A child aged 5 years with pulmonary arterial hypertension was admitted to the First Affiliated Hospital of Xiamen University in December 2017. A truncated mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene [Chr2(GRCh37):g.203395656delA] was detected, which might be responsible for the disease and the diagnosis of hereditary pulmonary arterial hypertension (HPAH) was confirmed. Genetic testing revealed that the child′s father also carried the same mutation in BMPR2 gene, but no gene mutation was detected in child′s mother and young brother; however, no HPAH was developed in child′s father and other family members. The child was treated with targeted drugs for pulmonary arteries with poor response, and died in April 2019. Later, the child′s mother accidentally became pregnant. Gene sequencing test of the amniotic fluid showed that the fetus also carried the BMPR2 gene mutation; the pregnancy was terminated after genetic counseling. HPAH has the clinical characteristics of early onset, rapid progression, and poor prognosis, and the BMPR2 gene mutation is an important pathogenic factor. For HPAH patients with unknown etiology, particularly for pediatric patients, genetic testing is recommended to identify the cause and to make an appropriate clinical management plan.

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* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

BACKGROUND: The primary limitation to kidney transplantation is organ shortage. Recent progress in gene editing and immunosuppressive regimens has made xenotransplantation with porcine organs a possibility. However, evidence in pig-to-human xenotransplantation remains scarce, and antibody-mediated rejection (AMR) is a major obstacle to clinical applications of xenotransplantation. METHODS: We conducted a kidney xenotransplantation in a brain-dead human recipient using a porcine kidney with five gene edits (5GE) on March 25, 2024 at Xijing Hospital, China. Clinical-grade immunosuppressive regimens were employed, and the observation period lasted 22 days. We collected and analyzed the xenograft function, ultrasound findings, sequential protocol biopsies, and immune surveillance of the recipient during the observation. RESULTS: The combination of 5GE in the porcine kidney and clinical-grade immunosuppressive regimens prevented hyperacute rejection. The xenograft kidney underwent delayed graft function in the first week, but urine output increased later and the single xenograft kidney maintained electrolyte and pH homeostasis from postoperative day (POD) 12 to 19. We observed AMR at 24 h post-transplantation, due to the presence of pre-existing anti-porcine antibodies and cytotoxicity before transplantation; this AMR persisted throughout the observation period. Plasma exchange and intravenous immunoglobulin treatment mitigated the AMR. We observed activation of latent porcine cytomegalovirus toward the end of the study, which might have contributed to coagulation disorder in the recipient. CONCLUSIONS 5GE and clinical-grade immunosuppressive regimens were sufficient to prevent hyperacute rejection during pig-to-human kidney xenotransplantation. Pre-existing anti-porcine antibodies predisposed the xenograft to AMR. Plasma exchange and intravenous immunoglobulin were safe and effective in the treatment of AMR after kidney xenotransplantation.
Transplantation, Heterologous/methods* ; Kidney Transplantation/methods* ; Heterografts/pathology* ; Immunoglobulins, Intravenous/administration & dosage* ; Graft Survival/immunology* ; Humans ; Animals ; Sus scrofa ; Graft Rejection/prevention & control* ; Kidney/pathology* ; Gene Editing ; Species Specificity ; Immunosuppression Therapy/methods* ; Plasma Exchange ; Brain Death ; Biopsy ; Male ; Aged

Objective To investigate the therapeutic effect of Formononetin on mice with Mycoplasma pneumoniae pneumonia(MPP)by regulating the mitogen-activated protein kinase(MAPK)/nuclear factor κB(NF-κB)signaling pathway.Methods Six-week-old SPF-grade male BALB/c mice were selected.The MPP mouse model was established as the model group by instillating Mycoplasma pneumoniae bacterial solution through the nose.On the second day after successful modeling,mice were intraperitoneally injected with 15,30,and 60 mg/kg of Formononetin and 60 mg/kg of Formononetin+20 mg/kg of Anisomycin respectively as the low-dose,medium-dose,and high-dose Formononetin groups and the high-dose Formononetin+Anisomycin group,with 12 mice in each group.Another 12 mice were intraperitoneally injected with the same amount of 0.9％sodium chloride injection as the control group.The cough frequency of mice in each group was detected through the cough induction test.The partial pressure of carbon dioxide(PCO2)and partial pressure of oxygen(PO2)in each group of mice were detected by a blood gas analyzer,and the oxygenation index(OI)was calculated.The levels of inflammatory factors in each group were detected by ELISA,and the apoptosis of lung tissue cells in each group of mice was detected by TUNEL.HE staining was performed to observe the pathological changes of lung tissues in each group.The expression of MAPK/NF-κB pathway-related proteins in the lung tissues of mice in each group was detected by Western blot method.Results The lung tissue morphology of the mice in the control group was normal.The alveolar ducts and alveolar structures of mice in the model group were damaged,the alveolar septa thickened,and there was a large amount of inflammatory cell infiltration.Compared with the model group,the lung tissue morphology was improved in the low-dose,medium-dose and high-dose Formononetin groups.The lung tissue injury in the high-dose Formononetin+Anisamycin group was more severe compared with the high-dose Formononetin group.Compared with the control group,the cough latency period in the model group was shortened,and PO2,OI,and interleukin-10(IL-10)were decreased,while the frequency of coughing,PCO2,interleukin-18(IL-18),tumor necrosis factor-α(TNF-α),apoptosis rate,and the ratios of p-P38 MAPK/P38 MAPK,p-NF-κB p65/NF-κB p65,p-extracellular signal-regulated kinase 1/2(ERK1/2)/ERK1/2,and p-C-jun N-terminal kinase(p-JNK)/JNK increased(P＜0.05).Compared with the model group,the low-,medium-and high-dose Formononetin groups had improved lung tissue morphology,prolonged cough latency,increased PO2,OI and IL-10,and reduced cough frequency.The PCO2,IL-18,TNF-α,apoptosis rate,and the ratios of p-p38 MAPK/P38 MAPK,p-NF-κB p65/NF-κB p65,ERK1/2/ERK1/2,and p-JNK/JNK decreased(P＜0.05).In the low-,medium-,and high-dose Formononetin groups,with the increase of Formononetin dose,the cough latency gradually prolonged,the cough frequency gradually decreased,and the PO2,oxygenation index,and IL-10 gradually increased.The PCO2,IL-18,TNF-α,apoptosis rate and the ratios of p-p38 MAPK/P38 MAPK,p-NF-κB p65/NF-κB p65,p-ERK1/2/ERK1/2,and p-JNK/JNK gradually decreased(P＜0.05).Compared with the high-dose Formononetin group,the high-dose Formononetin+Anisamycin group had shorter cough latency,lower PO2,OI and IL-10.The frequency of coughing,PCO2,IL-18,TNF-α,apoptosis rate,and the ratios of p-p38 MAPK/P38 MAPK,p-NF-κB p65/NF-κB p65,p-ERK1/2/ERK1/2,and p-JNK/JNK increased(P＜0.05).Conclusion Formononetin may improve lung injury in MPP mice by inhibiting the MAPK/NF-κB signaling pathway.

Objective To investigate the therapeutic effect of Formononetin on mice with Mycoplasma pneumoniae pneumonia(MPP)by regulating the mitogen-activated protein kinase(MAPK)/nuclear factor κB(NF-κB)signaling pathway.Methods Six-week-old SPF-grade male BALB/c mice were selected.The MPP mouse model was established as the model group by instillating Mycoplasma pneumoniae bacterial solution through the nose.On the second day after successful modeling,mice were intraperitoneally injected with 15,30,and 60 mg/kg of Formononetin and 60 mg/kg of Formononetin+20 mg/kg of Anisomycin respectively as the low-dose,medium-dose,and high-dose Formononetin groups and the high-dose Formononetin+Anisomycin group,with 12 mice in each group.Another 12 mice were intraperitoneally injected with the same amount of 0.9％sodium chloride injection as the control group.The cough frequency of mice in each group was detected through the cough induction test.The partial pressure of carbon dioxide(PCO2)and partial pressure of oxygen(PO2)in each group of mice were detected by a blood gas analyzer,and the oxygenation index(OI)was calculated.The levels of inflammatory factors in each group were detected by ELISA,and the apoptosis of lung tissue cells in each group of mice was detected by TUNEL.HE staining was performed to observe the pathological changes of lung tissues in each group.The expression of MAPK/NF-κB pathway-related proteins in the lung tissues of mice in each group was detected by Western blot method.Results The lung tissue morphology of the mice in the control group was normal.The alveolar ducts and alveolar structures of mice in the model group were damaged,the alveolar septa thickened,and there was a large amount of inflammatory cell infiltration.Compared with the model group,the lung tissue morphology was improved in the low-dose,medium-dose and high-dose Formononetin groups.The lung tissue injury in the high-dose Formononetin+Anisamycin group was more severe compared with the high-dose Formononetin group.Compared with the control group,the cough latency period in the model group was shortened,and PO2,OI,and interleukin-10(IL-10)were decreased,while the frequency of coughing,PCO2,interleukin-18(IL-18),tumor necrosis factor-α(TNF-α),apoptosis rate,and the ratios of p-P38 MAPK/P38 MAPK,p-NF-κB p65/NF-κB p65,p-extracellular signal-regulated kinase 1/2(ERK1/2)/ERK1/2,and p-C-jun N-terminal kinase(p-JNK)/JNK increased(P＜0.05).Compared with the model group,the low-,medium-and high-dose Formononetin groups had improved lung tissue morphology,prolonged cough latency,increased PO2,OI and IL-10,and reduced cough frequency.The PCO2,IL-18,TNF-α,apoptosis rate,and the ratios of p-p38 MAPK/P38 MAPK,p-NF-κB p65/NF-κB p65,ERK1/2/ERK1/2,and p-JNK/JNK decreased(P＜0.05).In the low-,medium-,and high-dose Formononetin groups,with the increase of Formononetin dose,the cough latency gradually prolonged,the cough frequency gradually decreased,and the PO2,oxygenation index,and IL-10 gradually increased.The PCO2,IL-18,TNF-α,apoptosis rate and the ratios of p-p38 MAPK/P38 MAPK,p-NF-κB p65/NF-κB p65,p-ERK1/2/ERK1/2,and p-JNK/JNK gradually decreased(P＜0.05).Compared with the high-dose Formononetin group,the high-dose Formononetin+Anisamycin group had shorter cough latency,lower PO2,OI and IL-10.The frequency of coughing,PCO2,IL-18,TNF-α,apoptosis rate,and the ratios of p-p38 MAPK/P38 MAPK,p-NF-κB p65/NF-κB p65,p-ERK1/2/ERK1/2,and p-JNK/JNK increased(P＜0.05).Conclusion Formononetin may improve lung injury in MPP mice by inhibiting the MAPK/NF-κB signaling pathway.

A child aged 5 years with pulmonary arterial hypertension was admitted to the First Affiliated Hospital of Xiamen University in December 2017. A truncated mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene [Chr2(GRCh37):g.203395656delA] was detected, which might be responsible for the disease and the diagnosis of hereditary pulmonary arterial hypertension (HPAH) was confirmed. Genetic testing revealed that the child′s father also carried the same mutation in BMPR2 gene, but no gene mutation was detected in child′s mother and young brother; however, no HPAH was developed in child′s father and other family members. The child was treated with targeted drugs for pulmonary arteries with poor response, and died in April 2019. Later, the child′s mother accidentally became pregnant. Gene sequencing test of the amniotic fluid showed that the fetus also carried the BMPR2 gene mutation; the pregnancy was terminated after genetic counseling. HPAH has the clinical characteristics of early onset, rapid progression, and poor prognosis, and the BMPR2 gene mutation is an important pathogenic factor. For HPAH patients with unknown etiology, particularly for pediatric patients, genetic testing is recommended to identify the cause and to make an appropriate clinical management plan.

ObjectiveTo construct a quantitative prediction model of three indicators（moisture absorption rate， film thickness and coating weight gain） during the coating process of Vitamin C Yinqiao tablets（VCYT） by near-infrared spectroscopy（NIRS）， and to realize the endpoint judgment. MethodReal-time NIRS data of 4 batches of VCYT during the coating process were collected by diffuse reflection method. The coating method employed was the rolling coating method， and the samples were obtained at the spray stage from the coater's sampling port every 10 minutes， and 57 batches of samples（about 1 800 tablets） were collected at various coating times， the tablets were embedded in molten paraffin， cut longitudinally， and observed by stereomicroscope. The film thickness， with a target value of 38 μm， was then measured using Motic Images Advanced 3.2 software. Furthermore， the mositure absorption rate of samples， aiming for a target value of 3%， was determined in accordance with guiding principles for drug hygroscopicity testing in the 2020 edition of Chinese Pharmacopoeia， and 3 samples were randomly selected from each batch（10 tablets per batch）， and the coating weight gain was calculated（target value of 4%）. Partial least squares regression（PLSR） was used to construct a quantitative model of the 3 coating indicators， and the predicted values of the coating indicators were smoothed using the moving average method and used to determine the coating endpoints. ResultThe prediction determination coefficients（R_p²） for moisture absorption rate， film thickness and coating weight gain were 0.933 4， 0.932 6 and 0.965 9， the root mean square errors of prediction（RMSEP） were 0.163 5%， 1.870 9 μm and 0.240 3%， the relative percent deviations（RPD） were 3.711 0， 2.760 7 and 5.415 8， respectively. The results of the external validation set demonstrated that the real-time predicted values obtained by the models exhibited the same trend as the measured values， and the coating endpoint could be accurately predicted（with a prediction error of less than 7.32 min and a relative error of less than 5.63%）. ConclusionThe established NIRS model exhibits excellent predictive performance and can be used for quality control of VCYT during the coating process.

Objective:To investigate the brain activity and related hypoxic indicators in early cognitive processing stage (200-600 ms) and late cognitive processing stage (600-1 000 ms) by comparing their cognitive processing in pilots performed classical Stroop task under hypoxic state.Methods:Fifteen male Air Force pilots who were qualified in aeromedical assessment were selected. The behavioral indicators (accuracy, response time), event related potentials (ERP) component metrics (N2), and spectral metrics (Alpha band, Beta band) were monitored and analyzed when the pilots complete the cognitive conflict control task in the simulated 5 000 m hypoxic state and normal state.Results:The main effect of relationship type factors in response time indicators was significant ( F=4.10, P=0.027), and no difference found in accuracy indicators (all P>0.05). The reaction time under conflict conditions was (543.360±21.202) ms, which was higher than the reaction time under consistent conditions (509.078±14.420) ms, and the difference was significant ( F=3.28, P=0.039). The reaction time under unrelated conditions was (521.697±15.073) ms, and there was no significant difference between the reaction time under consistent and conflicting conditions (all P>0.05). Hypoxic status resulted in a significant increases in early stage indicator N2 amplitude ( F=5.34, P=0.037), and the power of Alpha, Low beta and Mid beta of late stage ( F=7.76, 5.34, 4.92, P=0.015, 0.037, 0.044). Conclusions:The amplitude of N2 can be used as the ERP indicator to investigate the pilots′ brain activities at the early stage of cognitive processing under hypoxia state; Alpha, Low beta and Mid beta bands of the spectrum can be used as the indicators to evaluate the brain activity of pilots in the late stage of cognitive processing under hypoxia state, which can be used in the training evaluation of pilots to provide more objective physiological data to improve the training effect of pilots.

The incidence of osteoporotic thoracolumbar vertebral fracture (OTLVF) in the elderly is gradually increasing. The kyphotic deformity caused by various factors has become an important characteristic of OTLVF and has received increasing attention. Its clinical manifestations include pain, delayed nerve damage, sagittal imbalance, etc. Currently, the definition and diagnosis of OTLVF with kyphotic deformity in the elderly are still unclear. Although there are many treatment options, they are controversial. Existing guidelines or consensuses pay little attention to this type of fracture with kyphotic deformity. To this end, the Lumbar Education Working Group of the Spine Branch of the Chinese Medicine Education Association and Editorial Committee of Chinese Journal of Trauma organized the experts in the relevant fields to jointly develop Clinical guidelines for the diagnosis and treatment of osteoporotic thoracolumbar vertebral fractures with kyphotic deformity in the elderly ( version 2024), based on evidence-based medical advancements and the principles of scientificity, practicality, and advanced nature, which provided 18 recommendations to standardize the clinical diagnosis and treatment.

Objective:To investigate the brain activity and related hypoxic indicators in early cognitive processing stage (200-600 ms) and late cognitive processing stage (600-1 000 ms) by comparing their cognitive processing in pilots performed classical Stroop task under hypoxic state.Methods:Fifteen male Air Force pilots who were qualified in aeromedical assessment were selected. The behavioral indicators (accuracy, response time), event related potentials (ERP) component metrics (N2), and spectral metrics (Alpha band, Beta band) were monitored and analyzed when the pilots complete the cognitive conflict control task in the simulated 5 000 m hypoxic state and normal state.Results:The main effect of relationship type factors in response time indicators was significant ( F=4.10, P=0.027), and no difference found in accuracy indicators (all P>0.05). The reaction time under conflict conditions was (543.360±21.202) ms, which was higher than the reaction time under consistent conditions (509.078±14.420) ms, and the difference was significant ( F=3.28, P=0.039). The reaction time under unrelated conditions was (521.697±15.073) ms, and there was no significant difference between the reaction time under consistent and conflicting conditions (all P>0.05). Hypoxic status resulted in a significant increases in early stage indicator N2 amplitude ( F=5.34, P=0.037), and the power of Alpha, Low beta and Mid beta of late stage ( F=7.76, 5.34, 4.92, P=0.015, 0.037, 0.044). Conclusions:The amplitude of N2 can be used as the ERP indicator to investigate the pilots′ brain activities at the early stage of cognitive processing under hypoxia state; Alpha, Low beta and Mid beta bands of the spectrum can be used as the indicators to evaluate the brain activity of pilots in the late stage of cognitive processing under hypoxia state, which can be used in the training evaluation of pilots to provide more objective physiological data to improve the training effect of pilots.