Nonobstructive azoospermia (NOA), one of the most severe types of male infertility, etiology often remains unclear in most cases. Therefore, this study aimed to detect four biallelic detrimental variants (0.5%) in the minichromosome maintenance domain containing 2 ( MCMDC2 ) genes in 768 NOA patients by whole-exome sequencing (WES). Hematoxylin and eosin (H&E) demonstrated that MCMDC2 deleterious variants caused meiotic arrest in three patients (c.1360G>T, c.1956G>T, and c.685C>T) and hypospermatogenesis in one patient (c.94G>T), as further confirmed through immunofluorescence (IF) staining. The single-cell RNA sequencing data indicated that MCMDC2 was substantially expressed during spermatogenesis. The variants were confirmed as deleterious and responsible for patient infertility through bioinformatics and in vitro experimental analyses. The results revealed four MCMDC2 variants related to NOA, which contributes to the current perception of the function of MCMDC2 in male fertility and presents new perspectives on the genetic etiology of NOA.
Humans ; Male ; Azoospermia/genetics* ; Meiosis/genetics* ; Spermatogenesis/genetics* ; Adult ; Exome Sequencing ; Microtubule-Associated Proteins/genetics* ; Alleles ; Infertility, Male/genetics*

On March 19, 2021, the National Medical Products Administration(NMPA) issued the Regulations on the Supervision and Administration of Medical Devices (Order No. 739 of the State Council of the People's Republic of China), which clearly stipulated in Article 53 the basic definition and scope of use of in vitro diagnostic reagents developed by medical institutions. It also pointed out that the relevant administrative measures shall be formulated by the Drug Regulatory Department of the State Council in conjunction with the Health Department of the State Council. This initiative marks the re-incorporation of in vitro diagnostic reagents developed by medical institutions into China's regulatory system. This study reviewed the development of regulatory policies for self-developed in vitro diagnostic reagents at home and abroad, combined with the Key Points of On-site Verification of Self-developed In Vitro Diagnostic Reagents in Shanghai Medical Institutions issued by the Shanghai Municipal Drug Administration, in conjunction with the Shanghai Municipal Health Commission, and the specific verification work of pre-record evaluation, and sorted out the general requirements for the quality management system of self-developed in vitro diagnostic reagents. The purpose is to provide some references for the further development of this pilot work and its nationwide promotion.
China ; Quality Control ; Indicators and Reagents/standards* ; Reagent Kits, Diagnostic/standards*

Tezepelumab(AMG 157/MEDI9929)is a human monoclonal antibody against the epithelial cell-derived cytokine thymic stromal lymphopoietin(TSLP).It is primarily used to treat moderate to severe asthma,particularly in patients with a non-eosinophilic inflammatory phenotype,whose asthma remains uncontrolled despite the use of long-acting beta-agonists and moderate to high doses of inhaled glucocorticoids.This article will summarise the mechanism of action,clinical trial efficacy and safety and tolerability of Tezepelumab in order to provide a comprehensive understanding of the drug and inform clinical work.

The author analyzed the characteristics of phase Ⅰ clinical trials of macromolecular drugs,the characteristics of evaluation indicators of phase Ⅰ clinical trials of macromolecular drugs,such as safety evaluation,pharmacokinetic and pharmacodynamic evaluation,and efficacy evaluation.And the control points of subjects management,management of experimental macromolecule drugs,and identified and potential risk factors of macromolecule drugs in the implementation of risk management for phase Ⅰ clinical trials of macromolecule drugs were discussed in depth based on previous clinical trial research experience.Through discussion and analysis,the author suggests that each research center can formulate risk control strategies according to the actual situation,improve the efficiency of risk control,and facilitate the smooth implementation of clinical trials and improve the quality of clinical trials.

AIM: To analyze the mechanism of Usher syndrome(USH)caused by Adgrv1 gene variation through the Hedgehog(Hh)signaling pathway.METHODS: Based on Adgrv1 gene variant mice(Adgrv1-/-), taking wild type(WT)C57BL/6 mice as controls, the expression of Adgrv1 gene and the structure of retina and cell cilia were analyzed by qRT-PCR, HE, transmission electron microscopy, and immunofluorescence. Additionally, the changes of key factors in the Hh signaling pathway caused by Adgrv1 gene variation were observed.RESULTS: The Adgrv1 gene was expressed in both the retina and primary cultured lung fibroblasts of Adgrv1-/- mice, but the expression levels were significantly decreased. The Adgrv1 gene variation can cause dissolution of the outer disc membrane of the retinal photoreceptors and significantly shorten the cilia length in primary lung fibroblasts. In the Hh signaling pathway, the expression of Ptch1 and Gli genes of Adgrv1-/- was significantly reduced, while the expression of PKA genes was increased.CONCLUSION:The Adgrv1 gene variation leads to shortened cell cilia and dissolution of the outer disc membrane of the retinal photoreceptors, resulting in retinitis pigmentosa, which is related to decreased expression of PTCH1 and GLI1 proteins in the Hh pathway.

Nucleic acid-based molecular diagnostic methods are considered the gold standard for detecting infectious pathogens.However,when applied to portable or on-site rapid diagnostics,they still face various limitations and challenges,such as poor specificity,cumbersome operation,and portability difficulties.The CRISPR(Clustered regularly interspaced short palindromic repeats)/CRISPR-associated protein(Cas)-fluorescence detection method holds the potential to significantly enhance the specificity and signal-to-noise ratio of nucleic acid detection.In this study,we developed a portable grayscale reader detection system based on loop-mediated isothermal amplification(LAMP)-CRISPR/Cas.On one hand,in the presence of CRISPR RNA(crRNA),the CRISPR/Cas12a system was employed to achieve precise fluorescent detection of self-designed LAMP amplification reactions for influenza A and influenza B viruses.This further validated the high selectivity and versatility of the CRISPR/Cas system.On the other hand,the accompanying independently developed portable grayscale reader allowed for low-cost collection of fluorescence signals and high-reliability visual interpretation.At the end of the detection process,it directly provided positive or negative results.Practical sample analyses using this detection system have verified its reliability and utility,demonstrating that this system can achieve highly sensitive and highly specific portable analysis of influenza viruses.

Objective:To retrospectively analyze the clinical characteristics and prognosis of 85 newly diagnosed patients with follicular lymphoma (FL), as well as the prognostic value of comprehensive geriatric assessment (CGA) in patients with FL aged ≥ 60 years old.Methods:The clinical data and prognosis of 85 newly diagnosed FL patients admitted from August 2011 to June 2022 were collected. The clinical features, laboratory indicators, therapeutic efficacy, survival and prognostic factors of patients were statistically analyzed, and the prognosis of patients was stratified using various geriatric assessment tools.Results:① The patients with FL were mostly middle-aged and older, with a median age of 59 (20-87) years, including 41 patients (48.2%) aged ≥60 years. The ratio of male to female was 1∶1.36. Overall, 77.6% of the patients were diagnosed with Ann Arbor stage Ⅲ-Ⅳ, and 17 cases (20.0%) were accompanied by B symptoms. Bone marrow involvement was the most common (34.1%). ②Overall, 71 patients received immunochemotherapy. The overall response rate was 86.6%, and the complete recovery rate was 47.1% of 68 evaluated patients. Disease progression or relapse in the first 2 years was observed in 23.9% of the patient. Overall, 14.1% of the patients died during follow-up. ③Of the 56 patients receiving R-CHOP-like therapies, the 3-year and 5-year progression-free survival (PFS) rates were 85.2% and 72.8%, respectively, and the 3-year and 5-year overall survival (OS) rates were 95.9% and 88.8%, respectively. The univariate analysis showed that age ≥60 years old ( HR=3.430, 95% CI 1.256-9.371, P=0.016), B symptoms ( HR=5.030, 95% CI 1.903-13.294, P=0.016), Prognostic Nutritional Index (PNI) <45.25 ( HR=3.478, 95% CI 1.299-9.310, P=0.013), Follicular Lymphoma International Prognostic Index (FLIPI) high-risk ( HR=2.918, 95% CI 1.074-7.928, P=0.036), and PRIMA-prognostic index (PRIMA-PI) high-risk ( HR=2.745, 95% CI 1.057-7.129, P=0.038) significantly predicted PFS. Moreover, age ≥60 years old and B symptoms were independent risk factors for PFS. Progression of disease within 24 months (POD24) significantly predicted OS in the univariate analysis. Conclusions:FL is more common among middle-aged and older women. Age, B symptoms, PNI score, FLIPI high-risk, PRIMA-PI high-risk, and POD24 influenced PFS and OS. The CGA can be used for treatment selection and risk prognostication in older patients with FL.

Polatuzumab vedotin (Pola) is a novel antibody-drug conjugate targeting CD79b, which has been shown to be effective in treating newly diagnosed and relapsed/refractory diffuse large B cell lymphoma (DLBCL) during clinical trials. This study aims to conduct a retrospective analysis of the clinical characteristics, diagnosis, and treatment of a patient with refractory secondary central nervous system lymphoma at Beijing Hospital, alongside a review of relevant literature. This study included a 79-year-old female patient who was diagnosed with DLBCL affecting the ilium, sacrum, spinal cord, and nerve roots and had an IPI score of 5 and a high-risk score according to MSKCC. She showed a geriatric comprehensive assessment (IACA) score of 2, which was categorized under the unfit group. Her initial treatment comprised chemo-free therapy and radiotherapy, followed by progression. In the second-line treatment, a Pola-based regimen was applied, and the patient achieved a complete response, suggesting that this regimen may be a therapeutic option for patients with DLBCL involving the central nervous system.

Objective:To summarize the evidence of cognitive training in breast cancer patients with chemotherapy-related cognitive impairment, so as to provide evidence-based evidence for clinical decision-making and practice.Methods:The literature about the relevant cognitive training in breast cancer patients with chemotherapy-related cognitive impairment were searched for CNKI, VIP database, Wanfang, SinoMed, PubMed, Web of Science, CINAHL, Embase, Cochrane Library, JBI as well as home and abroad official website of relevant professional institutes, including clinical decisions, guidelines, evidence summaries, systematic reviews, best practice information manuals, expert consensuses, and high-quality original studies. The literature retrieval period was from the database construction to March 1, 2023. Two researchers screened and evaluated the quality of the included literature, and extracted, generalized and summarized evidence according to the topic.Results:A total of 17 articles were involved, including 3 clinical decisions, 4 guidelines, 2 evidence summaries, and 8 systematic reviews. Finally, 6 evidence topics and 25 pieces of best evidences were formed, including screening and evaluation, training principles, training time, training place, training content, training effect.Conclusions:Cognitive training can effectively improve cognitive function in breast cancer patients with chemotherapy-related cognitive impairment. Medical staff should carefully select the best evidence, early screen and dynamically evaluate the cognitive changes of patients, follow the principle of step by step and dynamic adjustment, and carry out individualized cognitive training as soon as possible according to the treatment cycle and patients wishes, so as to prevent or delay chemotherapy-related cognitive impairment and improve the quality of life of patients.

To investigate the value of self-developed air-free laparoscopic auxiliary instruments in the clinical application of thyroid diseases.The clinical data of 70 transaxillary and 45 transareolar air-free laparoscopic surgeries for thyroid cancer and 40 conventional open surgeries were retrospectively compared.The transaxillary and transareolar laparoscopic groups had significantly longer operative times than the open group,while the postoperative satisfaction was higher in the endoscopic group than in the open group.This set of instruments has advantage of novel design,scientific structure,safe application.It can be compatible with a variety of thyroid and breast air-free laparoscopic procedures,which can promote the development and popularization of laparoscopic technology.