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Good medicine tastes bitter, but it is often difficult to swallow because the drug is bitter and astringent, so that the compliance of patients with medication is poor. However, the use of taste masking technology can better improve this situation. Appropriate and effective taste masking technology can improve the drug compliance of patients, especially children, it can also improve the curative effect and the clinical value of drugs. Herein, we summarize the latest research progress of taste masking technology, and summarize the traditional taste masking technology from the aspects of action mechanisms and application scopes. Finally, the novel and efficient taste masking technologies were presented.
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The taste of drugs has an important impact on the compliance of patients, but most of the active drug ingredients have an uncomfortable taste, especially traditional Chinese medicine. Through a variety of pharmaceutical excipients with taste masking properties combined with corresponding technologies can improve the taste of drugs and the characteristics of other dosage forms, so as to improve patient compliance. Here, we mainly summarize the auxiliary materials used for taste masking, explain the mechanism of taste masking from the point of view of excipients and introduces related uses, so as to provide reference for further research on taste masking of pediatric preparations.
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Objective:To evaluate the predictive value of neutrophil-to-lymphocyte ratio (NLR) for adult severe tetanus by comparing the NLR in patients with severe and mild tetanus.Methods:A total of 65 adult tetanus patients from the Linyi Central Hospital from January 2009 to December 2020 were enrolled. The patients were divided into two groups including mild group and severe group according to the Ablett classification. The general conditions, laboratory data, and NLR of patients in two group were retrospectively compared using independent samples t test. Multivariate logistic regression analysis was used for the analysis of risk factors for severe tetanus. Spearman correlation method was used for the analysis of the correlation between risk factors and Ablett grades. Receiver operator characteristic (ROC) curve was used for the evaluation of the predictive value. Results:Among the 65 tetanus cases, 34 was in mild group and 31 in severe group. The latency period of patients in severe group was (7.00±3.19) d, which was shorter than that in mild group ((9.18±2.59) d), and the difference was statistically significant ( t=3.03, P=0.004). The NLR of patients in severe group was 4.251±1.936, which was higher than that of mild group (2.533±1.026) , and the difference was statistically significant ( t=4.41, P<0.001). Multivariate logistic regression analysis showed that NLR and latency period were independent risk factors for tetanus severity (odds ratio ( OR)=2.359, 95% confidence interval ( CI) 1.415 to 3.934, P=0.001 and OR=0.748, 95% CI 0.599 to 0.936, P=0.011, respectively). In tetanus patients, the NLR level was positively correlated with Ablett grade ( r=0.644, P<0.001). The ROC curve showed that NLR had good predictive value for adult severe tetanus at a cut-off value of 2.471 (area under the curve (AUC)=0.787), with the sensitivity and specificity of 87.1% and 61.8%, respectively. When combining NLR with latency period (cut-off value of 7.5 d), predictive efficiency was further improved (AUC=0.832) with the sensitivity of 87.1% and specificity of 67.6%( Z=3.43, P<0.001). Conclusions:NLR has a good predictive value for adult severe tetanus, and the predictive efficiency is further improved when combined with latency period.
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The occurrence and development of colorectal cancer as a complex disease involves the abnormality of multiple signaling pathways. Chinese medicine regulates a variety of biological processes such as tumor cell differentiation， cell proliferation， apoptosis， cell metastasis， cell cycle， and tumor angiogenesis to prevent the occurrence of colorectal cancer （inflammation-cancer transformation）， tumor metastasis （common metastases of colorectal cancer include liver metastasis， lung metastasis， bone metastasis， and lymphatic metastasis）， and multidrug resistance induced by chemotherapy， treat primary tumors， and mitigate the toxic and side effects of chemotherapy. The pathways of Chinese medicine in the treatment of colorectal cancer have been intensively studied. The available studies have demonstrated that Patrinia villosa Juss and Pien Tze Huang can regulate the Notch pathway to inhibit the growth of colorectal cancer cells. Curcumin and Quyu Jiedu decoction regulate Hippo pathway to inhibit the survival， proliferation， invasion， and migration of colorectal cancer cells. Kujin tea and luteolin suppress the proliferation of colorectal cancer cells and protect intestinal barrier by regulating Kelch-like epichlorohydrin-associated protein-1 （Keap1）/nuclear factor E2-related factor 2 （Nrf2）/antioxidant response element （ARE） pathway. Icariin and ginkgolide C can regulate hepatocyte growth factor （HGF）/cellular-mesenchymal to epithelial transition factor （c-Met） pathway to induce apoptosis of colorectal cancer cells and prevent liver metastasis of colorectal cancer. Verbascoside and apigenin regulate p53 protein to promote apoptosis of colorectal cancer cells， reverse thymidylate synthase （TS）， and alleviate the multidrug resistance of colorectal cancer. Resveratrol and lycopene regulate insulin-like growth factor （IGF）/insulin-like growth factor receptor 1 （IGF1R） pathway to inhibit cancer cell metastasis and prolong disease-free survival. Cordycepin and Galla Chinensis water extract activate AMP-activated protein kinase （AMPK） pathway to inhibit the migration and invasion of cancer cells as well as the lung metastasis of colorectal cancer. The above summary aims to provide reference for the in-depth research on the treatment of colorectal cancer with Chinese medicine and inspire new research ideas.
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Nonalcoholic fatty liver disease (NAFLD) is a type of metabolic disorder syndrome of abnormal lipid deposition in hepatocytes, and with the improvement of living standards, the incidence rate of NAFLD has reached a worrying level. Several anthropometric indicators, including waist circumference, waist-hip ratio, and waist-height ratio, have been used in the evaluation of obesity and the correlation study of various metabolic diseases. This article introduces the association between NAFLD and various anthropometric indicators for obesity and points out that anthropometric indicators for obesity can be used for the prevention and control of NAFLD.
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Objective To investigate the value of optical trocar insertion technique in establishing pneumoperitoneum in patients undergoing laparoscopic surgery after previous abdominal surgery. Methods A total of 29 patients, with a history of abdominal surgery, who planned to undergo laparoscopic liver surgery were enrolled and randomly divided into optical trocar insertion group and open approach group. The independent samples t -test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the Fisher's exact test was used for comparison of categorical data between groups; the Mann-Whitney U test was used for comparison of ranked data between groups. Results There were no procedure-related complications in either group. Compared with the open approach group, the optical trocar insertion group had a significantly shorter time required to establish pneumoperitoneum [35.00 (21.00-46.00) seconds vs 180.00 (152.50-252.50) seconds, U =0, P < 0.001] and a significantly smaller incision length [1.10(1.00-1.20) cm vs 2.80(2.45-3.00) cm, U =0, P < 0.001]. Conclusion Both optical trocar insertion and open approach for establishing pneumoperitoneum is relatively safe in patients undergoing laparoscopic liver surgery after previous abdominal surgery, while optical trocar insertion has the advantages of high efficiency and minimal invasiveness in establishing pneumoperitoneum.
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Nonalcoholic fatty liver disease (NAFLD) is a type of metabolic disorder syndrome of abnormal lipid deposition in hepatocytes, and with the improvement of living standards, the incidence rate of NAFLD has reached a worrying level. Several anthropometric indicators, including waist circumference, waist-hip ratio, and waist-height ratio, have been used in the evaluation of obesity and the correlation study of various metabolic diseases. This article introduces the association between NAFLD and various anthropometric indicators for obesity and points out that anthropometric indicators for obesity can be used for the prevention and control of NAFLD.
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Objective To investigate the value of optical trocar insertion technique in establishing pneumoperitoneum in patients undergoing laparoscopic surgery after previous abdominal surgery. Methods A total of 29 patients, with a history of abdominal surgery, who planned to undergo laparoscopic liver surgery were enrolled and randomly divided into optical trocar insertion group and open approach group. The independent samples t -test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the Fisher's exact test was used for comparison of categorical data between groups; the Mann-Whitney U test was used for comparison of ranked data between groups. Results There were no procedure-related complications in either group. Compared with the open approach group, the optical trocar insertion group had a significantly shorter time required to establish pneumoperitoneum [35.00 (21.00-46.00) seconds vs 180.00 (152.50-252.50) seconds, U =0, P < 0.001] and a significantly smaller incision length [1.10(1.00-1.20) cm vs 2.80(2.45-3.00) cm, U =0, P < 0.001]. Conclusion Both optical trocar insertion and open approach for establishing pneumoperitoneum is relatively safe in patients undergoing laparoscopic liver surgery after previous abdominal surgery, while optical trocar insertion has the advantages of high efficiency and minimal invasiveness in establishing pneumoperitoneum.
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Objective: To observe the growth inhibition effect of Aconiti Lateralis Radix Praeparata polysaccharide on the gastric cancer xenografts in nude mice and the expressions of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-14 (MMP-14) in tumor tissues. Method: The nude mice xenograft model was established and randomly divided into model group, 5-fluorouracil group (5-FU, 0.01 g · kg-1), high and low-dose Aconiti Lateralis Radix Praeparata polysaccharide groups (0.2, 0.1 g · kg-1). Each group was given drug by gavage for 15 days. The effect of Aconiti Lateralis Radix Praeparata polysaccharide on the weight of gastric cancer in nude mice was observed. Morphological changes of tumor cells were observed under light microscope. The content of transforming growth factor-β1 (TGF-β1) in serum was determined by enzyme-linked immunosorbent assay (ELISA). The protein and mRNA expressions of MMP-2, MMP-14 in tumor tissues were detected by immunohistochemistry, Western blot and Real-time PCR. Result: The tumor inhibition rates of high and low-dose Aconiti Lateralis Radix Praeparata polysaccharides were 52.83%,40.57%, respectively. Compared with model group, the tumor weight of high and low-dose Aconiti Lateralis Radix Praeparata polysaccharide was significantly lower (Pβ1 content in nude mice (PPPPPPPConclusion: Aconiti Lateralis Radix Praeparata polysaccharide can inhibit the growth of gastric cancer xenografts in nude mice and the expression of TGF-β1.The anti-tumor mechanism may be related to the down-regulation of MMP-2, MMP-14 protein and mRNA expressions.
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Objective@#To explore the expression of the N-methyl-D-aspartate (NMDA) receptor in the rat model of orchialgia and its possible mechanisms.@*METHODS@#According to Yoshioka's method, the male rats in the control group were injected with 0.2 ml saline, and those in the experimental group with 0.2 ml 2% acetic acid solution. Then we tested the behavioral responses of the rats and determined the expressions of the subunits NR1 and NR2B of the NMDA receptor in the dorsal root ganglion and spinal dorsal horn by Western blot, RT-qPCR and immunofluorescence staining.@*RESULTS@#The withdrawal latency was decreased in the model rats, reaching the lowest value at 4 hours after modeling, significantly lower than in the controls (［4.15 ± 0.84］ vs ［12.32 ± 1.05］, P 0.05).@*CONCLUSIONS@#The NMDA receptor plays an important role in pathogenesis of orchialgia in rats. In the early stage of pain, upregulating the expression of the subunit NR2B of the NMDA receptor can mediate peripheral hyperalgesia and consequently orchialgia.
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Objective: To explore the relevant gene, signaling pathway for permanent atrial fibrillation (pAF) occurrence in order to provide the molecular basis of the pathogenesis of pAF. Methods: Our research included in 2 groups: pAF group, n=7 patients and Control group, n=4 healthy subjects with sinus rhythm. Agilent 4x44K microarray was used to analyze the mRNA in left atrium for differential gene expression profile. Based on Gene Ontology, KEGG and Biocarta databases, differentially expressed genes were studied for their relevant function and signaling pathway. Furthermore, the genes with significant differences were verified by quantitative real time PCR (qRT-PCR) in pathological specimen from 5 pAF patients and 5 normal heart donors. Results: The expression profile identified 987 abnormally expressed genes, 567 of them were down-regulated and 420 were up-regulated. 9 genes with significant differences were verified by qRT-PCR in pathological specimen and the changes were similar to microarray; those genes were closely related to pAF by involving left atrium fibrosis, electrical remodeling, inflammation, cellular stress response, metabolism and transcription regulation. GO and Pathway analysis indicated that down-regulated genes were mainly involved in metabolic processes; up-regulated genes had the effects on cellular stress response, immune response and platelet activation. Conclusion: Microarray technology identified some important genes related to pAF occurrence; such genes involved in left atrial structural and functional remodeling via affecting cellular metabolism, inflammation, immune response and thrombogenesis in relevant patients.
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Objective To study the dose-time-toxicity relationship of hepatotoxicity in mice with multiple administration of Paracetamol Tablets (PT),Compound Paracetamol and Amantadine Hydrochloride Tablets (CPAH),Compound Dextromethorphan Hydrobromide Tablets (CDH),and Chaiqin Qingning capsules (CQC).Methods Mice were randomly divided into control,PT,CPAH,CDH,and CQC high,medium,and low dose groups.The acetaminophen contents of high,medium,and low doses were 266.24,425.98,and 681.57 mg/kg in PT,CPAH,and CDH groups,and the doses of CQC group were 1437.70,2300.31,and 3 680.50 mg/kg,ig administration,once daily for 5 d.General state and toxicity of mice were observed.The changes of ALT,AST,AKP,TBIL,and ALB levels in serum and organ indexes of liver,spleen,thymus,and kidney were tested on day 1,3,7,11,and 14 after multiple administration.Results CQC with the dosage range of 1 437.70-3 680.50 mg/kg to mice within 14 d,has not yet induced the increase of AST,ALT,AKP,TBIL,and ALB levels and changes of organ indexes of liver,thymus spleen,and kidney compared with normal control (P ＞ 0.05).PT,CPAH,and CDH with repeated dose of 425.98-681.57 mg/kg could induce significant increase of the levels ofALT,AST,AKP,and TBIL which reached the peak on day 1 (P ＜ 0.05),and then gradually decreased on day 3-14.The level of ALB significant decreased on day 1-11 (P ＜ 0.05),and then gradually recovered on day 11-14.The liver index significant increased on day 1-3 (P ＜ 0.05),and recovered on day 7-14.Conclusion Multiple administration of CQC could not induce liver injury in mice within 14 d,while multiple administration ofPT,CPAH,and CDH could induce hepatotocixity in mice with a certain dose,and show an obvious dose-time-toxicity relationship.
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Objective To study the time-toxicity and dose-toxicity relationship of hepatotoxicity induced by Paracetamol Tablets (PT),Compound Paracetamol and Amantadine Hydrochloride Tablets (CPAH),Compound Dextromethorphan Hydrobromide Tablets (CDH),and Chaiqin Qingning Capsules (CQC) with single dose in mice.Methods In the Time-Toxicity relationship study,Kunming mice were randomly divided into control,PT,CPAH,CDH,and CQC group,and mice of.each drug administration group were randomly divided into nine subgroups according to the time (1,2,4,8,12,24,48,72 and 96 h after administration) of blood collection.The acetaminophen contents in PT,CPAH,and CDH groups were 425.98 mg/kg,and the dose of CQC group was 3 680.50 mg/kg.In the Dosage-Time relationship study,mice were randomly divided into control,PT,CPAH,CDH,and CQC high,medium and low dose group.The acetaminophen contents of high,medium,and low dose were 266.24,425.98,and 681.57 mg/kg in PT,CPAH,and CDH group,and the dose of CQC group was 1437.70,2300.31,and 3680.50 mg/kg,10 mice in each group,sex in half.Blood was collected 12 h after administration.Animal behavior was observed every day,blood and organs were collected at the corresponding time points,serum alanine aminotransferase (ALT),aspartate aminotransferase (AST),and alkaline phosphatase (ALP) level were detected,and the organs index of spleen and thymus,liver were calculated.Results There were no significant changes of ALT,AST,ALP,and organs index after once ig administration of CQC at dosage of 1437.70 mg/kg to 3680.50 mg/kg in mice.The study on time-toxicity relationship indicated that,after once administration of PT,CPAH,and CDH at 425.98 mg/kg,mice showed toxic symptom such as hypokinesia,dry hair and so on,12 h was the most obvious,24 ～ 72 h disappeared.The level of ALT,AST,and ALP in serum increased and reached to the peak at 12 h and then restored near normality after 72,24,and 24 h in PT,CPAH,and CDH group.Their organ index of liver,spleen and thymus all had no significant changes.The study on the dosage-toxicity relationship indicated that,there were no significant changes of animal behavior,ALT,AST,ALP,and organs index after once ig administration of PT,CPAH,and CDH at 266.24 mg/kg.Obvious liver injury can be induced by the three drugs with dosage of 425.98 to 681.57 mg/kg and the level of ALT,AST,and ALP increased significantly with the increase of dosage.Their liver index increased significantly with dosage of 681.57 mg/kg,but the organs index of spleen,thymus had no significant changes.Conclusion There was no hepatotoxicity after once ig administration of CQC with dosage of 3680.50 mg/kg in mice.Mice were once ig administration ofPT,CPAH,and CDH with a large dose,may induce acute liver injury and show obvious time-toxicity and dose-toxicity relationships.
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Objective To compare the effect of thoracoscopic and laparoscopic surgery with conventional thoracic surgery on esophageal cancer and its influence on pulmonary function. Methods Ninety?four patients with esophageal cancer treated in the Second Affiliated Hospital of Chengdu Medical College from March 2010 to March 2016 were selected and were divided into the control group ( 54 cases) and the study group ( 40 cases) according to operation methods. The control group received traditional thoracotomy. The study group received thoracoscopic and laparoscopic surgery. The operation and pulmonary function indexes were compared. Results The operation time of the patients in the study group was significantly longer than that in the control group ( (218. 1±35. 8) min vs. (192. 3±40. 1) min,t=3. 23,P 0. 05 ) . Conclusion Thoracoscopic and laparoscopic surgery for esophageal cancer has the advantages of small trauma,rapid recovery and low incidence of complications and obvious protective effect on pulmonary function. It is safe and feasible.
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Objective To study the antipyretic effect of Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets,and Chaiqin Qingning Capsules on the fever model induced by LPS and dry yeast in rats.Methods Fever was induced by ip injecting LPS (100 μg/kg) or sc injecting dry yeast (20％) in rats.We observed the changes of temperature of the rats after administration of Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets (the acetaminophen contents were 205.67,102.83,and 51.42 mg/kg)and Chaiqin Qingning Capsules (1110.60,555.30,and 277.65 mg/kg).Maximum temperature rise height (△T) and temperature response index (TRI) were calculated,and the curve of average rise in temperature was drawn.Results Each dose group of Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets,and Chaiqin Qingning Capsules had obvious antipyretic effect on the fever model induced by LPS and dry yeast in rats,and there was a certain dose-effect relationship.Conclusion Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets,and Chaiqin Qingning Capsules has certain antipyretic effect on LPS and dry yeast fever model in rats,and on the whole,the Western medicine acts rapid but continue for a short time,while the traditional Chinese medicine acts slow but continues for a long time.
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Objective@#To explore the expressions of transient receptor potential vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) in the dorsal root ganglion (DRG) and their action mechanisms in the rat model of orchialgia.@*METHODS@#The models of orchialgia were established in male SD rats by injection of 2% acetic acid into the testis. Then the number of spontaneous pain responses and withdrawal latency in the model rats were recorded by behavioral tests and the expressions of TRPV1 and TRPA1 in T13－L1 DRGs determined by RT-qPCR, Western blot and immunofluorescence staining.@*RESULTS@#Compared with the normal control rats, the orchialgia models showed a significant increase in the number of spontaneous pain responses (0.13 ± 0.35 vs 22.63 ± 3.42, P<0.01) and a decrease in the withdrawal latency at 4 hours after injection (［12.75 ± 1.50］ vs ［4.85 ± 1.00］ s, P<0.05). The mRNA expressions of both TRPV1 and TRPA1 were observed in the membrane of the neurons in the DRG, the former increased by 1.77 times and the latter by 1.75 times that of the control (P<0.05).@*CONCLUSIONS@#The expressions of TRPV1 and TRPA1 were up-regulated in the DRG of the rat models of orchialgia, which may be involved in the allodynia and hyperalgesia of the rats.
Subject(s)
Animals , Male , Rats , Acetic Acid , Ganglia, Spinal , Metabolism , Hyperalgesia , Metabolism , Membrane Glycoproteins , Oxidoreductases , Rats, Sprague-Dawley , TRPA1 Cation Channel , Metabolism , TRPV Cation Channels , Metabolism , Testicular Diseases , Metabolism , Up-RegulationABSTRACT
Chlamydia trachomatis infection is one of the most prevalent sexually transmitted diseases in males and studies on its pathogenic and immunologic mechanisms are rather limited. Animal models play an important role in studying the pathogenesis, course and treatment of human diseases, and those of male genital tract chlamydial infection are relatively few and not well developed. This article focuses on the chlamydia species, animal species, infection route, infected organ, and infection process of chlamydia, as well as its impact on reproduction, aiming to provide some help for further studies of male genital tract chlamydial infection.
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Animals , Humans , Male , Chlamydia Infections , Chlamydia trachomatis , Disease Models, Animal , ReproductionABSTRACT
Objective To investigate the efficiency of intraoperative neurophysiological monitoring in cervical spinal tumor surgery.Methods Retrospective case-control study comparing 23 cervical spinal tumor patients received surgery under neurophysiological monitoring (case) and 23 cases without neurophysiological monitoring (control).Results All of 46 cases,there were no significant differences of age,gender and preoperative neurological function.Duration of operation and estimated blood loss in the IONM cohort was less than the control group with significant difference.The preoperative JOA score of IONM group and control group were 12.0±2.4 and 12.7±2.1,with no significant difference.The postoperative JOA score of each group were 15.0±1.5 and 15.2±1.7,with no significant difference.The rate of cervical cord neurological improvement of IONM group was higher than control group,but there was no significant difference.In the IONM cohort,abnormal signal appeared in 8 cases,with 1 case developed new postoperative deficit,and the sensitivity and specificity of SEP were 100％ and 77.3％,the sensitivity and specificity of MEP were 100％ and 86.4％.Compared with preoperative SEP,4 cases showed major improvement (baseline increase ＞ 40％),2 cases showed moderate improvement (baseline increase:15％-40％).The coincidence rate of the SEP improvement and the AISA grade was 66.7％.Conclusion IONM could reduce the duration of operation and intraoperative blood loss.Changes of IONM were correlated with postoperative neurological function improvement.
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Objective To retrospectively analyze the one-year outcomes of modified single-armed suture technique for microsurgical vasoepididymostomy in men with epididymal obstructive azoospermia (EOA).Methods From February,2012 to November,2013,microsurgical longitudinal intussusception vasoepididymostomies using a modified single-armed suture technique in 51 men with EOA was performed.The followed-up period was designed as 1 year.The correlations between the sperm motility in epididymal fluid,unilateral or bilateral procedure,anastomotic site,and the female partner age and the patency or pregnancy rate were analyzed.Results Followups were carried out for 39 (76.5％) men.The patency was noted in 24 (61.5％) men and pregnancy was reported in 15 (38.5％) female partners,including 1 received in vitro fertilization using fresh ejaculated sperm.Motile sperms in epididymal fluid were observed intraoperatively in 14 (58.3％) patent men and 3 (20.0％) nonpatent men,respectively (P ＜ 0.05).In patent cohort,the mean ages of the pregnant and non-pregnant female partners were 26.5 and 32.7 years(P ＜ 0.05),respectively.Conclusion The modified single-armed suture technique showed favourable patency and pregnancy rates in this study.It's a practical alternative in the areas without the specialized double armed suture.
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Chronic orchialgia (CO) is a common complaint in urology or andrology. Due to its complicated pathogenesis, the diagnosis and treatment of CO are quite challenging. Based on different etiologies, CO can be idiopathic or secondary. Idiopathic CO accounts for approximately 50% of the cases and is probably associated with Wallerian degeneration in the spermatic cord nerves and peripheral sensitization. Secondary CO can be attributed to direct causes and its treatment focuses on the pathologic condition identified. The main methods for the treatment of CO include conservative and surgical strategies, among which microsurgical spermatic cord denervation ( MSCD) is an effective and minimally invasive option, while orchiectomy is but the last alternative when no other means is left.