Asymmetric Intramolecular Amination Catalyzed with Cp*Ir-SPDO via Nitrene Transfer for Synthesis of Spiro-Quaternary Indolinone.

An asymmetric intramolecular spiro-amination to high steric hindering α-C-H bond of 1,3-dicarbonyl via nitrene transfer using inactive aryl azides has been carried out by developing a novel Cp*Ir(III)-SPDO (spiro-pyrrolidine oxazoline) catalyst, thereby enabling the first successful construction of structurally rigid spiro-quaternary indolinone cores with moderate to high yields and excellent enantioselectivities. DFT computations support the presence of double bridging H-F bonds between [SbF6]- and both the ligand and substrate, which favors the plane-differentiation of the enol π-bond for nitrenoid attacking. These findings open up numerous opportunities for the development of new asymmetric nitrene transfer systems.

Atroposelective synthesis of biaxial bridged eight-membered terphenyls via a Co/SPDO-catalyzed aerobic oxidative coupling/desymmetrization of phenols.

Bridged chiral biaryls are axially chiral compounds with a medium-sized ring connecting the two arenes. Compared with plentiful methods for the enantioselective synthesis of biaryl compounds, synthetic approaches for this subclass of bridged atropisomers are limited. Here we show an atroposelective synthesis of 1,3-diaxial bridged eight-membered terphenyl atropisomers through an Co/SPDO (spirocyclic pyrrolidine oxazoline)-catalyzed aerobic oxidative coupling/desymmetrization reaction of prochiral phenols. This catalytic desymmetric process is enabled by combination of an earth-abundant Co(OAc)2 and a unique SPDO ligand in the presence of DABCO (1,4-diaza[2.2.2]bicyclooctane). An array of diaxial bridged terphenyls embedded in an azocane can be accessed in high yields (up to 99%) with excellent enantio- (>99% ee) and diastereoselectivities (>20:1 dr).

Comparison of smokers' mortality with non-smokers following out-of-hospital cardiac arrests: a systematic review and meta-analysis.

OBJECTIVE: Although some studies have linked smoking to mortality after out-of-hospital cardiac arrests (OHCAs), data regarding smoking and mortality after OHCAs have not yet been discussed in a meta-analysis. Thus, this study conducted this systematic review to clarify the association. METHODS: The study searched Medline-PubMed, Web of Science, Embase and Cochrane libraries between January 1972 and July 2022 for studies that evaluated the association between smoking and mortality after OHCAs. Studies that reportedly showed relative risk estimates with 95% confidence intervals (CIs) were included. RESULTS: Incorporating a collective of five studies comprising 2477 participants, the analysis revealed a lower mortality risk among smokers in the aftermath of OHCAs compared with non-smokers (odds ratio: 0.77; 95% CI 0.61-0.96; P < 0.05). Egger's test showed no publication bias in the relationship between smoking and mortality after OHCAs. CONCLUSIONS: After experiencing OHCAs, smokers had lower mortality than non-smokers. However, due to the lack of data, this 'smoker's paradox' still needs other covariate effects and further studies to be considered valid.

Characterization of 15 CYP2J2 variants identified in the Chinese Han population on the metabolism of ebastine and terfenadine in vitro.

Genetic polymorphism of the cytochrome P450 (CYP) gene can significantly influence the metabolism of endogenous and xenobiotic compounds. However, few studies have focused on the polymorphism of CYP2J2 and its impact on drug catalytic activity, especially in the Chinese Han population. In this study, we sequenced the promoter and exon regions of CYP2J2 in 1,163 unrelated healthy Chinese Han individuals using the multiplex PCR amplicon sequencing method. Then, the catalytic activities of the detected CYP2J2 variants were evaluated after recombinant expression in S. cerevisiae microsomes. As a result, CYP2J2*7, CYP2J2*8, 13 variations in the promoter region and 15 CYP2J2 nonsynonymous variants were detected, of which V15A, G24R, V68A, L166F and A391T were novel missense variations. Immunoblotting results showed that 11 of 15 CYP2J2 variants exhibited lower protein expression than wild-type CYP2J2.1. In vitro functional analysis results revealed that the amino acid changes of 14 variants could significantly influence the drug metabolic activity of CYP2J2 toward ebastine or terfenadine. Specifically, 4 variants with relatively higher allele frequencies, CYP2J2.8, 173_173del, K267fs and R446W, exhibited extremely low protein expression and defective catalytic activities for both substrates. Our results indicated that a high genetic polymorphism of CYP2J2 could be detected in the Chinese Han population, and most genetic variations in CYP2J2 could influence the expression and catalytic activity of CYP2J2. Our data significantly enrich the knowledge of genetic polymorphisms in CYP2J2 and provide new theoretical information for corresponding individualized medication in Chinese and other Asian populations.

Assessments of CYP­inhibition­based drug-drug interaction between vonoprazan and poziotinib in vitro and in vivo.

CONTEXT: Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown. OBJECTIVE: To study the interaction mechanism and pharmacokinetics of poziotinib on vonoprazan. MATERIALS AND METHODS: In vitro experiments were performed with rat liver microsomes (RLMs) and the contents of vonoprazan and its metabolite were then determined with UPLC-MS/MS after incubation of RLMs with vonoprazan and gradient concentrations of poziotinib. For the in vivo experiment, rats in the poziotinib treated group were given 5 mg/kg poziotinib by gavage once daily for 7 days, and the control group was only given 0.5% CMC-Na. On Day 8, tail venous blood was collected at different time points after the gavage administration of 10 mg/kg vonoprazan, and used for the quantification of vonoprazan and its metabolite. DAS and SPSS software were used for the pharmacokinetic and statistical analyses. RESULTS: In vitro experimental data indicated that poziotinib inhibited the metabolism of vonoprazan (IC50 = 10.6 µM) in a mixed model of noncompetitive and uncompetitive inhibition. The inhibitory constant Ki was 0.574 µM and the binding constant αKi was 2.77 µM. In vivo experiments revealed that the AUC(0-T) (15.05 vs. 90.95 µg/mL·h) and AUC(0-∞) (15.05 vs. 91.99 µg/mL·h) of vonoprazan increased significantly with poziotinib pretreatment. The MRT(0-∞) of vonoprazan increased from 2.29 to 5.51 h, while the CLz/F value decreased from 162.67 to 25.84 L/kg·h after pretreatment with poziotinib. CONCLUSIONS: Poziotinib could significantly inhibit the metabolism of vonoprazan and more care may be taken when co-administered in the clinic.

Prenatal diagnosis and pregnancy outcome of fetuses with rare autosomal trisomies indicated by non-invasive prenatal testing / 中华医学遗传学杂志

OBJECTIVE@#To analyze the result of prenatal diagnosis and outcome of pregnancy for fetuses with rare autosomal trisomies (RATs) suggested by non-invasive prenatal testing (NIPT).@*METHODS@#A total of 69 608 pregnant women who underwent NIPT at Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University from January 2016 to December 2020 were selected as study subjects. The result of prenatal diagnosis and outcome of pregnancy for those with a high risk for RATs were retrospectively analyzed.@*RESULTS@#Among the 69 608 pregnant women, the positive rate of NIPT for high-risk RATs was 0.23% (161/69 608), with trisomy 7 (17.4%, 28/161) and trisomy 8 (12.4%, 20/161) being the most common, and trisomy 17 (0.6%, 1/161) being the rarest. For 98 women who had accepted invasive prenatal diagnosis, 12 fetal chromosomal abnormalities were confirmed, and in 5 cases the results were consistent with those of NIPT, which yielded a positive predictive value of 5.26%. Among the 161 women with a high risk for RATs, 153 (95%) were successfully followed up. 139 fetuses were ultimately born, with only one being clinically abnormal.@*CONCLUSION@#Most women with a high risk for RATs by NIPT have good pregnancy outcomes. Invasive prenatal diagnosis or serial ultrasonography to monitor fetal growth, instead of direct termination of pregnancy, is recommended.

Puerarin inhibits inflammation and lipid accumulation in alcoholic liver disease through regulating MMP8 / 中国天然药物

Alcoholic liver disease (ALD) is a growing global health concern, and its early pathogenesis includes steatosis and steatohepatitis. Inhibiting lipid accumulation and inflammation is a crucial step in relieving ALD. Evidence shows that puerarin (Pue), an isoflavone isolated from Pueraria lobata, exerts cardio-protective, neuroprotective, anti-inflammatory, antioxidant activities. However, the therapeutic potential of Pue on ALD remains unknown. In the study, both the NIAAA model and ethanol (EtOH)-induced AML-12 cell were used to explore the protective effect of Pue on alcoholic liver injury in vivo and in vitro and related mechanism. The results showed that Pue (100 mg·kg-1) attenuated EtOH-induced liver injury and inhibited the levels of SREBP-1c, TNF-α, IL-6 and IL-1β, compared with silymarin (Sil, 100 mg·kg-1). In vitro results were consistent within vivo results. Mechanistically, Pue might suppress liver lipid accumulation and inflammation by regulating MMP8. In conclusion, Pue might be a promising clinical candidate for ALD treatment.

Prenatal diagnosis and genetic counseling of fetuses with sex chromosome mosaicism / 中华检验医学杂志

Objective:To explore the clinical significance of the combined application of prenatal cellular and molecular genetics in the diagnosis of fetal sex chromosome mosaicism.Methods:A retrospective analysis was conducted on 14 034 pregnant women aged 20-46 years (mean age 27±3 years) who came to the Genetic Counseling Clinic of the First Affiliated Hospital of Zhengzhou University from May 1st 2017 to January 31th 2020 for G-banding karyotype analysis of fetal amniotic fluid chromosomes. They were 17-32 weeks pregnant and had no consanguineous marriage. The patients diagnosed as sex chromosome mosaicism were screened out and their prenatal diagnostic indications were analyzed. The results of whole-genome copy number variation sequencing (CNV-seq)/single nucleotide polymorphism-array(SNP-array)/fluorescence in situ hybridization(FISH) were comopared, combined with ultrasound findings, and the pregnancy outcomes of all pregnant women were followed up by access to our hospital′s electronic medical record system or telephone.Results:A total of 46 cases of sex chromosome mosaicism were found. There were 43 cases with two types of karyotype mosaicism, accounting for 93.48%, and 3 cases with three types of karyotype mosaicism, accounting for 6.52%. Comparison of karyotype and CNV-seq/SNP-array/FISH results showed that 4 cases had consistent results, 9 cases had consistent results but different proportion, and 10 cases had inconsistent results. Combined with the results of the cytogenetic/molecular genetic analysis and/or ultrasound findings, pregnant women will decide to continue or terminate the pregnancy.Conclusion:The combination of prenatal cytogenetic and molecular genetic methods is helpful for rapid diagnosis of fetal sex chromosome mosaicism, providing scientific basis for pregnant women′s pregnancy selection.

Effect of somatostatin on gastrointestinal hormone levels and clinical outcomes in critically ill infants after gastrointestinal surgery: a prospective randomized controlled study / 中国当代儿科杂志

OBJECTIVES@#To explore the effects of somatostatin on the levels of gastrointestinal hormones and clinical outcomes in critically ill infants after gastrointestinal surgery.@*METHODS@#Using a random number table method, critically ill infants after gastrointestinal surgery who were admitted to the Intensive Care Unit of Xuzhou Children's Hospital from June 2019 to June 2021 were randomly divided into an observation group (29 cases) and a control group (30 cases). The control group received routine treatment such as anti-infection and hemostasis after surgery, while the observation group received somatostatin in addition to the routine treatment [3.5 μg/(kg·h) infusion for 7 days]. The levels of serum gastrin (GAS), motilin (MTL), insulin, and glucagon-like peptide-1 (GLP-1) before surgery, on the 3rd day after surgery, and on the 7th day after surgery were compared between the two groups. The recovery progress and incidence of complications after surgery were also compared between the two groups.@*RESULTS@#There was no significant difference in the levels of serum GAS, MTL, insulin, and GLP-1 between the two groups before surgery (P>0.05). On the 3rd and 7th day after surgery, the levels of serum GAS, MTL, insulin, and GLP-1 in the observation group were higher than those in the control group (P<0.05). In the observation group, the levels of GAS, MTL, insulin, and GLP-1 on the 7th day after surgery were higher than those before surgery and on the 3rd day after surgery (P<0.05), and the levels on the 3rd day after surgery were higher than those before surgery (P<0.05). There was no significant difference in the levels of serum GAS, MTL, and insulin before surgery, on the 3rd day after surgery, and on the 7th day after surgery in the control group (P>0.05). The level of GLP-1 on the 7th day after surgery was higher than that before surgery and on the 3rd day after surgery (P<0.05), and the level on the 3rd day after surgery was higher than that before surgery (P<0.05) in the control group. The observation group had shorter first time of anal exhaust, recovery time of bowel sounds, and first time of defecation after surgery compared to the control group (P<0.05). The incidence of complications after surgery in the observation group was lower than that in the control group (10% vs 33%, P<0.05).@*CONCLUSIONS@#Somatostatin can increase the levels of serum GAS, MTL, insulin, and GLP-1 in critically ill infants after gastrointestinal surgery, promote the recovery of gastrointestinal function, and reduce the incidence of postoperative complications.

Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C9*72-*75 in the Chinese Han population.

Cytochrome 2C9 (CYP2C9), one of the most important drug metabolic enzymes in the human hepatic P450 superfamily, is required for the metabolism of 15% of clinical drugs. Similar to other CYP2C family members, CYP2C9 gene has a high genetic polymorphism which can cause significant racial and inter-individual differences in drug metabolic activity. To better understand the genetic distribution pattern of CYP2C9 in the Chinese Han population, 931 individuals were recruited and used for the genotyping in this study. As a result, seven synonymous and 14 non-synonymous variations were identified, of which 4 missense variants were designated as new alleles CYP2C9*72, *73, *74 and *75, resulting in the amino acid substitutions of A149V, R150C, Q214H and N418T, respectively. When expressed in insect cell microsomes, all four variants exhibited comparable protein expression levels to that of the wild-type CYP2C9 enzyme. However, drug metabolic activity analysis revealed that these variants exhibited significantly decreased catalytic activities toward three CYP2C9 specific probe drugs, as compared with that of the wild-type enzyme. These data indicate that the amino acid substitution in newly designated variants can cause reduced function of the enzyme and its clinical significance still needs further investigation in the future.

Effects of Simvastatin on the Metabolism of Vonoprazan in Rats Both in vitro and in vivo.

Purpose: To study the potential drug-drug interactions between simvastatin and vonoprazan and to provide the scientific basis for rational use of them in clinical practice. Methods: An incubation system was established with rat liver microsomes, and the main metabolite of vonoprazan M-I was detected by UPLC-MS/MS. The IC50 value of simvastatin was then calculated and its inhibitory mechanism against vonoprazan was also analyzed. Twelve SD rats were randomly divided into 2 groups, then they were given simvastatin or saline for 2 weeks continuously. On the day of the experiment, both groups were intragastrically administered with vonoprazan once, followed by the collection of blood at different time points. Then the plasma concentration of vonoprazan and M-I in rats were detected by UPLC-MS/MS. Results: In vitro experiments revealed that simvastatin could inhibit the metabolism of vonoprazan, and its inhibition type belonged to the mixed non-competitive and competitive inhibition model. In vivo experiments in rats demonstrated that the area under concentration time curve (AUC) of vonoprazan was decreased but the clearance (CLz/F) of it was increased in the simvastatin administrated group, as compared to those of the control group. However, M-I in simvastatin treated group exhibited the higher AUC and lower CLz/F values compared to those in the control group. These data indicated that multiple doses of simvastatin administration could reduce the plasma concentration of vonoprazan and accelerate its metabolic rate in rats. Conclusion: Simvastatin could inhibit the metabolism of vonoprazan in vitro but multiple doses of simvastatin exhibited the opposite effect In vivo. Altogether, our data indicated that an interaction existed between simvastatin and vonoprazan and additional cares might be taken when they were co-administrated in clinic.

The predictive value of the CHA 2DS 2-VASc score for in-hospital outcomes in patients with acute myocardial infarction: China PEACE-retrospective acute myocardial infarction study / 中华内科杂志

Objectives:This study aimed to evaluate the predictive value of the CHA 2DS 2-VASc score for in-hospital outcomes of patients with acute myocardial infarction (AMI). Methods:Data of 23 728 patients from the China patient-centered Evaluative Assessment of cardiac Events (China PEACE)Retrospective Acute Myocardial Infarction Study were analyzed retrospectively. The patients were categorized into 3 groups according to the CHA 2DS 2-VASc scores: the low score group (score 1-3), the middle score group (score 4-6) and the high score group (score 7-9). The in-hospital outcomes included major adverse cardiovascular events (MACE), death, death or withdrawal from treatment, reinfarction, ischemic stroke,etc. The CHA 2DS 2-VASc score was incorporated into multivariate Cox regression analyses to determine its independent impact on in-hospital outcomes. Receiver operating Characteristic (ROC) curves were constructed, and the area under the curve (AUC) was used to evaluate the predictive value of the CHA 2DS 2-VASc score for in-hospital mortality and death or withdrawal from treatment, respectively. Results:The patients had a median age of 66 (56,75) years, and 30.7% of them were females. Patients with higher CHA 2DS 2-VASc scores had a higher in-hospital mortality and more in-hospital complications (all P<0.001). After adjustment of baseline covariates, the subjects in the high score group were associated with high risks of in-hospital mortality ( OR=6.13, 95% CI 4.77-7.87, P<0.001), death or treatment withdrawal ( OR=6.43, 95% CI 5.16-8.00, P<0.001) and MACE ( OR=4.94, 95% CI 4.06-6.01, P<0.001). The AUCs of the CHA 2DS 2-VASc score were comparable with those of the mini-global registry of acute coronary events(mini-GRACE)score in evaluation of in-hospital mortality (0.699 vs. 0.696, P=0.752) and the death or treatment withdrawal risk (0.708 vs. 0.713, P=0.489). Conclusions:The CHA 2DS 2-VASc score is an independent predictor of in-hospital outcomes for patients with AMI. Its predictive value was comparable with the mini-GRACE score, which could be used as a simple tool for early and rapid outcome evaluation for AMI patients.

Genetic analysis of a family with 6q22 microdeletion and 10p15.3p13 microduplication in two consecutive pregnancies / 中华检验医学杂志

Objective:Cytogenetic and molecular genetic analysis was performed on two consecutive antenatal abnormal fetuses and their parents in a family to clarify the copy number variation(CNV) and its mechanism.Methods:The karyotypes of two fetuses and their parents were analyzed by conventional karyotyping techniques, and CNVs of two fetuses and their mother were analyzed by low-coverage whole-genome copy number variation sequencing (CNV-seq) techniques.Results:The amniotic fluid karyotype results of fetus 1 and 2 were 46, XN, der(4)t(4;10)(q35;p13). The mother′s peripheral blood karyotype result was 46, XX, t(4;10)(q35;p13), and the father′s karyotype was normal. The CNV-seq results of fetus 1 and 2 were seq[hg19]6q22.31(122740000-125440000)X1; 10p15.3p13(120000-17260000)X3, suggesting that there was a heterozygous deletion of about 2 700 000 bp in fetal 6q22.31 and a duplication of about 17 140 000 bp in fetal 10p15.3p13. The CNV-seq result of their mother was seq[hg19]6q22.31(122740000-125440000)X1, suggesting that there was a heterozygous deletion of about 2 700 000 bp in 6q22.31. The pregnant woman and her family chose to terminate the pregnancy after genetic consulting.Conclusion:The combined application of karyotyping and CNV-Seq is significantly beneficial to detecting microdeletions or microduplications of fetal chromosomes and effectively preventing the birth of defective children.

Effect of somatostatin on postoperative gastrointestinal function and stress level in children with acute abdomen: a prospective randomized controlled study / 中国当代儿科杂志

OBJECTIVES@#To study the effect of somatostatin on postoperative gastrointestinal function and stress level in children with acute abdomen.@*METHODS@#A total of 102 children with acute abdomen who underwent surgery in Xuzhou Children's Hospital from August 2019 to June 2021 were enrolled as subjects and were randomly divided into an observation group and a control group, with 51 children in each group. The children in the control group were given conventional treatment such as hemostasis and anti-infective therapy after surgery, and those in the observation group were given somatostatin in addition to conventional treatment. Peripheral blood samples were collected from both groups before surgery and on days 1 and 5 after surgery. The two groups were compared in terms of the serum levels of endothelin-1 (ET-1), adrenocorticotropic hormone (ACTH), cortisol, gastrin, and motilin, postoperative recovery, and the incidence rate of complications.@*RESULTS@#There was no significant difference in the serum levels of ET-1, ACTH, cortisol, gastrin, and motilin between the two groups before surgery (P>0.05). Compared with the control group, the observation group had significantly lower serum levels of ET-1, ACTH, and cortisol on days 1 and 5 after surgery (P<0.05) and significantly higher levels of motilin and gastrin on day 5 after surgery (P<0.05). Compared with the control group, the observation group had significantly shorter time to first passage of flatus, first bowel sounds, and first defecation after surgery, as well as a significantly shorter length of hospital stay (P<0.05). The incidence rate of complications in the observation group was significantly lower than that in the control group (6% vs 24%, P<0.05).@*CONCLUSIONS@#In children with acute abdomen, somatostatin can significantly reduce postoperative stress response, improve gastrointestinal function, and reduce the incidence rate of complications, thereby helping to achieve a good prognosis.

Functional characterization of the defective CYP2C9 variant CYP2C9*18.

Cytochrome P450 2C9 (CYP2C9) is one of the most important drugs metabolizing enzymes and accounts for the metabolism of about 13%-17% of clinical drugs. Like other members in CYP2 family, CYP2C9 gene exhibits great genetic polymorphism among different races and individuals. CYP2C9*18 is one CYP2C9 allelic variant identified in a Southeast Asian population and is estimated to cause the amino acid substitutions of I359L and D397A in CYP2C9 enzyme simultaneously. Limited by the low expression level in bacteria and COS-7 cells, no valuable enzyme kinetics have been reported on this CYP2C9 variant. In this study, the baculovirus-based system was used for the high expression of recombinant CYP2C9 s in insect cells. As a result, together with I359L substitution, D397A could significantly decrease the protein expression of CYP2C9.18 in insect cells, although substitution of D397A alone had no effect on the expression of CYP2C9 in vitro. As compared with that of wild-type enzyme, both CYP2C9.18 variant and D397A variant could decrease more than 80% of the catalytic activity of CYP2C9 enzyme toward three probe substrates, suggesting that caution should be exercised when patients carrying CYP2C9*18 taking medicines metabolized by CYP2C9 enzyme with a narrow therapeutic window.

Effect of painting intervention based on Mandala-self theory on mood and physiological state in patients in preoperative waiting room / 中南大学学报(医学版)

OBJECTIVES@#The waiting room for surgery is an area set up to improve the surgical turnover rate, but the waiting time for surgery is uncertain. Patients are prone to negative emotions that affect their physiological state during waiting time. This study aims to explore the effect of Mandala painting intervention based on Mandala-self theory on the emotion and physiological state of patients waiting before operation.@*METHODS@#The patients in the control group (@*RESULTS@#Diastolic pressure, heart rate, and happiness and excitement showed no statistical significance in the time effect, intervention effect, and interaction between the 2 factors (all @*CONCLUSIONS@#The application of Mandala painting in the operation waiting room is feasible and can effectively regulate the patients' negative mood and systolic pressure, as well as shorten the waiting time of perception.

Content Determination of Pulegone in Schizonepeta tenuifolia and Its Compound Preparation by Hollow Fiber Liquid-phase Microextraction Coupled with HPLC / 中国药房

OBJECTIVE：To establish t he metho d for the content determination of pulegone in Schizonepetae tenuifolia decoction pieces and its compound preparation. METHODS ：Hollow fiber liquid-phase microextraction coupled with HPLC （HF-LPME-HPLC） was adopted. Based on single factor tests ，HF-LPME condition of S. tenuifolia decoction pieces and its compound preparation （taking Compound S. tenuifolia granule as an expample ） was optimized by central composite design-response surface methodology using pulegone enrichment multiple as index ，with the concentration of sample phase solution （NaCl），extraction time and stirring speed as factors. Validation test was conducted. HPLC method was adopted to determine the content of pulegone. The determination was performed on Hypersil C 18 column with mobile phase consisted of methanol- 0.3％ phosphoric acid （gradient elution ）at the flow rate of 1.0 mL/min. The detection wavelength was set at 252 nm，the column temperature was 25 ℃. The sample size was 20 μL. The feasibility of HF-LPME-HPLC method established in this study was validated by using HPLC method stated in the item of S. tenuifolia decoction pieces in 2020 edition of Chinese Pharmacopoeia （part Ⅰ）as reference. RESULTS ：The optimum HF-LPME conditions included n-nonanol as the extraction solvent ，sample phase solution with 11％ NaCl and pH value of 7，stirring speed of 800 r/min，extraction time of 36 min. Results of HPLC methodology investigation showed that linear range of pulegone were 0.05-5 μg/mL（r＝0.999 0）. The limits of detection and quantitation were 0.4 and 1.3 ng/mL，respectively. RSDs of intra-day and inter-day precision were 1.8％-4.0％ and 1.5％-4.1％（n＝3），respectively. RSDs of reproducibility and stability tests （24 h）were all lower than 8％（n＝6）. Average recoveries of S. tenuifolia decoction pieces and Compound S. tenuifolia granule were 102.6％-105.1％ and 97.2％-102.3％，respectively；RSDs were not higher than 4.1％ and 6.2％（n＝3）. The average contents of pulegone in S. tenuifolia decoction pieces determined by pharmacopoeia method and established method were 0.84 mg/g（RSD＝4.3％ ，n＝3）and 0.87 mg/g（RSD＝5.5％ ，n＝3），respectively，with no significant difference （P＞0.05）. CONCLUSIONS ：The established HF-LPME-HPLC method can enrich and concentrate pulegone ， shows strong purification ability and high sensitivity ，and can be used to determine the contents of pulegone in S. tenuifolia decoction pieces and its compound preparation.

Application and the limitation of next generation sequencing for the diagnosis of methylmalonic acidemia / 中华医学遗传学杂志

OBJECTIVE@#To identify genetic variants among patients with methylmalonic acidemia and provide genetic evidence for prenatal diagnosis.@*METHODS@#Thirty-one probands and their parents were subjected to next generation sequencing (NGS). Suspected variants were verified by Sanger sequencing.@*RESULTS@#25 probands or their parents were found to harbor previously known pathogenic or likely pathogenic variants, and three probands were found to carry heterozygous MMACHC exonic deletion. The overall diagnostic yield was 90.32%.@*CONCLUSION@#NGS can improve the detection rate for methylmalonic acidemia for its accuracy and efficiency, yet the detection of exonic deletion is required to further improve the diagnostic yield. The identification of specific variants provided evidence for prenatal diagnosis.

Discharge heart rate and 1-year clinical outcomes in heart failure patients with atrial fibrillation / 中华医学杂志(英文版)

BACKGROUND@#The association between heart rate and 1-year clinical outcomes in heart failure (HF) patients with atrial fibrillation (AF), and whether this association depends on left ventricular ejection fraction (LVEF), are unclear. We investigated the relationship between discharge heart rate and 1-year clinical outcomes after discharge among hospitalized HF patients with AF, and further explored this association that differ by LVEF level.@*METHODS@#In this analysis, we enrolled 1760 hospitalized HF patients with AF from the China Patient-centered Evaluative Assessment of Cardiac Events Prospective Heart Failure study from August 2016 to May 2018. Patients were categorized into three groups with low (<65 beats per minute [bpm]), moderate (65-85 bpm), and high (≥86 bpm) heart rate measured at discharge. Cox proportional hazard models were employed to explore the association between heart rate and 1-year primary outcome, which was defined as a composite outcome of all-cause death and HF rehospitalization.@*RESULTS@#Among 1760 patients, 723 (41.1%) were women, the median age was 69 (interquartile range [IQR]: 60-77) years, median discharge heart rate was 75 (IQR: 69-84) bpm, and 934 (53.1%) had an LVEF <50%. During 1-year follow-up, a total of 792 (45.0%) individuals died or had at least one HF hospitalization. After adjusting for demographic characteristics, smoking status, medical history, anthropometric characteristics, and medications used at discharge, the groups with low (hazard ratio [HR]: 1.32, 95% confidence interval [CI]: 1.05-1.68, P = 0.020) and high (HR: 1.34, 95% CI: 1.07-1.67, P = 0.009) heart rate were associated with a higher risk of 1-year primary outcome compared with the moderate group. A significant interaction between discharge heart rate and LVEF for the primary outcome was observed (P for interaction was 0.045). Among the patients with LVEF ≥50%, only those with high heart rate were associated with a higher risk of primary outcome compared with the group with moderate heart rate (HR: 1.38, 95% CI: 1.01-1.89, P = 0.046), whereas there was no difference between the groups with low and moderate heart rate. Among the patients with LVEF <50%, only those with low heart rate were associated with a higher risk of primary outcome compared with the group with moderate heart rate (HR: 1.46, 95% CI: 1.09-1.96, P = 0.012), whereas there was no difference between the groups with high and moderate heart rate.@*CONCLUSIONS@#Among the overall HF patients with AF, both low (<65 bpm) and high (≥86 bpm) heart rates were associated with poorer outcomes as compared with moderate (65-85 bpm) heart rate. Among patients with LVEF ≥50%, only a high heart rate was associated with higher risk; while among those with LVEF <50%, only a low heart rate was associated with higher risk as compared with the group with moderate heart rate.@*TRAIL REGISTRATION@#Clinicaltrials.gov; NCT02878811.

Comprehensive evaluation of cardiovascular disease diagnosis and treatment service capacity in primary health care in Beijing-Tianjin-Hebei region / 中国医师杂志

Objective:To assess capacity of cardiovascular disease diagnosis and treatment service in primary health care (PHC) in Beijing-Tianjin-Hebei region.Methods:From September to December 2016, document acquisition and abstraction and in-person interviews were conducted on 327 PHC institutions and their medical staff from 43 districts/counties in the Beijing-Tianjin-Hebei region to comprehensively assess their infrastructure and services, human resources, health information system and drug availability related to cardiovascular disease diagnosis and treatment.Results:⑴ Infrastructure and services: 30.0% Community Health Center (CHC) and 100.0% Township healthcare center (THC) provided inpatient services, 20.5%, 98.1% village clinic (VC) could not provide blood glucose tests and lipid tests, respectively; ⑵ Human resources: in CHC, THC or CHS, 19.6% doctors' educational levels were below the requirement for a licensed assistant doctor, and in VC, 32.4% doctors' educational levels were below the requirement for village doctors. 56.3%CHC、THC and CHS, 99.5% VC could not provide government-funded " four insurances and one allowance" for non-registered staff, and 30.0% village doctors had exceeded 60 years old; ⑶ Health information system: 40.0% CHC, 41.7% THC, and 0 VC had electronic medical record (EMR), respectively; ⑷ Drug availability: 71.9% PHC institutions stored all four types of antihypertensive drugs [angiotensin-converting enzyme inhibitors/angiotensin receptor blockors (ACEIs/ARBs), β-blockers, calcium channel blockers (CCBS), diuretics], and 2.1% did not have any.Conclusions:The capacity of cardiovascular disease diagnosis and treatment services in PHC institutions in Beijing-Tianjin-Hebei region are fair in general, but efforts should still be made to enhance the infrastructure construction, improve the remuneration packages of PHC doctors, promote the comprehensive ability of PHC doctors, optimize the layout of urban and rural health resources, strengthen the information construction, and improve the joint development of medical system in the three cities and provinces.