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  • 01 December 2018 Volume 37 Issue 12
      

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  • Shiqi CHEN,Ziyi WU,Anqi WEI,Huaxu SHI,Yueqiu NI
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    Objective To study effect of ligustrazine (TMP) on auditory brainstem responses (ABR) threshold value and 8-hydroxy deoxyguanosine (8-OH-dG) of cochlea tissue in guinea pig with gentamicin (GM) ototoxicity. Methods Totally, 80 healthy white guinea pigs with red eyes, body mass 200-250 g, were randomly divided into 4 groups: TMP group, GM group, GM+TMP group and normal control (NS) group.The duration of treatment was 10 days continuously in all the groups.ABR threshold value was detected before and 10 days after administration.After drug withdrawal, the guinea pigs were sacrificed and cochlea tissues were collected.8-OH-dG in cochlea tissues was measured by Enzyme-linked immunosorbent assay (ELISA). Results Ten days after administration, ABR threshold value was significantly higher in GM group than in NS group (P<0.05); although ABR threshold value slightly increased in GM+TMP group, it significantly lower than that in the GM group (P<0.05).8-OH-dG was significantly higher in the GM group than in the NS group (P<0.05); although 8-OH-dG slightly increased in GM+TMP group, it significantly lower than that in the GM group (P<0.05).ABR threshold value was positively correlated with 8-OH-dG (P<0.05). Conclusion TMP can reduce the ABR threshold and the content of 8-OH-dG in guinea pig cochlea tissue with GM ototoxicity.

  • Min QU,Shunhong MAO,Baojie JIAO,Dandan SHI,Qiang YANG,Xiangge LIU,Zhihong MA,Huizhi LI
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    Objective To investigate the effects of methylprednisolone (Mp) on the expression of aquaporin 5 (AQP5) in lung tissue of rats with ventilation-induced lung injury and its mechanism. Methods The 100 SD rats were randomly divided into 5 groups: normal control group (group C), mechanical ventilation (group V) and methylprednisolone group with different doses (Mp1-3).The rats in group C had autonomous respiration with air, without mechanical ventilation.The rats in group V had large volume mechanical ventilation for 4 h.Oxygen concentration was 21%.The rats in group Mp1-3 were injected with different doses of methylprednisolone (2, 10, 30 mg·kg-1) about 10 min before mechanical ventilation. Femoral arterial blood was collected for arterial blood gas analysis and recorded the OI at the moment of intubation, 1, 2 and 4 h of mechanical ventilation (t1-4) .The LPI and lung wet dry weight (W/D) ratio were measured. The expression levels of p38MAPK,p-p38MAPK and AQP5 were detected with Western blotting.Expression of AQP5 mRNA was determined by RT-PCR.The pathological changes of lung tissue in each group were observed under light microscope, and injury alveolar rate (IAR) was calculated. Results Compared with group C, OI in group V and group Mp1 decreased, W/D ratio, LPI and IAR increased (P<0.05).The expression level of p-p38MAPK and p-p38MAPK/p38MAPK ratio increased (P<0.05), the expression level of AQP5 and AQP5 mRNA decreased (P<0.05).There were no statistically significant differences in the parameters mentioned above between group Mp2 and group Mp3 (P>0.05).Compared with group V, OI in group Mp2 and group Mp3 increased, W/D ratio, LPI and IAR decreased ( P<0.05), the expression level of p-p38MAPK and p-p38MAPK/p38MAPK ratio decreased (P<0.05).The expression levels of AQP5 and AQP5 mRNA increased (P<0.05).There were no statistically significant differences in the parameters mentioned above in group Mp2 and group Mp3 (P>0.05).The pathological injury of lung tissue in group Mp2 and group Mp3 was slighter than that in group V. Conclusion Methylprednisolone can relieve the ventilator-associated lung injury, and its mechanism is related to inhibiting the expression of p38MAPK phosphorylation and upregulation of AQP5.Medium dose of methylprednisolone is appropriate for lung protection.

  • Ying QIAN,Rongrong HUANG,Rui SUN,Jueping FENG,Senlin LI,Rui XIE,Qinyu HU,Ming XIANG
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    Objective To study the immune regulation function of ginsenoside Rh2. Methods Six-week-old C57BL/6J mice were treated with the whole body irradiation by X-ray once to establish a radiotherapy model or injected intraperitoneally with methotrexate to establish an immunosuppressive model. Both models consisted of blank control group (n=10),model control group (n=15),thymopentin group (n=15),and ginsenoside Rh2 group (n=15). Each mouse of blank control group and model control group was given 0.2 mL 0.9% NaCl solution intragastrically,each mouse of thymopentin group was treated with thymopentin intraperitoneally at a dose of 0.1 mg·kg-1,and ginsenoside Rh2 group was given ginsenoside Rh2 intragastrically at a dose of 10 mg·kg-1 ,once a day,respectively. The animal tissues of radiotherapy model were collected on the third,fifth and seventh days and those of the methotrexate model were collected on the fifteenth day. The immune cells in the spleen and thymus were detected by flow cytometry,and the content of cytokines in the serum was detected by enzyme-linked immunosorbent assay(ELISA)kit. Results Ginsenoside Rh2 relieved body weight loss resulted from irradiation and methotrexate in mice. As compared with model control group,Rh2 significantly increased the number of $CD^{+}_{4}$T cells and $CD^{+}_{8}$T cells in lymphocytes of spleen and thymus (P<0.05,P<0.01),increased the number of natural killer(NK) cells in spleen,improved the expression of T cell receptor(TCR)in spleen (P<0.05,P<0.01),decreased the number of myeloid-derived suppressor cells(MDSC)in spleen (P<0.05,P<0.01),improved the expression of co-stimulatory molecule MHCII on dendritic cells(DCs) (P<0.05),and reduced the expression of programmed death-1 ligands(PD-L1)on DCs (P<0.05), ehanced the secretion of Th1 cytokines, interleukin (IL-2) and tumor necrosis factor (TNF-α) in serum (P<0.05,P<0.01). Conclusion Ginsenoside Rh2 can improve the immune dysfunction in both models,which is related to promoting the differentiation and maturation of innate immune cells and the proliferation of immunological effector cells,and promoting the secretion of Th1 cytokines and ehancing immune function.

  • Yongjun GAO,Xihong YU,Zhijun ZHAO
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    Objective To investigate curative effect and safety of acupoint injection of triamcinolone acetonide injection in treating hand chronic eczema and its action mechanism. Methods Eighty patients with chronic hand eczema were randomly divided into 2 groups: treatment group, 42 cases were given triamcinolone acetonide injection in valley point; control group, 38 cases given triamcinolone acetonide injection in local lesion.They were treated once a week, three times for one course of treatment.The curative effect of treatment and adverse reactions were observed after 3 weeks. Results Three weeks after the treatment, effective rate of treatment group was 88.10%, and that of control group 89.47% (P>0.05), no obvious adverse reaction occurred.Compliance rate of treatment group and control group was 90.48% and 68.42%, respectively, with significant difference (P<0.05). Conclusion Injection in Hegu acupoint is equivalent to local injection treatment in skin lesions for treatment of hand chronic eczema, but point injection has the advantages of small area at the injection site, pain relief, higher patient satisfaction and better compliance, and it is easily accepted by patients.It is a good method to treat chronic hand keratinization eczema.

  • Qiuyun SHE,Yunhua DENG
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    Vitiligo is a common chronic acquired disease of depigmentation, which can destroy the appearance of the patients and bring a significantly negative impact on their psychology, social life, and personal life.Vitiligo has a complex pathogenesis and is difficult to treat.The current treatment is mainly to inhibit autoimmune inflammation and promote melanocyte pigment regeneration with limited effects.With the deepening of the research on the pathogenesis of vitiligo, more and more scholars have turned their research focus to emerging targeted therapies.This article will summarize the pathogenesis of vitiligo, the mechanism of action, efficacy and safety of targeted drug therapy.

  • Yuanyuan MA,Wei SONG,Wei HU,Zhangyin MING
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    Objective To explore the pharmacodynamics of Longzhu ointment about the effect on promoting wound healing and antimicrobial effects in vitro, and measure its minimal inhibitory concentration (MIC). Methods Forty Kunming mice were randomly divided into 4 groups in the wound healing experiment: blank control group, Longzhu ointment substrate group, recombinant human epidermal growth factor gel group and Longzhu ointment group.After anesthesia, a wound with diameter about 1.5 cm on the back of mice was made.After the wound healing, the new skin was harvested to be stained with masson and HE.The formation of granulation tissues and angiogenesis, the count of fibroblasts and inflammatory cells and the growth situation of collagen fiber were observed.It also tested the Longzhu ointment’s minimal inhibitory concentrations (MIC) respectively on the five kinds of bacteria: Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, MRSA and penicillin resistant Staphylococcus aureus. Results Longzhu ointment promoted callus generation at early phase, and shortened wound recovery time.And it also shortened wound healing time.The antibacteria experiment showed that the MIC of penicillin resistant Staphylococcus aureus and MRSA was 0.23 mg·mL-1, that of Escherichia coli was 0.94 mg·mL-1.The MIC of Pseudomonas aeruginosa and Staphylococcus aureus was above 1.25 mg·mL-1. Conclusion This result indicates that Longzhu ointment can improve the wound healing, and it also has a good inhibiting effect on common bacteria.

  • Xuyang CAI,Zhaohui JIN,Bin WU,Ting XU
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    Objective To systematically review the efficacy and safety of tacrolimus ointment in the treatment of psoriasis. Methods The databases such as Ovid Medline, EMBase, Cochrane Library, CNKI, CBM, VIP and WanFang Data were searched.The retrieval time was from inception to December 2016.Two reviewers independently screened the literature, extracted the data and assessed the methodological quality of the included studies.Then the meta-analysis was performed using RevMan 5.3 software. Results A total of 16 RCTs involving 1126 patients were included.The results of meta-analysis showed that, tacrolimus group was superior to control group, there were significant differences in the total effective rate [RR=1.38, 95%CI(1.27, 1.50), P<0.000 01] and physician’s global assessment result [RR=1.83, 95%CI(1.32, 2.53), P=0.000 3].There was no significant difference in the total incidence of adverse events [RR=2.05, 95%CI(0.89, 4.71), P=0.09] between the two groups.But in the subgroups of monotherapy and combined therapy, the incidence rates of pruritus [RR=3.19, 95%CI(1.00, 10.15), P=0.05, RR=5.80, 95%CI(1.55, 21.68), P=0.009] and skin burning sensation [RR=2.38, 95%CI(1.23, 4.60), P=0.01, RR=6.00, 95%CI(1.38, 26.09), P=0.02] in treatment group were significantly higher than those in control group.There was no obvious publication bias shown by funnel plot analysis. Conclusion Tacrolimus ointment can increase the effective rate of psoriasis.For the limitation of quality of included studies, this conclusion still needs to be proved by conducting RCTs with high quality and large sample size.

  • Cheng JIANG,Nian ZHANG,Yan ZHANG
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    Objective To observe the changes of pulmonary function and blood gas analysis in patients with chronic obstructive pulmonary disease-obstructive sleep apnea-hypopnea syndrome (COPD-OSAHS) overlap syndrome by treatment with tiotropium bromide powder inhalation, and to understand its clinical significance. Methods A randomized controlled study was conducted in 69 COPD-OSAHS overlap syndrome patients.The patients were divided into the treatment group (44 cases in the group, 36 cases completed) and the control group (39 cases in the group, 32 cases completed).The treatment group was given the conventional therapy and tiotropium bromide inhalation (1 pill per day, 18 μg/pill), and the control group was only given the conventional therapy.The total observation time was 12 weeks, the changes of PaO2, PaCO2, FEV1% pre and FEV1/FVC were observed after treatment. Results After treatment, PaO2 (10.05±1.15) kPa, PaCO2 (5.85±0.90) kPa, FEV1pre (52.73±6.72) %, FEV1/FVC (56.52±4.27) % in the treatment group and PaO2 (9.26±1.14) kPa, PaCO2 (5.98±1.00) kPa, FEV1 pre (48.12±6.45) %, FEV1/FVC (54.29±8.18) % in the control group were significantly different from those before the treatment (P<0.05).The difference values of the indexes before and after the treatment were significantly different between the two groups (P<0.05). Conclusion Inhalation of thiotitronium bromide can improve hypoxemia, carbon dioxide retention, hypercapnia and pulmonary function of the patients with COPD-OSAHS overlap syndrome.

  • Ting XIONG,Weizhi LIU
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    Procalcitonin is a bacterial infection indicator of high sensitivity and specificity.It shows a good application prospect in guiding rational usage of antibacterial drug for chronic obstructive pulmonary disease, respiratory infections, sepsis, surgical infection, etc.In clinical observation, procalcitonin can shorten the time of antimicrobial drug use and reduce its usage.

  • Chuanhua FENG,Jin ZHANG,Qi REN,Lan XU,Lang ZHANG,Xiaoxuan TAO,Gang LI
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    Objective To establish a method for determination of the content of berberine hydrochloride and hesperidin in Weite'an tablet by high performance liquid chromatography. Methods ODS2 C18 (4.6 mm×150 mm, 5 μm) was used as chromatographic column, Acetonitrile-0.1% phosphoric acid solution (19:81) as mobile phase, the flow rate was 1 mL·min-1, the detection wavelength was 265 nm, the column temperature was 30 ℃, and the injection volume was 10 μL. Results Berberine hydrochloride had good linear relationship in the concentration range of 5-250 μg·mL-1(r=0.999 5).The average recovery was 97.4%, RSD was 1.9%.Hesperidin linear relationship in the concentration range of 14-700 μg·mL-1 was good (r=0.999 2); the average recovery was 97.1%, and RSD was 1.9%. Conclusion The established method can quickly determine the content of berberine hydrochloride and hesperidin in Weite'an tablet, has the advantages of simple operation, accurate result,high sensitivity, and can be used for the quality control of Weite'an tablet.

  • Yi LV,Guangyu CHEN,Biqing ZHAO,Shi WANG,Xianghui ZHANG,Qun HE
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    Objective To optimize the thermosensitive in situ eye gel system containing New Muan by the central composite design-response surface methodology (CCD-RSM). Methods According to the index of the phase transition temperature of the solution-gel before and after the STF dilution, on the basis of single factor experiment, Poloxamer 407 and Poloxamer188 in thermosensitive in situ eye gel was isolated by CCD-RSM.And then the composition of gel matric was primarily confirmed by binomial regression analysis. Results Optimized matrix of in situ thermo-sensitive gel system containing antofloxacin for ocular use consisted of 19.34% Poloxamer 407 and 1.73% Poloxamer 188,which was a free-flowing liquid at 25 ℃ and converted to semisolid gel after tear dilution at 34 ℃. Conclusion The thermosensitive in situ gel system containing New Muan satisfies the requirement of ophthalmic application, and has clinical significance and application value.

  • Yingdong SUN,Fengqin WANG,Jinjie ZHANG,Wenwen LYU
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    Objective To optimize the formulation of fluconazole ophthalmic thermosensitive gel. Methods The matrix formulation was optimized by L9(34) orthogonal design, using the amounts of Poloxamer407(P407), Poloxamer188(P188) and propylene glycol as factors, gelation temperature (T1) and gelatinization temperature (T2) after diluted by simulated tear as index. Results The best formulation of fluconazole ophthalmic thermosensitive gel (mass to volume ratio) was: Poloxamer407 (P407) 22%, Poloxamer188 (P188) 4%, propylene glycol 6%. Conclusion The prescription of fluconazole ophthalmic thermosensitive gel was reasonable, and the quality of the ophthalmic gel is stable.

  • Yi ZUO,Luhua FEI
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    Objective Quality control chart was used to monitor the process of determination of metronidazole tablets. Methods To determine the content of the control sample of metronidazole tablets by HPLC, the data were drawn into control chart to monitor the process of determination. Results The action limit of the control chart (X chart) was 95.49%-100.65%, and the warning limit was 96.35%-99.79%. Conclusion Using quality control chart is helpful to identify the abnormality in the process of determination in time, control the test results and ensure the accurate and reliable testing data.

  • Nan HU,Jinfei ZHAO,Yan JIANG,Rui HAN,Jiajin YAN,Sulan ZOU
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    Objective To study the monitoring of tacrolimus (FK506) blood concentration at different time points after renal transplantation, and provide reference for safe and rational use of FK506 in clinic. Methods In total, 180 renal transplant recipients were included and analyzed in this study.The relationship between FK506 blood concentration and time after operation, dose, sex, age and CYP3A5 polymorphism was analyzed. Results At the time of one month after renal transplantation, FK506 dosage and blood concentration of patients decreased gradually with great individual differences.At the time of 0-7 days after transplantation, the FK506 blood concentration was significantly higher in females than in males (P<0.05).At other time period, there were no significant differences in dose and blood concentration between male and female patients.The dose in the elder age group (age>45 years) was lower than that in younger age group (16-45 years old) over the same period after transplantation, the difference was significant during 3-6 months (P<0.05).The polymorphism of CYP3A5*3 gene showed a great influence on FK506 blood concentration in renal transplant recipients.At the same time after operation, the FK506 dosage of patients with CYP3A5*1*1 genotype was higher than that with CYP3A5*1*3 and CYP3A5*3*3 (P<0.05), and the blood concentration of patients with CYP3A5*1*1 was lower than that with CYP3A5*1*3 and CYP3A5*3*3 (P<0.05). Conclusion The detection of FK506 blood concentration and gene polymorphism can reduce the occurrence of excessive/insufficient immunity, and adverse drug reactions, and improve the long-term survival rate of transplanted kidney.

  • Ping WU,Xiaolan LIANG,Zhiguo ZHANG
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    Objective To discuss whether dosage of herbal decoction of different dosage forms per day is equal to that of the primary herbal decotion per day. Methods By reviewing the pertinent literature, number of days of taking the herbal decoction of different dosage forms (according to “Pharmacopoeia of the People's Republic of China”) with the dosage equal to that of the herbal decoction of “Formulas of Chinese Medicine” was studied. Results The number of days was decreased after herbal decoction turning into Xiaochaihu effervescent tablet, Xiaojianzhong mixture and Siwu mixture.But the number of days was increased after the other kinds of herbal decoction turning into different dosage forms.The longest taking days belonged to Duhuojisheng pills, reaching 11.3 days, the lowest Xiaojianzhong particles, 1.1 days. Conclusion The number of days is not necessarily unchanged after herbal decoction turning into different dosage forms of the same prescription.

  • Huimin LIU,Shan WANG,Hua LI,Cong LI,Lin XIONG,Xiandi TIAN,Taiyang JI,Jiang SHAO,Fuchao CHEN
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    Objective To evaluate the effect of pharmacy intervention in promoting the use of proton pump inhibitors (PPIs) injection in the perioperative period of orthopedic surgery. Methods Clinical pharmacists monitored and interfered with the use of PPIs injection of patients with orthopedic surgery.The intervention process was divided into four stages: the pre-intervention stage (April 2017), the first stage (May 2017), the second stage (June 2017) and the third stage (July 2017).PPIs utilization rate, rate of medication for prevention with indications, mean frequency of use, mean daily dose, and mean duration of treatment were retrospectively statistically analyzed.After intervention course, the per capita cost of PPIs injections, the proportion of it to total cost of medical expenses and hospitalization were compared with those of pre-intervention. Results After the intervention, the utilization rate of PPIs was reduced from 65.85% to 11.72%, the average course of treatment was shortened from (6.60±5.41) days to (2.88±2.03) days.The per capita cost of PPIs decreased from (247.74±234.79) to (126.30±131.78) yuan , and the rate of medication for indications increased from 37.96% to 76.47%. Conclusion The mode of drug intervention can further regulate the prevention and treatment of PPIs in perioperative period of orthopedic surgery patients and reduce the economic burden of patients.

  • Yue ZHAO,Xiaoyu JU,Zhanjun DONG
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    Inappropriate polypharmacy, especially in older people, imposes a substantial burden of adverse drug events, disability, hospitalization, and even death.The single most important predictor of inappropriate prescribing and risk of adverse drug events in older patients is the number of prescribed drugs.Deprescribing is the process of tapering or stopping drugs, aimed at minimizing polypharmacy and improving quality of life.The aim of this narrative review is to provide an overview of “deprescribing”, firstly discussing the potential benefits.

  • Yue QIU,Hongliang ZHANG,Zhenguang HUANG,Huanhuan YU,Taotao LIU
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    Objective To systematically review the quality of guidelines for prevention of cancer chemotherapy-induced gastrointestinal adverse reactions, and to provide a reference for clinical evidence-based medicine. Methods Guidelines concerning preventing cancer chemotherapy-induced gastrointestinal adverse reactions were electronically retrieved in PubMed, EMbase, CBM, Wanfang Database, National Guideline Clearinghouse, TRIP, NICE and medical association websites.Two investigators independently screened literature according to the inclusion and exclusion criteria, and assessed the quality of guidelines using Appraisal of Guidelines for Research and Evaluation Ⅱ (AGREE Ⅱ).Intraclass correlation coefficient (ICC) was used to examine the conformance of the raters’ evaluation scores. Results A total of 6 guidelines were included, with a time range from 2004 to 2016, 2 guidelines were made by the USA, the others by China, UK, Spain and Switzerland, respectively.Six guidelines were generally low in quality, the levels of recommendations were Level B (4 guidelines) and Level C (2 guidelines).According to the AGREEⅡ, domain 4 showed the highest score, and scores were generally low in domain 3 and 5.Recommendations of 6 guidelines on the first day were consistent.If patients had dyspepsia, antacid therapy (eg, H2 receptor antagonist, proton pump inhibitors) should be considered to prevent hyperacidity and peptic, thus adverse effects such as nausea and vomiting were inhibited. Conclusion The development of relevant guidelines should be improved in domain 3 and 5.The use of proton pump inhibitors is not recommended routinely for patients with cancer chemotherapy.

  • Zhixing PAN,Zhenjue LEI,Jiale WU
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    Objective To summarize the experience of the clinical pharmacist involved in the treatment of acute upper respiratory tract infection combined with immune thrombocytopenic purpura (ITP) in a child patient, implicating the important role of the pharmacist in the therapeutic regimen management. Methods Through participating in the treatment of acute upper respiratory tract infection combined with childhood ITP, the clinical pharmacist took measures on optimizing the drug therapy, improvement of medication compliance for children, reasonable treatment on the possible adverse drug reactions and medication evaluation to implement pharmaceutical care. Results Clinical pharmacist provides pharmaceutical care and reasonable treatment advice during the whole therapeutic process.One acute upper respiratory tract infection child complicated with ITP was successfully cured. Conclusion Through participating in clinical practice, the clinical pharmacists can assist physicians in making a rational drug treatment plan and improving the safety of drug therapy.

  • Xiaoyan LIU,Xueyan ZHANG
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    Objective To investigate the clinical pharmacists in pharmaceutical care for prevention and treatment of venous thrombosis in perinatal process of patients with premature rupture of membranes. Methods A retrospective analysis of anticoagulant therapy participated by clinical pharmacists for a patient with premature rupture of membranes combined with lower limb vein thrombus was performed. Results Clinical pharmacists analyzed the risk factors of vein thrombus, and provided doctors with rational drug recommendations about selection of anticoagulant drugs, methods of administration, and course of medication before and after the patient’s delivery, which were accepted by doctors and achieved very good curative effects. Conclusion Clinical pharmacists conduct medical supervision on perinatal patients, which has positive significance for avoiding adverse events and promoting clinical rational drug use.

  • Jia LIANG,Weifang ZHANG,Shanshan XIE,Ruilai XU,Aizhen XIOGN
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    Objective To illustrate the feasibility of the use of global trigger tool (GTT) to improve the ADE detection rate in our institution. Methods By using hospital information system (HIS), the medical records from January to December 2016 in our hospital were randomly selected (60 medical records from each month).The records for examination were obtained based on the inclusion/exclusion criteria.A retrospective analysis of those records was conducted.The advantages of the global trigger tool in improving ADE rates were evaluated. Results In total, 720 medical records were randomly selected and 662 records were selected according to inclusion/exclusion criteria, 640 records were obtained after the repeated cases were eliminated.In total, 87 ADE cases were determined,78 ADE cases were detected by triggers, the ADE detection rate was 12.2%, but the ADE detection rate was 0.3% (320/103 906) by applying spontaneous reporting in the same period.Twenty-four out of the 35 triggers were positive, the positive rate was 68.6%.A total of 529 positive triggers were detected and only 94 were identified ADE with PPV being 17.8% (94/529).Among 78 cases of ADE, 23 cases were caused by chemotherapy drug (29.5%),10 cases were caused by antibiotics (12.8%), meanwhile 7 cases were caused by hypotensive drugs (9.0%), amcinonide (9.0%) and diuretics (9.0%) respectively. Among 78 cases of ADE, 98.7% were identified as temporary harm (category E 57.7 %, category F 41.0%). Conclusion The use of GTT for monitoring and evaluating ADE in inpatients has a positive role, but still needs further improvement.