Objective To analyze the nonlinear relationship between hypothermic machine perfusion (HMP) parameters and delayed graft function (DGF) and optimize the construction of a predictive model for DGF. Methods The data of 923 recipients who underwent kidney transplantation from deceased donors were retrospectively analyzed. According to the occurrence of DGF, the recipients were divided into DGF group (n=823) and non-DGF group (n=100). Donor data, HMP parameters and recipient data were analyzed for both groups. The nonlinear relationship between HMP parameters and the occurrence of DGF was explored based on restricted cubic splines (RCS). Over-sampling, under-sampling and balanced sampling were used to address the imbalance in the proportion of DGF to construct logistic regression predictive models. The area under the curve (AUC) of each model was compared in the validation set, and a nomogram model was constructed. Results Donor BMI, cold ischemia time of the donor kidney, and HMP parameters (initial and final pressures, resistance, and perfusion time) were significantly different between the DGF and non-DGF groups (all P<0.05). The RCS analysis revealed a threshold-like nonlinear relationship between HMP parameters and the risk of DGF. Among the models constructed using different sampling methods, the balanced sampling model had the highest AUC. Using this model, a nomogram was constructed to stratify recipients based on risk scores. Recipients in the high-risk group had higher serum creatinine levels at 1, 6, and 12 months after kidney transplantation compared to those in the low-risk group (all P<0.05). Conclusions There is a nonlinear relationship between HMP parameters and the risk of DGF, and the threshold is helpful for organ quality assessment and monitoring of graft function after transplantation. The predictive model for DGF constructed on the base of balanced sampling algorithms helps perioperative decision-making and postoperative graft function monitoring of kidney transplantation.

Objective To investigate the characteristics of adverse drug event(ADE)related to tacrolimus(Tac)in pediatric solid organ transplant recipients.Methods The data were retrieved from the US Food and Drug Administration Adverse Event Reporting System database from the first quarter of 2004 to the second quarter of 2023.The ADE data of pediatric organ transplant recipients with Tac as the primary suspected drug were extracted.The relationship between Tac and ADE was quantitatively analyzed by proportional imbalance method.Basic characteristics and signal strength of ADE related to Tac were analyzed.ADE related to Tac in children of different ages and different types of organ transplantation were analyzed.Results A total of 1 443 children's ADE reports involving Tac were screened,including 188 cases(13.0％)of heart transplantation,668 cases(46.3％)of liver transplantation,531 cases(36.8％)of kidney transplantation and 56 cases(3.9％)of lung transplantation.The median age of children was 10 years old.The top three countries with ADE reporting were the United States,France and the United Kingdom.China reported 26 cases,accounting for 1.8％.Infection and infectious diseases accounted for the highest proportion(20.96％)in ADE related to Tac,including EB virus and cytomegalovirus infection,etc.Infection and infectious diseases occupied the largest proportion of ADE related to Tac in children of different ages,whereas the pathogen types were different.Rejection,unstable immunosuppression level and renal function damage were also common ADE related to Tac in children of all ages.Nervous system disease was the main ADE in heart transplant recipients,while infection and infectious diseases were more common in liver and kidney transplant recipients.Rejection was the most common ADE in lung transplant recipients.Conclusions ADE related to Tac possess different distribution characteristics in different types of organ transplantation.Extensive attention should be paid to individualized drug monitoring and risk assessment in pediatric organ transplant recipients,thereby optimizing Tac treatment and reducing the risk of ADE.

miR-135 is a highly conserved miRNA in mammals and includes miR-135a and miR-135b.Recent studies have shown that miR-135b is a key regulatory factor in cardio-cerebrovascular diseases.It is involved in regulating the pathological process of myocardial infarction,myocardial ischemia/reperfusion injury,cardiac hypertrophy,atrial fibrillation,diabetic cardiomyopathy,atherosclerosis,pulmonary hyperten-sion,cerebral ischemia/reperfusion injury,Parkinson's disease,and Alzheimer's disease.Obviously,miR-135b is an emerging player in cardio-cerebrovascular diseases and is expected to be an important target for the treatment of cardio-cerebrovascular diseases.However,the crucial role of miR-135b in cardio-cerebrovascular diseases and its underlying mechanism of action has not been reviewed.Therefore,in this review,we aimed to comprehensively summarize the role of miR-135b and the signaling pathway mediated by miR-135b in cardio-cerebrovascular diseases.Drugs targeting miR-135b for the treatment of diseases and related patents,highlighting the importance of this target and its utility as a therapeutic target for cardio-cerebrovascular diseases,have been discussed.

Objective:To analyze and evaluate the items of the general module of multidimensional health measurement instruments system for elderly patients with chronic disease (MHIEC-GM)(V1.0) based on classical test theory (CTT) and item response theory (IRT).Methods:A self-administered survey of 2 375 elderly patients with chronic diseases was conducted using the MHIEC-GM(V1.0) scale. The quality of items was analyzed using the variability method, correlation coefficient method, factor analysis method, and Cronbach's α coefficient method based on CTT. The difficulty coefficient, differentiation coefficient, and information content of items were analyzed using the IRT analysis software MULTILOG 7.03.Results:The CTT results showed that the standard deviations of all nine items were greater than 0.9. The results of the correlation coefficient method, the factor analysis method and the Cronbach′s α coefficient method showed that except for the GMI9 item, the correlation coefficients between the other items and the total scale were all greater than 0.5, and the factor loads were all greater than 0.5, and the Cronbach′s α coefficients after the deletion of the items were all less than 0.763. Based on the results of the four analysis methods, except for the GMI9 item, all the other items had good characteristics. The IRT results showed that the information contents of all items were >0.333 (5/15) except for the GMI4, GMI6, and GMI8, and the differentiation coefficient of each item was 1.44. The items that difficulty coefficient met the [-4, 4] inclusion criteria were the GMI2, GMI3, GMI5, GMI7 and GMI9, showing a monotonically increasing trend with increasing difficulty level. The items of GMI1, GMI4, GMI6, and GMI8 needed further improvement.Conclusion:Most of items of the MHIEC-GM(V1.0) scale have good psychometric properties, but some items need to be further revised and validated according to the characteristics of chronic diseases in the elderly.

On December 22,2021,the United States Food and Drug Administration approved the first main protease inhibitor,i.e.,oral antiviral nirmatrelvir(PF-07321332)/ritonavir(Paxlovid),for the treatment of early severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.Nirmatrelvir inhibits SARS-CoV-2 infection,but high doses or long-term treatment may cause embryonic developmental toxicity and changes in host gene expression.The chiral structure of nirmatrelvir plays a key role in its antiviral activity.Ritonavir boosts the efficacy of nirmatrelvir by inactivating cytochrome P450 3A4 expression and occupying the plasma protein binding sites.Multidrug resistance protein 1 inhibitors may increase the efficacy of nirmatrelvir.However,Paxlovid has many contraindications.Some patients treated with Paxlovid experience a second round of coronavirus disease 2019(COVID-19)symptoms soon after re-covery.Interestingly,the antiviral activity of nirmatrelvir metabolites,such as compounds 12-18,is similar to or higher than that of nirmatrelvir.Herein,we review the advances and challenges in using nirmatrelvir and its derivatives with the aim of providing knowledge for drug developers and physicians in the fight against COVID-19.

Objective:To explore the clinical efficacy of ceftazidime/avibactam(CZA)plus aztreonam(ATM)for New Delhi metallo-β-lactamase(NDM)carbapenem-resistant Klebsiella pneumoniae(CRKP)infection after kidney transplantation.Methods:Clinical data are retrospectively reviewed for 11 RT recipients infected with NDM metallo-β-lactamase CRKP admitted into First Affiliated Hospital of Xi 'an Jiaotong University and Affiliated Renji Hospital of Shanghai Jiao Tong University from November 2018 to December 2019.Based upon treatment protocol, they are divided into two groups of ceftazidime/avibactam plus aztreonam(CZA-ATM, 5 cases)and other effective antibiotics(OAA, 6 cases).Age, gender, infection type, drug resistance gene, changes in body temperature and leucocyte count, treatment course and prognosis are summarized.Results:A total of 11 patients with NDM-producing CRKP infection after RT are recruited.There are seven males and four females with an age range of(19~66)(38.9±14.4)years.There are mixed pulmonary and urinary tract infections(3 cases), urinary tract infection(2 cases), pulmonary infection(1 case)and perirenal infection(5 cases).All isolates harbore NDM carbapenemase gene, 5 isolates carry Klebsiella pneumoniae carbapenemase(KPC)gene and 1 isolate contained both imipenemase metallo-β-lactamase(IMP)and verona integron-encoded metallo-β-lactamase(VIM)gene concurrently.Ceftazidime-avibactam plus aztreonam(CZA-ATM)is prescribed in five patients while the remainders receive OAA.No adverse reactions occurred in individuals on CZA-ATM and 2 cases on OAA have adverse reactions with a poor appetite and diarrhea.After 30-day infection, the curative cases of CZA-ATM and OAAs groups reach 4 and 5 respectively.No death occurred in neither groups at Day 30.And 90-day mortality is 0 and 1 respectively.Conclusions:For RT patients infected with NDM-producing CRKP, CZA-ATM combination therapy may be another effective treatment.

Objective:To compare the clinical characteristics and etiology changes of patients with bronchiolitis before the pandemic of coronavirus disease 2019(COVID-19)with those after the pandemic, and to provide a basis for the clinical diagnosis, treatment and prevention of bronchiolitis.Methods:Retrospective analysis were made on the clinical characteristics and etiological changes of patients who were hospitalized with bronchiolitis in the Department of Pulmonology, Children′s Hospital of Soochow University before COVID-19 pandemic(from February 1, 2019 to January 31, 2020, called as Group 2019-2020)and after COVID-19 pandemic(from February 1, 2020 to January 31, 2021, called as Group 2020-2021). Medical records were reviewed to compare general conditions, clinical manifestations, and laboratory tests.Nasopharyngeal secretion examination results were collected to compare the differences in pathogenic composition.Results:A total of 285 patients were enrolled in the Group 2019-2020, while 190 patients in the Group 2020-2021.There were no significant differences in gender, age, symptom duration prior to admission and length of stay between the two groups( P>0.05). The proportion of moderate/severe cases in the Group 2020-2021 was lower than that in the Group 2019-2020[10.53%(20/190)vs 21.75%(62/285)]and the difference was statistically significant( χ2=10.062, P<0.05). The proportion of stuffy nose rhinorrhea in the Group 2020-2021 was higher than that in the Group 2019-2020, while the proportion of gastrointestinal symptoms(vomiting and diarrhea)in the Group 2020-2021 was lower than that in the Group 2019-2020 [57.37%(109/190)vs 47.37%(135/285)and 15.79%(30/190)vs 24.56 %(70/285)]and the differences were statistically significant( χ2 were 4.563 and 5.278 respectively, all P<0.05). There were no significant differences in the proportions of fever, dyspnea, shortness of breath and cyanosis between the two groups(all P>0.05). The creatine kinase isoenzyme(CK-MB)in the Group 2020-2021 was lower than that in the Group 2019-2020[4.15(2.90~5.60)vs 6.70(4.20~22.10)]and the difference was statistically significant( Z=-8.757, P<0.05). There were no statistically significant differences in white blood cell count(WBC), percentage of neutrophil(N%), blood platelet count(PLT), percentage of eosinophil(EOS%), C-reactive protein(CRP), alanine aminotransferase(ALT)and lactate dehydrogenase(LDH)between the two groups(all P>0.05). The total pathogen detection rate, positive rate of respiratory syncytial virus(RSV), positive rate of mycoplasma pneumoniae(MP)and mixed infection rate in the Group 2020-2021 were lower than those in the Group 2019-2020[65.26%(124/190)vs 75.09%(214/285), 14.21%(27/190)vs 30.18%(86/285), 6.32%(12/190)vs 15.09%(43/285), 16.84%(32/190)vs 25.61%(73/285)], with statistically significant differences( χ2 were 5.361, 16.026, 8.568 and 5.094 respectively, all P<0.05). The positive rate of rhinovirus in the Group 2020-2021 was higher than that in the Group 2019-2020[13.16%(25/190)vs 4.91%(14/285)]and the difference was statistically significant( χ2=10.285, P<0.05). There were no significant differences in the positive rates of human metapneumovirus, Boca virus and parainfluenza virus 3 between the two groups(all P>0.05). Conclusion:The clinical characteristics and etiology of patients with bronchiolitis have changed after the COVID-19 pandemic.The quarantine and protection measures reduce the transmission of associated pathogens and the severity of the disease.

OBJECTIVE: To explore the role of small nuclear noncoding RNA 7SK in embryonic stem cell (ESCs) proliferation and the value of 7SK as a target for early diagnosis and treatment for primordial dwarfism (PD). METHODS: ESC line R1 was transfected with the CRISPR/Cas9 system, and sequencing of the PCR product and glycerol gradient analysis were performed to identify novel 7SK deletion mutations. A lentivirus system was used to knock down cyclin-dependent kinase 9 (CDK9) in clones with 7SK deletion mutations, and the effect of CDK9 knockdown on the protein level of cell division cycle 6 (CDC6) was analyzed with Western blotting. RESULTS: We identified a novel deletion mutation of 7SK at 128-179 nt in the ESCs, which resulted in deficiency of cell proliferation. 7SK truncation at 128-179 nt significantly reduced the protein expressions of La-related protein 7 (LARP7) and CDC6. CONCLUSIONS 7SK truncation at 128-179 nt can significantly impair proliferation of ESCs by downregulating CDC6. 7SK is a key regulator of proliferation and mediates the growth of ESCs through a mechanism dependent on CDK9 activity, suggesting the value of 7SK truncation at 128-179 nt as a potential target for early diagnosis and treatment of PD.
Cell Cycle Proteins ; Cell Proliferation ; Embryonic Stem Cells/metabolism* ; HeLa Cells ; Humans ; Nuclear Proteins ; Positive Transcriptional Elongation Factor B/metabolism* ; RNA, Long Noncoding/genetics* ; RNA-Binding Proteins ; Ribonucleoproteins ; Transcription Factors

Exosomes are vesicles with a double globular membrane of lipids that can be secreted by a variety of cells, including stem cells. Exosomes have unique biological characteristics and irreplaceable powerful functions which play an important role in intercellular communication. The various cytokines, signal proteins, lipids and regulatory nucleic acids contained in stem cell exosomes can play a protective role against the injury of kidney, liver, heart, blood vessels and nerves. Stem cell exosomes delay the process of intervertebral disc degeneration by inhibiting the apoptosis of nucleus pulposus cells and increasing the synthesis of extracellular matrix, etc. The mechanism of its role is mainly through miRNA and related signaling pathways. Exosomes contain complex components. Although the mechanism of action of exosomes in intervertebral discs has been preliminarily explored, the components contained in exosomes are complex and the specific situation has not been fully understood, which still needs further study. In this review, the characteristics and functions of stem cell exosomes, extraction, identification and storage methods, the impacttovarious other tissues, as well as the effects on intervertebral discs and their mechanisms were elaborated in order to provide a basis for the study of intervertebral disc degenerative diseases.

Objective To evaluate the clinical effect of hypothermic machine perfusion (HMP) in the storage of renal grafts from deceased donor (DD) with high-risk delayed graft function (DGF). Methods Clinical data of 52 donors with high-risk DGF were collected in this prospective randomized controlled study. Two renal grafts from each donor were randomly divided into the HMP group (n=52) and static cold storage (SCS) group (n=52). In the HMP group, the renal grafts were stored by LifePort under HMP, whereas the renal grafts in the SCS group were preserved in University of Wisconsin solution (UW solution). The incidence of DGF and primary nonfunction (PNF) after renal transplantation was statistically compared between two groups. The recovery of renal graft function, the survival rates of the recipients and renal grafts within postoperative 1 year were observed in two groups. Results The incidence of DGF in the HMP group was 4%(2/52), significantly lower than 17% (9/52) in the SCS group (P < 0.05). No PNF was reported in the HMP group and 1 case of PND was noted in the SCS group, the difference was not statistically significant (P > 0.05). The recovery time of graft function of the recipients in the HMP and SCS groups were (7.2±0.6) d and (7.7±1.0) d with no statistical significance (P > 0.05). In the HMP group, the urine volume of the recipients on the day of operation, postoperative 1 and2 d was significantly larger than that in the SCS group (all P < 0.05). In the HMP group, the levels of serum creatinine at each time point after operation were significantly lower than those in the SCS group (all P < 0.05). The 1-year survival rates of the recipient and kidney were 98.1%, 92.3% and 100%, 96.2% in the HMP and SCS groups with no statistical significance (all P > 0.05). Conclusions HMP can significantly reduce the incidence of DGF after renal transplantation from DD with high-risk DGF and promote the early recovery of graft function.