Publications by authors named "Ying Peng"

869 Publications

Prenatal case of Simpson-Golabi-Behmel syndrome with a de novo 370Kb-sized microdeletion of Xq26.2 compassing partial GPC3 gene and review.

Mol Genet Genomic Med 2021 Jul 22:e1750. Epub 2021 Jul 22.

Department of Medical Genetics, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China.

Background: Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is a rare X-linked recessive disorder characterized by pre- and postnatal overgrowth and a broad spectrum of anomalies including craniofacial dysmorphism, heart defects, renal, and genital anomalies. Due to the ultrasound findings are not pathognomonic for this syndrome, most clinical diagnosis of SGBS1 are made postnatally.

Methods: A pregnant woman with abnormal prenatal sonographic findings was advised to perform molecular diagnosis. Single nucleotide polymorphism array (SNP array) was performed in the fetus, and the result was validated with multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative PCR (qPCR).

Results: The prenatal sonographic presented with increased nuchal translucency at 13 gestational weeks, and later at 21 weeks with cleft lip and palate, heart defect, increased amniotic fluid index and over growth. A de novo 370Kb-deletion covering the 5'-UTR and exon 1 of GPC3 gene was detected in the fetus by SNP array, which was subsequently confirmed by MLPA and qPCR.

Conclusion: The de novo 370Kb hemizygous deletion of 5'-UTR and exon 1 of GPC3 results in the SGBS1 of this Chinese family. Combination of ultrasound and genetics tests helped us effectively to diagnose the prenatal cases of SGBS1. Our findings also enlarge the spectrum of mutations in GPC3 gene.
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http://dx.doi.org/10.1002/mgg3.1750DOI Listing
July 2021

A comparison study between dimethyl itaconate and dimethyl fumarate in electrophilicity, Nrf2 activation, and anti-inflammation .

J Asian Nat Prod Res 2021 Jul 22:1-12. Epub 2021 Jul 22.

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.

Dimethyl itaconate (DMI) is an analog of dimethyl fumarate (DMF), an approved NF-E2-related Factor 2 (Nrf2) activator for multiple sclerosis. This study evaluated the potential of DMI as an anti-inflammatory agent by comparing DMI with DMF in electrophilicity, Nrf2 activation, and anti-inflammation . The results showed that DMI was less electrophilic but better at inducing a durable activation of Nrf2 when compared with DMF. However, DMI demonstrated poor anti-inflammatory effects in Jurkat cells, bone marrow-derived dendritic cells, and RAW264.7 cells. Our study suggested that DMI was a potent electrophilic Nrf2 activator but was probably not a promising anti-inflammatory agent.
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http://dx.doi.org/10.1080/10286020.2021.1949303DOI Listing
July 2021

Contralateral S1 nerve root transfer for motor function recovery in the lower extremity among patients with central nervous system injury: study protocol for a randomized controlled trial.

Ann Palliat Med 2021 Jun;10(6):6900-6908

Trauma Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: Central nervous system injury (CNSI) comprises a series of common diseases that severely affect patients' motor function and quality of life and is associated with high disability and mortality rates. Previous studies have shown that contralateral lumbosacral nerve root transfer significantly improved the function of the paralyzed limb in rat models of CNSI. These studies showed that severing the sacral 1 nerve root (S1) did not damage the function of the ipsilateral lower extremity. Thus, we speculate that contralateral S1 nerve root transfer can improve the recovery of a paralyzed limb. Because no associated rigorously designed randomized controlled trial has evaluated the effectiveness of contralateral S1 nerve transfer thus far, we designed this clinical trial to compare the effects of this new treatment approach with those of traditional treatments in paralyzed patients after chronic CNSI.

Methods: This is a single-center, prospective, randomized controlled trial. Forty patients, who meet the inclusion criteria and have hemiplegia caused by chronic CNSI, will be randomly divided into the surgical or non-surgical group. The treatment effect in the 2 groups will be assessed before and 3, 6, 9, 12, 18, and 24 months after intervention by using numerous scales and resting-state functional magnetic resonance imaging. The primary outcome will be the Fugl-Meyer score for the lower limbs 24 months after treatment. The secondary outcomes include the modified Ashworth spasm scale, the modified Barthel scale, 10-m walking speed measurement results, three-dimensional gait analysis, muscle strength testing, electromyography, and resting-state functional magnetic resonance imaging findings. Safety outcomes and adverse events will be observed simultaneously.

Discussion: We expect that the surgery will improve the sensorimotor functions of the paralyzed limb, and the results of this trial will provide high-quality clinical evidence for a new efficient treatment strategy for disability after CNSI.

Trial Registration: Chinese Clinical Trial Registry: ChiCTR1800014414, registration date: 12 January 2018.
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http://dx.doi.org/10.21037/apm-21-183DOI Listing
June 2021

Infusion port level detection for intravenous infusion based on Yolo v3 neural network.

Math Biosci Eng 2021 Apr;18(4):3491-3501

Department of Anesthesiology, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, China.

Purpose: In order to improve the accuracy of liquid level detection in intravenous left auxiliary vein infusion and reduce the pain of patients with blood returning from intravenous infusion, we propose a deep learning based liquid level detection model of infusion levels to facilitate this operation.

Method: We implemented a Yolo v3-based detection model of infusion level images in intravenous infusion, and at the same time, compare it with SURF image processing technique, RCNN, and Fast-RCNN methods.

Results: The model in this paper is better than the comparison algorithm in Intersection over Union (IoU), precision, recall and test time. The liquid level detection model based on Yolo v3 has a precision of 0.9768, a recall rate of 0.9688, an IoU of 0.8943, and a test time of 2.9 s.

Conclusion: The experimental results prove that the liquid level detection method based on deep learning has the characteristics of high accuracy and good real-time performance. This method can play a certain auxiliary role in the hospital environment and improve work efficiency of medical workers.
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http://dx.doi.org/10.3934/mbe.2021175DOI Listing
April 2021

Oxypeucedanin is a mechanism-based inactivator of CYP2B6 and CYP2D6.

Curr Drug Metab 2021 Jun 29. Epub 2021 Jun 29.

Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, China.

Background: Herbal medicine Angelica dahurica is widely employed for the treatment of rheumatism and pain relief in China. Oxypeucedanin is a major component of the herb.

Objectives: The objectives of this study are aimed at the investigation of mechanism-based inactivation of CYP2B6 and CYP2D6 by oxypeucedanin, characterization of the reactive metabolites associated with the enzyme inactivation, and identification of the P450s participating in the bioactivation of oxypeucedanin.

Methods: Oxypeucedanin was incubated with liver microsomes or recombinant CYPs2B6 and 2D6 under designed conditions, and the enzyme activities were measured by monitoring the generation of the corresponding products. The resulting reactive intermediates were trapped with GSH and analyzed by LC-MS/MS.

Results: Microsomal incubation with oxypeucedanin induced a time-, concentration-, and NADPH-dependent inhibition of CYPs2B6 and 2D6 with kinetic values of KI/kinact 1.82 µM/0.07 min-1 (CYP2B6) and 8.47 µM/0.044 min-1 (CYP2D6), respectively. Ticlopidine and quinidine attenuated the observed time-dependent enzyme inhibitions. An epoxide and/or γ-ketoenal intermediate(s) derived from oxypeucedanin was/were trapped in microsomal incubations. CYP3A4 was the primary enzyme involved in the bioactivation of oxypeucedanin.

Conclusion: Oxypeucedanin was a mechanism-based inactivator of CYP2B6 and CYP2D6. An epoxide and/or γ-ketoenal intermediate(s) may be responsible for the inactivation of the two enzymes.
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http://dx.doi.org/10.2174/1389200222666210629114830DOI Listing
June 2021

Glutathione conjugation and protein modification resulting from metabolic activation of venlafaxine and .

Xenobiotica 2021 Jun 23:1-39. Epub 2021 Jun 23.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P. R. China.

Venlafaxine (VLF), an antidepressant agent, is widely used to combat major depressive disorders, particularly for the treatment of selective serotonin reuptake inhibitor-resistant depression. VLF has been shown to cause liver injury. The present study aimed to investigate the metabolic activation of VLF and explore the mechanisms of hepatotoxicity induced by VLF.One glutathione (GSH) conjugate and one cysteine conjugate were both detected in mouse and human liver microsomal incubations containing VLF and GSH or cysteine. The two conjugates were also detected in cultured mouse primary hepatocytes and bile of rats after exposure to VLF. The and studies demonstrated that VLF was metabolized to a quinone methide intermediate reactive to GSH and cysteine residues of hepatic protein. The observed protein covalent binding revealed dose-dependency. The metabolic activation of VLF was P450-dependent, and CYP3A4 was found as the predominant enzyme involved in the bioactivation process.These findings facilitate better understanding of the metabolic activation-hepatotoxicity relationship of VLF and provide chemists with information about new potential structural alerts during drug design process.
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http://dx.doi.org/10.1080/00498254.2021.1946204DOI Listing
June 2021

Electrochemical Deposition of Cu Metal-Organic Framework Films for the Dual Analysis of Pathogens.

Anal Chem 2021 06 21;93(25):8994-9001. Epub 2021 Jun 21.

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China.

Metal-organic framework (MOF) thin films with flexible nature and prominent qualities have opened doors to new technological applications in different fields. Herein, we propose an electrochemical biosensor for the dual detection of Staphylococcus aureus based on the electrodeposition of Cu metal-organic framework (Cu-MOF) thin films. The promising sensing layer with features of good electronic conductivity and enhanced electron-transfer property can not only identify through specific micrococcal nucleases in the supernatant but also detect the pathogen directly aptamer recognition. The dual analysis design ensures the accuracy of this method for detection in the range of 7-7 × 10 cfu/mL with the limits of detection of 1.9 and 5.2 cfu/mL. Moreover, the analytical method validation confirmed that the biosensor could efficiently work in complex biological samples, showing good selectivity and specificity and great potential for clinical diagnosis. More importantly, the current proposed strategy is simple and easy to implement without the need for extra signaling elements, which is convenient for timely clinical detection.
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http://dx.doi.org/10.1021/acs.analchem.1c01763DOI Listing
June 2021

Long Non-coding RNA Regulates the Regeneration of the Sciatic Nerve via the miR-331-3p-NLRP3/MAL Axis.

Front Cell Dev Biol 2021 4;9:641603. Epub 2021 Jun 4.

Department of Orthopedic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Peripheral nerve injury (PNI) is a common clinical problem, which can cause severe disability and dramatically affect a patient's quality of life. Neural regeneration after PNI is a complex biological process that involves a variety of signaling pathways and genes. Emerging studies demonstrated that long non-coding RNAs (lncRNAs) were abnormally expressed after PNI and played pivotal roles in peripheral nerve regeneration. Based on the rat sciatic nerve injury model, we found that the expression levels of several lncRNAs were increased significantly in the sciatic nerve after injury. Software prediction prompted us to focus on one up-regulated lncRNA, . Dual-luciferase reporter assay, RNA pull-down assay and RNA interference approach verified that regulated neuroregeneration via the miR-331-3p/nucleotide-binding oligomerization domain-like pyrin domain containing 3 (NLRP3)/myelin and lymphocyte protein (MAL) axis . Subsequently, we performed gastrocnemius muscle gravity and sciatic functional index experiments to evaluate the recovery of injured sciatic nerves after siRNA interference . In conclusion, knockdown of promotes the regeneration of the sciatic nerve via the miR-331-3p/NLRP3/MAL axis, which may provide a new strategy to evaluate and repair injured peripheral nerves clinically.
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http://dx.doi.org/10.3389/fcell.2021.641603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213216PMC
June 2021

Conservative oxygen supplementation versus usual oxygen supplementation among septic medical intensive care units patients: A before-after investigation.

Sci Prog 2021 Apr-Jun;104(2):368504211016953

Department of Emergency Medicine, Gongli Hospital, Pudong New Area, Shanghai, China.

Patients admitted in the intensive care unit (ICU) are always managed with excessive high fraction of inspired oxygen and have hyperoxia for a significant period of time, which has potential harms. The guidelines for the management of patients in ICUs do not provide the target values for partial pressure of oxygen or arterial oxyhemoglobin saturations. The study was a before-after investigation comparing two time periods in which different oxygenation strategies were applied. Data of oxygen control, outcome measures, and mortality of a total of 273 patients (>18 years) admitted at least for 2 days in ICUs and received treatment for the sepsis were retrospectively collected and analyzed. Patients were received usual oxygen supplementation (targeted partial pressure of oxygen: 150 mmHg; a high fraction of inspired oxygen: 0.4; UOS cohort;  = 142) or conservative oxygen supplementation (targeted partial pressure of oxygen: 70-100 mmHg; a high fraction of inspired oxygen as low as possible; COS cohort;  = 131). Mechanical ventilation-free hours were significantly higher for patients of COS cohort than those of UOS cohort (77.99 ± 21.26 h/patient vs 70.01 ± 23.57 h/patient,  = 0.016). ICUs length of stays of patients of COS cohort was fewer than those of UOS cohort (7.05 ± 2.13 days/patient vs 7.69 ± 2.43 days/patients,  = 0.016). The probability of survival of patients was higher among patients of COS cohort than those of UOS cohort ( = 0.049). A higher number of patients from UOS cohort needed vasopressors than those from COS cohort (55 vs 35,  = 0.039). Conservative oxygen supplementation to maintain partial pressure of oxygen was improved outcome measures and decreases mortality as compared to that of usual oxygen supplementation. III. 4.
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http://dx.doi.org/10.1177/00368504211016953DOI Listing
June 2021

Persistent Discrimination of TB in Southeastern China: Results from Four Repeated Population-Based Surveys During the Period of 2006-2018.

Risk Manag Healthc Policy 2021 3;14:2333-2344. Epub 2021 Jun 3.

Department of Tuberculosis Control and Prevention, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, People's Republic of China.

Objective: To analyze the changes in discriminatory attitudes and isolated behaviors of the public toward tuberculosis (TB) in the Zhejiang Province and to determine the associated factors with TB discrimination.

Methods: Data were obtained from four cross-sectional population-based investigations from 2006 to 2018. A total of 26,246 respondents were interviewed using unified questionnaires that measured knowledge, attitudes, and behaviors regarding TB. The changes in public attitudes and behaviors towards TB over time were analyzed. The effect of socio-demographic factors and the level of TB awareness on TB discriminatory attitudes and isolated behaviors were evaluated.

Results: The results of these four cross-sectional studies found that TB discrimination had not changed much over the decade. Overall, discriminatory attitudes were present in 63.5% of the respondents who knew about TB (81.2%). Nearly 31.2% of those who reported being surrounded by people with TB (5.8%) showed isolated behaviors. Older respondents, those with a low education level, and farmers were prone to having discriminatory attitudes or behaviors. Those aware of the infectiousness and transmission routes of TB, and those who felt that TB was serious were more likely to discriminate against TB ( < 0.001). Those aware that TB can be cured were non-discriminatory (aOR = 0.77, 95% CI: 0.72-0.82).

Conclusion: Discriminatory attitudes and isolated behaviors toward TB have not changed significantly in southeastern China over the survey years, and persistent discrimination against TB still exists among the public. The multiple causes of discrimination cannot be addressed through basic health education. Tailor-made strategies, relevant policy measures, and an enabling social environment for TB are urgently required.
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http://dx.doi.org/10.2147/RMHP.S311869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184293PMC
June 2021

A simple method to assay tumor cells based on target-initiated steric hindrance.

Chem Commun (Camb) 2021 Jul;57(53):6522-6525

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China and Center for Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, Shanghai 200444, P. R. China.

We have proposed a simple electrochemical method in this work for the assay of tumor cells through their own steric hindrance effect. Specifically, tumor cells can block the catalysis of terminal deoxynucleotidyl transferase to the aptamer previously immobilized on the electrode surface. By making use of the hindrance effect, cancer cells can be quantitatively analyzed in the range from 1.6 × 102 to 1.6 × 106 cells per mL without complicated design or cumbersome operation, while the detection limit can be about 53 cells per mL. This method can also show satisfactory performance in complex environments, indicating its potential in clinical application.
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http://dx.doi.org/10.1039/d1cc02532eDOI Listing
July 2021

Metabolic activation of zolmitriptan mediated by CYP2D6.

Xenobiotica 2021 Jun 7:1-29. Epub 2021 Jun 7.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P. R. China.

Zolmitriptan (ZOL), a member of triptans, has been used for the treatment of migraine with definite therapeutic effects. However, several cases of liver injury associated with ZOL have been reported and the underlying mechanisms remain unclear.The present study aimed to investigate the metabolic activation of ZOL and . ZOL-derived glutathione (GSH) and -acetyl cysteine (NAC) conjugates were detected in rat liver microsomal incubations. In addition, the GSH and NAC conjugates were also found in bile and urine of rats given ZOL, respectively.ZOL-derived GSH conjugate M1 was also observed in ZOL-treated rat primary hepatocytes, and the formation of M1 was inhibited by pre-cultured with quinidine (a selective inhibitor of CYP2D6). Combining with recombinant P450 enzymes incubations, we found that CYP2D6 was the predominant enzyme responsible for the metabolic activation of ZOL.ZOL can be metabolized to an ,-unsaturated imine intermediate by CYP2D6. Pre-treatment of primary hepatocytes with quinidine was able to reverse ZOL-induced cytotoxicity. The finding facilitates the understanding of the mechanisms involved in ZOL-associated liver adverse reactions.
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http://dx.doi.org/10.1080/00498254.2021.1938290DOI Listing
June 2021

Exploring stroke risk and prevention in China: insights from an outlier.

Aging (Albany NY) 2021 06 4;13(11):15659-15673. Epub 2021 Jun 4.

Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.

In contrast to the declining trend in most regions worldwide, the incidence of stroke is increasing in China and is leading to an alarming burden for the national healthcare system. In this review, we have generated new insights from this outlier, and we aim to provide new information that will help decrease the global stroke burden, especially in China and other regions sharing similar problems with China. First of all, several unsolved aspects fundamentally accounting for this discrepancy were promising, including the serious situation of hypertension management, underdiagnosis of atrial fibrillation and underuse of anticoagulants, and unhealthy lifestyles (e.g., heavy smoking). In addition, efforts for further alleviating the incidence of stroke were recommended in certain fields, including targeted antiplatelet regimes and protections from cold wave-related stroke. Furthermore, advanced knowledge about cancer-related strokes, recurrent strokes and the status preceding stroke onset that we called stroke-prone status herein, is required to properly mitigate patient stroke risk, and to provide improved outcomes for patients after a stroke has occurred.
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http://dx.doi.org/10.18632/aging.203096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221301PMC
June 2021

Magnesium Isoglycyrrhizinate Reduces Hepatic Lipotoxicity through Regulating Metabolic Abnormalities.

Int J Mol Sci 2021 May 30;22(11). Epub 2021 May 30.

Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.

The excessive accumulation of lipids in hepatocytes induces a type of cytotoxicity called hepatic lipotoxicity, which is a fundamental contributor to liver metabolic diseases (such as NAFLD). Magnesium isoglycyrrhizinate (MGIG), a magnesium salt of the stereoisomer of natural glycyrrhizic acid, is widely used as a safe and effective liver protectant. However, the mechanism by which MGIG protects against NAFLD remains unknown. Based on the significant correlation between NAFLD and the reprogramming of liver metabolism, we aimed to explore the beneficial effects of MGIG from a metabolic viewpoint in this paper. We treated HepaRG cells with palmitic acid (PA, a saturated fatty acid of C16:0) to induce lipotoxicity and then evaluated the antagonistic effect of MGIG on lipotoxicity by investigating the cell survival rate, DNA proliferation rate, organelle damage, and endoplasmic reticulum stress (ERS). Metabolomics, lipidomics, and isotope tracing were used to investigate changes in the metabolite profile, lipid profile, and lipid flux in HepaRG cells under different intervention conditions. The results showed that MGIG can indeed protect hepatocytes against PA-induced cytotoxicity and ERS. In response to the metabolic abnormality of lipotoxicity, MGIG curtailed the metabolic activation of lipids induced by PA. The content of total lipids and saturated lipids containing C16:0 chains increased significantly after PA stimulation and then decreased significantly or even returned to normal levels after MGIG intervention. Lipidomic data show that glycerides and glycerophospholipids were the two most affected lipids. For excessive lipid accumulation in hepatocytes, MGIG can downregulate the expression of the metabolic enzymes (GPATs and DAGTs) involved in triglyceride biosynthesis. In conclusion, MGIG has a positive regulatory effect on the metabolic disorders that occur in hepatocytes under lipotoxicity, and the main mechanisms of this effect are in lipid metabolism, including reducing the total lipid content, reducing lipid saturation, inhibiting glyceride and glycerophospholipid metabolism, and downregulating the expression of metabolic enzymes in lipid synthesis.
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http://dx.doi.org/10.3390/ijms22115884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198484PMC
May 2021

Implementation of fragile X syndrome carrier screening during prenatal diagnosis: A pilot study at a single center.

Mol Genet Genomic Med 2021 May 31:e1711. Epub 2021 May 31.

Department of Medical Genetics & the Prenatal Diagnosis Center of Hunan Province, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China.

Background: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. Prenatal screening of FXS allows for early identification and intervention. The present study explored the feasibility of FXS carrier screening during prenatal diagnosis for those who were not offered screening early in pregnancy or prior to conception.

Methods: Pregnant women to be offered amniotic fluid testing were recruited for the free voluntary carrier screening at a single center between August, 2017 and September, 2019. The number of CGG repeats in the 5' un-translated region of the fragile X mental retardation gene 1 (FMR1) was determined.

Results: 4286 of 7000 (61.2%) pregnant women volunteered for the screening. Forty (0.93%), five (0.11%), and three (0.07%) carriers for intermediate mutation (45-54 repeats), premutation (55-200 repeats) and full mutation (>200 repeats) of the FMR1 gene were identified respectively. None of the detected premutation alleles were inherited by the fetuses. Of the three full mutation carrier mothers, all had a family history and one transmitted a full mutation allele to her male fetus.

Conclusion: Implementation of FXS carrier screening during prenatal diagnosis may be considered for the need to increase screening for FXS.
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http://dx.doi.org/10.1002/mgg3.1711DOI Listing
May 2021

Rapamycin as a "One-Stone-Three-Birds" Agent for Cooperatively Enhanced Phototherapies Against Metastatic Breast Cancer.

ACS Appl Mater Interfaces 2021 Jun 27;13(22):25674-25684. Epub 2021 May 27.

Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.

Cooperative photothermal therapy (PTT) and photodynamic therapy (PDT) represents a promising strategy to conquer tumor with synergistic effect, while their long-term efficacy has been strictly limited by the multiple resistances of tumor. Here, we reported a core-shell nanoplatform for enhanced PTT/PDT combination against metastatic breast cancer. The nanosystem had photosensitizer chlorin e6 (Ce6) and rapamycin (RAP) pure drugs core and the polydopamine (PDA) shell, with surface PEGylation. Notably, we found that RAP was a highly robust sensitizer to boost the efficacy of both PTT and PDT by inhibiting the expression of heat shock protein 70 (HSP 70) and hypoxia inducible factor-1α (HIF-1α), respectively, resulting in cooperatively enhanced antitumor efficiency. Moreover, metastasis, the fatal risk of breast cancer, was also inhibited by virtue of RAP-mediated matrix metalloproteinases-2 (MMP-2) suppression. Upon intravenous injection, the nanosystem could passively accumulate into the tumor and impose potent phototherapies upon dual laser irradiations for complete tumor elimination and metastasis inhibition, giving rise to 100% mice survival over a long observation period. Collectively, this work offers a general solution to address the key limitations of tumor-resistant phototherapies and provides a highly promising nanoplatform for the management of metastatic cancer.
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http://dx.doi.org/10.1021/acsami.1c03312DOI Listing
June 2021

Cross-Model Comparison of Transcriptomic Dose-Response of Short-Chain Chlorinated Paraffins.

Environ Sci Technol 2021 06 26;55(12):8149-8158. Epub 2021 May 26.

State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, P. R. China.

Short-chain chlorinated paraffins (SCCPs) have attracted attention because of their toxicological potential in humans and wildlife at environmentally relevant doses. However, limited information is available regarding mechanistic differences across species in terms of the biological pathways that are impacted by SCCP exposure. Here, a concentration-dependent reduced human transcriptome (RHT) approach was conducted to evaluate 15 SCCPs in HepG2 cells and compared with our previous results using a reduced zebrafish transcriptome (RZT) approach in zebrafish embryos (ZFEs). Generally, SCCPs induced a broader suite of biological pathways in ZFEs than HepG2 cells, and all of the 15 SCCPs were more potent in HepG2 cells compared to ZFEs. Despite these general differences, the transcriptional potency of SCCPs in both model systems showed a significant linear relationship ( = 0.0017, = 0.57), and the average ratios of transcriptional potency for each SCCP in RZT to that in RHT were ∼100,000. CHCl was the most potent SCCP, while CHCl was the least potent in both ZFEs and HepG2 cells. An adverse outcome pathway network-based analysis demonstrated model-specific responses, such as xenobiotic metabolism that may be mediated by different nuclear receptor-mediated pathways between HepG2 cells (, CAR and AhR activation) and ZFEs (, PXR activation). Moreover, induced transcriptional changes in ZFEs associated with pathways and molecular initiating events (, activation of nicotinic acetylcholine receptor) suggest that SCCPs may disrupt neural development processes. The cross-model comparison of concentration-dependent transcriptomics represents a promising approach to assess and prioritize SCCPs.
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http://dx.doi.org/10.1021/acs.est.1c00975DOI Listing
June 2021

The complete mitogenome and phylogenetic analysis of Indian driftfish, (Scombriformes: Nomeidae).

Mitochondrial DNA B Resour 2021 May 10;6(5):1606-1607. Epub 2021 May 10.

School of Fishery, Zhejiang Ocean University, Zhoushan, China.

The Indian driftfish () is one of the most important commercial fish species in China, Japan and India. The complete mitogenome of was determined in this study. The assembled mitogenome was 16,507 bp and consisted of 13 protein-coding genes, 22 tRNAs, two rRNAs, and a control region. Nucleotide composition of the complete mitogenome was 27.5% A, 28.5% C, 17.5% G, and 26.5% T, with an A + T bias of 53.9%. The maximum-likelihood tree based on 13 protein-coding genes showed that and were the closest to .
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http://dx.doi.org/10.1080/23802359.2021.1914235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118399PMC
May 2021

Effective treatments for FGF12-related early-onset epileptic encephalopathies patients.

Brain Dev 2021 May 18. Epub 2021 May 18.

Department of Medical Genetics, Maternal, Child Health Hospital of Hunan Province, Changsha Hunan 410008, China; National Health Commission Key Laboratory of Birth Defects Research, Prevention and Treatment, Hunan Provincial Maternal and Child Health Care Hospital, Changsha 410008, China. Electronic address:

Background: FGF12 (FHF1) gene encodes voltage-gated sodium channel (Nav)-binding protein fibroblast growth factor homologous factor 1, which could cause seizures by regulating voltage dependence of Nav fast inactivation and neuron excitability. The most common pathogenic variant FGF12 c.341G > A related early-onset epileptic encephalopathies (EOEE) was characterized by intractable seizures and developmental disabilities.

Results: Using whole exome sequencing, a de novo hotspot variant c.341G > A (NM_021032.4) of FGF12 was identified in three unrelated EOEE probands. All probands were seizure free after a combination treatment of valproic acid (VPA) and topiramate (TPM). The motor and cognitive skills in two probands were improved due to the early and effective treatment. In order to compare the effectiveness of different treatment strategies for the disease, a review of treatments for FGF12-related epilepsy was made.

Conclusion: We reported three FGF12 c.341G > A related EOEE patients responded well to a combination antiepileptic therapy of VPA and TPM. The current study is the first to describe the combination therapy of VPA and TPM in FGF12 c.341G > A related EOEE patients. This study may contribute to future medication consultation for intractable epilepsy with FGF12 hotspot variants.
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http://dx.doi.org/10.1016/j.braindev.2021.04.010DOI Listing
May 2021

A cyclic nano-reactor achieving enhanced photodynamic tumor therapy by reversing multiple resistances.

J Nanobiotechnology 2021 May 21;19(1):149. Epub 2021 May 21.

Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China.

Background: Photodynamic therapy (PDT) is a clinically implemented modality to combat malignant tumor, while its efficacy is largely limited by several resistance factors from tumor microenvironment (TME), such as hypoxia, anti-oxidant systems, and ATP-dependent tumor adaptive resistances. The aim of this work is to construct a multifunctional nanoplatform to remodel multiple resistant TME for enhanced PDT.

Results: Here, a targeting nano-reactor was facilely constructed to reverse the multiple resistances of PDT by incorporating glucose oxidase (GOx) and chlorin e6 (Ce6) into poly (D, L-lactic-co-glycolic acid) (PLGA)/ metal-organic framework (MOF) core-shell nanoassembly, with surface deposition of hyaluronic acid (HA) stabilized MnO. The nano-reactor could selectively target tumor cells by virtue of surface HA modification, and once internalization, a few reactions were initiated to modulate TME. Glucose was consumed by GOx to inhibit ATP generation, and the produced HO was catalyzed by MnO to generate O for tumor hypoxia alleviation and photodynamic sensitization, and glutathione (GSH) was also effectively depleted by MnO to suppress the tumor antioxidant defense. Consequently, the nano-reactor achieved robust PDT with amplified tumor therapy via intravenous injection.

Conclusions: This nano-reactor offers a multifunctional nanoplatform to sensitize TME-limited tumor treatment means via reversing multiple resistances.
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http://dx.doi.org/10.1186/s12951-021-00893-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139056PMC
May 2021

Metabolic Activation of Deferiprone Mediated by CYP2A6.

Xenobiotica 2021 May 18:1-33. Epub 2021 May 18.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P. R. China.

Deferiprone (DFP) is a metal chelating agent generally used to treat patients with thalassemia, due to iron overload in clinical settings.Studies have revealed that long-term use of DFP can induce hepatotoxicity, however, mechanisms of its toxic action remain unclear. The present studies are aimed to characterize the reactive metabolite of DFP, to define the metabolic pathway, and to determine the P450 enzymes participating in the bioactivation.A demethylation metabolite (M1) was observed in rat liver microsomal incubations. Additionally, a glutathione (GSH) conjugate (M2) and an -acetylcysteine (NAC) conjugate (M3) were detected in microsomal incubations fortified with DFP and GSH/NAC.Biliary M2 and urinary M3 were respectively found in animals administered DFP.CYP2A6 enzyme dominated the catalysis to bioactivate DFP.
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http://dx.doi.org/10.1080/00498254.2021.1931729DOI Listing
May 2021

Nomogram and competing risk model to predict recurrence after curative surgical resection of PDAC.

Pancreatology 2021 May 7. Epub 2021 May 7.

Department of General Surgery, Peking University Third Hospital, Beijing, People's Republic of China. Electronic address:

Background: Surgical resection remains the only potentially curative treatment for pancreatic ductal adenocarcinoma (PDAC). However, a number of patients get disease recurred in a short time post-operation. Few studies have focused on the predictors of different recurrence patterns of PDAC.

Objective: To try to establish and verify a nomogram to predict recurrence free survival (RFS) in PDAC patients, and to distinguish the risk factors of local recurrence first and distant metastasis first via competing risk model.

Methods: Patients who underwent radical pancreatectomy for PDAC in our center from 2010 to 2018 were reviewed retrospectively. Kaplan-Meier methods and multivariate Cox regression analyses were used to identify the clinicopathological predictors of recurrence post-operation. And then, a nomogram was constructed and validated. Competing risk regression model was used to compare the predictors between local recurrence group and distant metastasis group.

Results: A total of 200 patients were included into the final analysis, and 153 patients got disease relapsed post-operation. CA19-9 level, vascular resection, tumor differentiation, lymph node ratio (LNR) and adjuvant chemotherapy were identified as independent risk factors for recurrence free survival (RFS) and incorporated into the nomogram. The C-index of the nomogram was 0.650. Competing risk model indicated that the status of lymph-node metastasis was significantly associated the patterns of first relapse.

Conclusions: Nomogram and competing risk model were constructed to quantify the risk of recurrence following surgery for PDAC. Our findings may be useful for predicting RFS and recurrence pattern in clinical work.
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http://dx.doi.org/10.1016/j.pan.2021.04.010DOI Listing
May 2021

An electrochemical biosensor for sensitive analysis of the SARS-CoV-2 RNA.

Biosens Bioelectron 2021 May 10;186:113309. Epub 2021 May 10.

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, PR China; Center for Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, Shanghai, 200444, PR China. Electronic address:

The pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is continuously worsening globally, herein we have proposed an electrochemical biosensor for the sensitive monitoring of SARS-CoV-2 RNA. The presence of target RNA firstly triggers the catalytic hairpin assembly circuit and then initiates terminal deoxynucleotidyl transferase-mediated DNA polymerization. Consequently, a large number of long single-stranded DNA products can be produced, and these negatively charged DNA products will bind a massive of positively charged electroactive molecular of Ru(NH) due to the electrostatic adsorption. Therefore, significantly amplified electrochemical signals can be generated for sensitive analysis of SARS-CoV-2 RNA in the range of 0.1-1000 pM with the detection limit as low as 26 fM. Besides the excellent distinguishing ability for SARS-CoV-2 RNA against single-base mismatched RNA, the proposed biosensor can also be successfully applied to complex matrices, as well as clinical patient samples with high stability, which shows great prospects of clinical application.
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http://dx.doi.org/10.1016/j.bios.2021.113309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107000PMC
May 2021

Mechanisms of DNA-protein cross-link formation and repair.

Biochim Biophys Acta Proteins Proteom 2021 Aug 3;1869(8):140669. Epub 2021 May 3.

Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, United States. Electronic address:

Covalent binding of DNA to proteins produces DNA-protein cross-links (DPCs). DPCs are formed as intermediates of enzymatic processes, generated from the reactions of protein nucleophiles with DNA electrophiles, and produced by endogenous and exogenous cross-linking agents. DPCs are heterogeneous due to the variations of DNA conjugation sites, flanking DNA structures, protein sizes, and cross-link bonds. Unrepaired DPCs are toxic because their bulky sizes physically block DNA replication and transcription, resulting in impaired genomic integrity. Compared to other types of DNA lesions, DPC repair is less understood. Emerging evidence suggests a general repair model that DPCs are proteolyzed by the proteasome and/or DPC proteases, followed by the peptide removal through canonical repair pathways. Herein, we first describe the recently discovered DPCs. We then review the mechanisms of DPC proteolysis with the focus on recently identified DPC proteases. Finally, distinct pathways that bypass or remove the cross-linked peptides following proteolysis are discussed.
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http://dx.doi.org/10.1016/j.bbapap.2021.140669DOI Listing
August 2021

Impact of therapy on cancer metabolism in high-risk localized prostate cancer treated with neoadjuvant docetaxel and androgen deprivation therapy.

Prostate 2021 Jun 27;81(9):560-571. Epub 2021 Apr 27.

Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.

Background: The application of neoadjuvant docetaxel and androgen deprivation therapy before radical prostatectomy has been clinically recognized as beneficial for the overall and progression-free survival of patients with advanced prostate cancer. However, the mechanism underlying its clinical efficacy has not yet been reported.

Methods: We conducted a randomized comparative study on about 100 patients with high-risk localized prostate cancer. Through nontarget metabolomics and tissue microarray immunohistochemistry, we investigated the difference in the endogenous metabolism of tumors in patients with prostate cancer who received or did not receive the neoadjuvant therapy.

Results: Many endogenous metabolic pathways, especially nucleotide synthesis, glutathione metabolism, citric acid cycle, and lipid synthesis, in prostate cancer tissue were altered after the neoadjuvant treatment, and the levels of nearly 90% of the differentially regulated metabolites were significantly decreased. Moreover, the levels of key enzymes in the cellular energy pathways were downregulated in tumor tissues and upregulated in adjacent tissues after the treatment. The positive and negative effects of the neoadjuvant therapy on normal and tumor cells in the prostate, respectively, resulted in the activation of the former and inhibition of the latter, which helped in reducing the number of tumors and weakened their aggressiveness.

Conclusions: From the perspective of endogenous metabolism in tumors, we have confirmed that neoadjuvant therapy can significantly downregulate important pathways for biosynthesis and energy metabolism in prostate cancer tissue, and thereby, inhibit tumor growth and metastasis.
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http://dx.doi.org/10.1002/pros.24134DOI Listing
June 2021

Case Report: Compound Heterozygous Variants in Identified in a Chinese Infant With Molybdenum Cofactor Deficiency.

Front Genet 2021 8;12:651878. Epub 2021 Apr 8.

Department of Medical Genetics, Maternal and Child Health Hospital of Hunan Province, Changsha, China.

The molybdenum cofactor (Moco) deficiency in humans results in the inactivity of molybdenum-dependent enzymes and is caused by pathogenic variants in (), (), and (). These genes along with () are involved in Moco biosynthesis and providing cofactors to Moco-dependent enzymes. Until now, there was no study to confirm that is a causative gene of Moco deficiency. Detailed clinical information was collected in the pedigree. The Whole-exome sequencing (WES) accompanied with Sanger sequencing validation were performed. We described the clinical presentations of an infant, born to a non-consanguineous healthy family, diagnosed as having variants caused Moco deficiency and showing typical features of Moco deficiency including severe neurologic symptoms and cystic encephalomalacia in the brain MRI, resulting in neonatal death. Compound heterozygous variants in the gene were identified by WES. Positive sulfite and decreased levels of uric acid in plasma and urine were detected. To our knowledge, this is the first case of variants causing Moco deficiency. Our study may contribute to genetic diagnosis of Moco deficiency and future genetic counseling.
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http://dx.doi.org/10.3389/fgene.2021.651878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060434PMC
April 2021

Metabolic Activation of Aegeline Mediated by CYP2C19.

Xenobiotica 2021 Apr 23:1-38. Epub 2021 Apr 23.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P. R. China.

1. Aegeline (AGL) is a natural alkaloidal amide mainly isolated from the leaves and fruits of tropical plant , with multiple pharmacological activities.2. As one component of several dietary supplements, AGL caused a series of acute and chronic liver injuries. Nevertheless, the mechanisms of AGL-induced hepatotoxicity remain unclear. This study was conducted to identify reactive metabolite(s), to determine related metabolic pathways, and define the possible association of the bioactivation with AGL cytotoxicity.3. A demethylation metabolite (M1) and a GSH conjugate (M2) were detected in rat liver microsomal incubations containing AGL and GSH. The two metabolites were both found in bile of rats and rat primary hepatocytes after AGL administration.4. Recombinant P450 enzyme incubations showed that CYP2C19 was the principal enzyme catalyzing this metabolic activation.5. Ticlopidine, a selective inhibitor of CYP2C19, decreased the formation of M1 and M2 in hepatocytes and attenuated the susceptibility of hepatocytes to the cytotoxicity of AGL. The results suggest that AGL was metabolized to a -quinone methide intermediate which could in part participate in AGL-induced cytotoxicity.
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http://dx.doi.org/10.1080/00498254.2021.1913666DOI Listing
April 2021

Stronger association of triglyceride glucose index than the HOMA-IR with arterial stiffness in patients with type 2 diabetes: a real-world single-centre study.

Cardiovasc Diabetol 2021 04 22;20(1):82. Epub 2021 Apr 22.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: The triglyceride-glucose index (TyG index) has been proposed as a simple and reliable alternative insulin resistance (IR) marker, while the homeostasis model assessment for IR (HOMA-IR) is the most frequently used index. Few studies have evaluated the role of IR assessed by the TyG index and HOMA-IR on arterial stiffness in a type 2 diabetes (T2D) population with a high risk of increased arterial stiffness. We aimed to investigate the association of the TyG index and HOMA-IR with arterial stiffness in patients with T2D.

Methods: We recruited 3185 patients with T2D, who underwent brachial-ankle pulse wave velocity (baPWV), an indicator of arterial stiffness, but without previous cardiovascular disease. Increased arterial stiffness was defined as a baPWV value greater than the 75th percentile (18.15 m/s) in the present study. The TyG index was determined as ln(fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2), and the HOMA-IR was calculated as (fasting insulin [μIU/mL] × fasting glucose [mmol/L])/22.5.

Results: The mean age of the study participants was 54.6 ± 12.0 years, and 1954 (61.4%) were men. Seemingly unrelated regression estimation analysis demonstrated that the TyG index had stronger associations with baPWV than the HOMA-IR (all P < 0.001). In the multivariable logistic analyses, each one-unit increase in the TyG index was associated with a 1.40-fold (95% CI 1.16-1.70, P < 0.001) higher prevalence of increased arterial stiffness, but the prominent association of the HOMA-IR with the prevalence of increased arterial stiffness was not observed. Subgroup analyses showed that a more significant association between the TyG index and the prevalence of increased arterial stiffness was detected in older patients with a longer duration of diabetes and poor glycaemic control (all P < 0.05).

Conclusions: Compared with the HOMA-IR, the TyG index is independently and more strongly associated with arterial stiffness in patients with T2D.
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http://dx.doi.org/10.1186/s12933-021-01274-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063289PMC
April 2021

Metabolic Activation and Cytotoxicity of Labetalol Hydrochloride Mediated by Sulfotransferases.

Chem Res Toxicol 2021 Jun 19;34(6):1612-1618. Epub 2021 Apr 19.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P.R. China.

Labetalol hydrochloride (LHCl), an α- and β-adrenoreceptor blocker, is widely used for the treatment of hypertension as well as angina pectoris. Previous reports have demonstrated the adverse events during clinical application of LHCl, such as liver injury and acute renal failure. The present study aimed to investigate metabolic activation of LHCl to initiate the elucidation of the mechanisms of its liver toxicity. One glutathione (GSH) conjugate was detected in rat and human primary hepatocytes as well as bile of rats after exposure to LHCl. The GSH conjugate was chemically synthesized and characterized by Q-TOF and H NMR. Pretreatment of 2,6-dichloro-4-nitrophenol (DCNP), a broad-spectrum sulfotransferase (SULT) inhibitor, significantly attenuated the formation of the GSH conjugate in LHCl-treated hepatocytes and animals, indicating the participation of SULTs in metabolic activation of LHCl. Moreover, pretreatment with DCNP displayed significant protection against the observed cytotoxicity in rat primary hepatocytes, which suggests a correlation of the bioactivation of LHCl mediated by SULTs with LHCl-induced hepatotoxicity.
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http://dx.doi.org/10.1021/acs.chemrestox.1c00060DOI Listing
June 2021

Policy changes and the screening, diagnosis and treatment of drug-resistant tuberculosis patients from 2015 to 2018 in Zhejiang Province, China: a retrospective cohort study.

BMJ Open 2021 04 12;11(4):e047023. Epub 2021 Apr 12.

Department of Global Health, Amsterdam Institute for Global Health and Development, Amsterdam University Medical Centres, Duivendrecht, The Netherlands.

Objectives: To examine changes in the screening, diagnosis, treatment and management of drug-resistant tuberculosis (DRTB) patients, and investigate the impacts of DRTB-related policies on patients of different demographic and socioeconomic characteristics.

Design: A retrospective cohort study using registry data, plus a survey on DRTB-related policies.

Setting: All prefecture-level Centres for Disease Control in Zhejiang Province, China.

Main Outcome Measures: Alongside the care cascade, we examined: (1) reported number of presumptive DRTB patients; (2) percentage of presumptive patients with drug susceptibility testing (DST) records; (3) percentage of DRTB/rifampicin-resistant (RR) patients registered; (4) percentage of RR/multidrug-resistant TB (MDRTB) patients that received anti-DRTB treatment; and (5) percentage of RR/MDRTB patients cured/completed treatment among those treated. Multivariate logistic regressions were conducted to explore the impacts of DRTB policies after adjusting for other factors.

Results: The number of reported presumptive DRTB patients and the percentage with DST records largely increased during 2015-2018, and the percentage of registered patients who received anti-DRTB treatment also increased from 59.0% to 86.5%. Patients under the policies of equipping GeneXpert plus expanded criteria for DST had a higher likelihood of being registered compared with no GeneXpert (adjusted OR (aOR)=2.57, 95% CI: 1.20 to 5.51), while for treatment initiation the association was only significant when further expanding the registration criteria (aOR=2.38, 95% CI: 1.19 to 4.79). Patients with registered residence inside Zhejiang were more likely to be registered (aOR=1.96, 95% CI: 1.52 to 2.52), treated (aOR=3.83, 95% CI: 2.78 to 5.28) and complete treatment (aOR=1.92, 95% CI: 1.03 to 3.59) compared with those outside.

Conclusion: The policy changes on DST and registration have effectively improved DRTB case finding and care. Nevertheless, challenges remain in servicing vulnerable groups such as migrants and improving equity in the access to TB care. Future policies should provide comprehensive support for migrants to complete treatment at their current place of residence.
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http://dx.doi.org/10.1136/bmjopen-2020-047023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047997PMC
April 2021