Given that ovarian stimulation is vital for assisted reproductive technology (ART) and results in elevated serum estrogen levels, exploring the impact of elevated estrogen exposure on oocytes and embryos is necessary. We investigated the effects of various ovarian stimulation treatments on oocyte and embryo morphology and gene expression using a mouse model and estrogen-treated mouse embryonic stem cells (mESCs). Female C57BL/6J mice were subjected to two types of conventional ovarian stimulation and ovarian hyperstimulation; mice treated with only normal saline served as controls. Hyperstimulation resulted in high serum estrogen levels, enlarged ovaries, an increased number of aberrant oocytes, and decreased embryo formation. The messenger RNA (mRNA)‍-sequencing of oocytes revealed the dysregulated expression of lysine-specific demethylase 6b (Kdm6b), which may be a key factor indicating hyperstimulation-induced aberrant oocytes and embryos. In vitro, Kdm6b expression was downregulated in mESCs treated with high-dose estrogen; treatment with an estrogen receptor antagonist could reverse this downregulated expression level. Furthermore, treatment with high-dose estrogen resulted in the upregulated expression of histone H3 lysine 27 trimethylation (H3K27me3) and phosphorylated H2A histone family member X (γ-H2AX). Notably, knockdown of Kdm6b and high estrogen levels hindered the formation of embryoid bodies, with a concomitant increase in the expression of H3K27me3 and γ-H2AX. Collectively, our findings revealed that hyperstimulation-induced high-dose estrogen could impair the demethylation of H3K27me3 by reducing Kdm6b expression. Accordingly, Kdm6b could be a promising marker for clinically predicting ART outcomes in patients with ovarian hyperstimulation syndrome.
Female ; Mice ; Demethylation/drug effects* ; Embryonic Stem Cells ; Estrogens/administration & dosage* ; Gene Expression/drug effects* ; Histones/metabolism* ; Jumonji Domain-Containing Histone Demethylases/metabolism* ; Mice, Inbred C57BL ; Oocytes ; Ovary/drug effects* ; Reproductive Techniques, Assisted ; Animals

ObjectiveTo investigate the etiology and epidemiological characteristics of pneumonia in children of different ages, to better characterize the co-infection patterns of pneumonia and their association with severe diseases. MethodsChildren aged 28 days to 13 years with pneumonia who were hospitalized in the Department of Pediatrics, Dongyang People's Hospital, Zhejiang Province from April 1 to December 28, 2023 were selected as the research subjects. Oropharynx swabs were collected from the patients within 24 hours of hospital admission, and PCR tests were conducted for 18 respiratory pathogens. Binary multivariate logistic regression analysis was used to analyze the status of viral and bacterial infection, patterns of co-infection in patients with different ages, and the risk factors for the outcome of severe pneumonia. ResultsA total of 2 191 hospitalized children with pneumonia were enrolled in the study. Severe cases were more common in children aged 5 years and older (53.3%) and in the second quarter of the year (46.5%). An average of (1.31±0.90) pathogens were detected in severe cases. Mycoplasma pneumoniae (44.4%, 973 cases) had the highest detection rate of pathogens. Streptococcus pneumoniae (21.7%, 476 cases) and rhinovirus (10.1%, 222 cases) were the most common bacteria and viruses, respectively, in hospitalized children with pneumonia in Dongyang City. Multivariate logistic regression analysis indicated positive interactions between different viral and bacterial pathogens. The adjusted OR (aOR) values for different respiratory pathogens in children with severe pneumonia varied significantly (all P<0.04). Among them, Chlamydia pneumoniae (aOR=9.74, 95%CI=2.36‒49.32, P<0.01), Mycoplasma pneumoniae (aOR=2.62, 95%CI=2.04‒3.37, P<0.01), and RSV (aOR=1.69, 95%CI=1.12‒2.54, P<0.01) were the risk factors for severe pneumonia. ConclusionIn the pathogen spectrum of children with pneumonia in Dongyang City, Zhejiang Province from April to December 2023, most viruses and bacteria exhibited positive interactions. Chlamydia pneumoniae, Mycoplasma pneumoniae, and RSV maybe the significant risk factors for severe pneumonia.

OBJECTIVE: To retrospectively analyze the clinical efficacy of anterior cruciate ligament (ACL) reconstruction combined with anterolateral complex repair and ACL reconstruction combined with ALL reconstruction in the treatment of anterior cruciate ligament injuries with high-grade pivot shift. METHODS: From January 2018 to June 2022, 49 patients combined ACL and ALL injuries with high-grade pivot shift were retrospectively studied from three hospitals, 29 of them underwent ACL reconstruction with anterolateral complex repair (repair group), including 23 males and 6 females with an average age of (27.5±4.8) years old, ranged from 20 to 37 years old;the injured sides were 13 on the left and 16 on the right, and 11 patients were suffered with meniscus injury. The other 20 patients underwent ACL and ALL reconstruction (reconstruction group) including 17 males and 3 females with the mean age of (27.1±4.5) years old, ranged from 20 to 38 years old;the injured sides were 8 on the left and 12 on the right, and 6 patients were suffered with meniscus injury. Knee stability (pivot shift test, KT-2000), range of motion, knee function (Lysholm scoring scale, Cincinnati sports activity scale (CSAS) scoring scale, and Tegner activity level score between two groups were compared. RESULTS: A total of 49 patients were followed up, the repair group receiving 13 to 20(15.3±1.8) months and the reconstruction group receiving 12 to 21(16.0±2.2) months. There was no statistically significant difference in the preoperative pivot shift test grading distribution between two groups (P>0.05). At the last postoperative follow-up, there were 24 patients with grade 0 and 5 patients with grade 1 in the repair group, and there were 18 patients with grade 0 and 2 patients with grade 1 in the reconstruction group, there is no significant difference in the distribution of axial shift test grading between two groups(P>0.05). The preoperative KT-2000 tibial displacement of two groups were (9.39±0.77) mm (repair group) and (9.14±0.78) mm (reconstruction group) respectively, with no statistically significant difference (P>0.05). At the final postoperative follow-up, there were 24 patients with KT-2000 tibial displacement <3 mm and 5 patients with 3 to 5 mm in the repair group, while 18 patients with <3 mm and 2 patients with 3 to 5 mm in the reconstruction group, KT-2000 tibial displacement distribution of two groups was no significant difference (P>0.05), but the KT-2000 tibial displacement in the reconstruction group (1.30±0.86) mm was significantly smaller than that in the repair group (1.99±1.11) mm (P<0.05). The final postoperative follow-up range of motion of the contralateral side knee between two groups was no significant difference (P>0.05). The range of motion of the suffering knee in the repair group was less than that in the reconstruction group (P<0.05). There was no significant difference in preoperative Lysholm and CSAS scores between two groups (P>0.05). At the final postoperative follow-up, both groups showed significant improvement in Lysholm and CSAS scores, while the Lysholm and CSAS scores of the reconstruction group were better than those of the repair group, and the difference was statistically significant (P<0.05). Significant differences was found in Tegner scores between two groups, which 16 patients in the repair group returned to their pre-injury activity level, and 17 patients in the reconstruction group returned to their pre-injury level (P<0.05). CONCLUSION Compared to anterolateral complex repair, combined ACL and ALL reconstruction in the treatment of ACL injuries with high-grade pivot shift results in better knee joint function and stability. This is advantageous in reducing the risk of ACL reconstruction failure.
Humans ; Male ; Female ; Adult ; Anterior Cruciate Ligament Reconstruction/methods* ; Anterior Cruciate Ligament Injuries/surgery* ; Young Adult ; Retrospective Studies ; Anterior Cruciate Ligament/surgery* ; Range of Motion, Articular

Three-dimensional printing is a technology that prints the products layer-by-layer, in which materials are deposited according to the digital model designed by computer aided design (CAD) software. This technology has competitive advantages regarding product design complexity, product personalization, and on-demand manufacturing. The emergence of 3D technology provides innovative strategies and new ways to develop novel drug delivery systems. This review summarizes the application of 3D printing technologies in the pharmaceutical field, with an emphasis on the advantages of 3D printing technologies for achieving rapid drug delivery, personalized drug delivery, compound drug delivery and customized drug delivery. In addition, this article illustrates the limitations and challenges of 3D printing technologies in the field of pharmaceutical formulation development.

Model informed precision dosing (MIPD) is a new concept to guide precision dosing for individual patient by modeling and simulation based on the available information about the individual patient, medications and the disease. Compared to the empirical dosing, MIPD could improve the efficacy, safety, economics and adherence of the pharmacotherapy according to the individual's pathophysiology, genotyping and disease progression. This consensus report provides a brief account of the concept, methodology and implementation of MIPD as well as clinical decision supporting systems for MIPD. The status and future advancing of MIPD was also discussed to facilitate the appropriate application and development of MIPD in China.

Objective: To investigate the clinical characteristics, memory and neuroimaging features of nonlesional temporal lobe epilepsy (TLE-NL). Methods: Forty-four patients with TLE-NL and 53 patients with unilateral temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) were recruited from the Second Affiliated Hospital of Zhejiang University from September 1st 2012 to August 31st 2017. The clinical characteristics were systematically analyzed and compared between TLE-NL and TLE-HS. Twenty healthy volunteers were also recruited. Memory assessment and high resolution magnetic resonance imaging (MRI) scanning were completed in the patients and healthy volunteers. Volume and shape of the hippocampus were compared between patients and healthy volunteers. Results: Compared with the TLE-HS, TLE-NL patients showed later seizure onset ((24.3±12.6) vs (15.8±10.3) years; t=3.684, P<0.01), shorter duration of epilepsy ((4.00 (2.00, 8.75)) vs (14.00 (7.50, 22.00)) years; Z=-4.675, P<0.01), less history of febrile convulsions (4.5% (2/44) vs 62.3% (33/53); χ²=32.270, P<0.01) and lower incidence of pharmacoresistant epilepsy (47.7% (21/44) vs 84.9% (45/53); χ²=15.282, P<0.01). However, there were no statistically significant differences between TLE-NL and TLE-HS in sex ratio, family history of epilepsy, lateralization of the epileptogenic zone, presence of aura, seizure types and seizure frequency. TLE-NL patients had normal memory quotient compared to normal controls (105.2±17.4 vs 103.8±16.2; P=1.000), while TLE-HS patients had significant memory impairment compared to normal controls (84.5±20.3 vs 103.8±16.2; P<0.01). Compared to normal controls, TLE-NL patients did not have significant alteration in hippocampal volume and shape, while TLE-HS patients had significant atrophy in the ipsilateral hippocampus ((2 953±481) mm³ vs (4 431±505) mm³; P<0.01), and shape analysis showed significant atrophy in the head and body of the hippocampus. Conclusion TLE-NL has different characteristics compared with TLE-HS, including later seizure onset, shorter duration of epilepsy, less history of febrile convulsions, better response to antiepileptic drugs, and no significant memory impairment and hippocampal atrophy.

With the increasing cost of drug development and clinical trials, it is of great value to make full use of all kinds of data to improve the efficiency of drug development and to provide valid information for medication guidelines. Model-based meta-analysis (MBMA) combines mathematical models with meta-analysis to integrate information from multiple sources (preclinical and clinical data, etc.) and multiple dimensions (targets/mechanisms, pharmacokinetics/pharmacodynamics, diseases/indications, populations, regimens, biomarkers/efficacy/safety, etc.), which not only provides decision-making for all key points of drug development, but also provides effective information for rational drug use and cost-effectiveness analysis. The classical meta-analysis requires high homogeneity of the data, while MBMA can combine and analyze the heterogeneous data of different doses, different time courses, and different populations through modeling, so as to quantify the dose-effect relationship, time-effect relationship, and the relevant impact factors, and thus the efficacy or safety features at the level of dose, time and covariable that have not been involved in previous studies. Although the modeling and simulation methods of MBMA are similar to population pharmacokinetics/pharmacodynamics (Pop PK/PD), compared with Pop PK/PD, the advantage of MBMA is that it can make full use of literature data, which not only improves the strength of evidence, but also can answer the questions that have not been proved or can not be answered by a single study. At present, MBMA has become one of the important methods in the strategy of model-informed drug development (MIDD). This paper will focus on the application value, data analysis plan, data acquisition and processing, data analysis and reporting of MBMA, in order to provide reference for the application of MBMA in drug development and clinical practice.

Objective To translate the Water Orientation Test of Alyn 2 (WOTA2) into Chinese, and to study its reliability and validity for patients with spinal cord injury. Methods After authorizing, the English version WOTA2 scale and its training package were translated into Chinese. From January to September, 2018, 137 patients with spinal cord injury were evaluated with the Chinese version WOTA2 by two evaluators independently, and evaluated again three days later by one of the evaluators. The Cronbach's α, Spearman-Brown coefficient, intra-group correlation coefficient (ICC) and Kappa coefficient were calculated to evaluate the reliability. Content Validity Index (CVI) of items (I-CVI) and scale (S-CVI) were used to evaluate the content validity, and factors analysis was used to evaluate the structure validity. Results The Cronbach's α was 0.947 in all items of the scale, 0.890 in mental adjustment items and 0.954 in aquatic skills items. Pearson correlation coefficient of the half scales separated by odd and even items was 0.948, and the Spearman-Brown coefficient was 0.973. The ICC of test-retest was 0.965 in total score, 0.965 in centesimal system total score, 0.847 in mental adjustment score and 0.970 in aquatic skills score. The ICC of inter-testers was 0.964 in total score, 0.965 in centesimal system total score, 0.847 in mental adjustment score and 0.970 in aquatic skills score. The Kappa coefficient was 0.528 to 0.927 in test-retest and 0.528 to 0.927 in inter-testers. The I-CVI was 0.8 to 1.0 and S-CVI was 0.63. Factors analysis extracted four factors, which met the theory, and contributed 67% of cumulative variance. Conclusion The Chinese version WOTA2 is good in reliability and validity for patients with spinal cord injury, and can be used in the clinical practice of aquatic therapeutic exercise in China.

OBJECTIVETo investigate the clinicopathologic characteristics and prognosis of multiple primary synchronous colorectal carcinoma (synchronous CRC) and single colorectal carcinoma (single CRC).

METHODSClinicopathological data of 39 patients with synchronous CRC and 528 patients with single CRC from May 1996 to June 2001 were reviewed retrospectively.

RESULTSThe patients with synchronous CRC accounted for 6.9% of all the patients with colorectal carcinoma treated in our hospital during the same period. Compared with concurrent lesions, Dukes stage of the index lesions of synchronous CRC was more developed and the lymph node metastasis and vessel invasion occurred more frequently. In addition, it also had poorer differentiation. There were significant differences of Dukes stages and lymph node metastasis between the index lesions and single CRC. The incidence of adenomatous polyp in synchronous CRC was higher than that in single CRC(59.0% vs 25.0%,P<0.01). The sensitivity of preoperative colonoscopy examination was 76.9%, which was significantly higher than that of barium examination and exploration during operation. The total 5-year survival rate of synchronous CRC was significantly lower than that of single CRC (5.1% vs 28.2%,P=0.042), and no significant difference of total 5-year survival rate was found between single CRC patients and synchronous CRC patients undergone radical operation. Synchronous CRC patients undergone radical operation had longer survival as compared to those undergone palliative operation(P<0.01). Multivariate analysis indicated that Dukes stages, lymph node metastasis, vessel invasion and the type of operation were independent prognostic factors of synchronous CRC.

CONCLUSIONSSynchronous CRC and single CRC are not always similar in clinicopathologic characteristics and prognosis. Early finding, early diagnosis and radical operation are the keys to improve the survival rate of synchronous CRC.

Aged ; Colorectal Neoplasms ; pathology ; Female ; Humans ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Staging ; Neoplasms, Multiple Primary ; pathology ; Prognosis ; Retrospective Studies ; Survival Rate