1.Association between photoreceptor gene mutation-caused diseases and myopia
Yunqing LIANG ; Jiali LI ; Shanshan LIU ; Xiaohe LU
International Eye Science 2026;26(3):452-457
Myopia has become a significant eye health problem, which is thought to result from the complex interactions of genetic and environmental factors. This review focuses on two types of hereditary retinal diseases caused by mutations in photoreceptor genes, including rod-cone cell dystrophy(retinitis pigmentosa)and cone dysfunction syndromes(achromatopsia, blue cone monochromatism and Bornholm eye disease). It systematically explores the intrinsic connection between these diseases and the myopia phenotype, and elaborates on the core mechanisms by which pathogenic genes such as RPGR and OPN1LW/OPN1MW, which cause defects in ciliary structure and protein transport and interfere with the visual signal pathway, jointly induce choroidal thinning and scleral remodeling, ultimately driving the elongation of axial length and the occurrence of myopia. By tracing the association of photoreceptor gene mutations with myopia, this article provides a new perspective for in-depth understanding of the genetic mechanism of myopia and is of great significance for the development of early risk warning and targeted intervention strategies.
2.Impact of portal vein tumor thrombus classification on rebleeding in hepatocellular carcinoma patients with esophagogastric variceal bleeding
Jiali MA ; Xiaohui YE ; Hongshan WEI ; Ping LI ; Xiuxia LIANG
Journal of Clinical Hepatology 2026;42(5):1101-1108
ObjectiveTo investigate the impact of portal vein tumor thrombus (PVTT) classification on rebleeding in hepatocellular carcinoma (HCC) patients with different PVTT subtypes and esophagogastric variceal bleeding (EGVB), and to provide a reference for formulating rational treatment regimens for such patients. MethodsA retrospective study was performed for 130 patients with HCC and PVTT who were treated due to EGVB in Beijing Ditan Hospital, Capital Medical University, from July 2020 to January 2025, and according to whether endoscopic treatment was performed, the patients were divided into endoscopic treatment group with 97 patients and conservative treatment group with 33 patients. Demographic and clinical data were collected from all patients, and the two groups were compared in terms of hemostasis success rate and rebleeding rate. 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 chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups. The Kaplan-Meier method was used to estimate the cumulative incidence rate of rebleeding in patients with different subtypes of PVTT. Propensity score matching (PSM) was performed for the endoscopic treatment group and the conservative treatment group to balance the baseline data of the two groups. The Cox proportional hazards model was used to perform univariate and multivariate analyses and identify independent risk factors for rebleeding. ResultsThe endoscopic treatment group had a significantly lower cumulative rebleeding rate within 6 months than the conservative treatment group (35.1% vs 57.6%, hazard ratio [HR]=0.480, 95% confidence interval [CI]: 0.272—0.851, P=0.019). The PVTT Ⅲ—Ⅳ group had a significantly higher cumulative rebleeding rate within 6 months than the PVTT Ⅱ group (52.2% vs 37.5%, HR=1.744, 95%CI: 1.008 — 3.018, P=0.022). After PSM, there was no significant difference in rebleeding rate between the endoscopic treatment group and the conservative treatment group (38.1% vs 14.3%,HR=1.500,95%CI:0.125 — 2.002, P=0.588), while the PVTT Ⅲ—Ⅳ group had a significantly higher cumulative rebleeding rate than the PVTT Ⅱ group (58.8% vs 12.5%,HR=1.561,95%CI:1.195 — 12.499,P=0.033). The multivariate Cox regression analysis showed that PVTT subtype (HR=1.412, 95%CI: 0.998 — 1.997, P=0.049), platelet count (HR=1.006, 95%CI: 1.001 — 1.010, P=0.021), C-reactive protein (HR=1.011, 95%CI: 1.001 — 1.021, P=0.026), and ascites (HR=1.803, 95%CI: 1.059 — 3.068, P=0.030) were independent risk factors for rebleeding. ConclusionFor HCC patients with PVTT and EGVB, endoscopic treatment can successfully achieve hemostasis, while it fails to significantly reduce rebleeding rates. PVTT classification can affect the risk of rebleeding, and patients with PVTT types Ⅲ—Ⅳ have a relatively high rebleeding rate.
3.Mechanism of active ingredient compatibility of Dimocarpus longan Lour. leaves in improving glucose and lipid metabolism disorders in type 2 diabetic mellitus rats
Yanli LIANG ; Shijia AN ; Fengsheng LI ; Jiani MAI ; Anqi HUO ; Jiali WEI ; Zejuan ZHANG ; Shuyan QIN ; Wenqing HUANG ; Jie LIANG
China Pharmacy 2026;37(13):1697-1703
OBJECTIVE To explore the mechanism of the active ingredient compatibility(quercetin, quercitrin and kaempferol at a mass ratio of 2∶9∶3)of Dimocarpus longan Lour. leaves(abbreviated as CDL) on ameliorating glucose and lipid metabolism disorders in type 2 diabetes mellitus (T2DM) rats. METHODS SD rats were randomly divided into blank control group, model group, metformin hydrochloride group (100 mg/kg), and CDL high-, medium- and low-dose groups (280, 140, 75 mg/kg), with 10 rats in each group. Rats in the blank control group were fed with standard chow, while rats in the other groups were given high-sugar and high-fat diet combined with intraperitoneal injection of streptozotocin to establish the T2DM rat model. After successful modeling, rats in each administration group were given corresponding drug solution, and rats in the blank control group and model group were intragastrically administered with equal volume of pure water, once a day, for consecutive 4 weeks. Fasting blood glucose (FBG) was detected at fixed time every week. The curves of oral glucose tolerance test (OGTT) and intraperitoneal insulin tolerance test (IPITT) were plotted, and the area under curve (AUC) was calculated. The pancreatic islet function indexes [fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), insulin sensitivity index (ISI)],blood lipid indexes [total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C)] and hepatic glycogen content were determined. The pathological morphological changes of liver and pancreatic tissues were observed. The protein and mRNA expression levels of molecules related to phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in liver tissues were detected. RESULTS Compared with the blank control group, the FBG, AUC of IPITT curve, AUC of OGTT curve, HOMA-IR, the levels of FINS, TC, TG and LDL-C, as well as the protein and mRNA expression of phosphatase and tensin homolog, forkhead box protein O1 and glycogen synthase kinase-3β in liver tissues were significantly increased in the model group ( P <0.05). ISI, the levels of HDL-C and hepatic glycogen content, along with the protein and mRNA expression of PI3K, insulin receptor substrate-1, Akt and protein expression of phosphorylated Akt in liver tissues were markedly decreased ( P <0.05). In model group rats, the arrangement of hepatocytes was irregular, the overall structure of pancreatic lobules was disordered, and a large number of inflammatory cell infiltration was observed. Compared with the model group, most of the above quantitative indexes were significantly reversed in the CDL high-dose group ( P <0.05), and the pathological lesions of liver and pancreas were obviously alleviated. CONCLUSIONS CDL can regulate glucose and lipid metabolism disorders, elevate insulin sensitivity and relieve insulin resistance in T2DM rats. Its mechanism may be related to the activation of the PI3K/Akt signaling pathway.
4.Mechanism of active ingredient compatibility of Dimocarpus longan Lour. leaves in improving glucose and lipid metabolism disorders in type 2 diabetic mellitus rats
Yanli LIANG ; Shijia AN ; Fengsheng LI ; Jiani MAI ; Anqi HUO ; Jiali WEI ; Zejuan ZHANG ; Shuyan QIN ; Wenqing HUANG ; Jie LIANG
China Pharmacy 2026;37(13):1697-1703
OBJECTIVE To explore the mechanism of the active ingredient compatibility(quercetin, quercitrin and kaempferol at a mass ratio of 2∶9∶3)of Dimocarpus longan Lour. leaves(abbreviated as CDL) on ameliorating glucose and lipid metabolism disorders in type 2 diabetes mellitus (T2DM) rats. METHODS SD rats were randomly divided into blank control group, model group, metformin hydrochloride group (100 mg/kg), and CDL high-, medium- and low-dose groups (280, 140, 75 mg/kg), with 10 rats in each group. Rats in the blank control group were fed with standard chow, while rats in the other groups were given high-sugar and high-fat diet combined with intraperitoneal injection of streptozotocin to establish the T2DM rat model. After successful modeling, rats in each administration group were given corresponding drug solution, and rats in the blank control group and model group were intragastrically administered with equal volume of pure water, once a day, for consecutive 4 weeks. Fasting blood glucose (FBG) was detected at fixed time every week. The curves of oral glucose tolerance test (OGTT) and intraperitoneal insulin tolerance test (IPITT) were plotted, and the area under curve (AUC) was calculated. The pancreatic islet function indexes [fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), insulin sensitivity index (ISI)],blood lipid indexes [total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C)] and hepatic glycogen content were determined. The pathological morphological changes of liver and pancreatic tissues were observed. The protein and mRNA expression levels of molecules related to phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in liver tissues were detected. RESULTS Compared with the blank control group, the FBG, AUC of IPITT curve, AUC of OGTT curve, HOMA-IR, the levels of FINS, TC, TG and LDL-C, as well as the protein and mRNA expression of phosphatase and tensin homolog, forkhead box protein O1 and glycogen synthase kinase-3β in liver tissues were significantly increased in the model group ( P <0.05). ISI, the levels of HDL-C and hepatic glycogen content, along with the protein and mRNA expression of PI3K, insulin receptor substrate-1, Akt and protein expression of phosphorylated Akt in liver tissues were markedly decreased ( P <0.05). In model group rats, the arrangement of hepatocytes was irregular, the overall structure of pancreatic lobules was disordered, and a large number of inflammatory cell infiltration was observed. Compared with the model group, most of the above quantitative indexes were significantly reversed in the CDL high-dose group ( P <0.05), and the pathological lesions of liver and pancreas were obviously alleviated. CONCLUSIONS CDL can regulate glucose and lipid metabolism disorders, elevate insulin sensitivity and relieve insulin resistance in T2DM rats. Its mechanism may be related to the activation of the PI3K/Akt signaling pathway.
5.Relationship between self-management behaviors and time perspective among patients with comorbid diabetes
YU Dandan ; ZHANG Yaping ; XU Huilin ; HE Dandan ; LIANG Tongtong ; YANG Jiali ; LI Jun
Journal of Preventive Medicine 2025;37(2):130-134
Objective:
To examine the relationship between self-management behaviors and time perspective among patients with comorbid diabetes, so as to provide the evidence for improving self-management behaviors among patients with comorbid diabetes.
Methods:
The patients with comorbid diabetes who were registered in the chronic disease health management system of Minhang District, Shanghai Municipality in 2021, followed up regularly, and lived in Meilong Town were recruited. Demographic information and family history of diabetes were collected through questionnaire surveys. Time perspective and self-management behaviors were assessed using the Zimbardo Time Perspective Inventory and Diabetes Self-Management Behavior Scale, respectively. The relationship between self-management behaviors and time perspective was analyzed using a multivariable ordinal logistic regression model.
Results:
A total of 907 patients with comorbid diabetes were enrolled, including 472 males (52.04%) and 435 females (47.96%). There were 652 cases aged 65 years and above, accounting for 71.89%. In terms of the types of time perspective, 280 patients were future-oriented (30.87%), 236 were balanced (26.02%), 162 were sensation-seeking (17.86%), 123 were fatalistic (13.56%), and 106 were negative (11.69%). In terms of the self-management behaviors, 46 patients were good (5.07%), 643 were moderate (70.89%), and 218 were poor (24.04%). Multivariable ordinal logistic regression analysis showed that after adjusting for age, gender, educational level, marital status, occupation status, monthly income, and family history of diabetes, the patients with comorbid diabetes who had a future-oriented time perspective had better self-management behaviors (OR=1.874, 95%CI: 1.204-2.915).
Conclusion
The self-management behaviors among patients with comorbid diabetes are moderate to poor, and patients with a future-oriented time perspective can better engage in self-management behaviors.
6.Safety and efficacy of puncture cyanoacrylate selective seal under endoscopic ultrasound versus traditional endoscopy in treatment of gastroesophageal varices: A randomized controlled trial
Jiali MA ; Lingling HE ; Hongshan WEI ; Ping LI ; Xiuxia LIANG
Journal of Clinical Hepatology 2025;41(6):1113-1119
ObjectiveTo investigate the safety and efficacy of puncture cyanoacrylate selective seal (PCSS) under endoscopic ultrasound in the treatment of gastroesophageal varices (GOV). MethodsA total of 100 patients with liver cirrhosis who underwent endoscopic therapy for the secondary prevention of GOV bleeding in Beijing Ditan Hospital, Capital Medical University, from March 1 to December 31, 2023 were enrolled and randomly divided into PCSS group and traditional endoscopy group. The patients were followed up for 6 months after surgery, and the two groups were compared in terms of clinical outcome and complications. The primary outcome measure was the rate of alleviation or disappearance of GOV, and the secondary outcome measure was variceal rebleeding and death. The independent-samples t test was used for comparison of normally distributed or approximately normally distributed quantitative data between two groups, and the Wilcoxon non-parametric test was used for comparison of non-normally distributed quantitative data between two groups; the chi-square test or the Fisher’s exact test was used for comparison of qualitative data between two groups. ResultsThere were 50 patients in the PCSS group, among whom 1 patient was lost to follow-up, and there were 50 patients in the traditional endoscopy group, among whom 3 patients were lost to follow-up. There were no significant differences between the two groups in baseline data such as age, sex, Child-Pugh class, varices grade, and GOV typing (all P>0.05). Compared with the traditional endoscopy group, the PCSS group had significantly better results of the number of endoscopic treatment sessions (t=-15.671, P=0.001), the total amount of tissue adhesive used (t=-2.830, P=0.006), and the rate of alleviation or eradication of varices sclerosis (χ2=7.078, P=0.029). Both groups had low rates of postoperative rebleeding, adverse reactions, and complications, and there were no significant differences between the two groups (all P>0.05). ConclusionCompared with traditional endoscopy, PCSS can significantly enhance treatment outcome while maintaining safety standards.
7.Construction of predictive model for continuous renal replacement therapy in early stage of sepsis children
Xin YE ; Qiyin CAI ; Jiali HUANG ; Qin LIU ; Guanghui CHEN ; Chaofu QIN ; Ting LIANG
China Modern Doctor 2025;63(32):12-16
Objective To screen the predictors of early initiation of continuous renal replacement therapy(CRRT)in children with sepsis and construct a linear model,based on LASSO regression analysis.Methods A total of 55 children diagnosed with sepsis at Jiangmen Maternity and Child Health Care Hospital from April 2023 to February 2025.They were divided into CRRT group(n=17)and non-CRRT group(n=38)based on CRRT treatment usage.Using LASSO regression screening,predictive factors were identified and a Logistic regression model was established.The model's performance was evaluated using receiver operating characteristic(ROC)curve and calibration curve.Results There were significant differences in age,respiratory rate,body temperature,and mechanical ventilation between two groups(P<0.05).Through LASSO regression analysis,four independent predictors of respiratory rate,body temperature,blood glucose,and C-reactive protein were identified.The constructed model demonstrated an area under the ROC curve of 0.94(95%CI:0.87-1.00),indicating good calibration accuracy.Conclusion The column line model based on body temperature,respiratory rate,blood glucose and C-reactive protein can effectively predict the need for early initiation of CRRT in sepsis children.
8.Guideline for the prevention of intraoperative acquired pressure injury in paraplegic patients with spinal cord injury (version 2025)
Aijun XU ; Shuixia LI ; Bo CHEN ; Mengyuan YE ; Lejiao LANG ; Ning NING ; Lin ZHANG ; Changqing LIU ; Zhonglan CHEN ; Weihu MA ; Weishi LI ; Xiaoning WANG ; Dongmei BIAN ; Jiancheng ZENG ; Xin WANG ; Yuan GAO ; Yaping CHEN ; Jiali CHEN ; Yun HAN ; Xiuting LI ; Yang ZHOU ; Xiaojing SU ; Qiong ZHANG ; Tianwen HUANG ; Ping ZHANG ; Hua LIN ; Xingling XIAO ; Ruifeng XU ; Fanghui DONG ; Bing HAN ; Luo FAN ; Yanling PEI ; Suyun LI ; Xiaoju TAN ; Rongchen GUO ; Yefang ZOU ; Xiaoyun HAN ; Junqin DING ; Yi WANG ; Shuhua DENG ; Jinli GUO ; Yinhua LIANG ; Yuan CEN ; Xiaoqin LIU ; Junru CHEN ; Haiyang YU ; Lunlan LI ; Ying REN ; Yunxia LI ; Jianli LU ; Ying YING ; Lan WEI ; Yin WANG ; Qinhong XU ; Yanqin ZHANG ; Yang LYU ; Shijun ZHANG ; Sui WENJIE ; Sanlian HU ; Shuhong YANG ; Guoqing LI ; Jingjing AN ; Baorong HE ; Leling FENG
Chinese Journal of Trauma 2025;41(6):530-541
Paraplegia caused by spinal cord injury is a serious neurological complication, for which surgery is currently the main treatment method. Due to different surgical approaches, patients are usually expected to maintain a passive prone position for a long time or switch between the supine and prone positions. Affected by multiple factors such as neurogenic sensory disorders, pathological changes in muscle tone and operative duration, the risk of intraoperative acquired pressure injury (IAPI) is significantly increased. Current clinical prevention strategies for IAPI in these patients predominantly focus on localized pressure relief during positioning, lacking systematic, standardized comprehensive prevention protocols or evidence-based guidelines. To address it, Department of Nursing, Orthopedics Branch, China International Exchange and Promotive Association for Medical and Health Care, Spinal Trauma Professional Committee, Orthopedics Branch, Chinese Medical Doctor Association, Nursing Group of Spine and Spinal Cord Professional Committee of Chinese Association of Rehabilitation Medicine organized experts in relevant fields to formulate Guideline for the prevention of intraoperative acquired pressure injury in paraplegic patients with spinal cord injury ( version 2025), based on evidence-based medical evidence and latest research results and clinical practice at home and abroad. Eleven recommendations were put forward from the aspects of preoperative risk assessment, intraoperative prevention strategies, postoperative handover and monitoring, and supportive mechanisms for IAPI prevention, aiming to standardize the prevention measures and management strategies of IAPI in paraplegic patients with spinal cord injury and accelerate the recovery of patients and improve the therapeutic effect.
9.The effects of transcranial direct current stimulation on ischemic stroke patients with cognitive impairment as assessed by using tract-based spatial statistics
Jiali ZHONG ; Xiaoshan JING ; Ying LIANG ; Ruchen PENG ; Ruiqiang XIN
Chinese Journal of Physical Medicine and Rehabilitation 2025;47(9):815-821
Objective:To evaluate any effect of transcranial direct current stimulation (tDCS) on cognitive impairment after an ischemic stroke (IS) using tract-based spatial statistics (TBSS).Methods:Fifty-one patients with mild or more serious cognitive impairment after an IS were divided into an electrical stimulation group (26 cases) and a control group (25 cases) using a random number table. In addition to conventional rehabilitation treatment, the electrical stimulation group was given tDCS, while the control group was given sham tDCS for 15 days. Before and after the treatment, both groups were evaluated using the Mini-mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Diffusion tensor imaging (DTI) was also performed. TBSS were computed for the differences in fractional anisotropy (FA) between the two groups before and after the treatment, and Pearson correlation analysis was applied to the pre-treatment and post-treatment FA differences within each group and the improvements in MMSE and MoCA scores.Results:After the treatment, the average MMSE and MoCA scores of both groups had improved significantly, but the improvement was significantly greater in the electrical stimulation group. After the treatment, the FA values among the electrical stimulation group had increased significantly in the bilateral genu of the corpus callosum, the bilateral inferior fronto-occipital fasciculus, the bilateral anterior thalamic radiation and the left superior longitudinal fasciculus. In the control group significant increases were recorded only in the left superior longitudinal fasciculus and the left anterior thalamic radiation. The FA change in the left superior longitudinal fasciculus of the electrical stimulation group was then positively correlated with the improvement in MMSE scores ( r=0.42), and that in the left anterior thalamic radiation was positively correlated with the improvement in MoCA scores ( r=0.45). Conclusions:tDCS can significantly improve the cognition of stroke survivors with cognitive impairment and promote the recovery of white matter fiber tracts. The FA values of the anterior thalamic radiation and the superior longitudinal fasciculus may be useful predictors and indicators of the recovery of cognitive function among such patients.
10.Effects of Modified Buyang Huanwu Decoction on Serum Fibroblast Growth Factor 21,25-Hydroxyvitamin D,Endothelin 1 Levels and Hypercoagulable State in Type 2 Diabetes Mellitus Patients with Peripheral Neuropathy of Qi Deficiency and Blood Stasis Type
Lanying DENG ; Linli PU ; Liang FAN ; Liang ZHENG ; Jiali WU ; Fang FU
Journal of Guangzhou University of Traditional Chinese Medicine 2025;42(1):86-93
Objective To investigate the therapeutic efficacy of modified Buyang Huanwu Decoction in the treatment of type 2 diabetes mellitus(T2DM)patients with peripheral neuropathy of qi deficiency and blood stasis type,and to observe its effects on serum fibroblast growth factor 21(FGF21),25-hydroxyvitamin D[25(OH)D],endothelin 1(ET-1)levels and hypercoagulable state of the patients.Methods A total of 124 T2DM patients with peripheral neuropathy of qi deficiency and blood stasis type who admitted to Haikou Hospital of Traditional Chinese Medicine from December 2019 to December 2022 were randomly divided into a control group and an observation group,with 62 cases in each group according to the random number table method.The control group was treated with conventional western medicine,and the observation group was treated with modified Buyang Huanwu Decoction on the basis of treatment for the control group.The course of treatment for the two groups covered 12 weeks.The changes of traditional Chinese medicine(TCM)syndrome scores,blood glucose indicators,hemorheology indicators,nerve conduction velocity(NCV)and levels of serum FGF21,25(OH)D,ET-1,interleukin 6(IL-6)in the two groups before and after treatment were observed.After treatment,the therapeutic efficacy of the two groups was evaluated.Results(1)After 12 weeks of treatment,the total effective rate of the observation group was 96.77%(60/62)and that of the control group was 83.87%(52/62),and the intergroup comparison(tested by chi-square test)showed that the therapeutic efficacy of the observation group was significantly superior to that of the control group(P<0.05).(2)After treatment,the total TCM syndrome scores and the scores of TCM symptoms such as limb pain,hypoesthesia,excessive eating with frequent hunger,and limb numbness in the two groups were decreased when compared with those before treatment(P<0.05),and the decrease in the observation group was significantly superior to that in the control group(P<0.05).(3)After treatment,the levels of hemorheology indicators such as hematocrit,whole blood viscosity at high-shear rate,and plasma viscosity in the two groups of patients were decreased when compared with those before treatment(P<0.05),and the decrease in the observation group was significantly superior to that in the control group(P<0.05).(4)After treatment,the motor conduction velocity of the common peroneal nerve and the median nerve in the two groups of patients was increased when compared with that before treatment(P<0.05),and the increase in the observation group was significantly superior to that in the control group(P<0.05).(5)After treatment,the serum levels of blood glucose indicators such as fasting blood glucose(FBG)and glycosylated hemoglobin(HbA1C)in the two groups of patients were decreased when compared with those before treatment(P<0.05),and the decrease in the observation group was significantly superior to that in the control group(P<0.05).(6)After treatment,the serum FGF21,ET-1,and IL-6 levels in the two groups were decreased(P<0.05),and serum 25(OH)D level was increased(P<0.05),and the decrease of serum FGF21,ET-1,and IL-6 levels as well as the increase of serum 25(OH)D level in the observation group was significantly superior to that in the control group(P<0.05).Conclusion For T2DM patients with peripheral neuropathy of qi deficiency and blood stasis type,the combination of modified Buyang Huanwu Decoction with conventional treatment in western medicine is helpful for reducing the inflammatory response,alleviating the damage of vascular endothelial function,regulating the levels of blood glucose,improving the neurologic function,and enhancing the clinical efficacy.


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