In recent years， adaptive design has gradually emerged in clinical trials， gaining widespread application and expansion. Compared with traditional randomized controlled trials， appropriate adaptive design can save time and resources to some extent， improve the validity of the trial results and strength of the evidence， align better with ethical requirements， and facilitate subsequent drug market research. However， due to the greater flexibility of adaptive design， controlling type Ⅰ error rates and truly enhancing research efficiency are challenging aspects of its application. Therefore， the normative application and optimization of adaptive design in research deserve early focus， including adhering to good adaptive design principles， conducting rigorous pre-design planning， scientifically applying various statistical methods such as Bayesian dynamic models and simulation methods， and utilizing monitoring tools like monitoring committees to ensure the scientific integrity of the research process. Moreover， the flexibility of adaptive design aligns well with the practical realities of traditional Chinese medicine （TCM） clinical practice. The main characteristics of TCM， such as the holistic concept and treatment based on syndrome differentiation， determine that TCM provides a dynamic and personalized treatment plan. In contrast， the traditional fixed development approach of western medicine limits the application of "human experience" in TCM. To address this bottleneck in TCM research and development， the innovative use of adaptive design， a modern scientific theory and methodology with multiplicity and variability， offers a feasible new approach for TCM clinical research and the innovation of Chinese herbal medicine. By learning from successful cases such as the first Food and Drug Administration （FDA）-approved oral botanical drug， Crofelemer， researchers can explore optimal solutions for adaptive design in clinical research protocols and its role in the "three-combination" evaluation system for Chinese herbal medicines， further refine trial design， clarify key trial points， and develop innovative research and development applications that adapt to the clinical positioning of TCM and highlight the characteristics and advantages of TCM， paving the way for the clinical efficacy， pharmacological mechanism exploration， and post-market efficacy evaluation of Chinese herbal compounds.

Objective:To summarize the clinical features and genetic characteristics of Congenital bile acid synthetic disorder type 3 (BASD3) disorder caused by CYP7B1 gene variation.Methods:This was a case series study. Clinical data and genetic results of 2 cases of congenital bile acid synthetic disorder type 3 caused by CYP7B1 gene variations in the Department of Infectious Diseases, Children′s Hospital of Fudan University at Xiamen and Department of Pediatrics, Women and Children′s Hospital, School of Medicine, Xiamen University from January 2021 to December 2023 were retrospectively collected and analyzed. Literature up to December 2023 was searched from electronic databases of China National Knowledge Infrastructure (CNKI), Wanfang Data and PubMed with the combined keywords of " Congenital bile acid synthetic disorder type 3""Oxysterol 7-alpha-hydroxylase""Oxysterol 7α-Hydroxylase Deficiency""BASD3" and "CYP7B1 liver" both in Chinese and English. The main clinical features and genetic characteristics of BASD3 disorder caused by CYP7B1 gene variations were summarized.Results:Two BASD3 patients, 1 male and 1 female, were admitted at the ages of 3 months and 18 days, and 2 months and 7 days, respectively. Both patients presented with neonatal cholestasis and hepatomegaly. Biochemical evidence indicated direct hyper-bilirubinemia with elevated aminotransferase levels, while gamma-glutamyltransferase (GGT) and total bile acid levels were normal or nearly normal. Patient 1 was a compound heterozygotes of the CYP7B1 gene variants c.525-526insCAAGTTGG(p.Asp176GInfs*15) and c.334C>T(p.Arg112Ter). Patient 1 jaundice resolved and liver function tests normalized after oral administration of chenodeoxycholic acid (CDCA). Patient 2 was homozygous for variant c.334C>T(p.Arg112Ter) in CYP7B1 gene. Patient 2 was in liver failure status already and not reactive to oral CDCA administration. Patient 2 received living-related liver transplantation for enhanced abdominal CT revealed a liver tumor likely vascular origin. Literature review revealed no cases of BASD3 reported in Chinese literature, including 2 patients in this study, while 12 patients (9 males and 3 females) were reported in 9 English literatures. All of the 12 manifested jaundice and hepatosplenomegaly in infancy, with cirrhosis, liver failure, kidney enlargement, hypoglycemia, and spontaneous bleeding in some cases, polycystic kidney disease was demonstrated in 5 cases of them. The c.334C>T (p.Arg112Ter) of the CYP7B1 gene was homozygous in 4 cases and compound heterozygous in 2 cases. Among the 12 children, 6 cases received CDCA treatment, while 6 cases not. Four survived with their native liver in the 6 cases who received CDCA therapy, while none in the 6 cases not received CDCA therapy.Conclusions:BASD3 is a rare hereditary cholestatic disorder. Markedly elevated levels of conjugated bilirubin and aminotransferases, with normal or nearly normal GGT and total bile acid levels can serve as diagnostic clue. c.334C>T is the most common pathogenic variant of the CYP7B1 gene. Timely administration of CDCA may save the liver.

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is an important regulator of plasma asymmetric dimethylarginine (ADMA) levels, which are associated with insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). To elucidate the role of hepatic DDAH1 in the pathogenesis of NAFLD, we used hepatocyte-specific Ddah1-knockout mice (Ddah1^HKO) to examine the progress of high-fat diet (HFD)-induced NAFLD. Compared to diet-matched flox/flox littermates (Ddah1^f/f), Ddah1^HKO mice exhibited higher serum ADMA levels. After HFD feeding for 16 weeks, Ddah1^HKO mice developed more severe liver steatosis and worse insulin resistance than Ddah1^f/f mice. On the contrary, overexpression of DDAH1 attenuated the NAFLD-like phenotype in HFD-fed mice and ob/ob mice. RNA-seq analysis showed that DDAH1 affects NF-κB signaling, lipid metabolic processes, and immune system processes in fatty livers. Furthermore, DDAH1 reduces S100 calcium-binding protein A11 (S100A11) possibly via NF-κB, JNK and oxidative stress-dependent manner in fatty livers. Knockdown of hepatic S100a11 by an AAV8-shS100a11 vector alleviated hepatic steatosis and insulin resistance in HFD-fed Ddah1^HKO mice. In summary, our results suggested that the liver DDAH1/S100A11 axis has a marked effect on liver lipid metabolism in obese mice. Strategies to increase liver DDAH1 activity or decrease S100A11 expression could be a valuable approach for NAFLD therapy.

Objective:To investigate the effects of repetitive transcranial magnetic stimulation combined with paroxetine hydrochloride on executive function in depressed adolescents with non-suicidal self-injury.Methods:The clinical data of 120 depressed adolescents with depressive disorders who were admitted to The Second Hospital of Jinhua from August 2021 to July 2022 were retrospectively analyzed. They were randomly assigned to undergo treatment either with paroxetine hydrochloride (control group, n = 60) or repetitive transcranial magnetic stimulation combined with paroxetine hydrochloride (observation group, n = 60). All patients were treated for 2 months. Hamilton Depression Rating Scale-24 (HAMD-24) score, Non-suicidal Self-injury Behavior and Function Scale for Adolescents (ANSSIQ) score, executive function, brain-derived neurotrophic factor, 5-hydroxytryptamine, and clinical efficacy were determined in each group. Results:After treatment, the Hamilton Depression Rating Scale-24 score in the observation group was significantly lower than that in the control group [(15.85 ± 1.08) points) vs. (18.72±1.21) points, t = 13.71, P < 0.001). After treatment, the number of self-injury attacks, number of self-injury impulsions, and the intensity of self-injury thought within 2 weeks in the observation group were significantly lower than those in the control group ( t = 3.42, 3.03, 1.92, all P < 0.05). The scores of the Trail Making Test, Stroop Word test, Stroop Color test, and Stroop Color-Word Interference Test were significantly higher in the observation group than those in the control group ( t = 2.66, 3.33, 3.97, 4.64, all P < 0.01). Brain-derived neurotrophic factor and 5-hydroxytryptamine levels in the observation group were (11.45 ± 1.79) μg/L and (136.68 ± 11.90) μg/L, respectively, which were significantly higher than (9.06±2.21) μg/L and (124.82 ± 10.34) μg/L in the control group ( t = 6.51, 5.83, both P < 0.001). The total response rate in the observation group was significantly higher than that in the control group (91.7% vs. 78.3%, Z = 2.73, P = 0.006). Conclusion:Repetitive transcranial magnetic stimulation combined with paroxetine hydrochloride is highly effective on depressive disorders in adolescents with non-suicidal self-injury. The combined therapy can reduce symptoms, improve executive function and cognitive function, and optimize serological indicators, and thereby deserves the clinical promotion.

Objective:To study the clinical characteristics and prognosis of Brucella and other pathogens infections complicated with anti-myelin oligodendrocyte glycoprotein-IgG associated disorders (MOGAD). Methods:The clinical data of a patient with brucellosis complicated with MOGAD diagnosed in the Department of Neurology of the First Affiliated Hospital of Zhengzhou University in April 2022 were reported, and related case reports of infection coexisting with MOGAD were reviewed and summarized.Results:This case was a 44-year-old male, with recurrent fever and anorexia, followed by sudden weakness, numbness, pain in both lower limbs and dysuria, and then pain in the right neck. Magnetic resonance imaging showed lesions in the spine and spinal cord. Due to the positive myelin oligodendrocyte glycoprotein antibodies in cerebrospinal fluid and serum, and the growth of Brucella in blood culture, he was diagnosed as brucellosis complicated with MOGAD. After anti-brucellosis and glucocorticoid therapy, his symptoms improved. The literature on infection coexisting with MOGAD was reviewed and 22 cases were included. The infection sources included COVID-19, Borrelia burgdorferi, etc. No case of Brucella infection complicated with MOGAD had been reported. The main clinical manifestations of the 22 cases included myelitis (63.6%, 14/22), optic neuritis (40.9%, 9/22), acute disseminated encephalomyelitis (18.2%, 4/22), multiphasic disseminated encephalomyelitis (4.5%, 1/22) and meningoencephalitis (4.5%, 1/22). Magnetic resonance imaging was performed in 20 cases, showing spinal cord lesions in 12 cases (60.0%, 12/20), intracranial lesions in 10 cases (50.0%, 10/20) and optic nerve lesions in 6 cases (30.0%, 6/20). Cerebrospinal fluid examination was performed in 19 patients, of whom 13 (13/19) had increased cerebrospinal fluid cell count and 10 (10/18) had increased cerebrospinal fluid protein. Twenty-two patients received glucocorticoid therapy, of which 95.5% (21/22) responded well and 95.5% (21/22) had a good prognosis. Conclusions:Brucella and other pathogens infection may complicate with MOGAD, with similar clinical manifestations, and glucocorticoid therapy is effective.

Objective:To investigate the clinical efficacy of multi-point acupuncture and lavage on removing facial filling material.Methods:From May 2015 to May 2020, the Department of Plastic Surgery of Tianjin Time Plastic Aesthetic Clinic removed the filling materials from 38 patients (4 males, 34 females; 19-55 years, with average 28 years). During the operation, multi-point acupuncture were performed with an 18G needle to perforate different cavities of the fillers to press them out; with injection syringe flushing fluid was injected with a needle into the filling material area with repeated lavage through puncture points.Results:On average, 90% of the filling materials were recovered by this method, 5 cases were removed twice; follow-up for 6-12 months after operation showed that postoperative appearance was natural, and no scar and hyperpigmentation occurred; there were no cases of postoperative infection with ideal effects.Conclusions:Multi-point acupuncture and lavage treatment can remove more facial filling material; although there is also small amount of filling material left, it is not affect clinical efficacy. This method basically does not damage the surrounding normal tissue, and therefore it is worthy of clinical application.

Objective To translate and revise the Atrial Fibrillation-Quality of Life -18 (AF-QoL-18),and to test its reliability and validity. Methods The Chinese version of AF-QoL-18 was developed through the process of translation, back- translation, cultural adaptation, and preliminary experiment. A total of 187 atrial fibrillation (AF) patients in eight hospitals in Jiangsu province were investigated using the Chinese version to test the reliability and validity. Results Exploratory factor analysis identified three factors, including physiological, psychological and sexual dimensions, which could explain 65.055%of the total variance. The content validity index was 0.969. The Cronbach α coefficient was 0.915 and the retest reliability was 0.948 for the total scale. Conclusions The Chinese version AF-QoL-18 has proved to be reliable and valid.It can be used to measure the quality of life of AF patients in China.

Objective:Discussion MKK4 protein expression in nasopharyngeal carcinoma and -1044 A/T polymorphism correlation.Methods:90 patients with nasopharyngeal carcinoma , MKK4 protein expression was determined by immunohistochemical staining,polymerase chain reaction-restriction fragment length polymorphism ( PCR-RFLP ) to detect the gene -1044A/T sites monocytes nucleotide polymorphism.Results:MKK4 protein expression in nasopharyngeal carcinoma (-) was 24.4%(22/90),(+) was 15.6%(14/90),(++) was 34.4%(31/90),(+++) was 25.6% (23/90).Low expression (-/+) patients with a total of 36 cases,-1044AA genotype accounted for 22 cases (61.11%),AT genotype accounted for 12 cases (33.33%),TT genotype accounted for two cases (5.56%),AT+TT gene type accounted for 14 cases (38.89%).The patients with high MKK4 expression of 54 cases,of which accounted for 38 cases of AA genotype (70.37%),AT genotype accounted with 15 cases (27.78%),TT genotype accounted for one case (1.85%),AT +TT genotype accounted for 16 cases (29.63%).Low expression and high expression of T gene mutation occurs no significant ( Z=0.323 , P=0.747 ) .Conclusion: MKK4 protein expression correlated with -1044 A/T gene promoter polymorphisms was no significant correlation .

OBJECTIVE: To investigate the association between-1304T/G polymorphism in the promoter of MKK4 gene and the susceptibility in sporadic nasopharyngeal carcinoma. METHOD: MKK4-1304T/G genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 90 NPC cases and 30 healthy controls. RESULT: The number of nasopharyngeal carcinoma patients carrying with TG+GG genotype was much higher than those of controls (82.2% vs 66.7%, χ² =10.076, P < 0.05). Analysis showed that compared with the-1304TT genotype, -1304TG heterozygous reduced risk of nasopharyngeal carcinoma 0.56 fold (95% CI = 0.164-1.178, P < 0.01) and-1304GG lower 0.58 fold (95% CI = 0.126-1.381, P < 0.01), TG+ GG genotype variation risk of nasopharyngeal carcinoma decreased 0.72 fold (95% CI = 0.105-0.753, P < 0.01). CONCLUSION MKK4 gene-1304TG genotype can reduce risk of nasopharyngeal carcinoma, and it may be an independent protection factor in sporadic nasopharyngeal carcinoma.
Carcinoma ; Genetic Predisposition to Disease ; Genotype ; Heterozygote ; Humans ; MAP Kinase Kinase 4 ; genetics ; Nasopharyngeal Carcinoma ; Nasopharyngeal Neoplasms ; genetics ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length ; Promoter Regions, Genetic

Objective:To investigate the expression of MKK 4 protein in the nasopharyngeal carcinoma and its clinical significance.Methods:Immunohistochemical methods were employed to analyze MKK 4 positive expression intensity and positive cells in freshly collected nasopharyngeal carcinoma of both 90nasopharyngeal carcinoma cases and 20 chronic nasopharyngitis control.The clinical pathological characteristic were analyzed.Results:The data obtained by MKK4 immunohistochemistry showed that the MKK 4 positive rate was higher in control group than in the NPC group (95.5%vs 75.6%,P<0.05).The expression of MKK4 was related to tumor differentiation and lymph node metastasis ( P<0.05 ) , but not to gender , age, tumor volum and TNM stage ( P>0.05 ) . Conclusion:Positive rate of MKK4 protein in nasopharyngeal carcinoma tissues is lower than in chronic nasopharyngitis.MKK4 protein expressions in nasopharyngeal carcinoma tissues negatively correlated with lymph node metastasis ,clincal stage ,invasive depth ,and TTP (Time to progression),but not with age,gender,location and tumor volume.