Objective To summarize and analyze what the listing in market of orphan drugs in China,the United States,the European Union,and Japan in 2023,and to provide empirical reference to Chinese phar-maceutical enterprises,pharmaceutical management,and new drug research and development departments.Methods Collect the 2023 drug market data released by official drug regulatory agencies in four countries and international organization-China,the United States,the European Union,and Japan categorize the market of rare disease drugs and and their indications,approval dates,R&D status in China,component therapeutic are-as,and special review and approval pathways were analyzed.Results Findings in 2023,28 orphan drugs were listed in the United States,mostly anti-tumor related,accounting for 32.1％(9 out of 28);17 orphan drugs were listed in the European Union,anti-tumor related accounting for 47.0％(8 of 17);22 listed in Japan;and 45 listed in China.In 2023,over 70％orphan drugs listed in the European Union and Japan entered the phase of clinical trials/marketing and applications/approved clinical applications in China(86.4％from Japan and 70.6％from European Union).Conclusions Currently,there is no qualification accreditation mechanism for orphan drugs in China.However,in 2023,the number of rare disease drugs listed in China was the greatest among the four countries/international organization.It reflects that China's Catalog for Rare Diseases played a guiding role in drug research and development.Meanwhile,the reform of drug approval and review in China and the issue of rare disease catalogs took place in a short period of time,so the review and approval,as well as re-search and development of rare disease drugs are still in the catching up stage.

Animals ; SARS-CoV-2 ; Antibodies, Neutralizing ; Macaca mulatta ; COVID-19/prevention & control* ; Antibodies, Viral ; Vaccines

Enterotoxigenic Escherichia coli（ETEC）infection can induce watery diarrhea，leading to dehydration，electrolyte disturbance，and even death in severe cases. Recombinant B subunit/inactivated whole-cell cholera（rBS/WC）vaccine is effective in preventing ETEC infectious diarrhea. On the basis of the latest evidence on etiology and epidemiology of ETEC，as well as the effectiveness，safety，and health economics of rBS/WC vaccine，National Clinical Research Center for Child Health（The Children’s Hospital，Zhejiang University School of Medicine）and Zhejiang Provincial Center for Disease Control and Prevention invited experts to develop expert consensus on rBS/WC vaccine in prevention of ETEC infectious diarrhea. It aims to provide the clinicians and vaccination professionals with guidelines on using rBS/WC vaccine to reduce the incidence of ETEC infectious diarrhea.

Objective:To explore the clinical and CT imaging features of immune checkpoint inhibitor-associated pneumonia (CIP) and to improve the early diagnostic ability of CIP.Methods:From June 1, 2020 to October 31, 2021, the clinical data and chest CT images of 2 067 patients with advanced malignant tumor treated with immune checkpoint inhibitor (ICI) in the First Medical Center, Chinese PLA General Hospital were retrospectively analyzed. Patients with CIP were enrolled according to the guidelines for CIP diagnosis, and the incidence, time from the start of medication to the onset of CIP, medication cycle, imaging features, imaging patterns, CT grade and outcomes were analyzed. χ 2 test was used to compare the incidence of CIP in patients with or without basic lung disease. Results:Among 2 067 patients with malignant tumors treated with ICI, 67 patients developed CIP, the incidence of CIP was 3.2%. The incidence of CIP was significantly different between 386 patients with basic lung disease (7.00%, 27/386) and 1 681 patients without basic lung disease (2.4%, 40/1 681) (χ 2=21.32, P<0.001). The time from the start of medication to the onset of CIP was 7-367 d (median 52 days), and the duration of medication was 1-12 cycles (median 2 cycles). The imaging features of CIP presented as ground glass opacities in 54 cases (80.6%), solid nodules in 26 cases (38.8%), consolidations in 25 cases (37.3%) and irregular reticular opacities in 24 cases (35.8%). The main radiologic pattern was organizing pneumonia (OP, 34 cases, 50.7%), and followed by diffuse alveolar damage (DAD) pattern (14 cases, 20.9%). According to CT grading, there were 26 cases in low risk grade, 17 cases in moderate risk grade and 24 cases in high risk grade. Of 43 low-and medium-risk grade cases, 25 were OP pattern, accounting for 58.1%, and among 24 high-risk grade patients, 13 were DAD pattern, accounting for 54.2%. Forty-three of the 52 patients were initially untreated, of which 23 patients progressed, 17 had lesion shrinkage, and 3 had resolution, and relapsed in 8 cases after resolution or drug withdrawal. Conclusions:The imaging manifestations of CIP are mainly ground glass opacities, nodules, consolidations, and irregular reticular opacities. The radiologic patterns are mainly OP and DAD. OP is the most common pattern in low-moderate risk grade CIP and DAD is the most common pattern in high risk grade CIP. Patients with basic lung disease are more likely to get CIP.

Objective:To assess the antibody persistence 3-5 years following vaccination of measles and rubella combined live-attenuated vaccine (MR) at 8 months of age and measles, mumps and rubella combined attenuated live vaccine (MMR) at 18 months of age.Methods:In 2016, 18-month-old children who were vaccinated with one dose of MR vaccine at the age of 8 months were recruited in Hebei Province as group 1; 4-, 5- and 6-year-old children who were vaccinated with one dose of MR vaccine at the age of 8 months and one dose of MMR vaccine at 18 months of age were recruited in Shanxi, Inner Mongolia and Beijing as group 2, group 3 and group 4, respectively. Serum samples were collected to detect IgG antibodies against measles, mumps and rubella by ELISA. Geometric mean concentrations (GMCs) of measles, mumps, and rubella antibodies were compared among groups by analysis of variance or non-parametric test. Seropositive rates were compared among groups by Chi-square test or Fisher′s exact test. Results:A total of 650 children were included in this study. Seropositive rates of measles, mumps and rubella antibodies 30 d after vaccination of 150 18-month-old children with one dose of MMR vaccine were 100%, 91.33% and 100%, respectively, and the GMCs were 1 846.87 mIU/ml, 299.91 IU/ml and 111.33 IU/ml, respectively. Seropositive rates of measles, mumps and rubella antibodies 3-5 years after vaccination one dose of MR vaccine at 8 months of age and one dose of MMR vaccine at 18 months of age were above 94%, 79% and 71%, respectively, and the GMCs were above 830 mIU/ml, 240 IU/ml and 31 IU/ml. No significant difference in the seropositive rates of the three antibodies was observed among groups 2, 3 and 4 ( P>0.05). There was no significant difference in the GMCs of measles or mumps antibodies among the three groups ( P>0.05), but the differences in the GMCs of rubella antibodies were statistically significant ( P=0.034). Conclusions:Measles, mumps and rubella antibodies persisted for 3-5 years without significant decrease after vaccination one dose of MR vaccine at 8 months of age and one dose of MMR vaccine at 18 months of age.

Objective To study the feasibility and value of magnetic resonance diffusion tensor imaging (DTI) to monitor non?arteritic anterior ischemic optic neuropathy (NAION). Methods Thirty eight NAION patients (56 eyes) were divided into acute period in 17 eyes, progressive period in 16 eyes and chronic period in 23 eyes at the base of onset time. According to matching principle, 56 eyes in 38 normal controls (NCs) were enrolled. All the patients and NCs underwent MR and DTI scan. The raw data were processed by two experienced radiologists, mean diffusivity (MD), axial diffusivities (λ//), radial diffusivities (λ┴), fractional anisotropy (FA) and Length value were got. The independent sample t test was used for the parameter values between the NAION group and the NCs group. A single factor variance analysis was used to compare the parameters among different stages of NAION group. Results Compared to the NCs group, the values of FA and Length in NAION group were reduced [0.20±0.11 vs 0.31±0.12, (5.85±0.92) vs (65.11± 6.89) mm], and the differences were statistically significant (t=-4.28,-5.25;P<0.05). The values of MD andλ┴were increased [(0.16±0.04)×10-3 vs (0.10±0.04)×10-3 mm2/s, (0.16±0.05)×10-3 vs (0.09±0.03)×10-3 mm2/s] in NAION group and the differences were statistically significant (t=6.83, 7.10;P<0.05). The value of FA and Length in acute period, progressive period and chronic period of the NAION group decreased differently compared to the NCs group. At the same time, the value of MD value and λ┴in the three periods of the NAION group increased compared to the NCs groupand the differences were statistically significant (P<0.05). The value of FA between the acute period, the progressive period, and the chronic period of NAION group were statistically signficant (F=10.88, P<0.05). However, no significant differences were found in the values of MD, λ┴and Length of the NAION group (F=0.23, 0.64, 0.33, 1.38;P=0.79, 0.54, 0.72, 0.27). Conclusion The parameters of DTI can be used to monitor the damage of optic nerve and development in NAION.

Objective:Immunoregulation study of umbilical mesenchymal stem cell (UCMSCs) on allogeneic umbilical cord blood(UCB) CD4+T lymphocytes,which proliferation,apoptosis and the differentiation to CD4+CD25+ regulatory T cell (Treg) in vitro. Methods:Establishing on direct contact or transwell co-culture system,adopt in different proportion of UCMCs with phytohaemag-glutinin (PHA)-activated UCB CD4+T lymphocytes were co-cultured. The proliferation of lymphocyte,percent of CD4+CD25+/CD4+and Foxp3 expression, regulatory T cell marker gene were measured. Apoptosis of CD4+T lymphocytes were observed in the direct contact or transwell coculture system of UCMSCs with desamethason( DXM)-stimulated UCB CD4+T lymphocytes. Results: The UCB CD4+T lymphocytes cocultured with UCMSCs with PHA-activating for 3 days,compared with the UCMSCs free control group,the amount of cells was reduced noticeably(P<0. 05) and the percent of CD4+CD25+in CD4+T lymphocytes and Foxp3 expression significantly in-creased(P<0. 01) in a dose dependent way(P<0. 05). The UCB CD4+T lymphocytes cocultured with UCMSCs with DXM-inducing for 7 days,the apoptosis rate was significantly lower than that of the control group without UCMSCs (P<0. 01). These effects were partially attenuated in transwell coculture but could not be eliminated. Conclusion: UCMSCs are negative effect on UCB CD4+T lymphocytes-mediated immunity effects,and mainly manifested in the regulation on cell proliferate ability and differentiation rather than promoting apoptosis.

Purpose To explore multi-slice spiral CT (MSCT) in differential diagnosis of esophageal leiomyoma and esophageal carcinoma.Material and Methods Plain chest CT scan and enhanced inspection image of 26 patients with esophageal leiomyoma and 68 patients with esophageal carcinoma at the same term which had been confirmed by surgery and pathology were retrospectively analyzed.Characteristics such as focus size,morphology,density and tumor-air surface,etc were recorded and compared.Results MSCT of esophageal leiomyoma showed uniform density,possible calcification,polylimited influence of esophageal wall,scarcity of depression in focus niche,smooth tumor-air surface,low degree of enhanced amplification,and cerioid expansion of related lumen of larger focus.However,MSCT in esophageal carcinoma was represented by thickened annulus of esophageal wall,no calcification of focus,familiarity of depression in focus niche,rough tumor-air surface and intermediate degree strengthening.Differences of contrast of calcification,polylimited influence of esophageal wall,scarcity of depression in focus niche,smooth tumor-air surface in sophageal leiomyoma with that of esophageal carcinoma were statistically significant (P＜0.05).Conclusion MSCT can accurately identify sophageal leiomyoma and esophageal carcinoma,offering evidence for clinical diagnosis and treatment.

We discussed the influence of liquid nitrogen cryopreservation to survive capability of Babesia microti standard strain.The whole blood of mice infected with Babesia microti was put in liquid nitrogen to cryopreservation for 1 month,3 months,6 months,9 months,the whole blood was get out respectively and recovery at room temperature,and infected 3 mice respectively,100 μL/ mouse (the first generation after redissolution,the experiment group).In the same time,3 mice were also infected with Babesia microti as the animal conservation control group.When the infection rate was at a high level,the whole blood of the experiment group mice were injected into 3 normal BALB/c mice (the second generation after redissolution),to observe the changes of the Babesia microti form and proliferation situation,and also to observe the infection rate of the first and the second generation after redissolution in different conserving time.Compared with Babesia microti of animal subcultivation,the form of Babesia microti of liquid nitrogen cryopreservation changed a little.Small trophozoites,annular trophozoites,schizont and immature and mature merozoite and other form can also be seen.Compared with Babesia microti of animal subcultivation,the first time to see the worms and the time attaining to the high infection level were 1 to 2 days later,but for the second generation after redissolution,it is the same.There was no significant difference in different conserving time of 1,3,6,9 months.The influence of liquid nitrogen cryopreservation to survive capability and worm form of Babesia microti is a little,so liquid nitrogen cryopreservation can be a better way to conserving Babesia microti.