PTPS Facilitates Compartmentalized LTBP1 S-Nitrosylation and Promotes Tumor Growth under Hypoxia.

GTP cyclohydrolase I (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), and sepiapterin reductase (SR) are sequentially responsible for de novo synthesis of tetrahydrobiopterin (BH4), a known co-factor for nitric oxide synthase (NOS). The implication of BH4-biosynthesis process in tumorigenesis remains to be investigated. Here, we show that PTPS, which is highly expressed in early-stage colorectal cancer, is phosphorylated at Thr 58 by AMPK under hypoxia; this phosphorylation promotes PTPS binding to LTBP1 and subsequently drives iNOS-mediated LTBP1 S-nitrosylation through proximal-coupling BH4 production within the PTPS/iNOS/LTBP1 complex. In turn, LTBP1 S-nitrosylation results in proteasome-dependent LTBP1 protein degradation, revealing an inverse relationship between PTPS pT58 and LTBP1 stability. Physiologically, the repressive effect of PTPS on LTBP1 leads to impaired transforming growth factor ß (TGF-ß) secretion and thereby maintains tumor cell growth under hypoxia. Our findings illustrate a molecular mechanism underlying the regulation of LTBP1-TGF-ß signaling by the BH4-biosynthesis pathway and highlight the specific requirement of PTPS for tumor growth.

Oxidative stress in hair follicle development and hair growth: Signalling pathways, intervening mechanisms and potential of natural antioxidants.

Hair follicle development and hair growth are regulated by multiple factors and multiple signalling pathways. The hair follicle, as an important skin appendage, is the basis for hair growth, and it has the functions of safeguarding the body, perceiving the environment and regulating body temperature. Hair growth undergoes a regular hair cycle, including anagen, catagen and telogen. A small amount of physiological shedding of hair occurs under normal conditions, always in a dynamic equilibrium. Hair loss occurs when the skin or hair follicles are stimulated by oxidative stress, inflammation or hormonal disorders that disrupt the homeostasis of the hair follicles. Numerous researches have indicated that oxidative stress is an important factor causing hair loss. Here, we summarize the signalling pathways and intervention mechanisms by which oxidative stress affects hair follicle development and hair growth, discuss existing treatments for hair loss via the antioxidant pathway and provide our own insights. In addition, we collate antioxidant natural products promoting hair growth in recent years and discuss the limitations and perspectives of current hair loss prevention and treatment.

TSLP enhances progestin response in endometrial cancer via androgen receptor signal pathway.

BACKGROUND: The enriched proteins within in vitro fertilisation (IVF)-generated human embryonic microenvironment could reverse progestin resistance in endometrial cancer (EC). METHODS: The expression of thymic stromal lymphopoietin (TSLP) in EC was evaluated by immunoblot and IHC analysis. Transcriptome sequencing screened out the downstream pathway regulated by TSLP. The role of TSLP, androgen receptor (AR) and KANK1 in regulating the sensitivity of EC to progestin was verified through a series of in vitro and in vivo experiments. RESULTS: TSLP facilitates the formation of a BMP4/BMP7 heterodimer, resulting in activation of Smad5, augmenting AR signalling. AR in turn sensitises EC cells to progestin via KANK1. Downregulation of TSLP, loss of AR and KANK1 in EC patients are associated with tumour malignant progress. Moreover, exogenous TSLP could rescue the anti-tumour effect of progestin on mouse in vivo xenograft tumour. CONCLUSIONS: Our findings suggest that TSLP enhances the sensitivity of EC to progestin through the BMP4/Smad5/AR/KANK1 axis, and provide a link between embryo development and cancer progress, paving the way for the establishment of novel strategy overcoming progestin resistance using embryo original factors.

The effect of deep and awake extubation on emergence agitation after nasal surgery: a randomized controlled trial.

BACKGROUND: Post-anesthetic emergence agitation is common after general anesthesia and may cause adverse consequences, such as injury as well as respiratory and circulatory complications. Emergence agitation after general anesthesia occurs more frequently in nasal surgery than in other surgical procedures. This study aimed to assess the occurrence of emergence agitation in patients undergoing nasal surgery who were extubated under deep anesthesia or when fully awake. METHODS: A total of 202 patients (18-60 years, American Society of Anesthesiologists classification: I-II) undergoing nasal surgery under general anesthesia were randomized 1:1 into two groups: a deep extubation group (group D) and an awake extubation group (group A). The primary outcome was the incidence of emergence agitation. The secondary outcomes included number of emergence agitations, sedation score, vital signs, and incidence of adverse events. RESULTS: The incidence of emergence agitation was lower in group D than in group A (34.7% vs. 72.8%; p < 0.001). Compared to group A, patients in group D had lower Richmond Agitation-Sedation Scale scores, higher Ramsay sedation scores, fewer agitation episodes, and lower mean arterial pressure when extubated and 30 min after surgery, whereas these indicators did not differ 90 min after surgery. There was no difference in the incidence of adverse events between the two groups. CONCLUSIONS: Extubation under deep anesthesia can significantly reduce emergence agitation after nasal surgery under general anesthesia without increasing the incidence of adverse events. TRIAL REGISTRATION: Registered in Clinicaltrials.gov (NCT04844333) on 14/04/2021.

Clinical study of two-dimensional speckle tracking to evaluate abnormal myocardial motion due to coronary lesions.

OBJECTIVE: To investigate the predictive ability of global longitudinal strain (GLS) and mechanical dispersion for coronary stenosis and provide a more reliable noninvasive method for diagnosis of obstructive coronary artery disease(OCAD). METHODS: Sixty-seven patients diagnosed with suspected CAD were included in the study. Patients with coronary stenosis greater than 50% were assigned as OCAD, while the others were assigned as non obstructive coronary artery disease(NOCAD). General information was collected and patients underwent speckle tracking echocardiogram(STE). RESULTS: Spearman's correlation analysis showed that GLS and mechanical dispersion were positively correlated with the degree of coronary stenosis (r = 0.383, 0.342, p < 0.05), and there was also a positive correlation between GLS and mechanical dispersion (r = 0.327, p < 0.05). GLS, longitudinal strain (LS) of each chamber, and mechanical dispersion were higher in the OCAD group than in the NOCAD group (p < 0.05). Univariate regression analysis showed that GLS, each lumen LS and mechanical dispersion were statistically significant (p < 0.05). Multifactorial regression analysis showed that elevated GLS (p = 0.007) and elevated mechanical dispersion (p = 0.030) were independent risk factors for OCAD. The ROC curves showed that GLS predicted OCAD (AUC area 0.745, 95% CI 0.624 to 0.865) versus mechanical discrete prediction of OCAD (AUC area 0.702, 95% CI 0.569 to 0.834) were more diagnostic than conventional cardiac ultrasound observations of ventricular wall motion abnormalities (AUC area 0.566, 95% CI 0.463 to 0.669). CONCLUSIONS: Combining GLS with mechanical dispersion can rapidly assess OCAD in a very short period, which has strong promotion value and in-depth research value.

Evaluating the quality of home care in community health service centres: A machine learning approach.

AIMS: The aim of the study is to develop a model using a machine learning approach that can effectively identify the quality of home care in communities. DESIGN: A cross-sectional design. METHODS: In this study, we evaluated the quality of home care in 170 community health service centres between October 2022 and February 2023. The Home Care Service Quality Questionnaire was used to collect information on home care structure, process and outcome quality. Then, an intelligent and comprehensive evaluation model was developed using a convolutional neural network, and its performance was compared with random forest and logistic regression models through various performance indicators. RESULTS: The convolutional neural network model was built upon seven variables, which encompassed the qualification of home nursing staff, developing and practicing emergency plan to cope with different emergency rescues in home environment, being equipped with medication and supplies for first aid according to specific situations, assessing nutrition condition of home patients, allocation of the number of home nursing staff, cases of new pressure ulcers and patient satisfaction rate. Remarkably, the convolutional neural network model demonstrated superior performance, outperforming both the random forest and regression models. CONCLUSION: The successful development and application of the convolutional neural network model highlight its ability to leverage data from community health service centres for rapid and accurate grading of home care quality. This research points the way to home care quality improvement. IMPACT: The model proposed in this study, coupled with the aforementioned factors, is expected to enhance the accuracy and efficiency of a comprehensive evaluation of home care quality. It will also help managers to take purposeful measures to improve the quality of home care. REPORTING METHOD: The reporting of this study (Observational, cross-sectional study) conforms to the STROBE statement. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The application of this model has the potential to contribute to the advancement of high-quality home care, particularly in lower-middle-income communities.

Design of Fluxgate Current Sensor Based on Magnetization Residence Times and Neural Networks.

This study introduces a novel fluxgate current sensor with a compact, ring-shaped configuration that exhibits improved performance through the integration of magnetization residence times and neural networks. The sensor distinguishes itself with a unique magnetization profile, denoted as M waves, which emerge from the interaction between the target signal and ambient magnetic interference, effectively enhancing interference suppression. These M waves highlight the non-linear coupling between the magnetic field and magnetization residence times. Detection of these residence times is accomplished using full-wave rectification circuits and a Schmitt trigger, with a digital output provided by timing sequence detection. A dual-layer feedforward neural network deciphers the target signal, exploiting this non-linear relationship. The sensor achieves a linearity error of 0.054% within a measurement range of 15 A. When juxtaposed with conventional sensors utilizing the residence-time difference strategy, our sensor reduces linearity error by more than 40-fold and extends the effective measurement range by 150%. Furthermore, it demonstrates a significant decrease in ambient magnetic interference.

Simultaneous Bilateral Cochlear Implantation in Very Young Children Improves Adaptability and Social Skills: A Prospective Cohort Study.

OBJECTIVES: To investigate the value of using the Gesell Development Diagnosis Scale (GDDS) to predict developmental outcomes in very young children who undergo simultaneous bilateral cochlear implantation. DESIGN: In this prospective cohort study, a repeated-measures investigation was conducted in a tertiary referral hospital. A total of 62 children receiving simultaneous bilateral cochlear implantations were enrolled from April 2017 to August 2018. They were divided into 2 groups depending on the operative age: "Infants" group (6 to 12 months, N = 38) or "Children" group (12 to 36 months, N = 24). Data on the surgical outcomes, auditory development, speech production, and developmental indicators were collected until 2 years after the initial fitting. The primary outcome measure was the GDDS, a neuropsychological development examination. Secondary outcomes included the following: complication rate, aided pure-tone average, Infant-Toddler Meaningful Auditory Integration Scale, Categories of Auditory Performance-II, Meaningful Use of Speech Scale, Speech Intelligibility Rating, and the LittlEARS Auditory Questionnaire. RESULTS: The mean ages at implantation in infants and children groups were 9.2 ± 1.17 and 16.6 ± 3.60 months, respectively. Significant differences were found in the social skills ( p = 0.001) and adaptability ( p = 0.031) domains of GDDS. The younger the age of bilateral cochlear implants surgery, the higher developmental quotient of language, social skills, and adaptability the child could achieve after 2 years. The complication rates in the infants and children groups were 0% versus 2.1% ( p = 0.57). There was no surgical complication in the infants group. In the children group, 1 case with enlarged vestibular aqueduct and Mondini malformation had a receiver-implant misplacement on the right side (2%, 1/48). In the two groups, auditory performance and speech production had improved similarly. In the infants group, social skills developmental quotient at baseline had a significant positive relationship with Meaningful Use of Speech Scale after 2 years. CONCLUSIONS: Simultaneous bilateral cochlear implantation in younger children improves adaptability and social skills. GDDS is a sensitive tool of evaluating short-term effect of bilateral cochlear implants in neuropsychological development and constitutes a reliable predictor of speech production for the very younger pediatric cochlear implant users.

Comparison of aneuploidy rate in spontaneous abortion chorionic villus between D6 and D5 thawed-frozen blastocyst transfer.

BACKGROUND: To compare the aneuploidy rate in spontaneous abortion chorionic villus (SA-CV) after D5 and D6 thawed-frozen blastocyst transfer(TBT). METHODS: This retrospective cohort study recruited 522 patients with early spontaneous abortion from March 2012 to January 2020 in the our center. The aneuploidy rate of SA-CV was compared according to the blastocyst development stage: D5 group (n = 398) and D6 group (n = 124). RESULTS: Patients' characteristics, including age, body mass index, follicle-stimulating hormone, fertilization methods, type of infertility, infertility duration, and gestational age when abortion, did not differ between the two groups (all P > 0.05). Although the mean number of embryos was significantly higher in D6 than in the D5 group (P < 0.001), the mean number of high-quality embryos was similar (P = 0.773). In the D5 group, 46.5% of SA-CV showed aneuploidy, which was comparable to 41.1% in the D6 group (P = 0.296). After further grouping according to age (> 35 years or ≤ 35 years), the difference between the D5 and D6 groups remained not statistically significant (P = 0.247 and P = 0.690). Multivariate logistic analysis showed that women's age was independently associated with the aneuploidy rate (OR = 0.891; 95% CI: [0.854-0.930]; P < 0.001). The rate of chromosomal aneuploidy was significantly higher in the age > 35 years group than in the age ≤ 35 years group (61.0% vs. 39.4%, P < 0.001). Other factors, including blastocyst formation speed, were not significant predictors of aneuploidy rate. CONCLUSIONS: The rate of chromosomal aneuploidy in SB-CV after D6 TBT was comparable to that after D5 TBT. Chromosomal aneuploidy may not be a main factor contributing to the high prevalence early pregnancy loss at D6 group.

Photoprotective Effects of Dendrobium nobile Lindl. Polysaccharides against UVB-Induced Oxidative Stress and Apoptosis in HaCaT Cells.

Acute ultraviolet (UV)-B radiation is the major external factor causing photodamage. In this study, we aimed to determine the effects of Dendrobium nobile Lindl. polysaccharides (DNPs) on photodamage in HaCaT keratinocytes after UVB irradiation and the underlying mechanisms. We found that DNPs significantly attenuated the decline in the viability and proliferation of HaCaT cells after UVB irradiation. Moreover, DNPs scavenged reactive oxygen species (ROS), improved the activities of endogenous antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase, and reduced the levels of malondialdehyde, while partially attenuating cell cycle arrest, suggesting their antioxidant and anti-apoptotic properties. The mitogen-activated protein kinase (MAPK) pathway was found to be important for the attenuation of UVB-induced photodamage in the HaCaT cells. Furthermore, DNPs exerted cytoprotective effects by downregulating UVB-induced ROS-mediated phosphorylation of MAPKs, including p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase, and by inhibiting p53 expression as well as the apoptotic cascade response. Therefore, DNPs ameliorated UVB-induced oxidative damage and apoptosis in HaCaT cells via the regulation of MAPKs. Our findings thus highlight the Dendrobium nobile Lindl polysaccharides as promising therapeutic candidates for UVB-induced photodamage.

Brusatol sensitizes endometrial hyperplasia and cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism.

Progestin resistance is the main obstacle for the conservative therapy to maintain fertility in women with endometrial cancer. Brusatol was identified as an inhibitor of the NRF2 pathway; however, its impact on progestin resistance and the underlying mechanism remains unclear. Here, we found that brusatol sensitized endometrial cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism. Brusatol transcriptionally suppressed AKR1C1 via modifying the hydroxymethylation status in its promoter region through TET1 inhibition. Suppression of AKR1C1 by brusatol resulted in decreased progesterone catabolism and maintained potent progesterone to inhibit endometrial cancer growth. This inhibition pattern has also been found in the established xenograft mouse and organoid models. Aberrant overexpression of AKR1C1 was found in paired endometrial hyperplasia and cancer samples from the same individuals with progestin resistance, whereas attenuated or loss of AKR1C1 was observed in post-treatment samples with well progestin response as compared with paired pre-treatment tissues. Our findings suggest that AKR1C1 expression pattern may serve as an important biomarker of progestin resistance in endometrial cancer.

Confining isolated chromophores for highly efficient blue phosphorescence.

High-efficiency blue phosphorescence emission is essential for organic optoelectronic applications. However, synthesizing heavy-atom-free organic systems having high triplet energy levels and suppressed non-radiative transitions-key requirements for efficient blue phosphorescence-has proved difficult. Here we demonstrate a simple chemical strategy for achieving high-performance blue phosphors, based on confining isolated chromophores in ionic crystals. Formation of high-density ionic bonds between the cations of ionic crystals and the carboxylic acid groups of the chromophores leads to a segregated molecular arrangement with negligible inter-chromophore interactions. We show that tunable phosphorescence from blue to deep blue with a maximum phosphorescence efficiency of 96.5% can be achieved by varying the charged chromophores and their counterions. Moreover, these phosphorescent materials enable rapid, high-throughput data encryption, fingerprint identification and afterglow display. This work will facilitate the design of high-efficiency blue organic phosphors and extend the domain of organic phosphorescence to new applications.

Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor and cognitive deficits.

Clinical surgical practices have found that children who undergo multiple anesthesia may have an increased risk of deficiencies in cognition and fine motor control. Here, we report that YT521-B homology domain family 1 (YTHDF1), a critical reader protein for N6-methyladenosine-modified mRNA, was significantly downregulated in the prefrontal cortex of young mice after multiple sevoflurane anesthesia exposures. Importantly, sevoflurane led to a decrease in protein synthesis in mouse cortical neurons that was fully rescued by YTHDF1, suggesting that anesthesia may affect early brain development by affecting m6A-dependent mRNA translation. Transcriptome-wide experiments showed that numerous mRNA targets related to synaptic functions in the prefrontal mouse cortex were associated with m6A methylation and YTHDF1. In particular, we found that synaptophysin, a critical presynaptic protein, was specifically modified by m6A methylation and associated with YTHDF1, and m6A methylation of synaptophysin decreased with multiple sevoflurane exposures. Importantly, we showed that fine motor control skills and cognitive functions were impaired in mice with multiple anesthesia exposures, and these effects were fully reversed by reintroducing YTHDF1 through a blood-brain barrier (BBB)-crossing viral delivery system. Finally, we found that the fine motor skills in children who underwent prolonged anesthesia were compromised 6 months after surgery. Our findings indicated that impairment in the translational regulation of mRNA via N6-methyladenosine methylation is a potential mechanism underlying the effects of anesthesia on neural development in the young brain. 1. N6-methyladenosine (m6A) modifications were involved in anesthesia-induced neurotoxicity. 2. Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor deficits in young mice. 3. YTHDF1, a m6A reader protein, rescued sevoflurane-induced protein synthesis inhibition and fine motor deficits in young mice.

Relationship between a novel non-insulin-based metabolic score for insulin resistance (METS-IR) and coronary artery calcification.

BACKGROUND AND AIMS: A novel non-insulin-based metabolic score for insulin resistance (METS-IR) index has been proposed as a simple and reliable alternative insulin resistance (IR) marker, but its the predictive value in asymptomatic adults with coronary artery calcification (CAC) remains unclear. METHODS AND RESULTS: We enrolled 1576 participants without cardiovascular disease (CVD), who underwent multidetector computed tomography. Logistic regression, restricted cubic spline models and receiver operating characteristic (ROC) curves were used to examine the association between METS-IR, the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) and triglyceride glucose index (TyG index) and CAC. In multivariate logistic regression analysis, the increase in METS-IR was independently associated with a higher prevalence of CAC (all P < 0.05 in Models 1-3). Furthermore, restricted cubic splines indicated that the significance of METS-IR in predicting CAC was higher than that of other IR indexes. In ROC curve analysis, without considering the P value, the area under the curve of CAC predicted by METS-IR was higher than that of other IR indexes (METS-IR, 0.607; TyG index, 0.603; TG/HDL-C, 0.577). CONCLUSION: Compared with other IR indexes, METS-IR may have better discrimination ability in predicting the incidence of CAC in asymptomatic adults without CVD.

A drug utilization study of oral anticoagulants in five representative cities of China between 2015 and 2019.

WHAT IS KNOWN AND OBJECTIVE: Oral anticoagulants (OACs), including warfarin and newer direct-acting OACs (DOACs), have been used for decades to prevent thromboembolic diseases. A drug utilization study was performed to determine the prescribing patterns of OACs. METHODS: Data were extracted from the Cooperation Project of Hospital Prescription Analysis in China. A total of 455,490 prescription records from 43 tertiary hospitals in five cities of China (Beijing, Shanghai, Guangzhou, Hangzhou and Chengdu) were selected for inclusion. Quarterly trends of defined daily doses (DDDs) and defined daily dose cost (DDDC) from 1 January 2015 to 31 December 2019 were calculated. RESULTS AND DISCUSSION: Warfarin was the most widely used OAC with DDDs between 189,982 and 176,323 from the first quarter (Q1) of 2015 to the fourth quarter (Q4) of 2019, whereas the use of DOACs increased rapidly during this period. DDDs of rivaroxaban increased from 5409 in Q1 of 2015 to 125,800 in Q4 of 2019, whereas the DDDC declined from 160.5 to 45.7. From Q1 of 2018, rivaroxaban became the most prescribed OAC, surpassing warfarin, in patients diagnosed with deep vein thrombosis. In addition, the DDDs of rivaroxaban exceeded those of warfarin in patients diagnosed with non-valvular atrial fibrillation since the second quarter (Q2) of 2019. DDDs in outpatients and inpatients increased by 80.6% and 71.4%, respectively, and the DDDC for outpatients in Q4 of 2019 was 6.7-fold higher than that in Q1 of 2015. Among patients of all ages, the DDDs in elderly patients increased from 36.8% in Q1 of 2015 to 59.4% in Q4 of 2019. Moreover, the departments of cardiology and cardiothoracic surgery prescribed the majority of the OACs. WHAT IS NEW AND CONCLUSION: In this study, we describe OAC prescription patterns in China. DOACs, especially rivaroxaban, contribute to the continuous increase in the use of OACs. In the investigated population of China, outpatients and elderly patients were observed to be administered the highest proportion of DOACs.

Physiological Concentration of H2O2 Supports Dopamine Neuronal Survival via Activation of Nrf2 Signaling in Glial Cells.

Traditionally, hydrogen peroxide (H2O2) was formed from cellular oxidative metabolism and often viewed as toxic waste. In fact, H2O2 was a benefit messenger for neuron-glia signaling and synaptic transmission. Thus, H2O2 was a double-edged sword and neuroprotection vs. neurotoxicity produced by H2O2 was difficult to define. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been implicated as an intracellular regulator of neuronal growth. Inactivation of Nrf2 participated in the development of Parkinson's disease (PD). Thus, suitable activation of Nrf2 was essential for the prevention and treatment of PD. This study aimed to explore whether H2O2-conferred neuroprotective effects to support neuronal survival. H2O2 were added into primary neuron-glia, neuron-astroglia and neuron-microglia co-cultures in concentration- and time-dependent manners. H2O2 increased dopamine (DA) neuronal survival in concentration- and time-dependent manners. In addition, glial cells Nrf2 activation involved in H2O2-supported DA neuronal survival with the following phenomenons. First, H2O2 activated Nrf2 signaling pathway. Second, H2O2 generated beneficial neuroprotection in neuron-glia, neuron-astroglia and neuron-microglia co-cultures but not in neuron-enriched cultures. Third, silence of Nrf2 in glial cells abolished H2O2-conferred DA neuronal survival. This study demonstrated that physiological concentration of H2O2-supported DA neuronal survival via activation of Nrf2 signaling in glial cells. Our data permit to re-evaluate the role of H2O2 in the pathogenesis and therapeutic strategies for PD.

Genetic and clinical determinants of mizoribine pharmacokinetics in renal transplant recipients.

AIM: Mizoribine (MZR) is an immunosuppressant for the prevention of allograft rejection in Asian countries, but the great variability in pharmacokinetics (PK) limits its clinical use. This study was to explore genetic and clinical factors that affect the MZR PK process. METHODS: Blood samples and clinical data were collected from 60 Chinese renal transplant recipients. MZR plasma concentration was measured at pre-dose (0 h) and 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 h post-dose by high performance liquid chromatography with an ultraviolet detector. PK parameters were calculated by non-compartmental analysis. High-throughput sequenced single nucleotide polymorphism was applied screening possible genetic factors. RESULTS: Extensive inter-individual MZR PK differences were reflected in the process of elimination (ke, CL/F, MRT and t1/2) and intestinal absorption (Cmax and Tmax), as well as in the dose-normalized exposure (AUC0-12h/D). From 146 SNPs within 39 genes screened, AUC0-12h/D was found higher in recipients with CREB1 rs11904814 TT than with G allele carriers (3.135 ± 0.928 versus 2.084 ± 0.379 µg h ml-1 mg-1, p = 0.007). Recipients with SLC28A3 rs10868138 TT had lower t1/2 as compared to C allele carriers (0.728 ± 0.189 versus 0.951 ± 0.196 h, p = 0.001). Serum creatinine (SCr) explained 35.5% of C0/D variability (p < 0.001). Pure effects of genotypes CREB1 and SLC28A3 were 13.7% (p = 0.004) and 17.5% (p = 0.001) for AUC0-12h/D and t1/2, respectively. When additionally taking SCr into models, CREB1 and SLC28A3 genotypes explained 20.0% (p = 0.038) and 46.5% (p < 0.001) of AUC0-12h/D and t1/2 variability, respectively. CONCLUSION: CREB1 and SLC28A3 genotypes, as well as SCr, are identified as determinants in predicting inter-individual MZR PK differences in renal transplant recipients.

Utilization of apnea-hypopnea index as a novel predictive factor for difficult mask ventilation in the Chinese population under general anesthesia.

PURPOSE: Difficult mask ventilation (DMV) is a potentially life-threatening situation that can arise during anesthesia. However, most clinical predictors of DMV are based on European and US populations. On the other hand, most predictive models consist of multiple factors and complicated assessments. Since obstructive sleep apnea (OSA) is among the most important risk factors associated with DMV, the apnea-hypopnea index (AHI) may play an important role in determining patient risk.The purpose of this study was to investigate the relationship between DMV and AHI, and to determine preoperative risk factors for DMV in Chinese patients. METHODS: A prospective cohort trial enrolled patients scheduled for elective surgery. After obtaining informed consent, patient demographic information was collected, and patients were tested with pre-operative polysomnography. The anesthesiologist who managed the airway graded the mask ventilation. The difficult mask ventilation was defined as the mask ventilation provided by an unassisted anesthesiologist without oral airway or other adjuvant. A logistic regression model was used to analyze the association between AHI and DMV. RESULTS: A total of 159 patients were analyzed. For both primary and secondary outcomes, the unadjusted and adjusted odds ratio for DMV showed significant increases by 5 AHI units. AHI, age, and the Mallampati classification were found to be independent predictive factors for DMV. CONCLUSIONS: AHI is associated with DMV as a novel independent risk factor in Chinese patients. Along with age and Mallampati classification, AHI should be included in establishing a superior predictive strategy for DMV screening. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-DDD-17013076.

Prospective case-control study of enterovirus detection differences in children's cerebrospinal fluid between multiplex PCR and real-time RT-PCR assay.

BACKGROUND: Viral encephalitis is common in childhood. It is an acute brain parenchymal inflammation caused by a variety of viral infection, and enterovirus accounts for the majority. Due to atypical clinical manifestations, pathogenic testing is important for assisting clinical diagnosis. The purpose of this study was to evaluate the performance of the multiplex PCR assay compared with quantitative real-time PCR for enterovirus detection. METHODS: A prospective case-control study was performed involving 103 pediatric patients suspected for viral encephalitis and cerebrospinal fluid (CSF) samples were collected and tested for 9 pathogens using multiplex PCR assay during April to November in 2018. In parallel, an aliquot of samples was tested for enterovirus infection by real-time PCR assay. RESULTS: There were 85.4% children were confirmed as viral encephalitis on discharge, the remaining ones were diagnosed as other CNS diseases, such as epilepsy. The specificity of the two methods was the same as that of the clinical diagnosis, but the sensitivity and consistency with clinical diagnosis of multiplex PCR were both higher than the real-time PCR. Besides of enterovirus, multiplex PCR could also detect coinfection of enterovirus with Epstein-Barr virus and mumps virus. CONCLUSION: Results of multiplex PCR method are more consistent with the clinical diagnosis and are superior to real-time PCR for detecting enterovirus in CSF.

Pregnancy outcomes in female patients exposed to cyclosporin-based versus tacrolimus-based immunosuppressive regimens after liver/kidney transplantation: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Pregnancy after transplantation is a challenge owing to the high risk of adverse maternal and foetal outcomes, and immunosuppressants may further impact these outcomes. There are no head-to-head randomized controlled trials comparing influences of cyclosporin and tacrolimus on pregnancy outcomes. Thus, we systematically reviewed and meta-analysed observational studies assessing the comparative influences of these two drugs on pregnancy outcomes in liver/kidney transplant recipients. METHODS: Relevant studies comparing pregnancy outcomes with tacrolimus and cyclosporin head-to-head were searched in PubMed, EMBASE and Web of Science (from 1 January 2000 to 20 March 2020). The weighted mean difference and odds ratio (OR) were calculated to compare continuous and dichotomous variables, respectively, with 95% confidence intervals (CIs). Publication bias was estimated using funnel plots. The study quality was assessed according to the modified Newcastle-Ottawa scale. RESULTS AND DISCUSSION: Overall, 10 observational studies of low quality, including a total of 1080 post-liver or kidney transplant pregnancies, were identified. Tacrolimus-treated recipients experienced a lower risk of gestational hypertension (28.0%; OR: 1.74; 95% CI: 1.27-2.39; p < 0.01). Cyclosporin-treated recipients showed a lower incidence of caesarean section (40.3%; OR: 0.62; 95% CI: 0.46-0.82; p < 0.01). Additionally, cyclosporin performed better in terms of the live birth rate (78.0%; OR: 1.38; 95% CI: 1.02-1.88; p = 0.04). No significant differences in the incidences of pre-eclampsia, gestational diabetes, preterm delivery and birth weight were observed. WHAT IS NEW AND CONCLUSION: Tacrolimus performed better in patients with gestational hypertension, while cyclosporin was associated with a lower incidence of caesarean section and a higher incidence of live birth. The findings are based on relatively low-quality evidence, but may provide a reference for clinicians in their clinical monitoring and obstetric care for post-transplant pregnancies.