Coronavirus-related diseases pose a significant challenge to the global health system. Given the diversity of coronaviruses and the unpredictable nature of disease outbreaks, the traditional "one bug, one drug" paradigm struggles to address the growing number of emerging crises. Therefore, there is an urgent need for therapeutic agents with broad-spectrum anti-coronavirus activity. Here, we provide evidence that ATV006, an anti-SARS-CoV-2 nucleoside analog targeting RNA-dependent RNA polymerase (RdRp), has broad antiviral activity against human and animal coronaviruses. Using mouse hepatitis virus (MHV) and human coronavirus NL63 (HCoV-NL63) as a model, we show that ATV006 has potent prophylactic and therapeutic activity against murine coronavirus infection in vivo. Remarkably, ATV006 successfully inhibits viral replication in mice even when administered 96 h after infection. Due to its oral bioavailability and potency against multiple coronaviruses, ATV006 has the potential to become a useful antiviral agent against SARS-CoV-2 and other circulating and emerging coronaviruses in humans and animals.

Objective:To assess the feasibility of first polar body transfer (PB1T) combined with preimplantation mitochondrial genetic testing for blocking the transmission of a pathogenic mitochondrial DNA 8993T>G mutation.Methods:A Chinese family affected with Leigh syndrome which had attended the Reproductive Medicine Centre of the First Affiliated Hospital of Anhui Medical University in September 2021 was selected as the study subject. Controlled ovarian hyperstimulation was carried out for the proband after completing the detection of the mitochondrial DNA 8993T>G mutation load among the pedigree members. Mature MII oocytes were inseminated by intracytoplasmic sperm injection (ICSI), cultured in vitro for 5 to 6 days to the blastocyst stage, and trophoblastocytes were obtained by microbiopsy. Mitochondrial DNA testing (PGT-MT) and chromosomal aneuploidy (PGT-A) analyses were carried out after whole-genome amplification, and the embryos with zero mutation load were selected for transfer. Amniotic fluid and umbilical cord blood samples were collected during middle pregnancy and after birth respectively for mitochondrial DNA testing to verify the reliability of embryo screening. As an attempt, PB1 with good morphology of MⅡ oocytes was selected for transfer into the enucleated oocytoplasm from healthy donors, followed by ICSI fertilization, blastocyst culture and PGT of embryos using the same procedure. This study has been approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (No. 2021zhyx-B12). Results:An antagonist protocol was used for ovarian stimulation, and a total of 19 oocytes were obtained, of which 14 MⅡ were fertilized by ICSI, and 2 had developed into blastocysts. PGT-MT was carried out on biopsied trophoblastocytes, in which the mitochondrial DNA 8993T>G mutation load was not detected in one embryo, the other was 100% mutated, and the mutation loads of the remaining unfertilized eggs and developmentally arrested embryos ranged from 0% ~ 100%, presenting a clear biased distribution. With fully informed consent, one PGT-MT zero mutation load blastocyst was transferred and clinical pregnancy was achieved. Mitochondrial DNA and chromosomal testing of amniotic fluid cells during middle pregnancy had revealed no abnormalities. The proband had delivered a healthy boy through Caesarean section at 39+ 5 weeks of gestation, and no mutation was detected in the cord blood sample. Five well-formed PBs from 14 eggs were selected for PB1 transfer, followed by ICSI and culture, and two of the reconstituted embryos had formed blastocysts, with none of the above mutations detected in the biopsied samples.Conclusion:The PGT-MT technology can help families affected with mitochondrial diseases to have healthy offspring. PB1 transfer in combination with ICSI and PGT-MT holds the promise of turning waste into treasure and providing an alternative means of fertility for such families.

OBJECTIVE: To assess the feasibility of first polar body transfer (PB1T) combined with preimplantation mitochondrial genetic testing for blocking the transmission of a pathogenic mitochondrial DNA 8993T>G mutation. METHODS: A Chinese family affected with Leigh syndrome which had attended the Reproductive Medicine Centre of the First Affiliated Hospital of Anhui Medical University in September 2021 was selected as the study subject. Controlled ovarian hyperstimulation was carried out for the proband after completing the detection of the mitochondrial DNA 8993T>G mutation load among the pedigree members. Mature MII oocytes were inseminated by intracytoplasmic sperm injection (ICSI), cultured in vitro for 5 to 6 days to the blastocyst stage, and trophoblastocytes were obtained by microbiopsy. Mitochondrial DNA testing (PGT-MT) and chromosomal aneuploidy (PGT-A) analyses were carried out after whole-genome amplification, and the embryos with zero mutation load were selected for transfer. Amniotic fluid and umbilical cord blood samples were collected during middle pregnancy and after birth respectively for mitochondrial DNA testing to verify the reliability of embryo screening. As an attempt, PB1 with good morphology of MII oocytes was selected for transfer into the enucleated oocytoplasm from healthy donors, followed by ICSI fertilization, blastocyst culture and PGT of embryos using the same procedure. This study has been approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (No. 2021zhyx-B12). RESULTS: An antagonist protocol was used for ovarian stimulation, and a total of 19 oocytes were obtained, of which 14 MII were fertilized by ICSI, and 2 had developed into blastocysts. PGT-MT was carried out on biopsied trophoblastocytes, in which the mitochondrial DNA 8993T>G mutation load was not detected in one embryo, the other was 100% mutated, and the mutation loads of the remaining unfertilized eggs and developmentally arrested embryos ranged from 0% ~ 100%, presenting a clear biased distribution. With fully informed consent, one PGT-MT zero mutation load blastocyst was transferred and clinical pregnancy was achieved. Mitochondrial DNA and chromosomal testing of amniotic fluid cells during middle pregnancy had revealed no abnormalities. The proband had delivered a healthy boy through Caesarean section at 39⁺⁵ weeks of gestation, and no mutation was detected in the cord blood sample. Five well-formed PBs from 14 eggs were selected for PB1 transfer, followed by ICSI and culture, and two of the reconstituted embryos had formed blastocysts, with none of the above mutations detected in the biopsied samples. CONCLUSION The PGT-MT technology can help families affected with mitochondrial diseases to have healthy offspring. PB1 transfer in combination with ICSI and PGT-MT holds the promise of turning waste into treasure and providing an alternative means of fertility for such families.
Humans ; Preimplantation Diagnosis/methods* ; Female ; DNA, Mitochondrial/genetics* ; Genetic Testing/methods* ; Pregnancy ; Mitochondrial Diseases/genetics* ; Polar Bodies ; Adult ; Feasibility Studies ; Sperm Injections, Intracytoplasmic/methods* ; Embryo Transfer/methods* ; Mutation ; Male ; Blastocyst/metabolism* ; Pedigree

Objective:To mine the risk signals of adverse events (AE) of satralizumab for treatment of neuromyelitis optica spectrum disorder (NMOSD) and provide reference for safe use of the drug in clinic.Methods:AE reports on satralizumab from the 1st quarter of 2020 to the 4th quarter of 2023 were collected by searching US Food and Drug Administration Adverse Event Reporting System (FAERS) database. AEs were classified and standardized according to the preferred term (PT) and system organ class (SOC) of Medical Dictionary for Regulatory Activities version 26.1. Reporting odds radio (ROR) method and Bayesian confidence progressive neural network (BCPNN) method were used to mine the AE risk signals. An AE with ≥3 reports, lower limit of the 95% confidence interval ( CI) of ROR >1, and the information component ( IC) of BCPNN method minus 2 times of standard deviation ( IC-2 SD) >0 were defined as a risk signal. Descriptive analysis on the signals was performed. Results:A total of 526 AE reports were collected, 39 risk signals (PT) were mined by ROR and BCPNN methods, involving 13 SOCs. Among the 39 PTs, 11 were adverse reactions recorded in the label, including blood triglycerides increased, hepatic function abnormal, cellulitis, and etc. Twenty-eight PTs were not recorded in the label, 11 of which involved infections and infestations. The top 5 PTs in signal intensity were atypical mycobacterium infection, pyelonephritis, compression fracture, spinal compression fractures, and lymphocyte count decreased. The top 5 PTs in number of reports were urinary tract infection, pneumonia, corona virus disease 2019, sepsis, and herpes zoster.Conclusion:In addition to the blood triglycerides increased, hepatic function abnormal, cellulitis, and other AEs recorded in the label, NMOSD treatment with satralizumab may also cause atypical mycobacterial infection, pyelonephritis, compression fracture and other AEs not recorded in the label, which clinical physicians should be vigilant.

Objective:To mine the risk signals of adverse events (AE) of satralizumab for treatment of neuromyelitis optica spectrum disorder (NMOSD) and provide reference for safe use of the drug in clinic.Methods:AE reports on satralizumab from the 1st quarter of 2020 to the 4th quarter of 2023 were collected by searching US Food and Drug Administration Adverse Event Reporting System (FAERS) database. AEs were classified and standardized according to the preferred term (PT) and system organ class (SOC) of Medical Dictionary for Regulatory Activities version 26.1. Reporting odds radio (ROR) method and Bayesian confidence progressive neural network (BCPNN) method were used to mine the AE risk signals. An AE with ≥3 reports, lower limit of the 95% confidence interval ( CI) of ROR >1, and the information component ( IC) of BCPNN method minus 2 times of standard deviation ( IC-2 SD) >0 were defined as a risk signal. Descriptive analysis on the signals was performed. Results:A total of 526 AE reports were collected, 39 risk signals (PT) were mined by ROR and BCPNN methods, involving 13 SOCs. Among the 39 PTs, 11 were adverse reactions recorded in the label, including blood triglycerides increased, hepatic function abnormal, cellulitis, and etc. Twenty-eight PTs were not recorded in the label, 11 of which involved infections and infestations. The top 5 PTs in signal intensity were atypical mycobacterium infection, pyelonephritis, compression fracture, spinal compression fractures, and lymphocyte count decreased. The top 5 PTs in number of reports were urinary tract infection, pneumonia, corona virus disease 2019, sepsis, and herpes zoster.Conclusion:In addition to the blood triglycerides increased, hepatic function abnormal, cellulitis, and other AEs recorded in the label, NMOSD treatment with satralizumab may also cause atypical mycobacterial infection, pyelonephritis, compression fracture and other AEs not recorded in the label, which clinical physicians should be vigilant.

Objective:To assess the feasibility of first polar body transfer (PB1T) combined with preimplantation mitochondrial genetic testing for blocking the transmission of a pathogenic mitochondrial DNA 8993T>G mutation.Methods:A Chinese family affected with Leigh syndrome which had attended the Reproductive Medicine Centre of the First Affiliated Hospital of Anhui Medical University in September 2021 was selected as the study subject. Controlled ovarian hyperstimulation was carried out for the proband after completing the detection of the mitochondrial DNA 8993T>G mutation load among the pedigree members. Mature MII oocytes were inseminated by intracytoplasmic sperm injection (ICSI), cultured in vitro for 5 to 6 days to the blastocyst stage, and trophoblastocytes were obtained by microbiopsy. Mitochondrial DNA testing (PGT-MT) and chromosomal aneuploidy (PGT-A) analyses were carried out after whole-genome amplification, and the embryos with zero mutation load were selected for transfer. Amniotic fluid and umbilical cord blood samples were collected during middle pregnancy and after birth respectively for mitochondrial DNA testing to verify the reliability of embryo screening. As an attempt, PB1 with good morphology of MⅡ oocytes was selected for transfer into the enucleated oocytoplasm from healthy donors, followed by ICSI fertilization, blastocyst culture and PGT of embryos using the same procedure. This study has been approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (No. 2021zhyx-B12). Results:An antagonist protocol was used for ovarian stimulation, and a total of 19 oocytes were obtained, of which 14 MⅡ were fertilized by ICSI, and 2 had developed into blastocysts. PGT-MT was carried out on biopsied trophoblastocytes, in which the mitochondrial DNA 8993T>G mutation load was not detected in one embryo, the other was 100% mutated, and the mutation loads of the remaining unfertilized eggs and developmentally arrested embryos ranged from 0% ~ 100%, presenting a clear biased distribution. With fully informed consent, one PGT-MT zero mutation load blastocyst was transferred and clinical pregnancy was achieved. Mitochondrial DNA and chromosomal testing of amniotic fluid cells during middle pregnancy had revealed no abnormalities. The proband had delivered a healthy boy through Caesarean section at 39+ 5 weeks of gestation, and no mutation was detected in the cord blood sample. Five well-formed PBs from 14 eggs were selected for PB1 transfer, followed by ICSI and culture, and two of the reconstituted embryos had formed blastocysts, with none of the above mutations detected in the biopsied samples.Conclusion:The PGT-MT technology can help families affected with mitochondrial diseases to have healthy offspring. PB1 transfer in combination with ICSI and PGT-MT holds the promise of turning waste into treasure and providing an alternative means of fertility for such families.

Objective To investigate the relationship between the levels of serum neuron-specific enolase(NSE)and tumor necrosis factor alpha(TNF-α)and the attack stage and prognosis of children with epilepsy secondary to viral encephalitis(VE).Methods A total of 96 children with VE admitted to the People's Hospital Affiliated to Inner Mongolia Medical University from January 2015 to January 2020 were selected as the research subjects,and they were divided into the control group(children with VE,n=30)and the observation group(children with epilepsy secondary to VE,n=66).In addition,30 healthy children who underwent physical examination in the hospital during the same period were selected as the health group.The levels of serum NSE and TNF-α in the health group,control group and observation group were compared.Children in the observation group were further divided into the 24h relapse group(n=48)and 24h non-relapse group(n=18)according to the attack of disease within 24h after admission.The levels of serum NSE and TNF-α were compared between the two groups.Pearson correlation was used to analyze the relationship between the levels of NSE,TNF-α and the attack stage of epilepsy secondary to VE.Children in the observation group were divided into the good prognosis group(n=45)and the poor prognosis group(n=21)according to the Glasgow Outcome Scale score at discharge.The serum levels of NSE,TNF-α and other possible prognostic factors were compared between the two groups.Multivariate logistic regression analysis was used to explore the prognostic factors of children with epilepsy secondary to VE,and the predictive value of serum NSE and TNF-αlevels on the prognosis of children with epilepsy secondary to VE was analyzed by drawing the receiver operating characteristic curve.Results The level of serum NSE in the control group was significantly higher than that in the health group(P＜0.05),and there was no significant difference in the level of serum TNF-α between the control group and the health group(P＞0.05).The serum levels of NSE and TNF-α in the observation group were significantly higher than those in the control group(P＜0.05).The serum levels of NSE and TNF-α in the observation group were significantly higher than those in the control group(P＜0.05).The levels of serum NSE and TNF-α in the 24 h relapse group were significantly higher than those in the 24 h non-relapse group(P＜0.05).The proportion of severe abnormal EEG,severe abnormal brain images and complicated respiratory failure,and serum levels of c-reactive protein,NSE and TNF-α in the good prognosis group were lower than those in the poor prognosis group(P＜0.05);there were no significant differences in sex,age,body mass,brain injury site,fever,hypokalemia,hyponatremia,previous convulsions,stress hyperglycemia,complicated organ dysfunction,viral infection,first episode of epilepsy,Glasgow Coma Scale score at admission,duration of convulsion,length of hospital stay,white blood cell count,aspartate transaminase,creatine kinase and cardiac troponin levels between the two groups(P＞0.05).The results of multivariate logistic regression analysis showed that complicated respiratory failure,serum NSE and TNF-α levels were correlated with the prognosis of children with epilepsy secondary to VE(P＜0.05).The area under the curve(AUC)of serum NSE and TNF-α levels in predicting the prognosis of children with epilepsy secondary to VE was 0.724(95％confidence interval:0.672-0.776)and 0.689(95％confidence interval:0.637-0.734),respectively,with a sensitivity of 82.22％and 75.56％and a specificity of 76.19％and 71.43％;the AUC of the combination of the two in predicting the prognosis of children with epilepsy secondary to VE was 0.826(95％confidence interval:0.774-0.873),with a sensitivity of 73.33％and a specificity of 80.95％.Conclusion The serum levels of NSE and TNF-α are abnormally high in children with epilepsy secondary to VE.Both of them are factors affecting the prognosis of children with epilepsy secondary to VE,showing a good predictive value for the prognosis of epilepsy secondary to VE.

Objective:To investigate the current status of vocational training for pediatric clinical research coordinators (CRC), and discuss the construction of base-based pediatric CRC training, and to promote the ability of pediatric CRCs.Methods:From July 25 to October 16, 2023, an anonymous self-designed questionnaire survey was conducted through the Wenjuanxing platform to investigate the current situation of pediatric CRC vocational training and base training needs. The data were collated using Excel. Categorical data were described as numbers and percentages.Results:A total of 328 usable questionnaires were returned. Only 7.62% (25 people) believed that existing CRC training was sufficient and could meet actual work needs; 4.88% (16 people) responded that there was no training; 46.34% (152 people) believed that the training was insufficient to support actual work needs; 87.50% (287 people) believed that continuous CRC training was needed; 46.95% (154 people) preferred experienced CRCs for teaching, who should have at least 3 years of CRC work experience; and 46.95% (154 people) preferred a duration of 3 months for CRC training. The preferred training methods were: practice under the direction of experienced CRCs (90.85%, 298 people), step-by-step teaching of practical skills (88.41%, 290 people), case analysis and discussion (87.20%, 286 people), process simulation (83.23%, 273 people), and lecture-based teaching (76.52%, 251 people). The preferred post-training assessment methods were: case analysis (76.52%, 251 people), operation simulation (74.09%, 243 people), process simulation (73.17%, 240 people), written examination (66.16%, 217 people), and interview (63.72%, 209 people).Conclusions:The current pediatric CRC training is not enough to meet actual work needs. It is urgent to develop and promote a CRC training system that can meet work needs, laying the foundation for the construction of pediatric clinical research ecology in China.

Objective:To explore the needs of parents of hospitalized neonates with the challenges of implementing family-centered care during the Covid-19 pandemic.Methods:Using a method of phenomenological interviewing and Colaizzi′s method of data analysis, the information of 18 parents of admitted infants of Children′s Hospital of Fudan University from January 1 to 20, 2022 were collected and analyzed.Results:In the post-epidemic era, 5 themes of needs for parents of hospitalized neonates during family-centered care were identified: closeness to babies; emotional support; training about feeding; accommodation services; financial support.Conclusions:In the post-epidemic era, experiencing worry, anxiety, uncertainty, helplessness, loss and other negative psychological experience, the parents of hospitalized neonates have many unsatisfied needs. Hospital administrators need to focus on the needs of parents for family-centered nursing care, and actively explore effective coping strategies.

Objective:To explore the adverse reaction risk signals of perampanel-related psychiatric disorders, and provide reference for the clinical safe application of perampanel.Methods:The US FDA Adverse Event Reporting System database was searched, and the adverse event (AE) reports on psychiatric disorders from the third quarter of 2012 to the third quarter of 2021, which judged perampanel as the primary suspect drug were collected. The expression of AE was standardized using the preferred term (PT) in the Medical Dictionary for Regulatory Activities. Data such as patient general condition and psychiatric AE outcomes was extracted from AE reports and was analyzed descriptively. Risk signal mining for psychiatric adverse reactions to perampanel was performed using the reporting odds ratio ( ROR) method. The positive signal PT was set as that the number of AE reports was 3 and more and the lower limit of the 95% confidence interval ( CI) of the ROR was greater than 1. Results:A total of 922 reports on psychiatric AE with perampanel as the primary suspect drug were collected. Of the 922 patients involved, 439 were male, 441 were female, and 42 were unknown in gender. Age were recorded in 676 patients, and the age was (38±19) years. AE outcomes were recorded in 807 patients, of which hospitalization/prolonged hospitalization, urgent treatment needs, life threatening, and death due to AE occurred respectively in 409 (44.4%), 316 (34.3%), 60 (6.5%) and 22 patients (2.4%). The 922 AEs involved 1 580 PTs, and 46 PTs were detected with positive signals by ROR method. The top 5 PTs mostly reported were aggression (286 AEs), irritability (128 AEs), suicidal ideation (110 AEs), suicide attempt (100 AEs), and anger (77 AEs). The top 5 PTs with strongest signal intensity ( ROR value) were postictal psychosis (383.13), schizophreniform disorder (355.27), homicidal ideation (203.56), dissociative disorder (119.64) and delusional perception (108.34), among which dissociative disorder and postictal psychosis were AEs not recorded in the drug labels. In the 46 PTs with positive signal, 14 (30.4%) were not recorded in the drug labels, and the other 12 PTs were listed as sexually inappropriate behaviour (81.43), suspiciousness (65.20), disinhibition (32.72), impulsive behaviour (31.18), personality change (22.56), abnormal behaviour (16.31), social avoidant behaviour (12.95), restlessness (6.15), bipolar disorder (5.23), affect lability (5.09), nightmare es (2.86), and fear (2.79). Conclusion:psychiatric adverse reaction is a common and serious adverse reaction of perampanel, which should be paid attention to clinically.