Obstructive sleep apnea and mental disorders: a bidirectional mendelian randomization study.

BACKGROUND: Previous studies have reported associations between obstructive sleep apnea (OSA) and several mental disorders. However, further research is required to determine whether these associations are causal. Therefore, we evaluated the bidirectional causality between the genetic liability for OSA and nine mental disorders by using Mendelian randomization (MR). METHOD: We performed two-sample bidirectional MR of genetic variants for OSA and nine mental disorders. Summary statistics on OSA and the nine mental disorders were extracted from the FinnGen study and the Psychiatric Genomics Consortium. The primary analytical approach for estimating causal effects was the inverse-variance weighted (IVW), with the weighted median and MR Egger as complementary methods. The MR Egger intercept test, Cochran's Q test, Rucker's Q test, and the MR pleiotropy residual sum and outlier (MR-PRESSO) test were used for sensitivity analyses. RESULT: MR analyses showed that genetic liability for major depressive disorder (MDD) was associated with an increased risk of OSA (odds ratio [OR] per unit increase in the risk of MDD, 1.29; 95% CI, 1.11-1.49; P < 0.001). In addition, genetic liability for OSA may be associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD) (OR = 1.26; 95% CI, 1.02-1.56; p = 0.032). There was no evidence that OSA is associated with other mental disorders. CONCLUSION: Our study indicated that genetic liability for MDD is associated with an increased risk of OSA without a bidirectional relationship. Additionally, there was suggestive evidence that genetic liability for OSA may have a causal effect on ADHD. These findings have implications for prevention and intervention strategies targeting OSA and ADHD. Further research is needed to investigate the biological mechanisms underlying our findings and the relationship between OSA and other mental disorders.

Trends in antidiabetic drug use and expenditure in public hospitals in Northwest China, 2012-21: a case study of Gansu Province.

BACKGROUND: Since the twenty-first century, the prevalence of diabetes has risen globally year by year. In Gansu Province, an economically underdeveloped province in northwest China, the cost of drugs for diabetes patients accounted for one-third of their total drug costs. To fundamentally reduce national drug expenditures and the burden of medication on the population, the relevant departments of government have continued to reform and improve drug policies. This study aimed to analyse long-term trends in antidiabetic drug use and expenditure in Gansu Province from 2012 to 2021 and to explore the role of pharmaceutical policy. METHODS: Data were obtained from the provincial centralised bidding and purchasing (CBP) platform. Drug use was quantified using the anatomical therapeutic chemistry/defined daily dose (ATC/DDD) method and standardised by DDD per 1000 inhabitants per day (DID), and drug expenditure was expressed in terms of the total amount and defined daily cost (DDC). Linear regression was used to analyse the trends and magnitude of drug use and expenditure. RESULTS: The overall trend in the use and expenditure of antidiabetic drugs was on the rise, with the use increasing from 1.04 in 2012 to 16.02 DID in 2021 and the expenditure increasing from 48.36 in 2012 to 496.42 million yuan in 2021 (from 7.66 to 76.95 million USD). Some new and expensive drugs changed in the use pattern, and their use and expenditure shares (as the percentage of all antidiabetic drugs) increased from 0 to 11.17% and 11.37%, but insulins and analogues and biguanides remained the most used drug class. The DDC of oral drugs all showed a decreasing trend, but essential medicines (EMs) and medical insurance drugs DDC gradually decreased with increasing use. The price reduction of the bid-winning drugs was over 40%, and the top three drugs were glimepiride 2mg/30, acarbose 50mg/30 and acarbose 100mg/30. CONCLUSIONS: The implementation of pharmaceutical policies has significantly increased drug use and expenditure while reducing drug prices, and the introduction of novel drugs and updated treatment guidelines has led to changes in use patterns.

Research progress on ecological adaptation and prevention of Parengyodontium album on the surface of cultural relics.

Cultural relics as the crystallization of human history are non-renewable and irreplaceable resources. Microorganisms are widely colonized on ancient wall paintings, stone cultural relics, and other types of cultural heritages to cause harm. The dominant disease fungus, Parengyodontium album, is extensively distributed and can seriously threaten the long-term preservation of precious cultural heritage due to surviving in various cultural relics and extreme environments. The classification and nomenclature of P. album have undergone several changes, so its impact on cultural relic received little attention. Here, we summarized the brief histories of its classification and development, distribution range, and cultural heritage preference of P. album. We further analyzed the physiological, biochemical, and ecological characteristics and potential biological degradation mechanism. We proposed that P. album could be used as an indicative species of microbial hazardous effects on cultural heritage. We discussed the prevention and control countermeasures of such typical mural microorganisms and pointed out key research directions in this field.

DAZL regulate germline, pluripotency, and proliferation related genes in chicken PGCs and cooperate with DDX4.

Primordial germ cells (PGCs) are the precursors of germ cells and play a crucial role in germline transmission. In chickens, PGCs can be cultured in vitro while maintaining their germline stem cell characteristics. The Deleted in Azoospermia-Like (DAZL) gene, which is highly expressed in PGCs, is essential for germ cell development. Here, through gene knockout experiments, we discovered that the loss of DAZL expression in chicken PGCs led to decreased proliferation and survival. By next employed techniques such as RIP-seq (RNA Binding Protein Immunoprecipitation) and Co-IP-MS/MS (Co-immunoprecipitation Mass Spectrometry), we identified genes directly regulated by DAZL or cooperating with DAZL at the transcriptomic and proteomic levels. DAZL was found to control genes related to germline development, pluripotency, and cell proliferation in PGCs. Additionally, we observed a significant overlap between RNAs and proteins that interact with both DAZL and DDX4, indicating their cooperation in the gene regulation network in chicken PGCs. Our research provides valuable insights into the function of the DAZL gene in germline cells.

MicroRNA-451a is a candidate biomarker and therapeutic target for major depressive disorder.

Background: Increasing evidence supports the role of microRNAs (miRNAs) in major depressive disorder (MDD), but the pathophysiological mechanism remains elusive. Aims: To explore the mechanism of microRNA-451a (miR-451a) in the pathology and behaviours of depression. Methods: Abnormal miRNAs such as miR-451a reported previously in the serum of patients with MDD were screened and then confirmed in a mouse model of depression induced by chronic restraint stress (CRS). Eight-week-old male C57BL/6 mice had miR-451a overexpression in the medial prefrontal cortex (mPFC) via adeno-associated virus serotype 9 vectors encoding a pri-mmu-miR-451a-GFP fusion protein followed by behavioural and pathological analyses. Finally, molecular biological experiments were conducted to investigate the potential mechanism of miR-451a against depression. Results: The serum levels of miRNA-451a were significantly lower in patients with MDD, with a negative correlation with the Hamilton Depression Scale scores. Additionally, a negative association between serum miR-451a and behavioural despair or anhedonia was observed in CRS mice. Notably, miR-451a expression was significantly downregulated in the mPFC of CRS-susceptible mice. Overexpressing miR-451a in the mPFC reversed the loss of dendritic spines and the depression-like phenotype of CRS mice. Mechanistically, miR-451a could inhibit CRS-induced corticotropin-releasing factor receptor 1 expression via targeting transcription factor 2, subsequently protecting dendritic spine plasticity. Conclusions: Together, these results highlighted miR-451a as a candidate biomarker and therapeutic target for MDD.

Deep learning models incorporating endogenous factors beyond DNA sequences improve the prediction accuracy of base editing outcomes.

Adenine base editors (ABEs) and cytosine base editors (CBEs) enable the single nucleotide editing of targeted DNA sites avoiding generation of double strand breaks, however, the genomic features that influence the outcomes of base editing in vivo still remain to be characterized. High-throughput datasets from lentiviral integrated libraries were used to investigate the sequence features affecting base editing outcomes, but the effects of endogenous factors beyond the DNA sequences are still largely unknown. Here the base editing outcomes of ABE and CBE were evaluated in mammalian cells for 5012 endogenous genomic sites and 11,868 genome-integrated target sequences, with 4654 genomic sites sharing the same target sequences. The comparative analyses revealed that the editing outcomes of ABE and CBE at endogenous sites were substantially different from those obtained using genome-integrated sequences. We found that the base editing efficiency at endogenous target sites of both ABE and CBE was influenced by endogenous factors, including epigenetic modifications and transcriptional activity. A deep-learning algorithm referred as BE_Endo, was developed based on the endogenous factors and sequence information from our genomic datasets, and it yielded unprecedented accuracy in predicting the base editing outcomes. These findings along with the developed computational algorithms may facilitate future application of BEs for scientific research and clinical gene therapy.

Undetectable off-target effects induced by FokI catalytic domain in mouse embryos.

The FokI catalytic domain can be fused to various DNA binding architectures to improve the precision of genome editing tools. However, evaluation of off-target effects is essential for developing these tools. We use Genome-wide Off-target analysis by Two-cell embryo Injection (GOTI) to detect low-frequency off-target editing events in mouse embryos injected with FokI-based architectures. Specifically, we test FokI-heterodimers fused with TALENs, FokI homodimers fused with RYdCas9, or FokI catalytic domains alone resulting in no significant off-target effects. These FokI genome editing systems exhibit undetectable off-target effects in mouse embryos, supporting the further development of these systems for clinical applications.

Improving error-correcting capability in DNA digital storage via soft-decision decoding.

Error-correcting codes (ECCs) employed in the state-of-the-art DNA digital storage (DDS) systems suffer from a trade-off between error-correcting capability and the proportion of redundancy. To address this issue, in this study, we introduce soft-decision decoding approach into DDS by proposing a DNA-specific error prediction model and a series of novel strategies. We demonstrate the effectiveness of our approach through a proof-of-concept DDS system based on Reed-Solomon (RS) code, named as Derrick. Derrick shows significant improvement in error-correcting capability without involving additional redundancy in both in vitro and in silico experiments, using various sequencing technologies such as Illumina, PacBio and Oxford Nanopore Technology (ONT). Notably, in vitro experiments using ONT sequencing at a depth of 7× reveal that Derrick, compared with the traditional hard-decision decoding strategy, doubles the error-correcting capability of RS code, decreases the proportion of matrices with decoding-failure by 229-fold, and amplifies the potential maximum storage volume by impressive 32 388-fold. Also, Derrick surpasses 'state-of-the-art' DDS systems by comprehensively considering the information density and the minimum sequencing depth required for complete information recovery. Crucially, the soft-decision decoding strategy and key steps of Derrick are generalizable to other ECCs' decoding algorithms.

Predicting lung cancer survival prognosis based on the conditional survival bayesian network.

Lung cancer is a leading cause of cancer deaths and imposes an enormous economic burden on patients. It is important to develop an accurate risk assessment model to determine the appropriate treatment for patients after an initial lung cancer diagnosis. The Cox proportional hazards model is mainly employed in survival analysis. However, real-world medical data are usually incomplete, posing a great challenge to the application of this model. Commonly used imputation methods cannot achieve sufficient accuracy when data are missing, so we investigated novel methods for the development of clinical prediction models. In this article, we present a novel model for survival prediction in missing scenarios. We collected data from 5,240 patients diagnosed with lung cancer at the Weihai Municipal Hospital, China. Then, we applied a joint model that combined a BN and a Cox model to predict mortality risk in individual patients with lung cancer. The established prognostic model achieved good predictive performance in discrimination and calibration. We showed that combining the BN with the Cox proportional hazards model is highly beneficial and provides a more efficient tool for risk prediction.

Opportunistic Screening With Low-Dose Computed Tomography and Lung Cancer Mortality in China.

Importance: Despite the recommendations of lung cancer screening guidelines and the evidence supporting the effectiveness of population-based lung screening, a common barrier to effective lung cancer screening is that the participation rates of low-dose computed tomography (LDCT) screening among individuals with the highest risk are not large. There are limited data from clinical practice regarding whether opportunistic LDCT screening is associated with reduced lung-cancer mortality. Objective: To evaluate whether opportunistic LDCT screening is associated with improved prognosis among adults with lung cancer in mainland China. Design, Setting, and Participants: This cohort study included patients diagnosed with lung cancer at Weihai Municipal Hospital Healthcare Group, Weihai City, China, from 2016 to 2021. Data were analyzed from January 2022 to February 2023. Exposures: Data collected included demographic indicators, tumor characteristics, comorbidities, blood indexes, and treatment information. Patients were classified into screened and nonscreened groups on the basis of whether or not their lung cancer diagnosis occurred through opportunistic screening. Main Outcomes and Measures: Follow-up outcome indicators included lung cancer-specific mortality and all-cause mortality. Propensity score matching (PSM) was adopted to account for potential imbalanced factors between groups. The associations between LDCT screening and outcomes were analyzed using Cox regression models based on the matched data. Propensity score regression adjustment and inverse probability treatment weighting were used for sensitivity analysis. Results: A total of 5234 patients (mean [SD] baseline age, 61.8 [9.8] years; 2518 [48.1%] female) with complete opportunistic screening information were included in the analytical sample, with 2251 patients (42.91%) receiving their lung cancer diagnosis through opportunistic screening. After 1:1 PSM, 2788 patients (1394 in each group) were finally included. The baseline characteristics of the matched patients were balanced between groups. Opportunistic screening with LDCT was associated with a 49% lower risk of lung cancer death (HR, 0.51; 95% CI, 0.42-0.62) and 46% lower risk of all-cause death (HR, 0.54; 95% CI, 0.45-0.64). Conclusions and Relevance: In this cohort study of patients with lung cancer, opportunistic lung cancer screening with LDCT was associated with lower lung cancer mortality and all-cause mortality. These findings suggest that opportunistic screening is an important supplement to population screening to improve prognosis of adults with lung cancer.

A Convolutional Neural Network for Automated Detection of Cervical Ossification of the Posterior Longitudinal Ligament using Magnetic Resonance Imaging.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: We aimed to develop and validate a convolutional neural network (CNN) model to distinguish between cervical ossification of posterior longitudinal ligament (OPLL) and multilevel degenerative spinal stenosis using Magnetic Resonance Imaging (MRI) and to compare the diagnostic ability with spine surgeons. SUMMARY OF BACKGROUND DATA: Some artificial intelligence models have been applied in spinal image analysis and many of promising results were obtained; however, there was still no study attempted to develop a deep learning model in detecting cervical OPLL using MRI images. MATERIALS AND METHODS: In this retrospective study, 272 cervical OPLL and 412 degenerative patients underwent surgical treatment were enrolled and divided into the training (513 cases) and test dataset (171 cases). CNN models applying ResNet architecture with 34, 50, and 101 layers of residual blocks were constructed and trained with the sagittal MRI images from the training dataset. To evaluate the performance of CNN, the receiver operating characteristic curves of 3 ResNet models were plotted and the area under the curve were calculated on the test dataset. The accuracy, sensitivity, and specificity of the diagnosis by the CNN were calculated and compared with 3 senior spine surgeons. RESULTS: The diagnostic accuracies of our ResNet34, ResNet50, and ResNet101 models were 92.98%, 95.32%, and 97.66%, respectively; the area under the curve of receiver operating characteristic curves of these models were 0.914, 0.942, and 0.971, respectively. The accuracies and specificities of ResNet50 and ResNet101 models were significantly higher than all spine surgeons; for the sensitivity, ResNet101 model achieved better values than that of the 2 surgeons. CONCLUSION: The performance of our ResNet model in differentiating cervical OPLL from degenerative spinal stenosis using MRI is promising, better results were achieved with more layers of residual blocks applied.

Algorithm for Predicting Respiratory Motion of Liver Tissue Based on Short-Term Respiratory Monitoring.

In this study, an algorithm for predicting respiratory motion of liver tissue based on the combination of subject-specific external surrogate signals and 2D ultrasound image sequences was investigated to achieve better respiratory monitoring in clinical procedures. To achieve non-invasiveness in clinical procedures, an EM position tracker and a Doppler ultrasound diagnostic system were used as data collectors. Firstly, the mapping relationship between the magnetic sensing surrogate signal and the internal motion of liver tissue was learned by the Ridge regression model to achieve the estimation of the internal motion of liver tissue by the magnetic sensing surrogate signal; then the motion prediction of the estimated internal motion of liver tissue was performed by the artificial neural network (ANN) as the prediction filter; finally, the prediction of the respiratory motion of liver tissue by the magnetic sensing surrogate signal was achieved. Through experimental tests on 16 subject volunteers, the experimental results show that the RMSE of the proposed algorithm for predicting the respiratory motion of liver tissue is 2mm, indicating the potential of this prediction algorithm to achieve the localization of the internal motion position of liver tissue by the human magnetic sensing surrogate signal.

Spatio-temporal evolution and trend prediction of urban ecosystem service value based on CLUE-S and GM (1,1) compound model.

Ecosystem service value (ESV) is a significant indicator related to regional ecological well-being. Evaluating ESV premised on continuous time series land benefit data can provide an accurate reference for regional ecological civilization construction and sustainable development. Taking Shijiazhuang, the capital city of Hebei Province as an example, the study analyzed land use changes based on the land use data of the continuous time series from 2000 to 2020 and introduced a socio-economic adjustment factor and biomass factor adjustment factor to construct a dynamic assessment model of ecosystem service value. The spatiotemporal changes of the ecosystem service value in Shijiazhuang City were evaluated, and the dynamic prediction of the ecosystem service value was made using the CLUE-S model and the GM (1,1) model. (1) The changes in the overall ESV and spatial pattern in Shijiazhuang are strongly linked to the change in land use, and the contribution of cultivated land, woodland, and grassland to ecosystem service value exceeds 90%. (2) Between 2000 and 2020, the value of ecosystem services illustrated a dynamic change and gradually declined, with the total amount falling from 28.003 to 19.513 billion yuan. Among individual ecosystem services, the value of regulation services suffered the most serious loss. (3) CLUE-S and GM (1,1) perform well in the prediction of ESV. The prediction outcomes illustrate that the ecosystem service value of Shijiazhuang will continue to decline by 2025, and the ecosystem value will drop to 16.771 billion yuan. This research may offer a reference for the dynamic assessment of ESV of the continuous sequence and help to promote regional ecological protection and sustainable development.

Increased expression of Nav1.6 of reactive astrocytes in the globus pallidus is closely associated with motor deficits in a model of Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease in elderly people, which is characterized by motor disabilities in PD patients. Nav1.6 is the most abundant subtype of voltage-gated sodium channels (VGSCs) in the brain of adult mammals and rodents. Here we investigated the role of Nav1.6 in the external globus pallidus (GP) involved in the pathogenesis of motor deficits in unilateral 6-OHDA(6-hydroxydopamine)lesioned rats. The results show that Nav1.6 is dramatically increased in reactive astrocytes of the ipsilateral GP in the middle stage, but not different from the control rats in the later stage of the pathological process in 6-OHDA lesioned rats. Furthermore, the down-regulation of Nav1.6 expression in the ipsilateral GP can significantly improve motor deficits in 6-OHDA lesioned rats in the middle stage of the pathological process. The electrophysiological experiments show that the down-regulation of Nav1.6 expression in the ipsilateral GP significantly decreases the abnormal high synchronization between the ipsilateral M1 (the primary motor cortex) and GP in 6-OHDA lesioned rats. Ca2+ imaging reveals that the down-regulation of Nav1.6 expression reduces the intracellular concentration of Ca2+ ([Ca2+ ]i) in primary cultured astrocytes. These findings suggest that the increased Nav1.6 expression of reactive astrocytes in the GP play an important role in the pathogenesis of motor dysfunction in the middle stage in 6-OHDA lesioned rats, which may participate in astrocyte-neuron communication by regulating [Ca2+ ]i of astrocytes, thereby contributing to the formation of abnormal electrical signals of the basal ganglia (BG) in 6-OHDA lesioned rats.

Comparing four immunosuppressive agents for chronic spontaneous urticaria-A network meta-analysis.

BACKGROUND: Immunosuppression is an integral part of treating chronic spontaneous urticaria (CSU), but there is no literature to evaluate the efficacy of multiple immunosuppressive agents. OBJECTIVE: The comparison of the efficacy, safety, and incidence of adverse effects of four immunosuppressive medicines (tripterygium glycosides, methotrexate, cyclosporine A, and azathioprine) in combination with antihistamines in treating CSU provides a clinical reference and evidence-based medicine for treating CSU. METHODS: PUBMED, The Cochrane Library, EMBASE, WANFANG, CNKI, CBM, and clinical trial registration platform were searched to collect relevant randomized controlled trials (RCT) and cohort studies of four immunosuppressive medicines combined with antihistamines for treating CSU. The primary outcomes were the efficacy of weekly urticaria activity score 7 (UAS7) and adverse effects. RESULTS: This study pooled data from seven randomized clinical trials with 410 participants. The standardized mean differences for change in UAS7 were 0.10 (95% confidence interval (CI), 0.01 to 0.68) for cyclosporine A plus antihistamine; 0.03 (95% CI, 0.00 to 0.23) for azathioprine plus antihistamine; 0.52 (95% CI, 0.32 to 0.85) for tripterygium glycosides plus antihistamine; and 1.54 (95% CI, 0.64 to 3.67) for methotrexate plus antihistamine. There were no significant differences in side effects between these medicines in the limited number of trials and clinical samples. CONCLUSION: Our results indicate that cyclosporine A combined with antihistamine resulted in greater improvements regarding the UAS7 in CSU patients and that tripterygium glycosides are also effective in treating CSU.

Human 8-cell embryos enable efficient induction of disease-preventive mutations without off-target effect by cytosine base editor.

Approximately 140 million people worldwide are homozygous carriers of APOE4 (ε4), a strong genetic risk factor for late onset familial and sporadic Alzheimer's disease (AD), 91% of whom will develop AD at earlier age than heterozygous carriers and noncarriers. Susceptibility to AD could be reduced by targeted editing of APOE4, but a technical basis for controlling the off-target effects of base editors is necessary to develop low-risk personalized gene therapies. Here, we first screened eight cytosine base editor variants at four injection stages (from 1- to 8-cell stage), and found that FNLS-YE1 variant in 8-cell embryos achieved the comparable base conversion rate (up to 100%) with the lowest bystander effects. In particular, 80% of AD-susceptible ε4 allele copies were converted to the AD-neutral ε3 allele in human ε4-carrying embryos. Stringent control measures combined with targeted deep sequencing, whole genome sequencing, and RNA sequencing showed no DNA or RNA off-target events in FNLS-YE1-treated human embryos or their derived stem cells. Furthermore, base editing with FNLS-YE1 showed no effects on embryo development to the blastocyst stage. Finally, we also demonstrated FNLS-YE1 could introduce known protective variants in human embryos to potentially reduce human susceptivity to systemic lupus erythematosus and familial hypercholesterolemia. Our study therefore suggests that base editing with FNLS-YE1 can efficiently and safely introduce known preventive variants in 8-cell human embryos, a potential approach for reducing human susceptibility to AD or other genetic diseases.

Decreased miR-451a in cerebrospinal fluid, a marker for both cognitive impairment and depressive symptoms in Alzheimer's disease.

Background: Alzheimer's disease (AD) patients are often accompanied by depressive symptoms, but its underlying mechanism remains unclear. The present study aimed to explore the potential role of microRNAs in the comorbidity of AD and depression. Methods: The miRNAs associated with AD and depression were screened from databases and literature and then confirmed in the cerebrospinal fluid (CSF) of AD patients and different ages of transgenic APP/PS1 mice. AAV9-miR-451a-GFP was injected into the medial prefrontal cortex (mPFC) of APP/PS1 mice at seven months, and four weeks later, a series of behavioral and pathological analyses were performed. Results: AD patients had low CSF levels of miR-451a, which was positively correlated with the cognitive assessment score, but negatively with their depression scale. In the mPFC of APP/PS1 transgenic mice, the miR-451a levels also decreased significantly in the neurons and microglia. Specific virus vector-induced overexpression of miR-451a in the mPFC of APP/PS1 mice ameliorated AD-related behavior deficits and pathologies, including long-term memory defects, depression-like phenotype, ß-amyloid load, and neuroinflammation. Mechanistically, miR-451a decreased the expression of neuronal ß-secretase 1 of neurons through inhibiting Toll-like receptor 4/Inhibitor of kappa B Kinase ß/ Nuclear factor kappa-B signaling pathway and microglial activation by inhibiting activation of NOD-like receptor protein 3, respectively. Conclusion: This finding highlighted miR-451a as a potential target for diagnosing and treating AD, especially for those with coexisting symptoms of depression.

Bonding Properties between Fly Ash/Slag-Based Engineering Geopolymer Composites and Concrete.

Concrete infrastructure repair remains a formidable challenge. The application of engineering geopolymer composites (EGCs) as a repair material in the field of rapid structural repair can ensure the safety of structural facilities and prolong their service life. However, the interfacial bonding performance of existing concrete with EGCs is still unclear. The purpose of this paper is to explore a kind of EGC with good mechanical properties, and to evaluate the bonding performance of EGCs with existing concrete using a tensile bonding test and single shear bonding test. At the same time, X-ray diffraction (XRD) and Scanning electron microscopy (SEM) were adopted to study the microstructure. The results showed that the bond strength increased with the increase in interface roughness. For polyvinyl alcohol (PVA)-fiber-reinforced EGCs, the bond strength increased with the increase in FA content (0-40%). However, with the change of FA content (20-60%), the bond strength of polyethylene (PE) fiber-reinforced EGCs have little change. The bond strength of PVA-fiber-reinforced EGCs increased with the increase in water-binder ratio (0.30-0.34), while that of PE-fiber-reinforced EGCs decreased. The bond-slip model of EGCs with existing concrete was established based on the test results. XRD studies showed that when the FA content was 20-40%, the content of C-S-H gels was high and the reaction was sufficient. SEM studies showed that when the FA content was 20%, the PE fiber-matrix bonding was weakened to a certain extent, so the ductility of EGC was improved. Besides, with the increase in the water-binder ratio (0.30-0.34), the reaction products of the PE-fiber-reinforced EGC matrix gradually decreased.

Cytosine base editors induce off-target mutations and adverse phenotypic effects in transgenic mice.

Base editors have been reported to induce off-target mutations in cultured cells, mouse embryos and rice, but their long-term effects in vivo remain unknown. Here, we develop a Systematic evaluation Approach For gene Editing tools by Transgenic mIce (SAFETI), and evaluate the off-target effects of BE3, high fidelity version of CBE (YE1-BE3-FNLS) and ABE (ABE7.10F148A) in ~400 transgenic mice over 15 months. Whole-genome sequence analysis reveals BE3 expression generated de novo mutations in the offspring of transgenic mice. RNA-seq analysis reveals both BE3 and YE1-BE3-FNLS induce transcriptome-wide SNVs, and the numbers of RNA SNVs are positively correlated with CBE expression levels across various tissues. By contrast, ABE7.10F148A shows no detectable off-target DNA or RNA SNVs. Notably, we observe abnormal phenotypes including obesity and developmental delay in mice with permanent genomic BE3 overexpression during long-time monitoring, elucidating a potentially overlooked aspect of side effects of BE3 in vivo.

Long-term trend of antibiotic use at public health care institutions in northwest China, 2012-20 -- a case study of Gansu Province.

BACKGROUND: Over the past 20 years, excessive antibiotic use has led to serious antimicrobial resistance (AMR) worldwide, and the phenomenon is particularly serious in China. To this end, the Chinese health sector took a series of measures to promote rational antibiotic use. In this study, to reveal the impact of policies on antibiotic use, we explored the long-term trend and patterns of antibiotic use at public health care institutions from 2012 to 2020 in northwest China, taking Gansu Province as an example. METHODS: Antibiotic procurement data were obtained from the provincial centralized bidding procurement (CBP) platform between 2012 and 2020. Antibiotic use was quantified using the Anatomical Therapeutic Chemical (ATC)/defined daily doses (DDD) methodology and standardized using the DDD per 1000 inhabitants per day (DID). Twelve relevant quality indicators were calculated for comparison with the European Surveillance of Antimicrobial Consumption (ESAC) project monitoring results. RESULTS: Total antibiotic use increased from 18.75 DID to 57.07 DID and then decreased to 19.11 DID, a turning point in 2014. The top three antibiotics used were J01C (beta-lactam antibacterials, penicillins), J01F (macrolides, lincosamides and streptogramins), and J01D (other beta-lactam antibacterials, cephalosporins), accounting for 45.15%, 31.40%, and 11.99% respectively. The oral antibiotics used were approximately 2.5 times the parenteral antibiotics, accounting for 71.81% and 28.19%, respectively. Different use preferences were shown in public hospitals and primary health care centres (PHCs), and the latter accounted for more than half of total use. The absolute use of all classes of antibiotics in Gansu is almost higher than any of the 31 European countries included in the ESAC, but the relative use of some focused antibiotics is lower than theirs. CONCLUSIONS: The intervention policies of the health department reduced antibiotic use in Gansu Province, but the proportion of broad-spectrum and parenteral antibiotics was still high. It is necessary to further improve the quality of antibiotic prescriptions and pay more attention to the rationality of antibiotic use in PHCs.