1.Preventive effect of LifePort combined with polymyxin B on donor-derived infections in kidney transplantation
Xiaomin LI ; Yuewei YIN ; Chenming ZHAO ; Yalin NIU ; Kailong LIU ; Pingying GUO ; Wei LI ; Baosai LU
Organ Transplantation 2026;17(2):227-234
Objective To evaluate the effect of LifePort combined with polymyxin B in preventing donor-derived infections caused by preservation solution contamination. Methods Clinical data of 110 kidney transplant recipients were retrospectively analyzed. According to the decontamination status of preservation solution, the recipients were divided into the decontamination group (n=62) and the non-decontamination group (n=48). The general data of the two groups were compared, and the preventive effect of polymyxin B on possible donor-derived infections (p-DDI) was analyzed, especially infections associated with multidrug-resistant Gram-negative bacteria (MDR GNB). Results There were no statistically significant differences in baseline data (gender, age, preservation solution contamination status, etc.) between the decontamination group and the non-decontamination group (all P > 0.05). The overall contamination rate of preservation solution was 80.0%, and 68 contaminated samples were with single microorganism and 20 with multiple microorganisms. Coagulase-negative staphylococci, Enterococcus and Klebsiella pneumoniae were the most common microorganisms in the positive samples. Fifteen cases of preservation solution were contaminated by MDR GNB, including 10 cases in the non-decontamination group and 5 cases in the decontamination group, with no statistically significant difference between the two groups (P = 0.053). Postoperative infection-related events occurred in 69 recipients, including 39 cases in the non-decontamination group and 30 cases in the decontamination group, with the incidence rate in the non-decontamination group significantly higher than that in the decontamination group (P < 0.001). Only 10 cases of infections were identified as p-DDI, all of which were positive for preservation solution culture, including 8 cases in the non-decontamination group and 2 cases in the decontamination group (P < 0.05). There were 5 cases of p-DDI related to MDR GNB in the non-decontamination group, while no such cases occurred in the decontamination group (P < 0.05). No adverse reactions related to polymyxin B were observed, and no recipient death or renal allograft dysfunction occurred in either group. Conclusions Adding polymyxin B to the preservation fluid during hypothermic machine perfusion with LifePort before renal transplantation may reduce p-DDI and its potential adverse consequences.
2.A practice guideline for therapeutic drug monitoring of mycophenolic acid for solid organ transplants.
Shuang LIU ; Hongsheng CHEN ; Zaiwei SONG ; Qi GUO ; Xianglin ZHANG ; Bingyi SHI ; Suodi ZHAI ; Lingli ZHANG ; Liyan MIAO ; Liyan CUI ; Xiao CHEN ; Yalin DONG ; Weihong GE ; Xiaofei HOU ; Ling JIANG ; Long LIU ; Lihong LIU ; Maobai LIU ; Tao LIN ; Xiaoyang LU ; Lulin MA ; Changxi WANG ; Jianyong WU ; Wei WANG ; Zhuo WANG ; Ting XU ; Wujun XUE ; Bikui ZHANG ; Guanren ZHAO ; Jun ZHANG ; Limei ZHAO ; Qingchun ZHAO ; Xiaojian ZHANG ; Yi ZHANG ; Yu ZHANG ; Rongsheng ZHAO
Journal of Zhejiang University. Science. B 2025;26(9):897-914
Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C0), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug-drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage*
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Drug Monitoring/methods*
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Humans
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Organ Transplantation
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Immunosuppressive Agents/administration & dosage*
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Delphi Technique
3.Advances in the application of artificial intelligence in the pathological practice of head and neck squamous cell carcinoma
Yalin CHENG ; Ying GUO ; Xinxin YANG ; Hongxue MENG
Chinese Journal of Clinical and Experimental Pathology 2025;41(4):498-503
Head and neck squamous cell carcinoma(HNSCC)is the most common pathological subtype of head and neck malignancies.The majority of patients are diagnosed at an advanced stage,losing the opportunity for curative surgery,and overall prognosis remains poor.With its exceptional capabilities in image analysis and powerful data pro-cessing,artificial intelligence(AI)has the potential to become a valuable tool in precision pathology,offering new op-portunities to improve the diagnosis and treatment of head and neck cancer.This article provides a systematic review of the current research status on AI-assisted pathological image analysis in the diagnosis,treatment strategy selection,and prognosis prediction of HNSCC,while also discussing future research directions.
4.Consistency analysis of IHC and PCR-CE in the detection of microsatellite insta-bility in 735 tumor cases
Ying GUO ; Yalin CHENG ; Xiangyu ZHAO ; Xinxin YANG ; Hongxue MENG
Chinese Journal of Clinical and Experimental Pathology 2025;41(8):1050-1056
Purpose To investigate the consistency and reliability of immunohistochemistry(IHC)staining and polymerase chain reaction-capillary electrophoresis(PCR-CE)in the detection of microsatellite instability.Methods The clinical data of 735 patients with solid tumors who underwent biopsy or surgical resection were collected,and the microsatellite status of tissue samples was detected by IHC and PCR-CE.Results Among the 344 cases of colorectal cancer(CRC),IHC results showed that 290 cases(84.3%)had proficient mismatch repair(pMMR),and 54 cases(15.7%)had deficient mismatch repair(dMMR).The results of PCR-CE showed that 53 patients(15.4%)had high microsatellite instability(MSI-H),and 291 patients(84.6%)had microsatellite stable(MSS).The consistency analysis of IHC and PCR-CE results showed that the Kappa value was 0.923(P<0.001).Among the 168 cases of en-dometrial cancer(EC),IHC results showed that 42 cases(25.0%)had dMMR and 126 cases(75.0%)had pMMR;The results of PCR-CE showed that 39 cases(23.2%)had MSI-H and 129 cases(76.8%)had MSS.The consisten-cy analysis of the two methods showed that the Kappa value was 0.854(P<0.001).Among the 165 cases of gastric cancer,IHC results showed that 22(13.3%)had dMMR and 143(86.7%)had pMMR;The results of PCR-CE showed that 22 cases(13.3%)had MSI-H and 143 cases(86.7%)had MSS/low microsatellite instability(MSI-L).The consistency analysis of IHC and PCR-CE results showed that the Kappa value was 0.843(P<0.001).Among the 58 cases of head and neck squamous cell carcinoma(HNSCC),IHC results showed that 3 cases(5.2%)had dMMR and 55 cases(94.8%)had pMMR;The results of PCR-CE showed that 3 cases(5.2%)had MSI-H and 55 cases(94.8%)had MSS.The consistency analysis of the two methods showed that the Kappa value was 1.000(P<0.001).Conclusion IHC and PCR-CE have high consistency and reliability in detecting MSI status in patients with CRC,EC,gastric cancer and HNSCC,and their combined application is helpful to improve the accuracy of MSI detec-tion in patients with solid tumors.
5.Advances in the application of artificial intelligence in the pathological practice of head and neck squamous cell carcinoma
Yalin CHENG ; Ying GUO ; Xinxin YANG ; Hongxue MENG
Chinese Journal of Clinical and Experimental Pathology 2025;41(4):498-503
Head and neck squamous cell carcinoma(HNSCC)is the most common pathological subtype of head and neck malignancies.The majority of patients are diagnosed at an advanced stage,losing the opportunity for curative surgery,and overall prognosis remains poor.With its exceptional capabilities in image analysis and powerful data pro-cessing,artificial intelligence(AI)has the potential to become a valuable tool in precision pathology,offering new op-portunities to improve the diagnosis and treatment of head and neck cancer.This article provides a systematic review of the current research status on AI-assisted pathological image analysis in the diagnosis,treatment strategy selection,and prognosis prediction of HNSCC,while also discussing future research directions.
6.Consistency analysis of IHC and PCR-CE in the detection of microsatellite insta-bility in 735 tumor cases
Ying GUO ; Yalin CHENG ; Xiangyu ZHAO ; Xinxin YANG ; Hongxue MENG
Chinese Journal of Clinical and Experimental Pathology 2025;41(8):1050-1056
Purpose To investigate the consistency and reliability of immunohistochemistry(IHC)staining and polymerase chain reaction-capillary electrophoresis(PCR-CE)in the detection of microsatellite instability.Methods The clinical data of 735 patients with solid tumors who underwent biopsy or surgical resection were collected,and the microsatellite status of tissue samples was detected by IHC and PCR-CE.Results Among the 344 cases of colorectal cancer(CRC),IHC results showed that 290 cases(84.3%)had proficient mismatch repair(pMMR),and 54 cases(15.7%)had deficient mismatch repair(dMMR).The results of PCR-CE showed that 53 patients(15.4%)had high microsatellite instability(MSI-H),and 291 patients(84.6%)had microsatellite stable(MSS).The consistency analysis of IHC and PCR-CE results showed that the Kappa value was 0.923(P<0.001).Among the 168 cases of en-dometrial cancer(EC),IHC results showed that 42 cases(25.0%)had dMMR and 126 cases(75.0%)had pMMR;The results of PCR-CE showed that 39 cases(23.2%)had MSI-H and 129 cases(76.8%)had MSS.The consisten-cy analysis of the two methods showed that the Kappa value was 0.854(P<0.001).Among the 165 cases of gastric cancer,IHC results showed that 22(13.3%)had dMMR and 143(86.7%)had pMMR;The results of PCR-CE showed that 22 cases(13.3%)had MSI-H and 143 cases(86.7%)had MSS/low microsatellite instability(MSI-L).The consistency analysis of IHC and PCR-CE results showed that the Kappa value was 0.843(P<0.001).Among the 58 cases of head and neck squamous cell carcinoma(HNSCC),IHC results showed that 3 cases(5.2%)had dMMR and 55 cases(94.8%)had pMMR;The results of PCR-CE showed that 3 cases(5.2%)had MSI-H and 55 cases(94.8%)had MSS.The consistency analysis of the two methods showed that the Kappa value was 1.000(P<0.001).Conclusion IHC and PCR-CE have high consistency and reliability in detecting MSI status in patients with CRC,EC,gastric cancer and HNSCC,and their combined application is helpful to improve the accuracy of MSI detec-tion in patients with solid tumors.
7.Multicenter retrospect analysis of early clinical features and analysis of risk factors on prognosis of elderly patients with severe burns
Qimin MA ; Wenbin TANG ; Xiaojian LI ; Fei CHANG ; Xi YIN ; Zhaohong CHEN ; Guohua WU ; Chengde XIA ; Xiaoliang LI ; Deyun WANG ; Zhigang CHU ; Yi ZHANG ; Lei WANG ; Choulang WU ; Yalin TONG ; Pei CUI ; Guanghua GUO ; Zhihao ZHU ; Shengyu HUANG ; Liu CHANG ; Rui LIU ; Yongji LIU ; Yusong WANG ; Xiaobin LIU ; Tuo SHEN ; Feng ZHU
Chinese Journal of Burns 2024;40(3):249-257
Objective:To investigate the early clinical characteristics of elderly patients with severe burns and the risk factors on prognosis.Methods:This study was a retrospective case series study. Clinical data of 124 elderly patients with severe burns who met the inclusion criteria and were admitted to the 12 hospitals from January 2015 to December 2020 were collected, including 4 patients from the Fourth People's Hospital of Dalian, 5 patients from Fujian Medical University Union Hospital, 22 patients from Guangzhou Red Cross Hospital of Jinan University, 5 patients from Heilongjiang Provincial Hospital, 27 patients from the First Affiliated Hospital of Naval Medical University, 9 patients from the First Affiliated Hospital of Nanchang University, 10 patients from Affiliated Hospital of Nantong University, 9 patients from Tongren Hospital of Wuhan University & Wuhan Third Hospital, 12 patients from the 924 th Hospital of PLA, 6 patients from Zhangjiagang First People's Hospital, 4 patients from Taizhou Hospital of Zhejiang Province, and 11 patients from Zhengzhou First People's Hospital. The patients' overall clinical characteristics, such as gender, age, body mass index, total burn area, full-thickness burn area, inhalation injury, causative factors, whether combined with underlying medical diseases, and admission time after injury were recorded. According to the survival outcome within 28 days after injury, the patients were divided into survival group (89 cases) and death group (35 cases). The following data of patients were compared between the two groups, including the basic data and injuries (the same as the overall clinical characteristics ahead); the coagulation indexes within the first 24 hours of injury such as prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time, D-dimer, fibrinogen degradation product (FDP), international normalized ratio (INR), and fibrinogen; the blood routine indexes within the first 24 hours of injury such as white blood cell count, platelet count, neutrophil-to-lymphocyte ratio, monocyte count, red blood cell count, hemoglobin, and hematocrit; the organ function indexes within the first 24 hours of injury such as direct bilirubin, total bilirubin, urea, serum creatinine, aspartate aminotransferase, alanine aminotransferase, total protein, albumin, globulin, blood glucose, triglyceride, total cholesterol, alkaline phosphatase, creatine kinase, electrolyte indexes (potassium, sodium, chlorine, calcium, magnesium, and phosphorus in blood), uric acid, myoglobin, and brain natriuretic peptide; the infection and blood gas indexes within the first 24 hours of injury such as procalcitonin, C-reactive protein, pH value, oxygenation index, base excess, and lactate; treatment such as whether conducted with mechanical ventilation, whether conducted with continuous renal replacement therapy, whether conducted with anticoagulation therapy, whether applied with vasoactive drugs, and fluid resuscitation. The analysis was conducted to screen the independent risk factors for the mortality within 28 days after injury in elderly patients with severe burns. Results:Among 124 patients, there were 82 males and 42 females, aged 60-97 years, with body mass index of 23.44 (21.09, 25.95) kg/m 2, total burn area of 54.00% (42.00%, 75.00%) total body surface area (TBSA), and full-thickness burn area of 25.00% (10.00%, 40.00%) TBSA. The patients were mainly combined with moderate to severe inhalation injury and caused by flame burns. There were 43 cases with underlying medical diseases. The majority of patients were admitted to the hospital within 8 hours after injury. There were statistically significant differences between patients in the 2 groups in terms of age, total burn area, full-thickness burn area, and inhalation injury, and PT, APTT, D-dimer, FDP, INR, white blood cell count, platelet count, urea, serum creatinine, blood glucose, blood sodium, uric acid, myoglobin, and urine volume within the first 24 hours of injury (with Z values of 2.37, 5.49, 5.26, 5.97, 2.18, 1.95, 2.68, 2.68, 2.51, 2.82, 2.14, 3.40, 5.31, 3.41, 2.35, 3.81, 2.16, and -3.82, respectively, P<0.05); there were statistically significant differences between two groups of patients in whether conducted with mechanical ventilation and whether applied with vasoactive drugs (with χ2 values of 9.44 and 28.50, respectively, P<0.05). Age, total burn area, full-thickness burn area, serum creatinine within the first 24 hours of injury, and APTT within the first 24 hours of injury were the independent risk factors for the mortality within 28 days after injury in elderly patients with severe burns (with odds ratios of 1.17, 1.10, 1.10, 1.09, and 1.27, 95% confidence intervals of 1.03-1.40, 1.04-1.21, 1.05-1.19, 1.05-1.17, and 1.07-1.69, respectively, P<0.05). Conclusions:The elderly patients with severe burns had the injuries mainly from flame burns, often accompanied by moderate to severe inhalation injury and enhanced inflammatory response, elevated blood glucose levels, activated fibrinolysis, and impaired organ function in the early stage, which are associated with their prognosis. Age, total burn area, full-thickness burn area, and serum creatinine and APTT within the first 24 hours of injury are the independent risk factors for death within 28 days after injury in this population.
8.Efficacy of oliceridine for patient-controlled intravenous analgesia after bone tumor resection
Yalin SUN ; Ge LI ; Yujie GAO ; Yixin GUO ; Shiya LIU ; Xihua LU
Chinese Journal of Anesthesiology 2024;44(12):1424-1428
Objective:To evaluate the efficacy of oliceridine for patient-controlled intravenous analgesia (PCIA) after bone tumor resection.Methods:In this prospective randomized controlled study, 72 patients of either sex, aged 18-64 yr, with a body mass index of 18-28 kg/m 2, of American Society of Anesthesiologists Physical Status classification Ⅰ-Ⅲ, who underwent elective bone tumor resection under general anesthesia, were selected and divided into 2 groups ( n=36 each) by the random number table method: sufentanil group (group S) and oliceridine group (group O). Combined intravenous-inhalational anesthesia was used in both groups. PCIA was performed from the end of surgery until 48 h after surgery. PCIA solution contained sufentanil 2 μg/kg in normal saline 100 ml in group S and oliceridine 0.4 mg/kg in normal saline 100 ml in group O. The background infusion rate was 2 ml/h, the bolus dose was 2 ml, the lockout interval was 15 min, and the maximum dose per hour was 10 ml in both groups. Flurbiprofen ester 50 mg was intravenously injected as rescue analgesic after operation when numerical rating scale score at rest≥4 or numerical rating scale score during activity≥7. The number of effective pressing times of patient-controlled analgesia (PCA), total pressing times of PCA, consumption of analgesics and requirement for rescue analgesia were recorded within 48 h after operation. Ramsay sedation scores were recorded at 2, 6, 12, 24 and 48 h after surgery. The occurrence of adverse reactions and requirement for rescue antiemetic within 48 h after surgery were recorded.The 15-item quality of recovery scale scores were assessed at 24 h before surgery and 24 and 48 h after surgery. The patient satisfaction score and satisfaction rate were recorded. Results:Compared with group S, the number of effective pressing times of PCA, total pressing times of PCA and consumption of analgesics were significantly reduced within 48 h after operation, the Ramsay sedation score was significantly increased at 12 h after surgery, the incidence of nausea and vomiting and rescue antiemetic rate were decreased, and the 15-item quality of recovery scale scores, satisfaction score and satisfaction rate were increased in group O ( P<0.05). There were no significant differences in the rate of rescue analgesia and incidence of respiratory depression, dizziness, pruritus and urinary retention within 48 h after operation ( P>0.05). Conclusions:Oliceridine has similar effect to sufentanil for postoperative PCIA, reduces the development of postoperative nausea and vomiting, improves satisfaction, and promotes early postoperative recovery when used in the patients undergoing bone tumor resection.
9.Association Between Ultrasonography Signs of Midurethral Sling and Clinical Outcome
Zhenzhen QING ; Yalin YANG ; Baihua ZHAO ; Yuyang GUO ; Shan ZHOU ; Lieming WEN
Chinese Journal of Medical Imaging 2024;32(9):945-949
Purpose To study the association between ultrasonography signs of midurethral sling(MUS)and postoperative bladder neck mobility,and urethral segmental mobility,to explore ultrasound parameters that measure the biomechanical effects of MUS and to analyze the relationship between them and the clinical outcomes.Materials and Methods This was a retrospective analysis of the clinical material and ultrasound imaging data of the patients who underwent MUS surgery and had postoperative clinic follow-up in the Second Xiangya Hospital,Central South University,from September 2017 to July 2022.According to the surgical outcome,all patients were divided into three groups:stress urinary incontinence(SUI)cure group,SUI recurrence group and postoperative voiding dysfunction(VD)group.Bladder neck mobility,urethral segmental mobility,MUS position,and sling-pubic gap(SPG)during maximal Valsalva manoeuvre were measured by pelvic floor ultrasound.Ultrasound results among the three groups were compared,respectively.The relationships between ultrasound signs of the sling(MUS position and SPG),bladder neck and urethral mobility,and the surgical outcomes were analyzed,respectively.Results A total of 117 women had valid data.The median follow-up interval was 10(6,18)months.On clinical examination and diagnosis,44 women(37.6%)had cured SUI,46(39.3%)had recurrence SUI,and 27(23.1%)had postoperative VD.The mean SPG of the 117 slings was(12.0±3.5)mm(range 4.7 to 23.0 mm),and the mean position of the MUS was the 53%(range 33%-75%).There was no significant difference in MUS position and SPG between the SUI cured group and the postoperative VD group(P>0.05).The SUI recurrence group had farther MUS position[(56±11)%vs.(49±10)%,P=0.003]relative to the bladder neck and wider SPG[(13.9±3.7)mm vs.(11.2±2.7)mm,P<0.001]than SUI cure group.No significant correlation was found between the ultrasound signs of MUS(MUS position and SPG)and bladder neck mobility(r=-0.138-0.205,all P≥0.05).MUS position and SPG were correlated with midurethral mobility(MUS position vs.point 2 and 3,r=0.322,0.322,both P<0.01;SPG vss.point 3 to 6,r=0.288-0.434,all P<0.01):the closer the MUS position was relative to the distal urethra,the higher the midurethral mobility.The wider the SPG,the higher the midurethral mobility.Logistic regression showed a positive correlation between SPG and SUI recurrence with an odds ratio(OR)of 1.401(95%CI 1.189-1.652,P<0.001),and a negative correlation with postoperative VD with an OR of 0.755(95%CI 0.627-0.909,P=0.003).Conclusion SPG during the Valsalva manoeuvre can be used to measure the tightness of MUS.The larger the measured value of SPG,with the looser the MUS,the greater the likelihood of postoperative SUI recurrence,and the lower the risk of postoperative VD.
10.Clinical observation of letrozole combined with methylprednisolone in the treatment of infertile patients with polycystic ovary syndrome resistant to clomiphene
Shan LIU ; Jing GUO ; Yalin CUI ; Yayu CHENG ; Wei DUAN
China Pharmacy 2024;35(9):1118-1122
OBJECTIVE To explore the effects of letrozole combined with methylprednisolone on clinical outcomes, ovarian reserve function, serum sex hormones, and safety in infertile patients with polycystic ovary syndrome resistant to clomiphene. METHODS The clinical data of 78 infertile patients with polycystic ovary syndrome resistant to clomiphene in the Department of Gynecology of Qingdao Central Hospital from February 2021 to January 2022 was analyzed retrospectively, and all patients were divided into control group (42 cases) and observation group (36 cases) based on the treatment methods. The control group took letrozole 5 mg/d orally on the 5th to 9th day of the menstrual cycle. Vaginal ultrasound was used to monitor the development of the endometrium and follicles; estradiol valerate was used to correct endometrial thickness, and measures such as inducing ovulation with follicle-stimulating hormone were taken to promote pregnancy. On the basis of treatment in the control group, the observation group began taking methylprednisolone orally at a dose of 4 mg/d starting from the third day of natural menstruation or withdrawal bleeding. Both groups were treated for 6 menstrual cycles. The ovulation and pregnancy within one year, serum levels of sex hormones [estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone] and anti-Müllerian hormone (AMH), ovulation indicators (follicle growth time, the number of ovulations, and the number of dominant follicles), and the occurrence of adverse drug reactions were compared between the two groups. RESULTS After treatment, the biochemical pregnancy rate (72.22%) and clinical pregnancy rate (47.22%) of the observation group were significantly higher than those of control group (47.62%, 19.05%); the serum levels of E2, LH, FSH, testosterone and AMH were significantly lower than the control group; the follicle growth time was significantly shorter than the control group; the number of ovulation and dominant follicles were significantly higher than the control group (P<0.05). There was no statistically significant difference in ovulation rate (94.44% vs. 83.33%) and total incidence of adverse drug reactions (8.33% vs. 9.52%) between the observation group and the control group (P>0.05). CONCLUSIONS Compared with letrozole alone, the combination of letrozole and methylprednisolone can significantly improve the pregnancy rate, the sex hormone levels and ovarian reserve function in infertile patients with polycystic ovary syndrome resistant to clomiphene, with high safety profiles.

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