Background/Aims: Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1–3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. Methods: We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. Results: The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. Conclusions Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.

Patchoulol is an important sesquiterpenoid in the volatile oil of Pogostemon cablin, and is also considered to be the main contributing component to the pharmacological efficacy and fragrance of P. cablin oil, which has antibacterial, antitumor, antioxidant, and other biological activities. Currently, patchoulol and its essential oil blends are in high demand worldwide, but the traditional plant extraction method has many problems such as wasting land and polluting the environment. Therefore, there is an urgent need for a new method to produce patchoulol efficiently and at low cost. To broaden the production method of patchouli and achieve the heterologous production of patchoulol in Saccharomyces cerevisiae, the patchoulol synthase(PS) gene from P. cablin was codon optimized and placed under the inducible strong promoter GAL1 to transfer into the yeast platform strain YTT-T5, thereby obtaining strain PS00 with the production of(4.0±0.3) mg·L~(-1) patchoulol. To improve the conversion rate, this study used protein fusion method to fuse SmFPS gene from Salvia miltiorrhiza with PS gene, leading to increase the yield of patchoulol to(100.9±7.4) mg·L~(-1) by 25-folds. By further optimizing the copy number of the fusion gene, the yield of patchoulol was increased by 90% to(191.1±32.7) mg·L~(-1). By optimizing the fermentation process, the strain was able to achieve a patchouli yield of 2.1 g·L~(-1) in a high-density fermentation system, which was the highest yield so far. This study provides an important basis for the green production of patchoulol.
Saccharomyces cerevisiae/metabolism* ; Sesquiterpenes/metabolism* ; Pogostemon ; Oils, Volatile/metabolism*

Valencene, a kind of sesquiterpenoid with a citrus flavor, is mainly found in Valencia orange and is commonly used in cosmetics and food additives, as well as industrial synthetic nootkatone. In this study, synthetic biology was used to create a Saccharomyces cerevisiae cell factory to produce valencene. Fistly, valencene synthase gene (CnVS) from Callitropsis nootkatensis was inserted into the chromosome of the chassis strain YTT-T5. The resulting strain VAL-01 could produce 1.1 mg·L^-1 valencene. Protein fusion technique was used, different valencene synthases were compared and the copy number of key genes was adjusted, yielding valencene to 436.4 mg·L^-1. Then, knocking-out the transcription factor ROX1 resulted in valencene improvement by 17.4%. Moreover, the induction system of galactose was regulated, transcription factor PDR3 and INO2 were overexpressed. The engineered strain VAL-10 could produce 2 798.6 mg·L^-1 valencene by high cell density fermentation method (nearly 2 500 times higher than VAL-01). This study provides a basis for green production of valencene.

Objective: To investigate the clinical characteristics, cytogenetics, molecular biology, treatment, and prognosis of patients with therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) secondary to malignancies. Methods: The clinical data of 86 patients with t-MDS/AML in West China Hospital of Sichuan University between January 2010 and April 2023 were retrospectively analyzed. The clinical characteristics, primary tumor types, and tumor-related therapies were analyzed. Results: The study enrolled a total of 86 patients with t-MDS/AML, including 67 patients with t-AML, including 1 patient with M(0), 6 with M(1), 27 with M(2), 9 with M(3), 12 with M(4), 10 with M(5), 1 with M(6), and 1 with M(7). Sixty-two patients could be genetically stratified, with a median overall survival (OS) of 36 (95% CI 22-52) months for 20 (29.9%) patients in the low-risk group and 6 (95% CI 3-9) months for 10 (14.9%) in the intermediate-risk group. The median OS time was 8 (95% CI 1-15) months in 32 (47.8%) patients in the high-risk group. For patients with non-acute promyelocytic leukemia (APL) and AML, the median OS of the low-risk group was 27 (95% CI 18-36) months, which was significantly longer than that of the non-low-risk group (χ(2)=5.534, P=0.019). All 9 APL cases were treated according to the initial treatment, and the median OS was not reached, and the 1-, 2-, and 3-year OS rates were 100.0%, (75.0±6.2) %, and (75.0±6.2) % respectively. Of the 58 patients with non-APL t-AML (89.7%), 52 received chemotherapy, and 16 achieved complete remission (30.8%) after the first induction chemotherapy. The 1-, 2-, and 3-year OS rates of the non-APL t-AML group were (42.0 ± 6.6) %, (22.9±5.7) %, and (13.4±4.7) %, respectively. The median OS of patients who achieved remission was 24 (95% CI 18-30) months, and the median OS of those who did not achieve remission was 6 (95% CI 3-9) months (χ(2)=10.170, P=0.001). Bone marrow CR was achieved in 7 (53.8%) of 13 patients treated with vineclar-containing chemotherapy, with a median OS of 12 (95% CI 9-15) months, which was not significantly different from that of vineclar-containing chemotherapy (χ(2)=0.600, P=0.437). In 19 patients with t-MDS, the 1-, 2-, and 3-year OS rates were (46.8±11.6) %, (17.5±9.1) %, and (11.7±9.1) % with a median OS of 12 (95% CI 7-17) months, which was not significantly different from that in t-AML (χ(2)=0.232, P=0.630) . Conclusions: Breast cancer, bowel cancer, and other primary tumors are common in patients with t-MDS/AML, which have a higher risk of adverse genetics. Patients with APL had a high induction remission rate and a good long-term prognosis, whereas patients without APL had a low remission rate and a poor long-term prognosis.
Humans ; Retrospective Studies ; Leukemia, Myeloid, Acute/drug therapy* ; Leukemia, Promyelocytic, Acute/therapy* ; Prognosis ; Myelodysplastic Syndromes/drug therapy* ; Neoplasms, Second Primary/drug therapy* ; Remission Induction ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use*

Astragali Radix, a medicinal herb for invigorating Qi, has anti-aging, anti-tumor, immunoregulatory, blood sugar-and lipid-lowering, anti-fibrosis, anti-radiation and other pharmacological effects. This article reviewed the studies about the chemical components and pharmacological effects of Astragali Radix. According to the theory of quality markers(Q-markers) of Chinese medicinal materials, we predicted the Q-markers of Astragali Radix from traditional efficacy, chemical component validity, measurability, plant phylogeny, and pharmacokinetis. The results showed that total polysaccharides, flavonoids(e.g., calycosin-7-O-β-D-glucoside, formononetin, calycosin, quercetin, and ononin), and saponins(e.g., astragalosides Ⅱ, Ⅲ, and Ⅳ) can be taken as the main Q-markers. This review lays a foundation for regulating the quality research and standard establishment of Astragali Radix, and benefits the control and quality supervision of the production process of Astragali Radix and its related products.
Astragalus Plant ; Chromatography, High Pressure Liquid/methods* ; Drugs, Chinese Herbal/pharmacology* ; Flavonoids ; Plant Roots

Objective:To explore the clinical features and risk factors of systemic lupus erythematosus(SLE) concomitant with interstitial lung disease(ILD) in children.Methods:A retrospective analysis was performed.A total of 111 hospitalized children diagnosed with SLE in the Department of Rheumatology and Immunology, Children′s Hospital of Soochow University from February 2016 to November 2018 were selected as the research subjects and divided into the SLE-ILD group(18 cases) and the SLE-non-ILD group(93 cases)according to the lung high-resolution CT manifestations. T-test and Wilcoxon rank sum test were used to compare and analyze the general situation, clinical manifestations and laboratory results.Multivariate Logistic regression was used to analyze the risk factors of SLE-ILD. Results:The prevalence of SLE-ILD was 16.2%(18/111 cases). There were significant differences between the SLE-ILD group and the SLE-non-ILD group in the course of disease [14.00 (12.00-24.25) months vs.1.00(1.00-2.00) months], the incidence of serositis [55.6%(10/18 cases) vs.8.6%(8/93 cases)], post-activity shortness of breath [83.3%(15/18 cases) vs.25.8%(24/93 cases)], nervous system damage [27.8%(5/18 cases) vs.6.5%(6/93 cases)], cardiovascular system damage [38.9%(7/18 cases) vs.9.7%(9/93 cases)], the occu-rrence of increased erythrocyte sedimentation rate [66.7%(12/18 cases) vs.31.2%(29/93 cases)], the decreased C 3[88.9%(16/18 cases) vs.62.4%(58/93 cases)], positive anti neutrophil cytoplasmic antibody (ANCA) [88.9%(16/18 cases) vs.18.3%(17/93 cases)], positive anti-Sm antibody [61.1%(11/18 cases) vs.15.1%(14/93 cases)] and anti ribonucleoprotein antibody (anti RNP antibody)[66.7%(12/18 cases) vs.16.1%(15/93 cases)](all P<0.05). Logistic regression analysis demonstrated that serositis( OR=30.535, 95% CI: 2.167-430.336, P=0.011), shortness of breath after exercise( OR=55.115, 95% CI: 1.117-2 579.852, P=0.041), positive ANCA( OR=65.090, 95% CI: 4.488-944.071, P=0.002) and positive anti-RNP antibody( OR=10.007, 95% CI: 1.362-73.500, P=0.024) were risk factors for SLE-ILD. Conclusions:The longer the course of SLE, the higher the incidence of ILD; serositis, shortness of breath after exercise, positive ANCA and positive anti RNP antibody may be risk factors for SLE-ILD.

Xiao Xumingtang in The Catalogue of Famous Ancient Classics （The First Batch） issued by the National Administration of Traditional Chinese Medicine is derived from the Important Prescriptions Worth a Thousand Gold for Emergency （Bei Ji Qian Jin Yao Fang） written by SUN Si-miao in the Tang dynasty. The present study systematically explored the origin， development， historical evolution， and clinical application of Xiao Xumingtang. As revealed by the results， Xiao Xumingtang as well as its analogues are primary prescriptions indicated for apoplexy before the Tang and Song dynasties and serve as the benchmark for the treatment of apoplexy. After the Song dynasty， due to the changes in the understanding of the pathogenesis of apoplexy and the limitations of the understanding of Xiao Xumingtang， its clinical application to apoplexy gradually decreased. In modern times， it has been re-recognized and applied， during which its clinical applications have undergone great changes. Its clinical applications are extensive， involving a variety of diseases related to the brain and nervous systems， such as stroke and its sequelae， peripheral facial paralysis， rheumatoid arthritis， hypertension， and other diseases related to the motor nervous system. Its primary indications are stroke and its sequelae， followed by peripheral facial paralysis. Other new indications are gradually found. This study is expected to provide references for the clinical application of Xiao Xumingtang and the transformation of new drugs.

Objective To investigate the prevalence of Schistosoma japonicum infection in wild mice in Shitai County, Anhui Province, so as to provide insights into precise control of the source of S. japonicum infections. Methods Wild mice were captured using the trapping method for three successive nights at snail-infested settings from Jitan Village of Jitan Township, and Shiquan Village and Xibai Village of Dingxiang Township, Shitai County, Anhui Province in June and October, 2018. All trapped wild mice were sacrificed and liver and mesenteric vein specimens were collected for detection of S. japonicum eggs using microscopy, while the fecal samples in mouse intestines were collected for identification of S. japonicum infections using Kato-Katz technique. In addition, the population density of trapped wild mice was estimated and the prevalence of S. japonicum infection was calculated in trapped wild mice. Results A total of 376 wild mice were trapped from three villages in Shitai County. The population density of trapped wild mice was 9.1% (376/4 124), and the prevalence of S. japonicum infection was 24.2% (91/376) in trapped wild mice. The highest prevalence of S. japonicum infection was detected in Shiquan Village of Dingxiang Township (30.1%), and the lowest prevalence was seen in Xibai Village of Dingxiang Township; however, there was no significant difference in the prevalence of S. japonicum infection in trapped wild mice among three villages (χ²= 4.111, P > 0.05). In addition, there was no significant difference in the prevalence of S. japonicum infection in wild mice captured between on June (26.8%, 34/127) and October (22.9%, 57/249) (χ² = 0.690, P = 0.406). The trapped wild mice included 6 species, including Rattus norvegicus, Niviventer niviventer, R. losea, Apodemus agrarius, Mus musculus and N. coning, and the two highest prevalence of S. japonicum infection was detected in R. losea (34.9%, 22/63) and R. norvegicus (31.2%, 44/141). Conclusions The prevalence of S. japonicum infections is high in wild mice in Shitai County, and there is a natural focus of schistosomiasis transmission in Shitai County.

Background/Aims: Direct‐acting antivirals (DAAs) have been approved for hepatitis C virus (HCV) treatment in patients with end-stage renal disease (ESRD) on hemodialysis. Nevertheless, the complicated comedications and their potential drug-drug interactions (DDIs) with DAAs might limit clinical practice in this special population. Methods: The number, class, and characteristics of comedications and their potential DDIs with five DAA regimens were analyzed among HCV-viremic patients from 23 hemodialysis centers in Taiwan. Results: Of 2,015 hemodialysis patients screened in 2019, 169 patients seropositive for HCV RNA were enrolled (mean age, 65.6 years; median duration of hemodialysis, 5.8 years). All patients received at least one comedication (median number, 6; mean class number, 3.4). The most common comedication classes were ESRD-associated medications (94.1%), cardiovascular drugs (69.8%) and antidiabetic drugs (43.2%). ESRD-associated medications were excluded from DDI analysis. Sofosbuvir/velpatasvir/voxilaprevir had the highest frequency of potential contraindicated DDIs (red, 5.6%), followed by glecaprevir/pibrentasvir (4.0%), sofosbuvir/ledipasvir (1.3%), sofosbuvir/velpatasvir (1.3%), and elbasvir/grazoprevir (0.3%). For potentially significant DDIs (orange, requiring close monitoring or dose adjustments), sofosbuvir/velpatasvir/voxilaprevir had the highest frequency (19.9%), followed by sofosbuvir/ledipasvir (18.2%), glecaprevir/pibrentasvir (12.6%), sofosbuvir/velpatasvir (12.6%), and elbasvir/grazoprevir (7.3%). Overall, lipid-lowering agents were the most common comedication class with red-category DDIs to all DAA regimens (n=62), followed by cardiovascular agents (n=15), and central nervous system agents (n=10). Conclusions HCV-viremic patients on hemodialysis had a very high prevalence of comedications with a broad spectrum, which had varied DDIs with currently available DAA regimens. Elbasvir/grazoprevir had the fewest potential DDIs, and sofosbuvir/velpatasvir/voxilaprevir had the most potential DDIs.

Objective To analyze the overall functioning of children with learning disabilities, and develop individualized exercise rehabilitation protocol using International Classification of Functioning, Disability and Health (ICF). Methods Based on the theoretical framework of ICF and the disease diagnosis of International Classification of Diseases (ICD-11), and with the perspective of child development, the functional profiles of cognition, understanding, attention, thinking, motor, and activity and participation of children with learning disabilities were analyzed. A function-oriented and individulized exercise rehabilitation protocol for children with learning disabilities was constructed in light of ICF bio-psycho-social health paradignm and the theory of somatic and mental interaction. Results The functional performance of children with learning disabilities mainly demonstrated in mental dysfunction in physical functioning in the activities and participation limitations, such as learning and applying knowledge, general tasks and demands, and communication. For the environment factors, products and technology for education, products and technology for culture, recreation and sports, and services, systems and policies could also affect children with learning disabilities. Physical activity was beneficial for children with learning disabilities to improve mental and motor functioning and to effectively enhance intellectual, cognitive, attentional, communication, and mobility skills for the overall development of the children. Physical activity for children with learning disabilities was selected according to WHO guidelines for physical activity and sedentary behavior for children, and moderate to vigorous physical activity for at least 60 minutes, as well as high-intensity training no less than three times a week, together with appropriate physical games and leisure physical activities could effectively improve learning outcomes and reduce learning disabilities. Conclusion The health condition, functioning and motor development of children with learning disability had been analyzed using ICD-11 and ICF, and with the theories of somatic and metal interaction and ICF bio-psycho-social model, the holistic and function-oriented exercise rehabilitation program was developed that recommended at least 60 minutes of moderate intensity physical activity, including aerobic exercise and physical games, per day, and at least three times a week of high intensity physical activity of no less than 30 minutes, including plyometrics and physical competition. The development of individualized function-based exercise rehabilitation programs incorporating the learning disability and motor function characteristics of children could effectively improve the cognitive, attentional, and thinking functions of children with learning disabilities, reduce learning disabilities, and promote the overall development of children.