Since its establishment in 2016, the National Rare Diseases Registry System of China (NRDRS) has accumulated valuable case data and bio-specimen for basic and clinical research on rare diseases in China. However, the emerging challenges in clinical diagnosis and treatment of rare diseases make it unable for data and resource platform to fully meet the diversified needs. Under this backdrop, we have developed a protocol to optimize and upgrade the system based on the core functions of the NRDRS platform. The goal is to leverage intelligent digital technologies to transform NRDRS into a new platform integrating multimodal data and auxiliary diagnostic and treatment functions. It is specified as the development and construction of "one platform and four intelligent tools." Currently, we have upgraded and developed NRDRS platform, intelligent tool for genotype-phenotype analysis of rare diseases, AI-assisted diagnostic tool for rare diseases, remote multidisciplinary diagnosis and teaching tool for rare diseases, drug screening and validation tool for rare diseases. The next step will focus on the promotion of the application of these tools in clinical settings in order to address the issue of severe imbalance in the allocation of resources for the diagnosis and treatment of rare diseases. This article provides an overview of the digital and intelligent upgrades of the NRDRS, the trials in applications in clinical settings, and direction in the future.

AIM: To explore the efficacy of internal limiting membrane(ILM)flap technique and simple ILM peeling in the treatment of idiopathic macular hole(IMH)and related influencing factors.METHODS: A retrospective cohort study was conducted on totally 32 patients(35 eyes)with IMH who received surgery at our department from January 2023 to November 2024. All the patients simultaneously received phacoemulsification combined with intraocular lens implantation, and they were divided into study group(19 eyes)and control group(16 eyes), with ILM flap technique and simple ILM peeling received in the two groups, respectively. The closure situation of macular hole, best corrected vision acuity(BCVA), and macular structure were observed in the two groups of patients. Furthermore, the correlation of BCVA and healing type of macular hole at the last time of follow-up with each parameter was analyzed.RESULTS: There was no statistical difference between the two groups of patients in preoperative general characteristics(all P>0.05). At the last time of follow-up, the macular hole was heeled in both groups, with 7 eyes of U-shaped heeling, 6 eyes of V-shaped heeling, and 6 eyes of irregular heeling in the study group, and with 13 eyes of U-shaped of heeling, 1 eye of V-shaped heeling and 2 eyes of irregular heeling in the control group(χ2=7.167, P=0.028). The postoperative BCVA was better than preoperative level(all P<0.05), there were no statistical significant differences between the two groups of patients in macular choroidal thickness before and after surgery(P>0.05), but the macular retinal thickness of the study group was thinner than that of the control group(168.11±92.11 vs 235.56±92.18 μm, P=0.03). Pearson correlation analysis indicated that BCVA at the last time of follow-up was positively correlated with the preoperative minimum diameter(r=0.476, P<0.05)and the diameter hole index(r=0.361, P<0.05), and negatively correlated with traction hole index(r=-0.364, P=0.031); Keendall correlation analysis showed that the postoperative closure types positively correlated with the basal diameter(τ=0.296, P=0.029), minimum diameter(τ=0.366, P=0.007), and visual acuity at the last time of follow-up(τ=0.412, P=0.003), while negatively correlated with macular hole index(τ=-0.415, P=0.002)and traction hole index(τ=-0.511, P<0.01). During the follow-up period, neither group of patients experienced postoperative complications.CONCLUSION: Both ILM flap technique and simple ILM peeling are safe and effective in treating IMH. As the smaller the basal diameter and minimum diameter of the macular hole, the larger the macular hole index and traction hole index, the probability of U-shaped heeling after surgery is greater and the visual acuity is better.

This article combs and summarizes the entire process of rare disease selection and priority theme determination,including the application and preliminary review of rare diseases,standardization of disease theme information,the evaluation methods of evidence sorting and disease selection for priority se-lection of disease themes,and other aspects of the content were analyzed in depth.It is expected to provide reference for the subsequent selection of rare diseases,improve the fairness,rationality and scientificity of rare disease selection,and further promote research and decision-making in China's rare disease-related fields.

Objective To prepare an ophthalmic solution of dihydromyricetin(DMY)based on dipotassium glycyr-rhizinate(DG)nanomicelle solubilization(DG-DMY)and evaluate its effect on dry eyes of mice.Methods DG-DMY was prepared using the thin-film hydration method,and its micelle size,potential,encapsulation efficiency and storage sta-bility at room temperature were tested.The ocular safety of DG-DMY was tested on mice.Dry eye models were built in mice,which were divided into normal control group(normal mice without intervention),PBS control group(dry eye mouse models,intervened by PBS),HA treatment group[dry eye mouse models,intervened by 1 g·L-1 hyaluronic acid(HA)]and DG-DMY treatment group(dry eye mouse models,intervened by DG-DMY),with 10 mice in each group.The fluorescein sodium staining of corneal epithelium and surface tear secretion were recorded after 10 days of intervention.Morphological changes in corneal epithelium,corneal stroma and endothelial cells were monitored by hematoxylin & eosin staining.The enzyme-linked immunosorbent assay(ELISA)was adopted to measure the expression levels of interleukin-6(IL-6)and interleukin-1β(IL-1β).Results DG-DMY is a light yellow,transparent solution with a nanomicelle size of(208.8±3.9)nm,polydispersity index of 0.277,Zeta potential of-(17.6±1.42)mV,encapsulation efficiency of 76.72％,and drug loading efficiency of 10.21％.It is stable at room temperature(25℃)and storage temperature(4 ℃).The mouse studies showed that DG-DMY displayed good in vivo tolerance in mice eyes.The therapeutic results showed that mice in the PBS treatment group still had extensive corneal staining,mice in the HA treatment group had reduced corneal staining,and mice in the DG-DMY treatment group had almost no corneal staining.The tear secretion of mice in the normal control group,PBS control group,HA treatment group and DG-DMY treatment group was(5.15±0.47)mm,(2.26±0.41)mm,(4.02±0.53)mm,and(4.11±0.54)mm.The histopathological results showed that the corneal epithelium,loose collagen structure and basal layer were damaged in the PBS control group;the corneal histopathological injury of mice in the HA treatment group and DG-DMY treatment group were mitigated,with normal corneal epithelium,corneal stroma and endothelial tissues.ELISA results showed that the expression level of IL-6 in the normal control group,PBS control group,HA treatment group and DG-DMY treatment group was(22.98±0.69)ng·g-1,(108.1±6.06)ng·g-1,(56.79±4.87)ng·g-1 and(44.01±0.99)ng·g-1,respectively,and the expression level of IL-1β was(27.97±2.74)ng·g-1,(115.70±5.16)ng·g-1,(50.36±1.56)ng·g-1 and(42.21±1.46)ng·g-1,respectively.Compared with the HA treatment group,the expression levels of IL-6 and IL-1β in the cornea of mice in the DG-DMY treatment group were lower,and the differences were statistically significant(both P＜0.05).Conclusion DG-DMY nano-preparation successfully prepared in this study is verified to act on benzalkonium chloride-induced dry eye effectively and control the inflammatory response of dry eye mouse models by inhibiting the expressions of IL-6 and IL-1β with high safety.

Objective:To compare the clinical characteristics and changes in inhaled drugs of newly diagnosed chronic obstructive pulmonary disease (COPD) patients in some hospitals in Hunan and Guizhou from 2017 to 2023, in order to further understand the current status of COPD diagnosis and treatment.Methods:This cross-sectional study included stable COPD patients who were initially diagnosed in the respiratory and critical care departments of 13 hospitals in China from January 1, 2017 to December 31, 2023. They were divided into 7 groups based on the time of their initial visit: the 2017, 2018, 2019, 2020, 2021, 2022, and 2023 groups. Basic information of the patients, the percentage of forced expiratory volume per second (FEV 1% pred), FEV 1/forced vital capacity (FVC), COPD assessment questionnaire (CAT) scores, the number of acute weightings in the past year, and inhalation drug regimens were collected. Results:The CAT scores of patients with COPD who visited from 2017 to 2019 were significantly higher than those from 2020 to 2023 (all P<0.05); The FEV 1% pred and FEV 1/FVC of patients with COPD showed an increasing trend from 2017 to 2023; The proportion of patients using long-acting muscarine anticholinergic (LAMA) gradually decreased between 2017 and 2023, with 8.0% (134/1 665) of patients with COPD using single drug LAMA in 2023. The proportion of patients using double branch dilators has been increasing year by year in 2018, 2019, 2020, and 2021, and the proportion of patients using double branch dilators for COPD has stabilized in 2021, 2022, and 2023, with no statistically significant difference between groups ( P>0.05). The proportion of patients with COPD who used triple inhalation drugs was the lowest in 2020 and 2021 ( P<0.05). In 2017, 2018, 2019, 2022, and 2023, the proportion of patients with COPD who used triple inhalation drugs was 45.2%(364/806), 54.0%(730/1 352), 55.5%(742/1 337), 45.8%(717/1 565), and 51.1%(851/1 665), respectively. The compliance with inhalation prescriptions and Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) documents for newly diagnosed patients with COPD from 2017 to 2023 was 47.9%(386/806), 35.1%(474/1 352), 33.7%(451/1 337), 40.3%(405/1 005), 31.2%(372/1 193), 28.4%(445/1 565), and 58.8%(979/1 665), respectively. Conclusions:With the migration of time, the clinical symptoms of newly diagnosed COPD patients have been alleviated, indicating a trend of forward shift in treatment time; The proportion of double bronchodilators used has increased, and the proportion of triple inhaled drugs used is relatively high. The compliance with GOLD documents is still not ideal.

Objective:To compare the differences in inhaled medication prescriptions among patients with chronic obstructive pulmonary disease (COPD) who visited the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD 2023) one year after its release and the previous year, and to analyze the impact of GOLD 2023 on physician inhaled medication prescriptions.Methods:This study was a cross-sectional study, with data sourced from the RealDTC study. The study subjects were chronic obstructive pulmonary disease patients who visited the respiratory and critical care departments of 13 hospitals in southern China from November 14, 2021 to November 15, 2023. According to the time of patient visits, they are divided into the following two groups: the group 1 year before the release of GOLD 2023 (November 14, 2021 to November 14, 2022), and the group 1 year after the release of GOLD 2023 (November 15, 2022 to November 15, 2023). We collected demographic characteristics, lung function, symptom scores, history of acute exacerbation in the past year, and inhaled medication prescriptions from patients. According to the symptom score of COPD patients in GOLD 2023 and their history of acute exacerbation in the past year, they were divided into three groups: A, B, and E. The treatment status of inhaled drugs in groups A, B, and E before and after the release of GOLD 2023 was compared.Results:There were statistically significant differences in COPD Assessment Test (CAT) scores, Modified Medical Research Council (mMRC) scores, and the number of acute exacerbations in the past year between patients with COPD before and after the release of GOLD 2023 (all P<0.05). Compared with the group one year before the release of GOLD 2023, the proportion of patients in the group one year after the release of GOLD 2023 using long-acting muscarinic antagonists (LAMA) and inhaled corticosteroids (ICS)+ long-acting β2-receptor agonists (LABA) was lower, while the proportion of patients using LABA+ LAMA and ICS+ LABA+ LAMA was higher (all P<0.05). There was no statistically significant difference ( P>0.05) in the proportion of patients in group A using LAMA between the year before and after the release of GOLD 2023. Compared to the year before the release of GOLD 2023, the proportion of patients in group A who prescribed ICS+ LABA was lower, while the proportion of using LABA+ LAMA and ICS+ LABA+ LAMA was higher (all P<0.05); The proportion of patients in group B who prescribed LAMA and ICS+ LABA was lower (all P<0.05), while the proportion of using LABA+ LAMA and ICS+ LABA+ LAMA was higher (all P<0.05); The proportion of patients in group E who prescribed LAMA and ICS+ LABA was lower (all P<0.05), while the proportion of using LABA+ LAMA and ICS+ LABA+ LAMA was higher (all P<0.05). Conclusions:After the release of GOLD 2023, the prescription of ICS+ LAMA in groups A, B, and E decreased, and the prescriptions of LABA+ LAMA and ICS+ LABA+ LAMA increased compared to before; However, in the real world, the compliance of physicians with GOLD 2023 is still not ideal.

OBJECTIVE To investigate the role of the complement C3/C3aR signaling pathway in the prefrontal cortex and colon neuroglia cell interactions during meth-amphetamine(METH)addiction,to observe the effects of TLR4 inhibitors as well as complement C3 elimination on METH reward and relapse behavior,and to explore the neuroinflammatory mechanisms of complement C3 acti-vation in METH addiction.METHODS ①A 14 d and 28 d rat METH addiction model was established to observe the effects of TLR4 antagonist ibudilast 3 mg·kg-1 and 10 mg·kg-1 on self-administration,reward motivation,relapse,and natural reward behavior in METH-trained 14 d rats and the effects of 0.02 mg·kg-1 complement C3 antago-nist on self-administration behavior in METH-trained 28 d rats.② Differences in the expression of TLR4,NF-κB,GRP94,C3,cathepsin L,CD68,and GFAP in the pre-frontal cortex of each group were examined using West-ern blotting.③ In addition,the expression of ATF6 in the prefrontal cortex of each group and the effects on neuro-nal and microglia/macrophage INOS,CD206 GRP94,and complement C3/C3aR.RESULTS ① Endoplasmic reticulum stress occurred in neurons and microglia after METH exposure depending on GRP94 and unfolded pro-tein responses to the ATF6 pathway.In addition,it acti-vates the TLR4-NF-κB pathway.② Microglia with high complement C3/C3aR expression in the prefrontal cortex were recruited to synaptic pruning and phagocytic responses around neurons with high GRP94,comple-ment C3/C3aR expression and these effects were blocked by complement C3 antagonists.③ In the rec-tum,GRP94 functions as a molecular chaperone for com-plement C3 and cathepsin L.Crosstalk occurs between enteric neurons high in GRP94,complement C3,and macrophages high in C3aR,located in the submucosa,lamina propria,and muscular,respectively,and all of these effects are blocked by complement C3 antago-nists.④ Treatment with the TLR4 antagonist ibudilast inhibits self-administration,reward motivation,and cue-or METH-priming in METH-trained 14 d rats,but fails to affect natural reward behavior.Ibudilast treatment attenu-ates the TLR4-NF-κB inflammatory pathway and comple-ments C3/C3aR pathway in the prefrontal cortex.CON-CLUSION Activation of the complement C3/C3aR signal-ing pathway by TLR4-NF-κB inflammatory signaling in the prefrontal cortex mediates the METH addiction pro-cess,providing an experimental basis for the clinical treatment of METH addiction,and targeting TLR4/NF-κB inflammatory signaling and complement C3/C3aR may be a new way to intervene in METH addiction.

Objective:To explore the predictive value of exhaled nitric oxide (FeNO) for the risk of acute exacerbation in stable chronic obstructive pulmonary disease (COPD) patients over the next year and evaluate whether it can guide the use of inhaled corticosteroids (ICS).Methods:This study was a multicenter, retrospective and observational cohort study. The subjects of this study were stable COPD patients who were hospitalized in 12 hospitals in Hunan Province and Guangxi from January 2017 to December 2021. The patient′s basic Demography information, previous acute exacerbation history, pulmonary function, FeNO, chronic obstructive pulmonary disease assessment test questionnaire (CAT) score, modified British Medical Research Council dyspnea questionnaire (mMRC) score, chronic obstructive pulmonary disease control questionnaire (CCQ) score, and detailed treatment plan were collected. Based on FeNO 25 ppb, patients were divided into a high FeNO group and a normal FeNO group. All patients were followed up for 1 year and information on acute exacerbation was recorded.Results:A total of 825 patients were included, aged (63.5±9.1)years, with a median of 25 ppb of FeNO. A number of 825 patients were followed up for 1 year, of which 262(31.8%) experienced acute exacerbation. Multivariate logistic regression found that FeNO, CAT score, smoking cessation, and past history of acute exacerbation were independent factors predicting acute exacerbation in COPD patients in the next year (all P<0.05). High FeNO was a protective factor for acute exacerbation in COPD patients in the next year, with an OR value of 0.10 ( P<0.001). Further analysis found that the proportion of patients in the high FeNO group using ICS was significantly higher than that in the normal FeNO group [58.8%(247/420) vs 48.6%(197/405), P=0.003]. In the high FeNO group, using ICS can reduce the incidence of acute exacerbation of COPD in the next year [8.9%(22/247) vs 15.6%(27/173), P<0.05], while in the normal FeNO group, there was no statistically significant difference in the frequency of acute exacerbation between patients using ICS and those not using ICS ( P>0.05). Conclusions:FeNO is an independent factor predicting the acute exacerbation of COPD in the next year, and patients with high FeNO levels may consider using ICS in combination.

OBJECTIVE To study the mechanism of interfering with long non-coding RNA nicotinamide nucleotide transhydrogenase-antisense RNA1 （LncRNA NNT-AS1） expressing to reduce paclitaxel （TAX） resistance in non-small cell lung cancer （NSCLC） cells. METHODS NSCLC TAX-resistant cell line （A549/TAX） was constructed， and the expressions of LncRNA NNT-AS1 in normal， parental， and drug-resistant cells were observed. The targeting relationship of microRNA-582-5p （miR-582- 5p） with LncRNA NNT-AS1 and high mobility group box2 （HMGB2） was verified. A549/TAX cells were cultured in vitro to observe the effects of interfering with LncRNA NNT-AS1 alone or interfering with LncRNA NNT-AS1 and miR-582-5p on the expressions of LncRNA NNT-AS1 and miR-582-5p， the mRNA and protein expressions of HMGB2， cell viability， clone formation and apoptosis. The effects of interfering with LncRNA NNT-AS1 on tumor growth and the expression of miR-582-5p and the mRNA and protein expressions of HMGB2 in tumor tissue were observed in nude mice. RESULTS Compared with normal cells， LncRNA NNT-AS1 was highly expressed in parental and drug-resistant cells （P＜0.05）， showing an increasing trend. It was validated that miR-582-5p had a targeting relationship with LncRNA NNT-AS1 and HMGB2. After interfering with the expression of LncRNA NNT-AS1， the expression of LncRNA NNT-AS1 and the mRNA and protein expressions of HMGB2， cell viability and the number of cloned cells in A549/TAX cell， decreased significantly， while the expression of miR-582-5p and the apoptotic rate increased significantly （P＜0.05）； simultaneously interfering with the expression of miR-582-5p could reverse above changes （P＜ 0.05）. Interfering with the expression of LncRNA NNT-AS1 in tumor cell could significantly reduce tumor volume and tumor weight of nude mice bearing tumors； at the same time， the expression of miR-582-5p was up-regulated significantly and the mRNA and protein expressions of HMGB2 were down-regulated significantly （P＜0.05）. CONCLUSIONS Interfering with the expression of LncRNA NNT-AS1 may alleviate TAX chemotherapy resistance in NSCLC through targeted up-regulation of miR-582-5p and down-regulation of HMGB2.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. At present, no definite ALS biomarkers are available. In this study, exosomes from the plasma of patients with ALS and healthy controls were extracted, and differentially expressed exosomal proteins were compared. Among them, the expression of exosomal coronin-1a (CORO1A) was 5.3-fold higher than that in the controls. CORO1A increased with disease progression at a certain proportion in the plasma of patients with ALS and in the spinal cord of ALS mice. CORO1A was also overexpressed in NSC-34 motor neuron-like cells, and apoptosis, oxidative stress, and autophagic protein expression were evaluated. CORO1A overexpression resulted in increased apoptosis and oxidative stress, overactivated autophagy, and hindered the formation of autolysosomes. Moreover, CORO1A activated Ca²⁺-dependent phosphatase calcineurin, thereby blocking the fusion of autophagosomes and lysosomes. The inhibition of calcineurin activation by cyclosporin A reversed the damaged autolysosomes. In conclusion, the role of CORO1A in ALS pathogenesis was discovered, potentially affecting the disease onset and progression by blocking autophagic flux. Therefore, CORO1A might be a potential biomarker and therapeutic target for ALS.
Mice ; Animals ; Amyotrophic Lateral Sclerosis/pathology* ; Calcineurin/metabolism* ; Motor Neurons/pathology* ; Microfilament Proteins/metabolism* ; Cytoskeletal Proteins/metabolism*