P1) rats to systemic hypoxia. The rats were intraperitoneally injected with normal saline (Hy group) or minocycline (Hy + M group) 2 h after hypoxia exposure. Some other P1 rats that were not subjected to systemic hypoxia were used as normal control (NG group). The Y-maze test was used to evaluate learning and memory ability on postnatal day 30. Inflammatory mediators (Iba-1, IL-1β, TNF-α and TGF-β1), glutamate transporters (EAAT1 and EAAT2), total Tau and phosphorylated Tau (phosphorylation sites: Tyr18, Thr205, Thr231, Ser396 and Ser404) protein expressions in the hippocampus were detected by Western blot 7 d after hypoxic exposure. The results showed that hypoxia induced learning and memory impairments of the neonatal rats, and minocycline administration could reverse the effects of hypoxia. The protein expression levels of Iba-1, IL-1β, TNF-α, EAAT2 and Tau phosphorylated at T231 were increased, but the total Tau expression was decreased in the hippocampus of the rats from Hy group 7 d after hypoxia exposure. In the hypoxia-treated rats, minocycline down-regulated Iba-1, IL-1β, TNF-α and EAAT2 protein expressions significantly, but did not affect total Tau and phosphorylated Tau protein expressions. Our results suggest that minocycline can prevent cognitive deficits of rats with hypoxia exposure, and the underlying mechanism may involve the inhibition of neuroinflammation and dysfunctional glutamate transporters but not the regulation of the Tau hyperphosphorylation.

The two-dimensional model of cell culture is an important method in the study of testicular development and spermatogenesis but can not effectively mimic and regulate the testicular microenvironment and the whole process of spermatogenesis due to the lack of relevant cell factors and the disruption of a three-dimensional spatial structure. In the past 20 years, the development and optimization of the in vitro model such as testis organotypic culture and in vivo model such as testis transplantation achieved a transformation from two- to three-dimension. The maintenance and optimization of the testicular niche structure could mimic the testicular microenvironment and cell types including Leydig, Sertoli and germ cells, which showed similar biological behaviors to those in vivo. Besides, the cell suspension or tissue fragment floats in the gas-liquid interface so that the development of somatic and germ cells is well maintained in vitro whilst the feedback linkage between grafted testis tissue and hypothalamus-pituitary of the host rebuilt in the in vitro model provides an endocrinological basis for spermatogenesis, which serves as an effective methodology to better understand the organogenesis and development of the testis as well as testicular function regulation, advancing the concept of treatment of male infertility. Al- though each of the methods may have its limitations, the progress in the processing, freezing, thawing, and transplantation of cells and tissues will surely promote their clinical application and present their value in translational medicine.

Soil moisture variation in dryland sloping jujube. orchard was investigated after introducing two economic crops, i.e., feed Brassica napus (JR) and Hemerocallis fulva (JH) planted between jujube rows. Jujube tree without inter-row crop was set as control (CK). The results showed that mean soil moisture for JR and JH in the 0-180 cm soil layer increased by 6.2% and 10.1% compared with CK, respectively. Soil moisture changed mainly in the 0-60 cm soil layer in growth stage of Jujube trees. Soil moisture in JR and JH treatments significantly increased in the 0-60 cm soil layer, which could meet the demand in water resource of jujube plantation. The water consumption of jujube trees also mainly concentrated in the 0-60 cm soil layer. There was a significant decay exponential relationship between the soil moisture in the 0-20 cm layer and the drought duration after rainfall. During the 18-day dry period after rain, the soil moisture contents of JR and JH were apparently higher than that of CK. In conclusion, the jujube-crop intercropping system improved the soil moisture condition. It was an effective measure to overcome the seasonal drought in jujube orchards on the loess hilly region.

Objective: To study the effect of Modified Guipi Decoction (MGD) on blood pressure and quality of life (QOL) in hypertension patients complicated depression., Methods: Totally 245 hypertension patients complicated depression were randomly assigned to the treatment group (125 cases, treated with MGD) and the control group (120 cases, treated with Sertraline). Final recruited qualified patients were 117 cases in the treatment group and 111 cases in the control group. The therapeutic course for all was 4 weeks. Changes of blood pressure, scores rated by Hamilton Depression Scale-17 (HAMD-17), Hamilton Anxiety Rating Scale (HAMA), short-form 36 health survey questionnaire (SF-36), and Treatment Emergent Symptom Scale (TESS) were observed before and after treatment, thereby judging their efficacies., Results: (1) Compared with before treatment in the same group, systolic and diastolic blood pressures significantly decreased in the treatment group after 2 weeks of treatment; systolic blood pressure significantly-decreased after 2 weeks of treatment and diastolic blood pressure significantly decreased after 3 weeks of treatment in the control group (all P < 0.05, P < 0.01). Decreased valley values of systolic and diastolic blood pressures at week 2, 3, and 4 after treatment were obviously higher than those at week 1 after treatment in the two groups (P < 0.05, P < 0.01). Compared with the control group at week 4 after treatment, valley value of systolic blood pressure obviously decreased in the treatment group (P <0. 01). Decreased valley values of systolic and diastolic blood pressures in the treatment group were higher than those of the control group (P <0. 01). The success rate of target blood pressure was 60. 7% (71/117 cases) in the treatment group and 42. 3% (47/111 cases) in the control group, with statistical difference (χ² = 7.6781, P < 0.01). (2) Compared with before treatment in the same group, the score of HAMD-17 at week 2, 3, and 4 after treatment all decreased in the two groups (P < 0.01). Compared with the control group, the score of HAMD-17 at week 4 after treatment decreased more obviously in the treatment group, with higher difference in decreased value (P < 0.05). The effective rate was 79.5% (93/117) in the treatment group, higher than that in the control group [66.7% (74/111); χ² = 4.7741, P < 0.05]. (3) Compared with before treatment in the same group, the score of HAMA at week 1, 2, 3, and 4 after treatment all obviously decreased in the two groups (P <0. 05, P <0. 01). Compared with the control group, the score of HAMA at week 3 and 4 after treatment decreased more obviously in the treatment group, with higher difference in decreased value (P < 0.05, P < 0.01). (4) After 4 weeks of treatment, except physical function in the control group, SF-36 total score and the score for each factor were obviously higher in the two groups (P < 0.05, P < 0.01). MGD showed superior effect in improving physical function, physical activity, overall health, emotion activity, and health changes to that of Sertraline (P < 0.05, P < 0.01). (5) The incidence of insomnia, tremor, liability to agitation, dizziness was obviously less in the treatment group than in the control group (P < 0.05)., Conclusions: MGD had favorable clinical effect on hypertension patients complicated depression. Meanwhile, it also could improve their blood pressure and QOL.

Objective: To study the supercritical CO2 fluids extraction (SFE) method to extract the components from Taxus yunnanensis., Methods: Medicinal meterials were extracted by supercritical CO2, and then purified by industrial chromatography. Using the extraction yield of 10-DAB as the index,single factor test was carried out to investigate the effect of co-solvent, extraction time, extraction pressure, extraction temperature, pressure and temperature of separation kettle I. Then orthogonal experiment was used to optimize the best extraction condition., Results: The suitable extraction condition was as follows: the ratio of co-solvent (80% ethanol) amount and the madicinal materials was 3: 1, Separation kettle I pressure was 14 MPa, separation kettle I temperature was 40 °C, extraction pressure was 25 MPa, extraction temperature was 60 T and extraction time was 90 min. The extract was separated by industrial chromatographic and then crystallized., Conclusion: The supercritical CO2 extraction and purification process of 10-DAB were simple and feasible.

In this study, UPLC-MS/MS was adopted to determine the contents of five ephedrine alkaloids (Norephedrine, Norpseudoephedrine, Ephedrine, Pseudoephedrine, Methylephedrine) in plasma and urine in rats after the combined administration of Ephedrae Herba-Gypsum Fibrosum and calculate relevant pharmacokinetic parameters, in order to discuss the effect of the combined administration of Ephedrae Herba-Gypsum Fibrosum on plasma pharmacokinetics and urinary excretion characteristics. According to the results, after being combined with Gypsum, the five ephedrine alkaloids showed similar pharmacokinetic changes, such as shortened t(max), accelerated absorption rate, but reduced AUC(0-t) and V(z)/F, which may be related to the increase in urine excretion. Besides, Gypsum was added to enhance C(max) of Pseudoephedrine and prolong MRT(0-t) of Methylephedrine, so as to enhance the anti-asthmatic effect of Ephedrae Herba and resist the toxic effect of Norephedrine and Ephedrine. This study proved the scientific compatibility of Ephedrae Herba-Gypsum Fibrosum and provided a reference for studies on the prescription compatibility regularity and relevant practices.

Objective: Five kinds of Ephedra alkaloids (NME, NMP, E, PE and ME) in Ephedrae Herba extracts and Ephedrae Herba-Atractylodis Macrocephalae Rhizoma herbal pair extracts of plasma pharmacokinetic and tissue distribution study in rats were carried out, to discuss the changes of Ephedrae Herba compatibility with Atractylodis Macrocephalae Rhizoma before and after, Methods: HPLC- MS method was used and the condition was as flollows: ZORBAX SB-C18 column (100 mm x 2.1 mm, 3.5 µm), column temperature of 35 °C, mobile phase of ACE-0.1% formic solution in gradient elution mode, flow rate at 0.4 mL/min; MRM positive ion detection mode., Results: The distribution trends of Ephedra alkaloids were changing in plasma and tissues of rats after Ephedrae Herba compati- bility with Atractylodis Macrocephalae Rhizoma., Conclusion: Ephedrae Herba compatibility with Atractylodis Macrocephalae Rhizoma may increase drug efficacy and reduce the toxicity of Ephedra alkaloids at the same time.

Soil moisture is a key factor affecting jujube growth in the semiarid Northern Shaanxi Province. The impacts of different engineering and mulching measures on soil moisture were investigated via in situ measurements in a typical dryland jujube orchard. The results showed that the mean soil moistures (0-180 cm) of scale-like pit + branch mulching, scale-like scale + straw mulching, and soil moisture of scale-like pit with no mulching were increased by 14.2%, 9.4%, and 4.8% than control, respectively. Different measures, especially for the scale-like pit + branch mulching, significantly increased the soil moisture in the soil surface (0-20 cm) and the main root zone layer (20-100 cm) during the jujube growth stage. Individual precipitation events had great impacts on soil moisture in the 0-100 cm, while its effect on soil moisture in deep layers was not apparent. There was no significant difference among the soil moistures in different soil depths of scale-like pit with no mulching when compared with the control under high, medium, and low soil humidity conditions. This study indicated that using the clipped jujube branches as mulching could both save materials cost and achieve the goal of reserving more water in dryland jujube orchard in north Shaanxi Province.

In order to have a better understanding of the species diversity of medical plants in Enshi, Hubei of China, extensive field investigations and specimen collections were conducted in Enshi and adjacent regions. Based on field observations of plants in their living habitats and comparative morphological studies on specimens in herbarium of Hubei minzu University and other available herbaria as well, three new records of medical plants in Hubei, Scutellaria yunnanensis, Alangium faberi var. heterophyllum, and Drymaria diandra, were reported in this paper.

Objective: To investigate the protective effect of hypothermia combined with dexamethasone on spermatogenesis and the expression of intercellular adhesion molecule 1 (ICAM1) after testicular torsion-detorsion., Methods: We made unilateral testicular torsion models in 100 pubertal male Sprague-Dawley rats by 720 degree torsion of the left testis and then randomly divided them into four groups of equal number to be treated with normal temperature + physiological saline (group A), hypothermia + physiological saline (group B), normal temperature + dexamethasone (group C), and hypothermia + dexamethasone (group D). After 48 hours, we collected the testes, observed pathological changes of the testicular tissue by HE staining under the light microscope, detected the apoptosis of spermatogenic cells by TUNEL, and determined the expression of ICAM1 by Western blot., Results: HE staining showed different degrees of testicular tissue injury in the four groups of rats, most obvious in group A, but mild in the other three. The ICAM1 protein expression was significantly higher in group A (0.68 +/-0. 03) than in B (0. 49 +/- 0. 06, P <0. 05) , C (0. 46 +/- 0. 09, P < 0.05) , and D (0.17 +/- 0.08, P <0.01). The nuclei were deep brown or brown. Lots of apoptotic spermatogenic cells were seen in the torsion testis of group A, with a significantly higher apoptosis index ( [33. 13 +/- 3.21 ]%) than in B ( [ 17. 12 +/-5.23 ]%, P < 0.05), C ([14.13 +/- 2.03]%, P <0.05), and D ([9.05 +/- 1.03]%, P <0.01)., Conclusion: Hypothermia combined with dexamethasone can protect the testis from injury as well as the reproductive function of the testis after testicular torsion-detorsion and reduce the expression of ICAM1.