The pharmaceutical industry faces challenges in quality digitization for complex multi-stage processes, especially in small-sample systems. Here, an intelligent quality prediction and diagnostic (IQPD) framework was developed and applied to Tong Ren Tang's Niuhuang Qingxin Pills, utilizing four years of data collected from four production units, covering the entire process from raw materials to finished products. In this framework, a novel path-enhanced double ensemble quality prediction model (PeDGAT) is proposed, which combines a graph attention network and path information to encode inter-unit long-range and sequential dependencies. Additionally, the double ensemble strategy enhances model stability in small samples. Compared to global traditional models, PeDGAT achieves state-of-the-art results, with an average improvement of 13.18% and 87.67% in prediction accuracy and stability on three indicators. Additionally, a more in-depth diagnostic model leveraging grey correlation analysis and expert knowledge reduces reliance on large samples, offering a panoramic view of attribute relationships across units and improving process transparency. Finally, the IQPD framework integrates into a Human-Cyber-Physical system, enabling faster decision-making and real-time quality adjustments for Tong Ren Tang's Niuhuang Qingxin Pills, a product with annual sales exceeding 100 million CNY. This facilitates the transition from experience-driven to data-driven manufacturing.

Objective To investigate the diagnosis and treatment of multiple testicular Leydig cell tumors presenting with azoospermia.Methods Clinical data of a case of multiple testicular Leydig cell tumors presenting with azoospermia as well as re-lated article were reviewed.Results The patient visited the doctor due to"failure to conceive after 3 years of regular unprotect-ed sexual intercourse",and two consecutive semen analyses both indicated azoospermia.Testicular color Doppler ultrasound,en-hanced CT and pelvic MRI all suggested testicular space-occupying lesions.Preoperative evaluation suggested benign testicular tumors.Intraoperative frozen section pathology confirmed Leydig cell tumors.Microscopic testis-sparing tumor enucleation and microsurgical testicular sperm extraction(mTESE)were performed,with no sperm identified intraoperatively.The patient under-went successful tumor resection without complications.During the 12-month follow-up period,no tumor recurrence or metastasis was observed.Seminal volume increased compared to pre-operative levels,but azoospermia persisted.Conclusions Testicular Leydig cell tumor is a rare neoplasms originating from the gonadal stroma.Preoperative diagnosis is difficult.Radical orchiectomy is the primary treatment modality.However,testis-sparing tumor enucleation may be a safe and effective alternative for patients with bilateral testicular tumors.Tumor enucleation with testicular preservation is also a safe and effective choice for the patients with small-sized lesions or prepubertal status,whereas a long-term close follow-up is strictly implemented.

Objective To identify the taste critical quality attribute and design and optimize the flavor-correcting formulation of the traditional Chinese medicine oral preparation Qingre Jiedu Oral Liquid,in order to improve its taste and enhance patient medication adherence.Methods The taste assignment method was employed to identify the taste critical quality attribute of Qingre Jiedu Oral Liquid.Based on human sensory evaluation and the standardized Euclidean distance in electronic tongue analysis,suitable types of corrigent were determined.Subsequently,under constraints such as maximum allowable dosage,solubility,and sweetness,the optimal taste formulation for the sugar-free intermediate of Qingre Jiedu Oral Liquid was determined using Box-Behnken experimental design combined with electronic tongue and human sensory evaluation results.The study was reviewed and approved by the Ethics Committee of Beijing University of Chinese Medicine(Ethics Approval Number 2020BZYLL0609).Results The quantitative score for bitter taste of Qingre Jiedu Oral Liquid accounted for 30.36%,confirming bitterness as the taste critical quality attribute requiring attention.The optimal taste formulation for the sugar-free intermediate of Qingre Jiedu Oral Liquid was determined to be 120 mg·mL?1 erythritol,12 mg·mL?1 acesulfame potassium,and 2.4 mg·mL?1 stevioside.This formulation achieved an 11.75-point improvement in sensory evaluation scores compared to the original commercially available oral liquid.Conclusion This study successfully improved the taste of Qingre Jiedu Oral Liquid and established a comprehensive strategy for flavor-correcting formulation optimization,including a method for identifying taste critical quality attribute.This strategy provides a referential paradigm for palatability enhancement of similar traditional Chinese medicine oral preparations,laying a crucial technical foundation for elevating the clinical value of Chinese herbal medicines and promoting the high-quality development of traditional Chinese medicine(TCM).

Objective To identify the taste critical quality attribute and design and optimize the flavor-correcting formulation of the traditional Chinese medicine oral preparation Qingre Jiedu Oral Liquid,in order to improve its taste and enhance patient medication adherence.Methods The taste assignment method was employed to identify the taste critical quality attribute of Qingre Jiedu Oral Liquid.Based on human sensory evaluation and the standardized Euclidean distance in electronic tongue analysis,suitable types of corrigent were determined.Subsequently,under constraints such as maximum allowable dosage,solubility,and sweetness,the optimal taste formulation for the sugar-free intermediate of Qingre Jiedu Oral Liquid was determined using Box-Behnken experimental design combined with electronic tongue and human sensory evaluation results.The study was reviewed and approved by the Ethics Committee of Beijing University of Chinese Medicine(Ethics Approval Number 2020BZYLL0609).Results The quantitative score for bitter taste of Qingre Jiedu Oral Liquid accounted for 30.36%,confirming bitterness as the taste critical quality attribute requiring attention.The optimal taste formulation for the sugar-free intermediate of Qingre Jiedu Oral Liquid was determined to be 120 mg·mL?1 erythritol,12 mg·mL?1 acesulfame potassium,and 2.4 mg·mL?1 stevioside.This formulation achieved an 11.75-point improvement in sensory evaluation scores compared to the original commercially available oral liquid.Conclusion This study successfully improved the taste of Qingre Jiedu Oral Liquid and established a comprehensive strategy for flavor-correcting formulation optimization,including a method for identifying taste critical quality attribute.This strategy provides a referential paradigm for palatability enhancement of similar traditional Chinese medicine oral preparations,laying a crucial technical foundation for elevating the clinical value of Chinese herbal medicines and promoting the high-quality development of traditional Chinese medicine(TCM).

Objective To investigate the diagnosis and treatment of multiple testicular Leydig cell tumors presenting with azoospermia.Methods Clinical data of a case of multiple testicular Leydig cell tumors presenting with azoospermia as well as re-lated article were reviewed.Results The patient visited the doctor due to"failure to conceive after 3 years of regular unprotect-ed sexual intercourse",and two consecutive semen analyses both indicated azoospermia.Testicular color Doppler ultrasound,en-hanced CT and pelvic MRI all suggested testicular space-occupying lesions.Preoperative evaluation suggested benign testicular tumors.Intraoperative frozen section pathology confirmed Leydig cell tumors.Microscopic testis-sparing tumor enucleation and microsurgical testicular sperm extraction(mTESE)were performed,with no sperm identified intraoperatively.The patient under-went successful tumor resection without complications.During the 12-month follow-up period,no tumor recurrence or metastasis was observed.Seminal volume increased compared to pre-operative levels,but azoospermia persisted.Conclusions Testicular Leydig cell tumor is a rare neoplasms originating from the gonadal stroma.Preoperative diagnosis is difficult.Radical orchiectomy is the primary treatment modality.However,testis-sparing tumor enucleation may be a safe and effective alternative for patients with bilateral testicular tumors.Tumor enucleation with testicular preservation is also a safe and effective choice for the patients with small-sized lesions or prepubertal status,whereas a long-term close follow-up is strictly implemented.

AIM:To investigate the effect of hydrogen sulfide(H2S)on ferroptosis and functional impairment induced by oxidized high-density lipoprotein(ox-HDL)in human umbilical vein endothelial cells(HUVECs),and to ex-plore its mechanisms.METHODS:The HUVECs were cultured in vitro and exposed to 200 mg/L ox-HDL,ferroptosis in-hibitor ferrostatin-1(Fer-1),protein kinase B(PKB/Akt)inhibitor MK-2206 2HCl(MK),Akt agonist SC79,and/or H2S for 24 h.Western blot was used to identify the relevant proteins.Intracellular levels of reactive oxygen species(ROS)were analyzed by flow cytometry and immunofluorescence staining.Intracellular iron was measured using an iron detection kit.The number of monocytes adhering to endothelial cells was counted using the monocyte adhesion assay.RESULTS:Compared with control group,acyl-CoA synthetase long-chain family member 4(ACSL4)protein expression in ox-HDL group was elevated by 1.45-fold(P<0.01),glutathione peroxidase 4(GPX4)protein expression was decreased by 29.79%(P<0.05),and ROS levels and iron ion content were elevated by 4.81-fold and 1.40-fold,respectively(P<0.01).The ratios of p-PI3K/PI3K and p-Akt/Akt were decreased by 45.65%and 41.68%,respectively(P<0.01),endo-thelial cell function-related protein IL-6,ICAM-1 and TNF-α expression was elevated 1.18-fold,1.24-fold and 1.41-fold(P<0.05),respectively,eNOS protein expression was decreased by 35.24%(P<0.01),and monocyte adhesion was ele-vated 3.43-fold(P<0.01).Compared with ox-HDL group,the endothelial cell iron death-related protein ACSL4 was de-creased by 22.32%(P<0.05),GPX4 was increased by 1.27-fold(P<0.01),and the p-Akt/Akt ratio was increased by 1.52-fold(P<0.01)in ox-HDL+H2S group.The fluorescence microscopy results showed that the ROS was decreased by 50.35%(P<0.01).The IL-6,ICAM-1 and TNF-α protein expression was decreased by 13.34%,9.83%and 13.46%(P<0.05),respectively,eNOS was elevated by 1.22-fold(P<0.01),and the number of monocyte adhesion was de-creased by 59.05%(P<0.01).Compared with ox-HDL group,GPX4 protein expression in ox-HDL+SC79 group was ele-vated by 1.49-fold(P<0.01),ACSL4 expression was decreased by 20.72%(P<0.05),and ROS and iron ions were de-creased by 59.31%and 23.85%(P<0.05),respectively.Compared with ox-HDL+H2S group,GPX4 protein expression was decreased by 21.28%,and ACSL4 protein expression was increased by 1.16-fold in ox-HDL+H2S+MK group(P<0.05).CONCLUSION:H2S activates Akt to inhibit ox-HDL-induced ferroptosis in HUVECs and alleviate their func-tional damage.

BACKGROUND:With the increase of patients with cubital tunnel syndrome,ulnar groove plasty does not affect the normal anatomical structure and distribution of the ulnar nerve,which is one of the main surgical procedures for the treatment of cubital tunnel syndrome.3D printing combined with ulnar groove plasty can more accurately position the expansion depth and width of the ulnar groove to avoid some surgical complications. OBJECTIVE:To investigate the effect of 3D printing technology combined with ulnar groove plasty on nerve electrophysiology and prognosis in patients with cubital tunnel syndrome. METHODS:A total of 70 patients with moderate and severe cubital tunnel syndrome who were treated in Cangzhou Integrated Traditional Chinese and Western Medicine Hospital from March 2020 to March 2022 were selected as the study subjects.They were divided into two groups,with 35 cases in each group.The control group underwent traditional ulnar groove plasty.The observation group underwent 3D printing technology combined with ulnar groove plasty.The patients were followed up for 3 months.The clinical efficacy,latency,amplitude of compound muscle action potential of abductor pollicis brevis of the affected limb and ulnar nerve motor conduction velocity,grip strength on the affected side,pinch strength of the middle and thumb fingers,S-W monofilament of the little finger,two-point discrimination of the little finger,and Disabilities of the Arm,Shoulder and Hand Questionnaire score were compared between the two groups. RESULTS AND CONCLUSION:(1)Compared with the control group(74%),the excellent and good rate was significantly higher in the observation group(91%)(P<0.05).(2)Compared with pre-treatment,the latency of compound muscle action potential of abductor pollicis brevis of affected limb was significantly shorter and the wave amplitude and ulnar nerve motor conduction velocity were significantly higher in the two groups after treatment.The latency was significantly shorter and the wave amplitude and ulnar nerve motor conduction velocity were significantly higher in the observation group than those in the control group(P<0.05).(3)Compared with pre-treatment,the grip strength,middle finger and thumb pinch strength of the affected side,S-W monofilament of the little finger and two-point discrimination of the little finger were significantly decreased in the two groups after treatment.The grip strength,middle finger and thumb pinch strength on the affected side were greater,S-W monofilament of the little finger and two-point discrimination of the little finger were significantly smaller in the observation group than those in the control group(P<0.05).(4)Compared with pre-treatment,the Disabilities of the Arm,Shoulder and Hand Questionnaire scores of the two groups were significantly reduced after treatment,and the Disabilities of the Arm,Shoulder and Hand Questionnaire scores of the observation group were significantly lower than those of the control group(P<0.05).(5)It is concluded that 3D printing technology combined with ulnar groove plasty in the treatment of cubital tunnel syndrome can effectively improve its clinical efficacy,promote the neurophysiological recovery of patients,and enhance the function of fingers and upper limbs,which has high clinical application value.

Objective:To investigate the efficacy, safety and recurrence rate of oral atenolol in the treatment of infantile hemangioma, so as to provide evidence-based medicine basis and reference for clinic.Methods:Search on the following public databases from January 1, 2008 to June 13, 2022: Web of Science, PubMed, Cochrane Library, Embase, U. S. National Library of Medicine Clinical Trials Registry Platform; China National Knowledge Infrastructure(CNKI), Chinese Biomedical Literature Service System(SinoMed), Chinese Science and Technology Journal Database and Wanfang Data. According to inclusion and exclusion criteria, studies on oral atenolol for the treatment of infantile hemangioma were selected. The outcome indicators were efficiency (complete response rate), incidence of adverse effects and recurrence rate. The single-arm meta-analysis was performed using R software version 4.1.2. Egger’s test was employed and funnel plots were drawn to assess publication bias in the literature.Results:A total of 14 studies were included, comprising 5 randomized controlled trials, 5 single-arm studies, 3 non-randomized controlled trials, and 1 case-control study. The oral administration of atenolol for the treatment of infantile hemangiomas resulted in an efficacy rate (complete remission rate) of 62% (95% CI 52%~71%). The incidence rate of adverse reactions related to the digestive system was 18% (95% CI 7%~30%), while that related to β2 receptor blockade was 4% (95% CI 2%~6%), central nervous system-related adverse reactions occurred at a rate of 10% (95% CI 5%~16%), the recurrence rate was 5% (95% CI 2%~9%). Egger’s test indicated that there was no significant publication bias in the efficacy rate, central nervous system-related adverse reaction rate, and gastrointestinal-related adverse reaction rate of oral atenolol treatment for infantile hemangiomas ( P>0.05). The sensitivity analysis for the efficacy rate, adverse reaction rate, and recurrence rate of oral atenolol treatment for infantile hemangiomas suggested that the result were stable and reliable. Conclusion:Oral administration of atenolol for the treatment of infantile hemangiomas demonstrates significant efficacy, fewer adverse reactions, and a low recurrence rate, making it a promising candidate as a reasonable alternative to oral propranolol for treating infantile hemangiomas.

Smart manufacturing still remains critical challenges for pharmaceutical manufacturing. Here, an original data-driven engineering framework was proposed to tackle the challenges. Firstly, from sporadic indicators to five kinds of systematic quality characteristics, nearly 2,000,000 real-world data points were successively characterized from Ginkgo Folium tablet manufacturing. Then, from simplex to the multivariate system, the digital process capability diagnosis strategy was proposed by multivariate C_pk integrated Bootstrap-t. The C_pk of Ginkgo Folium extracts, granules, and tablets were discovered, which was 0.59, 0.42, and 0.78, respectively, indicating a relatively weak process capability, especially in granulating. Furthermore, the quality traceability was discovered from unit to end-to-end analysis, which decreased from 2.17 to 1.73. This further proved that attention should be paid to granulating to improve the quality characteristic. In conclusion, this paper provided a data-driven engineering strategy empowering industrial innovation to face the challenge of smart pharmaceutical manufacturing.

Oligoasthenospermia is the primary cause of infertility. However, there are still enormous challenges in the screening of critical candidates and targets of oligoasthenospermia owing to its complex mechanism. In this study, stem cell factor (SCF), c-kit, and transient receptor potential vanilloid 1 (TRPV1) biosensors were successfully established and applied to studying apoptosis and autophagy mechanisms. Interestingly, the detection limit reached 2.787 × 10^-15 g/L, and the quantitative limit reached 1.0 × 10^-13 g/L. Furthermore, biosensors were used to investigate the interplay between autophagy and apoptosis. Schisandrin A is an excellent candidate to form a system with c-kit similar to SCF/c-kit with a detection constant (K_D) of 5.701 × 10^-11 mol/L, whereas it had no affinity for SCF. In addition, it also inhibited autophagy in oligoasthenospermia through antagonizing TRPV1 with a K_D of up to 4.181 × 10^-10 mol/L. In addition, in vivo and in vitro experiments were highly consistent with the biosensor. In summary, high-potency schisandrin A and two potential targets were identified, through which schisandrin A could reverse the apoptosis caused by excessive autophagy during oligoasthenospermia. Our study provides promising insights into the discovery of effective compounds and potential targets via a well-established in vitro-in vivo strategy.