Pharmaceutical research and development of vaccines is the core link to ensure their successful transition from laboratory research to commercial stable production. In view of the fact that my country's current vaccine development still mostly draws on traditional processes, the construction of the quality management system(QMS) for the entire life cycle of pharmaceutical development is not yet perfect, and there are challenges such as data reliability management, it is very important to establish a scientific and effective quality management strategy. Based on a systematic analysis of international and domestic regulatory guidelines, this paper proposes to establish a phased and differentiated quality management system, and emphasizes the concept of Quality by Design(QbD) as the core guide. The application of this system in the entire life cycle of vaccine development is systematically expounded, covering the key control points such as seed lot management for bacterial and viral strains, manufacturing process development and optimization, and quality research, as well as quality management strategies at each stage, in order to provide systematic reference for improving the compliance and reliability of vaccine development and meeting the regulatory expectations, so as to ultimately ensure the quality and safety of marketed vaccines.

Objective:To report the follow-up status of patients participating phase Ⅲ clinical trial (ZGDD3) of Donafenib tosilate (abbreviated as Donafenib) in the treatment of progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC), and to explore its efficacy, safety and prognostic factors.Methods:This study was a randomized controlled trial, and the clinicopathological data and follow-up results of 29 patients (16 males, 13 females, age 40-68 years) who participated in the clinical trial ZGDD3 between August 2018 and March 2021 were analyzed. Patients were divided into Donafenib group and placebo group using the central dynamic randomization method with the ratio of 2∶1. Adverse reactions (AE) during the trial were observed. Independent-sample t test, Mann-Whitney U test and Fisher exact test were used to analyze the differences of baseline characteristics between the two groups. Progression-free survival (PFS) and overall survival (OS) were followed up. Kaplan-Meier method was used to draw the survival curve (log-rank test) and Cox regression analysis was used to analyze the prognostic factors. Results:There were 22 patients in Donafenib group and 7 patients in placebo group. There were no significant differences of baseline characteristics between the two groups ( t values: -0.68, Z values: from -1.47 to -0.56, all P>0.05). The follow-up was 32.07(21.07, 49.85) months. During the trial, drug-related AEs occurred in all patients in Donafenib group, mostly was grade Ⅰ-Ⅱ, no grade Ⅳ or Ⅴ AEs were found. The median PFS was significantly longer in Donafenib group than that in placebo group (13.23 vs 4.03 months; χ2=9.68, P=0.002), and the median OS was 55.00 and 24.30 months respectively ( χ2=2.07, P=0.150). Metastasis to less common sites was the independent risk factor for OS (hazard ratio ( HR)=6.789, 95% CI: 1.272-36.246, P=0.025). Conclusions:Donafenib shows good clinical application in the treatment of RAIR-DTC, demonstrating good safety and efficacy. Metastasis to less common sites is closely related to OS.

BACKGROUND:Zinc-based alloy medical implant materials have excellent mechanical properties,complete degradability and good biocompatibility,and are mainly used in orthopedic implants,cardiovascular stents,bile duct stents,tracheal stents,nerve catheters,etc. OBJECTIVE:To review the research progress of biodegradable zinc-based alloys in bone defect repair and prospect the promising research direction and achievements of zinc-based materials. METHODS:After searching PubMed,Web of Science,WanFang Data,and CNKI databases from the establishment of the database to June 2023,various relevant articles on biodegradable zinc-based alloys for bone implant material research were collected.The basic characteristics of biodegradable zinc based alloys were summarized,and the role of zinc-based alloys in promoting bone tissue repair was sorted and summarized.The current research hotspots and shortcomings were discussed. RESULTS AND CONCLUSION:(1)Zinc-based alloys have good biocompatibility.Using zinc-based alloys as the matrix material,with the help of scaffold structure construction technology and coating optimization process,the bone conductivity of zinc-based alloys will be effectively improved,and their degradation products will have efficient bone induction to regulate the gene expression of osteoblasts and osteoclasts,thereby promoting the repair and reconstruction of bone defects.(2)However,in the research on optimizing zinc-based alloys,the coating process is relatively insufficient,and additive loading technology is still lacking.(3)Zinc-based alloys have excellent mechanical and biological properties.Through special processes,their bone conductivity and osteoinductivity can be increased to effectively improve their ability to promote bone repair and reconstruction,and it is expected to further achieve the development of personalized transplant materials.Further research and development are needed to optimize the integration of coating and additive loading technologies into zinc-based alloys.

Objective:To report the follow-up status of patients participating phase Ⅲ clinical trial (ZGDD3) of Donafenib tosilate (abbreviated as Donafenib) in the treatment of progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC), and to explore its efficacy, safety and prognostic factors.Methods:This study was a randomized controlled trial, and the clinicopathological data and follow-up results of 29 patients (16 males, 13 females, age 40-68 years) who participated in the clinical trial ZGDD3 between August 2018 and March 2021 were analyzed. Patients were divided into Donafenib group and placebo group using the central dynamic randomization method with the ratio of 2∶1. Adverse reactions (AE) during the trial were observed. Independent-sample t test, Mann-Whitney U test and Fisher exact test were used to analyze the differences of baseline characteristics between the two groups. Progression-free survival (PFS) and overall survival (OS) were followed up. Kaplan-Meier method was used to draw the survival curve (log-rank test) and Cox regression analysis was used to analyze the prognostic factors. Results:There were 22 patients in Donafenib group and 7 patients in placebo group. There were no significant differences of baseline characteristics between the two groups ( t values: -0.68, Z values: from -1.47 to -0.56, all P>0.05). The follow-up was 32.07(21.07, 49.85) months. During the trial, drug-related AEs occurred in all patients in Donafenib group, mostly was grade Ⅰ-Ⅱ, no grade Ⅳ or Ⅴ AEs were found. The median PFS was significantly longer in Donafenib group than that in placebo group (13.23 vs 4.03 months; χ2=9.68, P=0.002), and the median OS was 55.00 and 24.30 months respectively ( χ2=2.07, P=0.150). Metastasis to less common sites was the independent risk factor for OS (hazard ratio ( HR)=6.789, 95% CI: 1.272-36.246, P=0.025). Conclusions:Donafenib shows good clinical application in the treatment of RAIR-DTC, demonstrating good safety and efficacy. Metastasis to less common sites is closely related to OS.

The precise assessment and management of the axillary lymph nodes in breast cancer is crucial for regional control, disease staging, selection of adjuvant chemotherapy strategies, and prediction of prognosis, with a general downward trend in surgical management. For early breast cancer with negative axillary lymph node metastases, sentinel lymph node biopsy (SLNB) has replaced axillary lymph node dissection (ALND) as the criterion for axillary status measurement. Patients can be exempted from ALND if they have negative SLNB results. However, it remains to be carefully decided in China whether patients with one or two positive nodes in SLNB can be spared from ALND. However, consensus has been met that patients who meet the criteria of the Z0011 study can be exempted from ALND. For breast cancer patients with positive axillary lymph nodes metastases at the beginning of treatment, the clearance of lymph node disease can be achieved by neoadjuvant therapy, with a reduced rate of complications related to ALND. In particular, there are still many debates associated with SLNB after neoadjuvant therapy, such as whether patients who remain axillary lymph node positive can be spared from ALND. Exploratory and validation studies related to the SLNB avoidance criteria are still controversial. In the future, clinicians should consider the characteristics of patients, the risk of recurrence, and adjuvant treatment regimens to develop individualized axillary lymph node management.

The precise assessment and management of the axillary lymph nodes in breast cancer is crucial for regional control, disease staging, selection of adjuvant chemotherapy strategies, and prediction of prognosis, with a general downward trend in surgical management. For early breast cancer with negative axillary lymph node metastases, sentinel lymph node biopsy (SLNB) has replaced axillary lymph node dissection (ALND) as the criterion for axillary status measurement. Patients can be exempted from ALND if they have negative SLNB results. However, it remains to be carefully decided in China whether patients with one or two positive nodes in SLNB can be spared from ALND. However, consensus has been met that patients who meet the criteria of the Z0011 study can be exempted from ALND. For breast cancer patients with positive axillary lymph nodes metastases at the beginning of treatment, the clearance of lymph node disease can be achieved by neoadjuvant therapy, with a reduced rate of complications related to ALND. In particular, there are still many debates associated with SLNB after neoadjuvant therapy, such as whether patients who remain axillary lymph node positive can be spared from ALND. Exploratory and validation studies related to the SLNB avoidance criteria are still controversial. In the future, clinicians should consider the characteristics of patients, the risk of recurrence, and adjuvant treatment regimens to develop individualized axillary lymph node management.

Background: Excessive delivery of free fatty acids (FFAs) to the liver promotes steatosis and insulin resistance (IR), with IR defined as reduced glucose uptake, glycogen synthesis and anti-lipolysis stimulated by normal insulin levels. Whether the associations between FFAs and diabetes development differ between patients with and without nonalcoholic fatty liver disease (NAFLD) remains unclear. Methods: Consecutive subjects (2,220 NAFLD subjects and 1,790 non-NAFLD subjects according to ultrasound imaging) were enrolled from the First Affiliated Hospital of Sun Yat-sen University between 2009 and 2019. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Results: There was an approximate J-shaped relationship between FFA levels and HOMA-IR in the NAFLD group. Higher FFA concentration quartiles were associated with higher risks of IR (odds ratio [OR], 9.24; 95% confidence interval [CI], 6.43 to 13.36), prediabetes (OR, 10.48; 95% CI, 5.66 to 19.39), and type 2 diabetes mellitus (T2DM; OR, 19.43; 95% CI, 12.75 to 29.81) in the NAFLD group but not in the non-NAFLD group. The cut-off points for the FFA levels increased in a stepwise manner in discriminating IR, prediabetes and T2DM (573, 697, and 715 μmol/L) in the NAFLD group but not in non-NAFLD individuals. Conclusion A distinct dose-dependent relationship of FFA levels was found with IR, prediabetes and T2DM in NAFLD patients. Screening serum FFA levels in NAFLD patients would be valuable in preventing diabetes development.

Background: Excessive delivery of free fatty acids (FFAs) to the liver promotes steatosis and insulin resistance (IR), with IR defined as reduced glucose uptake, glycogen synthesis and anti-lipolysis stimulated by normal insulin levels. Whether the associations between FFAs and diabetes development differ between patients with and without nonalcoholic fatty liver disease (NAFLD) remains unclear. Methods: Consecutive subjects (2,220 NAFLD subjects and 1,790 non-NAFLD subjects according to ultrasound imaging) were enrolled from the First Affiliated Hospital of Sun Yat-sen University between 2009 and 2019. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Results: There was an approximate J-shaped relationship between FFA levels and HOMA-IR in the NAFLD group. Higher FFA concentration quartiles were associated with higher risks of IR (odds ratio [OR], 9.24; 95% confidence interval [CI], 6.43 to 13.36), prediabetes (OR, 10.48; 95% CI, 5.66 to 19.39), and type 2 diabetes mellitus (T2DM; OR, 19.43; 95% CI, 12.75 to 29.81) in the NAFLD group but not in the non-NAFLD group. The cut-off points for the FFA levels increased in a stepwise manner in discriminating IR, prediabetes and T2DM (573, 697, and 715 μmol/L) in the NAFLD group but not in non-NAFLD individuals. Conclusion A distinct dose-dependent relationship of FFA levels was found with IR, prediabetes and T2DM in NAFLD patients. Screening serum FFA levels in NAFLD patients would be valuable in preventing diabetes development.

Objective:This study aims to investigate the prevalence of internet addiction, morningness-eveningness preference of sleep-wake chronotype, and sleep quality and the correlates of internet addition among first-year undergraduate students.Methods:The newly admitted undergraduates ( n=9 157) of a comprehensive university in 2019 were invited to participate in an online survey from September 2019 to December 2019. The Young′s 20-item Internet Addiction Test, the Pittsburgh sleep quality index, and the Morningness-Eveningness Questionnaire (MEQ) were used to measure internet addiction, sleep quality, and the types of morningness-eveningness preference respectively. Logistic regression analysis was used to analyze factors independently related to internet addiction with demographic variables (i.e., gender and age), sleep problems, and morningness-eveningness preference adjusted. Results:A total of 7 457 (81.4%) newly admitted undergraduates completed the questionnaires. The prevalence of internet addiction in the total sample was 8.86% (661/7 457), while the corresponding figures were 10.04% (348/3 466) in female students and 7.84% (313/3 991) in male students. The prevalence of sleep problems was 11.73% (875/7 457). For chronotype, the prevalence of evening type, intermediate type, and morning type was 54.73% (4 081/7 457), 43.02% (3 208/7 457) and 2.25% (168/7 457) respectively. After adjusting the interaction of related factors in the logistic regression analysis, being female ( OR=1.26), having sleep quality ( OR=4.12), and having sleep-wake chronotype of intermediate type ( OR=0.37) and morning type ( OR=0.24) were independently associated with internet addiction. Conclusions:Female students had higher prevalence of internet addiction than male students. Majority of students had a chronotype of intermediate or evening type. The sleep-wake chronotype was independently associated with internet addiction after controlling sleep quality, which indicated that sleep biological rhythm may be involved in the mechanism of the occurrence of internet addiction.

Objective:This study aims to investigate the prevalence of internet addiction, morningness-eveningness preference of sleep-wake chronotype, and sleep quality and the correlates of internet addition among first-year undergraduate students.Methods:The newly admitted undergraduates ( n=9 157) of a comprehensive university in 2019 were invited to participate in an online survey from September 2019 to December 2019. The Young′s 20-item Internet Addiction Test, the Pittsburgh sleep quality index, and the Morningness-Eveningness Questionnaire (MEQ) were used to measure internet addiction, sleep quality, and the types of morningness-eveningness preference respectively. Logistic regression analysis was used to analyze factors independently related to internet addiction with demographic variables (i.e., gender and age), sleep problems, and morningness-eveningness preference adjusted. Results:A total of 7 457 (81.4%) newly admitted undergraduates completed the questionnaires. The prevalence of internet addiction in the total sample was 8.86% (661/7 457), while the corresponding figures were 10.04% (348/3 466) in female students and 7.84% (313/3 991) in male students. The prevalence of sleep problems was 11.73% (875/7 457). For chronotype, the prevalence of evening type, intermediate type, and morning type was 54.73% (4 081/7 457), 43.02% (3 208/7 457) and 2.25% (168/7 457) respectively. After adjusting the interaction of related factors in the logistic regression analysis, being female ( OR=1.26), having sleep quality ( OR=4.12), and having sleep-wake chronotype of intermediate type ( OR=0.37) and morning type ( OR=0.24) were independently associated with internet addiction. Conclusions:Female students had higher prevalence of internet addiction than male students. Majority of students had a chronotype of intermediate or evening type. The sleep-wake chronotype was independently associated with internet addiction after controlling sleep quality, which indicated that sleep biological rhythm may be involved in the mechanism of the occurrence of internet addiction.