Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.
Humans ; Leukodystrophy, Metachromatic/genetics* ; Pilot Projects ; Genetic Therapy/methods* ; Hematopoietic Stem Cell Transplantation ; Male ; Follow-Up Studies ; Female ; Lentivirus/genetics* ; Child ; Child, Preschool ; Hematopoietic Stem Cells/metabolism* ; Cerebroside-Sulfatase/metabolism* ; Adolescent

Objective To investigate the relationship between the expression of keratin 15(KRT15)and keratin 18(KRT18)proteins in colorectal cancer tissue and their clinicopathological features and prognosis.Methods A total of 97 patients with colorectal cancer who underwent surgical treatment in a hospital from June 2018 to June 2019 were selected as the study objects.Immunohistochemistry was used to detect the ex-pression of KRT15 and KRT18 protein in colorectal cancer tissues and adjacent tissues,and the differences of KRT15 and KRT18 protein expression in colorectal cancer patients with different clinicopathological features were compared.The patients with colorectal cancer were followed up for 3 years after discharge,and their o-verall survival(OS)during the follow-up period was analyzed.Kaplan-Meier survival curve and Log-rank test were used to analyze the difference in OS rate among colorectal cancer patients with different KRT15 and KRT18 protein expression.Univariate and multivariate COX proportional regression analysis was performed to analyze the factors affecting the prognosis of patients with colorectal cancer.Results The positive expres-sion rates of KRT15 and KRT18 protein in colorectal cancer tissues were higher than those in adjacent tis-sues,and the difference was statistically significant(P＜0.05).The positive expression rates of KRT15 and KRT18 protein in colorectal cancer tissues of patients with low differentiation,TNM Ⅲ stage,perineural inva-sion and preoperative carcinoembryonic antigen(CEA)level ≥5 ng/mL were higher than those of patients with medium-high differentiation,TNM Ⅰ-Ⅱ stage,without perineural invasion and preoperative CEA level＜5 ng/mL,the difference was statistically significant(P＜0.05).The 3-year OS rates of colorectal cancer patients with positive expression of KRT15 and KRT18 protein were 64.29％and 60.00％respectively,which were lower than those of patients with negative expression of KRT15 and KRT18 protein(83.64％and 85.96％respec-tively),and the difference was statistically significant(x2=6.497,7.987,P＜0.05).Multivariate COX pro-portional regression analysis showed that TNM stage Ⅲ,positive expression of KRT15 protein and positive expression of KRT18 protein were risk factors affecting the survival of patients with colorectal cancer(P＜0.05).Conclusion The expression of KRT15 and KRT18 protein in colorectal cancer tissues can provide ref-erence for prognosis assessment of patients with colorectal cancer.

Objective To summarize the best evidence of nutritional support therapy with food for special medi-cal purpose for patients undergoing adjuvant chemotherapy after oncology surgery,and to provide a reference basis for standardizing the application of food for special medical purpose and guiding clinical nutritional therapy practice for oncology patients.Methods Computer search was conducted on UpToDate,Guidelines International Network(GIN),National Guideline Clearinghouse,National Comprehensive Cancer Network,National Institute for Health and Clinical Excellence,Oncology Nursing Society,American Society for Parenteral Enteral Nutrition,European Society for Clinical Nutrition and Metabolism,Chinese Society for Parenteral and Enteral Nutrition,Joanna Briggs Institute Evidence-Based Health Care Centre database,Cochrane Library,PubMed,CINAHL,Scopus,Web of Science,Em-base,CBM,Wanfang,and China Knowledge Network on the nutritional support treatment of food for special medical purpose for postoperative adjuvant chemotherapy patients.The retrieval period was from January 2012 to August 2022.Quality evaluation of the literature was completed independently by 2 evidence-based trained researchers and combined with expert advice to extract and summarise evidence for the literature that met quality standards.Results A total of 14 articles were included,including 4 guidelines,1 clinical decision,2 systematic re views,4 expert consen-suses,and 3 randomized controlled trials.The 14 pieces of best evidence were compiled,covering 6 aspects of nu-tritional screening and assessment,nutritional education,recommended dose,formulation selection,nutritional treat-ment,and management of adverse effects.Conclusion This study summarises the best evidence on the nutritional management of food for special medical purpose in postoperative adjuvant chemotherapy patients with cancer,which is scientific and systematic.When administering nutritional therapy to patients,healthcare professionals should fully assess the nutritional status of patients,make clear and prudent choices on the dosage and type of food for special medical puipose to be used by patients,and guide patients to improve their nutritional status safely and effectively to improve their quality of life.To improve the quality of life.

Objective To explore potential genes associated with the pathogenesis of hypospadias using weighted Gene co-expression network analysis(WGCNA).Methods The WGCNA algorithm was used to process the hypospadias-related dataset GSE35034,and then a gene co-expression weight network was constructed to screen the modules with the highest correlation with hypospadias,and the genes in the modules were enriched and detected by gene ontology(GO),Kyoto Encyclopedia of Genes and Genomes(KEGG).Differential analysis was also performed to screen out differential genes.The differential genes were imported into the String database.Using Cytoscape software,the hub genes in the network were identified.The results screened by the above three methods were combined and analyzed,and the core genes in the intersection set were screened.Using the external dataset GSE121712,the core genes were verified by mRNA expression changes and subject work characterization receiver operating characteristic(ROC)curve diagnosis.Results Fifteen co-expression modules were obtained based on the WGCNA method.Ninety-three common differential genes meeting the conditions were obtained by differential analysis.Ten core genes were finally obtained by Cytoscape software analysis.Finally MEbrown module,differential genes and the 10 core genes yielded a total of 2 intersecting genes:FBXL16 and SYNDIG1.ROC curves verified that the intersecting genes were differentially expressed in patients with hypospadias versus normal subjects.Conclusion In this study,two key genes with significant correlation with hypospadias were obtained by WGCNA,which may be used for the early diagnosis and treatment of hypospadias after further study.

Objective:To analyze the costs and effectiveness of five common screening modes and genetic screening for thalassemia in China in order to find the optimal way and provide evidence for the implementation of thalassemia prevention and control projects in Hunan Province.Methods:From June 2020 to April 2021, 12 971 couples from 14 cities and autonomous prefectures in Hunan Province were selected as the study population. The diagnosis of thalassemia was based on the results of genetic testing. Results of routine blood test and hemoglobin electrophoresis were collected and analyzed. The efficacy of five screening modes, at the cut-off value of <80 fl or 82 fl for the mean corpuscular volume (MCV), was analyzed by positive predictive value, negative predictive value, Jorden index and cost-effectiveness ratio. Sensitivity analysis was used to assess the feasibility of genetic screening at different costs after fixing the costs of routine blood and hemoglobin electrophoresis. The five thalassemia screening models are as follows: Mode 1: The woman had a blood routine test first. If the result was positive, the spouse required a blood routine test. If both results were positive, a thalassemia gene test should be offered to the couple. Mode 2: Both husband and wife were screened by blood routine and hemoglobin electrophoresis. If one or both of them were positive, both would be tested for thalassemia gene. Mode 3: The couple received blood routine tests initially. If either was positive, both should receive hemoglobin electrophoresis testing. If either was positive, both parties will conduct thalassemia gene testing. Mode 4: The woman was screened by blood routine and hemoglobin electrophoresis. If any one of them was positive, the woman would be tested for thalassemia gene. If the gene test result was positive, the spouse should receive thalassemia gene. Mode 5: Both spouses conducted a blood routine test. If either was positive, both would conduct hemoglobin electrophoresis test. If both were positive, both spouses should receive thalassemia gene testing. Gene testing mode: The woman would be tested for thalassemia, and her spouse would have thalassemia test too if her result was positive.Results:When using MCV<80 fl as the cut-off for diagnosing thalassemia, the Youden indices of the five prenatal screening modes in Hunan Province were 0.551, 0.639, 0.898, 0.555 and 0.356, while when using MCV<82 fl as the cut-off, the Youden indices were 0.549, 0.629, 0.851, 0.548 and 0.356. When the MCV cut-off value was <80 fl, the missed diagnosis rates of the five screening modes were 44.44%, 0.00, 0.00, 18.52% and 62.96%, and the cost-effectiveness ratios were 21 709, 250 939, 76 870, 138 463 and 92 860 yuan (RMB)/couple, respectively. When the price of genetic testing was lower than 55 yuan (RMB), the cost-effectiveness ratio of genetic screening was lower than that of Mode 3.Conclusions:MCV<80 fl can be considered as the positive criteria in blood routine screening for thalassemia in Hunan Province, and the cost-effectiveness ratio of Mode 3 (the couple received blood routine tests initially. If either was positive, both should receive hemoglobin electrophoresis testing. If either was positive, both parties will conduct thalassemia gene testing) is the best. Genetic screening has certain advantages with the decreasing price.

Alzheimer's disease (AD) is the first degenerative disease of the nervous system, but no drugs have been found to reverse AD progression. Starting from 2 major pathogenesis of AD, namely amyloid beta (Aβ) cascade and Tau protein, this study systematically reviews anti-Aβ or Tau protein AD new drugs that have entered clinical research; this study also expounds their clinical trial findings and mechanisms, and analyzes the reasons for their success or failure to provide a theoretical basis for AD drug exploitation.

Recent studies have found that the pathological changes of Tau proteinopathy, such as Alzheimer's disease (AD) and progressive supranuclear palsy (PSP), involve transmission or circulatory disturbance of synaptic vesicles. This article reviews the relations of AD/PSP with circulatory disturbance of synaptic vesicles and explore the pathogenesis of these diseases, aiming to provide a new perspective for new therapeutic drugs.

【Objective】 To develop a quick and accurate crossmatching test technology without the power equipment and additional reagents before blood transfusion, so as to improve the timeliness and safety of blood transfusion treatment in sudden situations as war or natural disasters. 【Methods】 The irregular antibodies quickly promote coagulants (QPC) were used as the reaction medium reagent. The 200 μL QPC were wrapped in the bursts bead and preset within different recess of the detection tubes. The bursts beads were squeezed with the reagent left in the well, then the blood samples were dropped in the main(recipient plasma: 200 μL, donor 3%—5% RBC: 100 μL) and secondary(donor plasma: 200 μL, recipient 3%—5% RBC: 100 μL)reaction grooves. The result interpretated by hand wrestling or 1 500 g centrifugation of 15 seconds. Meanwhile, the comparing experiments with the prior methods were implemented to evaluate the method’s reliability. 【Results】 The results of the bursting reagent, being stored at 37℃ for one week, were consistent with those of the freshly prepared cross-matching reagent, indicating that the bursting reagent was practical in the field and had good stability at normal temperature. No statistical difference between the sensitivity and the results of the microcolumn gel method was noticed by paired data t test (P>0.05). The parallel cross matching tests of 50 clinical samples were performed by microcolumn gel method and coagulant-bursting technique; the Kappa value was 0.973 2, and irregular antibodies were detected in 2 cases, with concordance rate at 100%, showing good consistency. 【Conclusion】 The improved method is simple and fast, and also safe and reliable for compatibility testing before blood transfusion, which is especially suitable for the field rescue of the wounded in wartime and sudden natural disasters, and is worthy of popularization.

Objective:To investigate the effect of astragaloside Ⅳ on the apoptosis of thyroid cells in Hashimoto's thyroiditis(HT)rats and Ras homolog gene family member A(RhoA)/Rho-associated coiled-coil containing kinase 2(ROCK2)pathway.Methods:The HT rat model was induced by subcutaneous injection of thyroglobulin combined with high iodine drinking water and randomly divided into model group,astragaloside(80 mg/kg)group,Rhosin(RhoA inhibitor,40 mg/kg)group,astragaloside Ⅳ(80 mg/kg)+ Rhosin(40 mg/kg)group(12 rats in each group),another 12 SD rats were selected and drank water normally and injected the same dose of saline subcutaneously as control group.After the drugs were grouped and processed,the serum anti-thyroglobulin antibody(TGAb),anti-thyroid peroxidase antibody(TPOAb)levels and the inflammatory factors IL-6,IL-17,IL-1β contents were measured by ELISA kits;the pathological changes of thyroid tissue in each group were detected by hematoxylin-eosin(HE)staining;the apopto-sis rate of rat thyroid cells in each group were detected by TUNEL staining;the expressions of RhoA/ROCK2 pathway proteins in thy-roid tissues of rats in each group were detected by Western blot.Results:Compared with the control group,the thyroid follicles in the model group had abnormal structure,some atrophy or disappearance,disordered arrangement,surrounding inflammatory cell infiltra-tion,and obvious pathological damage to the thyroid tissue,the serum TGAb,TPOAb,IL-6,IL-17 and IL-1β levels,thyroid cell apoptosis rate,and thyroid tissue RhoA and ROCK2 protein expression levels were significantly increased(P<0.05);compared with model group,the pathological damage of the thyroid tissue of rats in the drug intervention group were reduced,the serum TGAb,TPOAb,IL-6,IL-17 and IL-1β levels,thyroid cell apoptosis rate,and thyroid tissue RhoA and ROCK2 protein expression levels were decreased(P<0.05);compared with astragaloside Ⅳ group and the Rhosin group respectively,the pathological damage of the thyroid tissue of rats in the astragaloside Ⅳ+Rhosin group were further reduced,the serum TGAb,TPOAb,IL-6,IL-17 and IL-1β levels,thyroid cell apoptosis rate,thyroid tissue RhoA and ROCK2 protein expression levels were decreased(P<0.05).Conclusion:Astragaloside Ⅳ may down-regulate the expression of RhoA/ROCK2 pathway to reduce the inflammatory injury of thyroid tissue,inhib-it thyroid cell apoptosis,and improve the symptoms of HT in rats.

Objective To analyze the educational characteristics of physical therapy in universities of United States, and provide reference for the international development of rehabilitation therapy education in China.Methods Based on the data collected from the official websites of three universities in the United States and the databases at home and abroad, combined with the author's learning experience, the characteristics of physical therapy education in universities of United States in detail was analyzed.Results Characteristics of physical therapy education in universities of United States had strict accreditation system, course objectives oriented by practicing competence, comprehensive curriculum plan, educational concept of student-centered, high level of teaching informatization, diversified teaching and learning evaluation system, which conformed to the goal of rehabilitation competency of World Health Organization.Conclusion Physical therapy education in United States has remarkable characteristics and a well-developed system, which has certain reference value for China.