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Mild cognitive impairment (MCI) is an unstable cognitive impairment state between normal aging and Alzheimer's disease (AD). The symptoms of MCI are mild and it has four different types of outcomes: reversing normal, maintaining stability, progression and death. However, 2/3 of MCI patients may still progress to dementia. Therefore, early identification of stable MCI (sMCI) and progressive MCI (pMCI) is beneficial for timely intervention, and delaying the progression of MCI, then improving patients' quality of life. Structural magnetic resonance imaging (sMRI) can predict dementia related neurodegeneration and cognitive decline. A large number of studies have found that, in addition to abnormalities in clinical scales, there are significant changes in sMRI during the progression of sMCI to pMCI, mainly including differences in cortical thickness and brain atrophy, hippocampal volume, and structural brain network connectivity. Especially, machine learning methods such as big data based neural convolutional networks are helpful in early prediction of sMCI and pMCI. These studies contribute to the discovery of early imaging markers for the conversion of sMCI to pMCI.
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Objective@#On the basis of the dominant frequency index of functional connectivity, the "brain age" analysis method was used to explore abnormal development patterns of sensorimotor networks in boys with autism spectrum disorder(ASD).@*Methods@#The resting state functional magnetic resonance data (7-12 years old) for 105 boys with ASD and 102 matched boys with normal development from the ABIDE public database were screened. Functional connection networks in different frequency bands of sensorimotor related brain regions were constructed for each individual, and the frequency of the strongest connection were constructed as the optimal frequency of the connection. Brain age analysis was used to explore the difference between brain age and chronological age in boys with ASD.@*Results@#The brain sensorimotor network of boys with ASD showed an abnormal development pattern of overdevelopment followed by underdevelopment, and the transition between the two patterns occurred at approximately 7.8 years of age. Older boys with ASD (older than 10 years) whose underdevelopment trend was suppressed had lower ASD severity( r=-0.43, P < 0.05 ).@*Conclusion@#The brain sensorimotor network in boys with ASD has an abnormal development process, and the brain chronological age difference in the sensorimotor network has potential as a neuroimaging marker to measure the development of ASD.
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This study employed bibliometrics tools to review the studies of traditional Chinese medicine(TCM) treatment of Alzheimer's disease(AD) in recent ten years, aiming to explore the research status, hotspots, and future trends in this field at home and abroad. The relevant literature published from January 1, 2012 to August 15, 2022 was retrieved from Web of Science and CNKI. CiteSpace 6.1R2 and VOSviewer 1.6.15 were used for the visual analysis of authors, countries, institutions, keywords, journals, etc. A total of 2 254 Chinese articles and 545 English articles were included. The annual number of articles published showed a rising trend with fluctuations. The country with the largest number of relevant articles published and the largest centrality was China. SUN Guo-jie and WANG Qi were the authors publishing the most Chinese articles and English articles, respectively. Hubei University of Chinese Medicine and Beijing University of Chinese Medicine published the most articles in Chinese and English, respectively. Journal of Ethnopharmacology and Neuroscience Letters published the articles with the highest cited frequency and the highest centrality. According to the keywords, the research on TCM treatment of AD mainly focused on the mechanism of action and treatment methods. Metabolomics, intestinal flora, oxidative stress, tau hyperphosphorylation, β-amyloid(Aβ), inflammatory cytokines, and autophagy were the focuses of the research on mechanism of action. Acupuncture, clinical effect, kidney deficiency and phlegm stasis, and dredging governor vessel to revitalize mind were the hotspots of clinical research. This research field is still in the stage of exploration and development. Exchanges and cooperation among institutions should be encouraged to carry out more high-quality basic research on TCM treatment of AD, obtain high-level evidence, and clarify the pathogenesis and prescription mechanism.
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Humanos , Doença de Alzheimer/tratamento farmacológico , Medicina Tradicional Chinesa , Terapia por Acupuntura , Medicina , Peptídeos beta-AmiloidesRESUMO
Objective: The survival rate of gastric cancer cases in the whole population of Qidong City of Jiangsu Province from 1972 to 2016 was analyzed to provide a data basis for prevention and control of gastric cancer. Methods: The observed survival rate (OSR) was calculated by the life table method, the relative survival rate (RSR) was calculated by SURV 3.01 software, and the trend test was performed by Hakulinen's likelihood ratio test. Age-standardized relative survival rate (ARSR) was calculated using the International Cancer Survival Standard (ICSS). The Joinpoint regression model was used to calculate the average annual percentage change (AAPC) of survival rate, and the trend analysis of the overall survival rate of gastric cancer and the survival rates of different sexes and ages was conducted. The ARIMA model was used to predict the survival rate. Results: From 1972 to 2016, there were 18 067 new cases of gastric cancer in Qidong City. The OSRs at 1, 5, and 10 years were 37.12%, 17.16%, and 12.86%, respectively, and the RSRs at 1, 5, and 10 years were 38.83%, 21.73%, and 21.20%. Dividing 1972-2016 into 9 periods at 5-year intervals, compared with 1972-1976, the 5-year RSR in 2012-2016 increased from 12.53% to 36.26%, and the RSR in the 9 periods increased with statistical significance (χ(2)=747.19, P<0.001). Both OSR and RSR were slightly higher in men than in women, and decreased with age. The AAPC results showed that the AAPC of the 5-year RSR of gastric cancer in Qidong was 2.88%, 2.75% in males and 3.05% in females, and the upward trend was statistically significant (P<0.001). From 1972 to 2016, the 5-year RSR of gastric cancer in all age groups showed an upward trend. Except for the 35-44-year-old group (AAPC=1.07%, t=2.16, P=0.067), the age groups had statistical significance ( AAPC=2.59% in the 45-54-year-old group, AAPC=3.19% in the AAPCs of other 55-64-year-old group, AAPC=3.99% in the 65-74-year-old group, and AAPC=2.97% in the 75-year-old group, all P<0.05). The prediction results of the ARIMA model showed that in 2026, the 5-year OSR of gastric cancer in Qidong will increase to 39.82%, and the 5-year RSR will increase to 49.23%. Conclusion: The overall survival rate of registered gastric cancer cases in Qidong has been greatly improved, but there is still large room for improvement. More attention should be paid to the prevention and treatment of gastric cancer.
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Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , China/epidemiologia , Incidência , Software , Neoplasias Gástricas , Taxa de SobrevidaRESUMO
@#Abstract: The loop-mediated isothermal amplification (LAMP) technique is a technique for the specific and efficient amplification of target fragments at a constant temperature using two pairs of specially designed primers and a strand displacement activity DNA polymerase. LAMP technique is a simple, rapid, specific, sensitive and cost-effective nucleic acid amplification method, and therefore has a promising future in the field rapid detection of Mycobacterium tuberculosis and grassroots applications. In this review, the basic principles and characteristics of the LAMP technique, the main molecular markers for the diagnosis of tuberculosis, and the use of different molecular markers and various types of novel techniques in the diagnosis of pulmonary tuberculosis, extrapulmonary tuberculosis, and drug-resistant tuberculosis were described. The LAMP technique has been widely used in the diagnosis of tuberculosis with high sensitivity and specificity, but the technique still has some shortcomings. This paper reviews the progress of its application in tuberculosis in recent years and provides an outlook on its development, with a view to providing a rational research direction for rapid diagnosis of tuberculosis in a resource-limited environment.
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Ovarian cancer has the characteristics of difficulty in early diagnosis, easy recurrence and resistance, so its mortality rate ranks first in gynecological tumors. Existing treatment methods such as surgery, radiotherapy and chemotherapy are not very effective, thus immunotherapy has emerged. Immune checkpoint programmed death-1 (PD-1) and its ligand PD-L1 can inhibit T cell proliferation and mediate tumor immune escape. At present, PD-1/PD-L1 inhibitors have made breakthrough progress in a variety of solid tumors, and they have achieved initial efficacy in clinical treatment of ovarian cancer.
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Focusing on the diversified training environment of the Chinese navy and the peculiar injuries of the soldiers, we created a navy military medical geography information system based on ArcGIS two-dimensional development platform by using the large sample survey data of a certain naval medical support unit. This established system can link the naval injury data, civilian and military health resources and spatial geographic data, contributing to the monitoring and early warning of the navy injury, information management of medical resources, and decision-making in medical support.
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Cytotoxic anti-tumor drugs are characterized by narrow therapeutic indexes, severe toxicity and great difference in the effects of individualized therapies, while studies of pharmacogenomics (PGx) can provide biomarkers for predicting the efficacy and toxicity of chemotherapy drugs. PGx biomarkers play an important role in predicting the safety, toxicity and effects of drugs in the treatment of tumors. By identifying specific polymorphisms of PGx biomarkers, physicians could select and customize medication regimens based on the patient's genetic profile. This review focuses on the germline PGx biomarkers that are currently used for guiding therapeutic decisions and have potential clinical application values, including thiopurine S-methyltransferase and thiopurine, NUDT15 and thiopurine, UGT1A1 and irinotecan, DPYD and fluorouracil, CYP2D6 and tamoxifen, and TPMP and cisplatin.
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Atherosclerosis is an immune-mediated inflammatory disease of the arterial wall, with both the innate and adaptive immune systems responding to many endogenous and exogenous antigens. Both proatherogenic as well as atheroprotective roles have been identified for the immune system in atherosclerosis. Hence, it is conceivable that an immuno-modulatory strategy via active immunization against many of these antigens could potentially alter the natural history of atherosclerosis. Cholesterol ester transfer protein (CETP) plays an important role in lipid metabolism, suggesting it might prevent atherosclerosis. This review discusses the recent advances of vaccine targeting the development of atherosclerosis, mainly about the CETP targeting vaccines.
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Atherosclerosis is an immune-mediated inflammatory disease of the arterial wall,with both the innate and adaptive immune systems responding to many endogenous and exogenous antigens.Both proatherogenic as well as atheroprotective roles have been identified for the immune system in atherosclerosis.Hence,it is conceivable that an immuno-modulatory strategy via active immunization against many of these antigens could potentially alter the natural history of atherosclerosis.Cholesterol ester transfer protein (CETP) plays an important role in lipid metabolism,suggesting it might prevent atherosclerosis.This review discusses the recent advances of vaccine targeting the development of atherosclerosis,mainly about the CETP targeting vaccines.
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AIM:To evaluate the therapeutic effects of the fine sight training with the smartphones and pads on hyperopia amblyopia of children.METHODS:One hundred and twenty children (120 eyes) with hyperopia amblyopia were randomly divided into two groups in this prospective study.All the children in these two groups received the basic treatments of spectacle correction,penalization therapy and amblyopia trainings.The treatments of red-light blinking and grating as well as traditional fine sight training were used for the children in the control group.However,the smartphones and pads were applied instead of the traditional performances for the fine sight training in the experimental group.Best corrected visual acuity of every child was tested for every 3mo,to observe the time for the visual improvement and efficacy.RESULTS:In comparison with the control group,significant shorter time (80.54 ± 30.87d,P< 0.05) for promoted one line of LogMAR visual acuity and average treatment time (15.34±7.24mo,P<0.05) were harvested in the experimental group.The efficacy in the experimental group was significantly higher than that in the control group (Z=-2.37,P=0.02).CONCLUSION:The fine sight training with the smartphones and pads can improve vison faster than traditional methods and decrease the time of therapy in children with hyperopia amblyopia,thus providing a new strategy for the treatment of hyperopia amblyopia.
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OBJECTIVE To investigate how MLKL functions on the membrane and explore its electrophysiological characters and structure. METHODS The full-length human MLKL were expressed in SF21 cells and purified using glutathione-sepharose affinity chromatography. The currents of purified MLKL proteins were recorded in avoltage-clamp mode using a Warner BC-535 bilayer clamp amplifier. The currents were digitized using pCLAMP 10.2 software. HEK293 cells were cultured and transfected with MLKL plasmid. Cell viability was examined using the CellTiter- Glo Luminescent Cell Viability Assay kit. RESULT MLKL forms cation channels that are permeable preferentially to Mg2+ rather than Ca2+ in the presence of Na+ and K+. Moreover,each MLKL monomer contains five transmembrane helices:H1, H2, H3 , H5 and H6 of the N-terminal domain which is sufficient to form channels. Finally, MLKL-induced membrane depolarization and cell death exhibit a positive correlation to its channel activity.
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OBJECTIVE We want to investigate the mechanism of organophosphate- induced delayed neuropathy (OPIDN) and find appropriate therapeutic medicine. OPIDN, often leads to pares?thesias, ataxia and paralysis, occurs in the late-stage of acute poisoning or after repeated exposures to organophosphate (OP) insecticides or nerve agents, and may contribute to the Gulf War Syndrome. METHODS FDSS Ca2 +-influx assays, single-cell calcium imaging and patch-clamp electrophysiology were the major testing techniques. Transfected HEK293 cells and dorsal root ganglion (DRG) neurons were used to evaluate the effects of compounds. Wild type and trpa1 knockout mice and adult hyline brown hens were used to evaluate the neuropathological damages caused by the OPs. Transmission electron microscopy imaging was used to observe the nerve injuries ultrastructurally. High-throughput screen for TRPA1 inhibitors was accomplished by Ion Works Barracuda (IWB) automated electrophysiology assay. RESULTS TRPA1 (Transient receptor potential cation channel, member A1) channel mediates OPIDN. A variety of OPs, exemplified by malathion, activates TRPA1 but not other neuronal TRP channels. Malathion increases the intracellular calcium levels and upregulates the excitability of mouse DRG neurons in vitro. Mice with repeated exposures to malathion also develop local tissue nerve injuries and pain-related behaviors, which resembles the early symptoms of OPIDN. Both the neuropathological changes and the nocifensive behaviors can be attenuated by treatment of TRPA1 antagonist HC030031 or abolished by knockout of Trpa1 gene. In the classic hens OPIDN model, malathion causes nerve injuries and ataxia to a similar level as the positive inducer tri-ortho-cresyl phosphate (TOCP), which also activates TRPA1 channel. Treatment with HC030031 reduces the damages caused by malathion or TOCP. Duloxetine and Ketotifen, two commercially available drugs exhibiting TRPA1 inhibitory activity, show neuroprotective effects against OPIDN and might be used in emergency situations. CONCLUSION TRPA1 is the major mediator of OPIDN and targeting TRPA1 is an effective way for the treatment of OPIDN.
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@#Objective To explore the variation tendency and influencing factors of the hospitalization costs and hospital day of soldiers in a navy hospital,so as to provide reference for the health resource allocation of military hospitals.Methods The data of 16 278 military patients who were hospitalized and treated from Jan.2008 to Dec.2016 were extracted from the military health system.The hospitalization costs and status,variation tendency and influencing factors of hospital stay were analyzed by descriptive analysis,Mann-Whitney U test and Kruskal-Wallis H test.Results The average age of admission was (28.33± 13.40) years,and the hospitalization period showed a shortening trend,while the hospitalization costs showed an increasing trend during 2008-2016.The polytomous variables,including services,patient's condition,hospitalized times,hepatitis B surface antigen,hepatitis C antibody,human immunodeficiency virus (HIV) antibody,military appointment,age and outcomes,and the dichotomous variables,including severe condition,critical condition,ICU admission,special-grade nursing care,first-grade nursing care,allergies and operation,were the influencing factors of hospitalization expenses (P<0.05).The polytomous variables,including services,patient's condition,hospitalized times,HIV antibody,military appointment,age and outcomes,and the dichotomous variables,including gender,severe condition,critical condition,special-grade nursing care,first-grade nursing care and operation,were the influencing factors of hospitalization stay (P<0.05).Conclusion The decreasing hospitalization day of military patients and increasing hospitalization costs suggest that the medical technology and hospital management efficiency are continuously improving,but facing the pressure of increasing medical costs.From a cost-effective perspective,we should strengthen the graded referral and control hospitalization costs and length of hospital stay.
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Objective To evaluate the performance of diluted thrombin time (dTT) assay for detecting Dabigatran levels and observe whether this assay may meet the requirements of clinical laboratory.Methods According to EP15-A2,EP6-A,EP7-A and C-24 documents of the Clinical and Laboratory Standards Institute (CLSI),the precision,trueness,analytical measurement range,carryover rate and anti-biological interference of dTT assay were evaluated and the stability of specimen for dTT assay was observed.Results Both the within-day and between-day coefficient of variation (CV) of dTT assay for detecting Dabigatran levels were consistent with manufacturer's stated CV.Compared with target values of Dabigatran,the relative bias of 3 levels of proficiency test materials from College of American Pathologists (CAP) were less than 10%.The results meet linear verification when Dabigatran concentration was between 30.92 and 249.13 ng/mL.The carryover rate was-0.84%.There was no interference for Dabigatran levels by dTT assay for detecting Dabigatran when Hb≤3 g/L,triglyceride≤873 mg/dL,heparin≤2.2 IU/mL and FDP≤29 mg/L.The results of stability showed that plasma specimens for dTT could not be stored at room temperature more than 4 hours,at 4 ℃ more than 4 days,at-20 ℃ exceed 1 month,while at-80℃ the plasma specimens could be stored at least 6 months for dTT assay.Conclusion The precision,trueness,analytical measurement range,carryover rate,anti-biological interference of dTT assay may meet the requirement of clinical laboratory.The stability of the specimen can fulfill the clinical requirements.
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As it becomes normal for the PLA navy to sail to the open sea for training and the the multiple kinds of offshore military tasks it will face on the sea, the navy officers and soldiers will face more complicated health care problems, which brings greater challenges to the naval medical service support. In this review, we started from the problems in the medical service support; using the spatial analysis functions of geographic information' system (GIS), and designed a navalmedical service support GIS functional model, which included three functional modules: monitoring of the woundedand diseased, informationmanagement of naval medical service resource, and assistant decision-making for military medical service; and we also discussed the application of GIS in monitoring and early warning of the diseases, analysis and evaluation of risk factors, health resource allocation and decision-making support for health service.
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<p><b>OBJECTIVE</b>To investigate the effect of Xianxiong decoction on the mice with acute lung injury induced by lipopolysaccharide.</p><p><b>METHOD</b>Eighty female ICR mice were randomly divided into 8 groups: model group, Xianxiong decoction group, Daxianxiong decoction group, Xianxiong decoction group without Kansui Radix group, Xianxiong decoction group without Glycyrrhizae Radix et Rhizoma group, Glycyrrhizae Radix et Rhizoma and Kansui Radix group, normal group and control group. Animals of each group, except normal group, were undertaken intraperitoneal injection and intranasal inhalation of lipopolysaccharide (LPS) on day 1, 2, 3 to establish acute lung injury (ALI) model. 30 min after modeling, 0.2 mL corresponding drugs were administrated to each mice, dexam ethasone and normal saline were given to the mice of control group and normal group respectively. White blood cell in blood, neutrophil percentage of blood and bronchoalveolar lavage fluid (BALF) supernatant, the ratio of wet and dry lung tissue ( W/D), histopathological changes of lung tissue were estimated. Sixty ICR mice were randomly divided into normal, model, control, high, middle and low dose Xianxiong decoction groups and were modeled in the same way. ELISA was applied to detect the level of NF-kappaB, TNF-alpha and IL-6 in BALF, PCR for NF-kappaB and TNF-alpha mRNA in lung tissue, and Western blot for NF-kappaB and TNF-alpha. Half of 20 ICR mice were administrated with Xianxiong decoction of its maximum tolerant normal saline.</p><p><b>RESULT</b>Compared with model group, the number of WBC in blood of Xianxiong decoction group mice decreased (P < 0.01), percentage of neutrophils in both blood and BALF decreased as well (P < 0.01, P < 0.05); it also significantly reduced the ratio of W/D (P < 0.01); and found the alveolar wall, the number of inflammatory cells infiltrating improved, compared with model group. Xianxiong decoction reduced the level of NF-kappaB, TNF-alpha and IL-6 in BALF (P < 0.01, P < 0.01, P < 0.05); its high and low dose groups only found TNF-alpha level declined. Five mice died 24 h after administration of Xianxiong decoction which indicated its toxicity when other influential factors were considered.</p><p><b>CONCLUSION</b>Xianxiong decoction is effective on the ALI mice induced by LPS, but it is of toxicity at 3 g x mL(-1).</p>
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Animais , Feminino , Humanos , Camundongos , Lesão Pulmonar Aguda , Tratamento Farmacológico , Genética , Metabolismo , Patologia , Líquido da Lavagem Broncoalveolar , Química , Medicamentos de Ervas Chinesas , Interleucina-6 , Genética , Metabolismo , Lipopolissacarídeos , Pulmão , Metabolismo , Patologia , Camundongos Endogâmicos ICR , NF-kappa B , Genética , Metabolismo , Fator de Necrose Tumoral alfa , Genética , MetabolismoRESUMO
<p><b>OBJECTIVE</b>To explore the current application and features of Aconite prescriptions with incompatible herbs in grade A class three hospitals in east China and central China through a clinical study and comparative analysis.</p><p><b>METHOD</b>Clinical prescriptions containing Aconite with incompatible herbs were collected. Association rules were utilized to analyze the compatible features of these herbs.</p><p><b>RESULT</b>This analysis found that the frequently used incompatible herba; pairs are Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma, with the support rate of 44.45%, occupying nearly half of the surveyed prescriptions; Pinelliae Rhizoma is the most frequently used herb in the two areas, with support rate up to 76.24%. Among the top 10 herbal pairs in the support rate, except for Aconiti Lateralis Radix Praeparata and Pinelliae Rhizoma, the top 10 herbs in Central China were mostly for warming the middle jiao and tonifying qi, such as Zingiberis Rhizoma, Atractylodis Macrocephalae Rhizoma and Codonopsis Radix; Whereas those in east China were mostly for activating and nourishing blood, such as Angelicae Sinensis Radix, Chuanxiong Rhizoma, and Salviae Miltiorrhizae Radix et Rhizoma. Among the top 10 herbal pairs in the support rate, except for Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma, the core herbal pairs applied in central China were mainly for resolving phlegm and warming the middle jiao, such as Pinelliae Rhizoma-Glycyrrhizae Radix et Rhizoma, Pinelliae Rhizoma-Zingiberis Rhizoma; Whereas those in east China were principally for activating blood and tonifying qi, like Atractylodis Macrocephalae Rhizoma and Pinelliae Rhizoma, Angelicae Sinensis Radix and Pinelliae Rhizoma. Among the core herbal groups in the two areas, the most frequently used herbal groups in the two areas are Aconiti Lateralis Radix Praeparata, Glycyrrhizae Radix et Rhizoma and Pinelliae Rhizoma with the support rate of 59.73%, accounting for the highest proportion among all of herbal groups.</p><p><b>CONCLUSION</b>There are the combined clinical application of Aconite with incompatible herbs, mostly with Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma, but with differences in the combined application in east China and central China.</p>
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Humanos , Aconitum , Química , Incompatibilidade de Medicamentos , Prescrições de Medicamentos , Medicamentos de Ervas Chinesas , Química , Farmacologia , Pinellia , Química , Sophora , QuímicaRESUMO
People′s misunderstandings about the radiological check in health examination: Equalize the price of the medical check equipment with the accuracy of the check .The health examinees′misunderstanding about the harm which X-Ray can cause , thinking that low dose chest CT only can do very little harm to human body .The health examination unit makes the rate of finding out early lung tumor a main basis of assessing a medical personnel ′s achievement , which caused medical staff go against epidemiological laws when diagnosing tiny nodules .Misun-derstandings about some biological features such as the scale or the growing speed of the nidus , and laying exces-sive importance on the check accuracy , which caused some examinees received excessive X -Ray, overdiagnosis and overtreatment .So, people must treat radiological check in health examination rationally and dialectically , in order to further realize the legitimation and rationalization of radiological check .
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This study aimed to use computer simulation to describe the fluid dynamic characteristics in patients with obstructive sleep apnea syndrome (OSAS) and to evaluate the difference between during quiet respiration and the Muller maneuver (MM). Seven patients with OSAS were involved to perform computed tomographic (CT) scanning during quiet respiration and the MM. CT data in DICOM format were transformed into an anatomically three-dimensional computational fluid dynamics (CFD) model of the upper airway. The velocity magnitude, relative pressure, and flow distribution were obtained. Numerical simulation of airflow was performed to discuss how the MM affected airflow in the upper airway. To measure the discrepancy, the SPSS19.0 software package was utilized for statistic analysis. The results showed that the shape of the upper airway became narrower, and the pressure decreased during the MM. The minimal cross-sectional area (MCSA) of velopharynx was significantly decreased (P<0.05) and the airflow velocity in MCSAs of velopharynx and glossopharynx significantly accelerated (P<0.05) during the MM. This study demonstrated the possibility of CFD model combined with the MM for understanding pharyngeal aerodynamics in the pathophysiology of OSAS.