Alternative polyadenylation quantitative trait methylation mapping in human cancers provides clues into the molecular mechanisms of APA.

Genetic variants are involved in the orchestration of alternative polyadenylation (APA) events, while the role of DNA methylation in regulating APA remains unclear. We generated a comprehensive atlas of APA quantitative trait methylation sites (apaQTMs) across 21 different types of cancer (1,612 to 60,219 acting in cis and 4,448 to 142,349 in trans). Potential causal apaQTMs in non-cancer samples were also identified. Mechanistically, we observed a strong enrichment of cis-apaQTMs near polyadenylation sites (PASs) and both cis- and trans-apaQTMs in proximity to transcription factor (TF) binding regions. Through the integration of ChIP-signals and RNA-seq data from cell lines, we have identified several regulators of APA events, acting either directly or indirectly, implicating novel functions of some important genes, such as TCF7L2, which is known for its involvement in type 2 diabetes and cancers. Furthermore, we have identified a vast number of QTMs that share the same putative causal CpG sites with five different cancer types, underscoring the roles of QTMs, including apaQTMs, in the process of tumorigenesis. DNA methylation is extensively involved in the regulation of APA events in human cancers. In an attempt to elucidate the potential underlying molecular mechanisms of APA by DNA methylation, our study paves the way for subsequent experimental validations into the intricate biological functions of DNA methylation in APA regulation and the pathogenesis of human cancers. To present a comprehensive catalog of apaQTM patterns, we introduce the Pancan-apaQTM database, available at https://pancan-apaqtm-zju.shinyapps.io/pancanaQTM/.

Allele-Specific Suppression of Variant MHC With High-Precision RNA Nuclease CRISPR-Cas13d Prevents Hypertrophic Cardiomyopathy.

BACKGROUND: Familial hypertrophic cardiomyopathy has severe clinical complications of heart failure, arrhythmia, and sudden cardiac death. Heterozygous single nucleotide variants (SNVs) of sarcomere genes such as MYH7 are the leading cause of this type of disease. CRISPR-Cas13 (clustered regularly interspaced short palindromic repeats and their associated protein 13) is an emerging gene therapy approach for treating genetic disorders, but its therapeutic potential in genetic cardiomyopathy remains unexplored. METHODS: We developed a sensitive allelic point mutation reporter system to screen the mutagenic variants of Cas13d. On the basis of Cas13d homology structure, we rationally designed a series of Cas13d variants and obtained a high-precision Cas13d variant (hpCas13d) that specifically cleaves the MYH7 variant RNAs containing 1 allelic SNV. We validated the high precision and low collateral cleavage activity of hpCas13d through various in vitro assays. We generated 2 HCM mouse models bearing distinct MYH7 SNVs and used adenovirus-associated virus serotype 9 to deliver hpCas13d specifically to the cardiomyocytes. We performed a large-scale library screening to assess the potency of hpCas13d in resolving 45 human MYH7 allelic pathogenic SNVs. RESULTS: Wild-type Cas13d cannot distinguish and specifically cleave the heterozygous MYH7 allele with SNV. hpCas13d, with 3 amino acid substitutions, had minimized collateral RNase activity and was able to resolve various human MYH7 pathological sequence variations that cause hypertrophic cardiomyopathy. In vivo application of hpCas13d to 2 hypertrophic cardiomyopathy models caused by distinct human MYH7 analogous sequence variations specifically suppressed the altered allele and prevented cardiac hypertrophy. CONCLUSIONS: Our study unveils the great potential of CRISPR-Cas nucleases with high precision in treating inheritable cardiomyopathy and opens a new avenue for therapeutic management of inherited cardiac diseases.

The Effect of Nationwide Organized Cancer Screening Programs on Gastric Cancer Mortality: A Synthetic Control Study.

BACKGROUND & AIMS: Nationwide organized gastric cancer (GC) screening programs have been running for decades in South Korea and Japan. This study conducted a quasi-experimental analysis to assess the population impact of these programs on GC mortality. METHODS: We used the flexible synthetic control method (SCM) to estimate the effect of the screening programs on age-standardized GC mortality and other upper gastrointestinal (UGI) diseases (esophageal cancer and peptic ulcer) among people aged ≥40 years. World Health Organization mortality data and country-level covariates from the World Bank and the Global Burden of Diseases study were used for the analyses. We compared postintervention trends in outcome with the counterfactual trend of the synthetic control and estimated average postintervention rate ratios (RRs) with associated 95% confidence intervals (CIs). A series of sensitivity analyses were conducted. RESULTS: The preintervention fits were acceptable for the analyses of South Korea and Japan's GC mortality but poor for Japan's other UGI disease mortality. The average postintervention RRs were 0.83 (95% CI, 0.71-0.96) for GC mortality and 0.72 (95% CI, 0.57-0.90) for other UGI disease mortality in South Korea. The RR reached 0.59 by the 15th year after the initiation of nationwide screening. For Japan, the average RRs were 0.97 (95% CI, 0.88-1.07) for GC mortality and 0.93 (95% CI, 0.68-1.28) for other UGI disease mortality. Sensitivity analysis reveals the result for Japan may potentially be biased. CONCLUSIONS: South Korea's nationwide GC screening has apparent benefits, whereas the Japanese program's effectiveness is uncertain. The experiences of South Korea and Japan could serve as a reference for other countries.

Identification of potential functional variants and genes at 18q21.1 associated with the carcinogenesis of colorectal cancer.

Genome-wide association studies (GWAS) have identified more than 160 susceptibility loci for colorectal cancer (CRC). The effects of these variants, particularly their mechanisms, however, remain unclear. In this study, a comprehensive functional annotation of CRC-related GWAS signals was firstly conducted to identify the potential causal variants. We found that the SNP rs7229639 in intron 3 of SMAD7 at 18q21.1 might serve as a putative functional variant in CRC. The SNP rs7229639 is located in a region with evidence of regulatory potential. Dual-luciferase reporter assays revealed that three other SNPs (rs77544449, rs60385309 and rs72917785), in strong linkage disequilibrium (LD) with rs7229639, exhibited allele-specific enhancer activity, of which one of the target genes may conceivably be LIPG, as suggested by eQTL association data and Hi-C data. We also verified that LIPG promoted malignancy of CRC cells in vitro, with supporting clinical data indicating that LIPG is upregulated and correlated with a poor prognosis in CRC. Finally, pitavastatin was observed to exhibit an anti-CRC activity and modest inhibition of LIPG mRNA levels. Collectively, our data suggest that these functional variants at 18q21.1 are involved in the pathogenesis of CRC by modulating enhancer activity, and possibly LIPG expression, thus indicating a promising therapeutic target for CRC. The results of functional annotation in our investigation could also serve as an inventory for CRC susceptibility SNPs and offer guides for post-GWAS downstream functional studies.

LARP7 overexpression alleviates aortic senescence and atherosclerosis.

Atherosclerosis, characterized by the accumulation of lipid plaques on the inner walls of arteries, is the leading cause of heart attack, stroke and severe ischemic injuries. Senescent cells have been found to accumulate within atherosclerotic lesions and contribute to the progression of atherosclerosis. In our previous study, we discovered that suppressing Larp7 accelerates senescence by inhibiting Sirt1 activity, resulting in increased atherosclerosis in high-fat diet (HFD) fed and ApoE deficient (ApoEKO) mice. However, there has been no direct evidence demonstrating Larp7 per se could attenuate atherosclerosis. To this end, we generated a tetO-controlled and Cre-activated Larp7 gain-of-function mouse. Through RT-PCR and western blotting, we confirmed Larp7 overexpression in the aortas of HFD-fed ApoEKO; Larp7tetO mice. Larp7 overexpression led to increased Sirt1 activity and decreased cellular senescence signals mediated by p53/p65 in the aortas. Additionally, Larp7 overexpression reduced the presence of p16-positive senescent cells in the aortic lesions. Furthermore, Larp7 overexpression resulted in a decrease in pro-inflammatory macrophages and SASP factors. Consequently, Larp7 overexpression led to a reduction in the area of atherosclerotic lesions in HFD-fed ApoEKO; Larp7tetO mice. In summary, our study provides evidence that Larp7 overexpression holds promise as an approach to inhibit cellular senescence and prevent atherosclerosis.

Analyzing lung cancer risks in patients with impaired pulmonary function through characterization of gut microbiome and metabolites.

BACKGROUND: Lung cancer (LC) is one of the most devastating diseases worldwide, there is growing studies confirm the role of impaired lung function in LC susceptibility. Moreover, gut microbiota dysbiosis is associated with LC severity. Whether alterations in gut microbiota and metabolites are associated with long-term lung dysfunction in LC patients remain unclear. Our study aimed to analyze the risk factors in LC patients with impaired pulmonary function based on the characteristics of the gut microbiome and metabolites. METHODS: Fecal samples from 55 LC patients and 28 benign pulmonary nodules patients were collected. Pulmonary ventilation function was graded according to the American Thoracic Society/ European Respiratory Society (ATS/ERS) method. LC patients were divided into 3 groups, including 20 patients with normal lung ventilation, 23 patients with mild pulmonary ventilation dysfunction and 12 patients with moderate or above pulmonary ventilation dysfunction. The fecal samples were analyzed using 16 S rRNA gene amplicon sequencing and metabolomics. RESULTS: The gut microbiome composition between LC patients and benign pulmonary nodules patients presented clearly differences based on Partial Least Squares Discriminant Analysis (PLS-DA). Pulmonary ventilation function was positively correlated with LC tumor stage, the richness and diversity of the gut microbiota in LC patients with moderate or above pulmonary ventilation dysfunction increased significantly, characterized by increased abundance of Subdoligranulum and Romboutsia. The metabolomics analysis revealed 69 differential metabolites, which were mainly enriched in beta-Alanine metabolism, styrene degradation and pyrimidine metabolism pathway. The area under the curve (AUC) combining the gut microbiome and metabolites was 90% (95% CI: 79-100%), indicating that the two species and four metabolites might regarded as biomarkers to assess the prediction of LC patients with impaired pulmonary function. CONCLUSIONS: Our results showed that microbiome and metabolomics analyses provide important candidate to be used as clinically diagnostic biomarkers and therapeutic targets related to lung cancer with impaired pulmonary function.

Gene editing in a Myo6 semi-dominant mouse model rescues auditory function.

Myosin VI（MYO6） is an unconventional myosin that is vital for auditory and vestibular function. Pathogenic variants in the human MYO6 gene cause autosomal-dominant or -recessive forms of hearing loss. Effective treatments for Myo6 mutation causing hearing loss are limited. We studied whether adeno-associated virus (AAV)-PHP.eB vector-mediated in vivo delivery of Staphylococcus aureus Cas9 (SaCas9-KKH)-single-guide RNA (sgRNA) complexes could ameliorate hearing loss in a Myo6WT/C442Y mouse model that recapitulated the phenotypes of human patients. The in vivo editing efficiency of the AAV-SaCas9-KKH-Myo6-g2 system on Myo6C442Y is 4.05% on average in Myo6WT/C442Y mice, which was ∼17-fold greater than editing efficiency of Myo6WT alleles. Rescue of auditory function was observed up to 5 months post AAV-SaCas9-KKH-Myo6-g2 injection in Myo6WT/C442Y mice. Meanwhile, shorter latencies of auditory brainstem response (ABR) wave I, lower distortion product otoacoustic emission (DPOAE) thresholds, increased cell survival rates, more regular hair bundle morphology, and recovery of inward calcium levels were also observed in the AAV-SaCas9-KKH-Myo6-g2-treated ears compared to untreated ears. These findings provide further reference for in vivo genome editing as a therapeutic treatment for various semi-dominant forms of hearing loss and other semi-dominant diseases.

Comparison of 3 CT Perfusion Software Packages in Estimation of Ischemic Lesions in Acute Ischemic Stroke Patients.

OBJECTIVE: The aim of this study was to compare 3 computed tomography perfusion (CTP) software packages in the estimation of infarct core volumes, hypoperfusion volumes, and mismatch volumes. METHODS: Forty-three patients with large vessel occlusion in the anterior circulation who underwent CTP imaging were postprocessed by 3 software packages: RAPID, advantage workstation (AW), and NovoStroke Kit (NSK). Infarct core volumes and hypoperfusion volumes were generated by RAPID with default settings. The AW and NSK threshold settings were the following: infarct core (cerebral blood flow [CBF] <8 mL/min/100 g, CBF <10 mL/min/100 g, CBF <12 mL/min/100 g, and cerebral blood volume [CBV] <1 mL/100 g) and hypoperfusion (T max >6 seconds). Mismatch volumes were then obtained for all the combinations of the settings. Bland-Altman, intraclass correlation coefficient (ICC), and Spearman ρ or Pearson correlation coefficient were applied for statistical analysis. RESULTS: In the estimation of infarct core volumes, good agreement was observed between AW and RAPID when CBV <1 mL/100 g (ICC, 0.767; P < 0.001). For hypoperfusion volumes, good agreement (ICC, 0.811; P < 0.001) and strong correlation ( r = 0.856; P < 0.001) were observed between NSK and RAPID. For mismatch volumes, the setting of CBF <10 mL/min/100 g combined with hypoperfusion with NSK resulted in moderate agreement (ICC, 0.699; P < 0.001) with RAPID, which was the best among all other settings. CONCLUSIONS: The estimation results varied among different software packages. Advantage workstation had the best agreement with RAPID in the estimation of infarct core volumes when CBV <1 mL/100 g. NovoStroke Kit had better agreement and correlation with RAPID in the estimation of hypoperfusion volumes. NovoStroke Kit also had moderate agreement with RAPID in estimating mismatch volumes.

Automated ASPECTS in acute ischemic stroke: comparison of the overall scores and Hounsfield unit values of two software packages and radiologists with different levels of experience.

BACKGROUND: ASPECTS is a simple, rapid, and semi-quantitative method for detecting early ischemic changes (EIC). However, the agreement between software applications and neuroradiologists varies greatly. PURPOSE: To compare ASPECTS calculated by using automated software tools to neuroradiologists evaluation in patients with acute ischemic stroke (AIS). MATERIAL AND METHODS: Retrospectively, 61 patients with large vessel occlusion (LVO) who underwent multimodal stroke computed tomography (CT) were evaluated using two automated ASPECTS software tools (NSK and RAPID) and three neuroradiologists with different experiences (two senior neuroradiologists and one junior neuroradiologist). Four weeks later, the same three neuroradiologists re-evaluated the ASPECTS in consensus using the baseline CT and follow-up non-contrast CT (NCCT). Interclass correlation coefficients (ICCs) and Pearson correlation coefficients were applied for statistical analysis. RESULTS: The HU value exhibited the greatest correlation in the insular lobe (r = 0.81; P < 0.001) and the lowest correlation in the internal capsule (r = 0.65; P < 0.001) between NSK and RAPID. Software analysis and human readers showed excellent agreement with the consensus reading. Compared with the consensus reading, the correlation of the two senior radiologists (ICC = 0.975 and 0.969, respectively) were higher than that of junior radiologist (ICC = 0.869), and the consistency values of the NSK and RAPID software tools after 6 h of onset to imaging (ICC = 0.894 and 0.874, respectively) were greater than those within 6 h of onset (ICC = 0.746 and 0.828, respectively). CONCLUSION: For patients experiencing AIS due to LVO, the ASPECTS calculated with automated software agrees well with the predefined consensus score but is inferior to that of senior radiologists.

Feature Pyramid Networks and Long Short-Term Memory for EEG Feature Map-Based Emotion Recognition.

The original EEG data collected are the 1D sequence, which ignores spatial topology information; Feature Pyramid Networks (FPN) is better at small dimension target detection and insufficient feature extraction in the scale transformation than CNN. We propose a method of FPN and Long Short-Term Memory (FPN-LSTM) for EEG feature map-based emotion recognition. According to the spatial arrangement of brain electrodes, the Azimuth Equidistant Projection (AEP) is employed to generate the 2D EEG map, which preserves the spatial topology information; then, the average power, variance power, and standard deviation power of three frequency bands (α, ß, and γ) are extracted as the feature data for the EEG feature map. BiCubic interpolation is employed to interpolate the blank pixel among the electrodes; the three frequency bands EEG feature maps are used as the G, R, and B channels to generate EEG feature maps. Then, we put forward the idea of distributing the weight proportion for channels, assign large weight to strong emotion correlation channels (AF3, F3, F7, FC5, and T7), and assign small weight to the others; the proposed FPN-LSTM is used on EEG feature maps for emotion recognition. The experiment results show that the proposed method can achieve Value and Arousal recognition rates of 90.05% and 90.84%, respectively.

Effectiveness of Localized Lockdowns in the COVID-19 Pandemic.

Nonpharmaceutical interventions, such as social distancing and lockdowns, have been essential to control of the coronavirus disease 2019 (COVID-19) pandemic. In particular, localized lockdowns in small geographic areas have become an important policy intervention for preventing viral spread in cases of resurgence. These localized lockdowns can result in lower social and economic costs compared with larger-scale suppression strategies. Using an integrated data set from Chile (March 3-June 15, 2020) and a novel synthetic control approach, we estimated the effect of localized lockdowns, disentangling its direct and indirect causal effects on transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results showed that the effects of localized lockdowns are strongly modulated by their duration and are influenced by indirect effects from neighboring geographic areas. Our estimates suggest that extending localized lockdowns can slow down SARS-CoV-2 transmission; however, localized lockdowns on their own are insufficient to control pandemic growth in the presence of indirect effects from contiguous neighboring areas that do not have lockdowns. These results provide critical empirical evidence about the effectiveness of localized lockdowns in interconnected geographic areas.

Two-dimensional Ti3C2Tx MXene promotes electrophysiological maturation of neural circuits.

BACKGROUND: The ideal neural interface or scaffold for stem cell therapy shall have good biocompatibility promoting survival, maturation and integration of neural stem cells (NSCs) in targeted brain regions. The unique electrical, hydrophilic and surface-modifiable properties of Ti3C2Tx MXene make it an attractive substrate, but little is known about how it interacts with NSCs during development and maturation. RESULTS: In this study, we cultured NSCs on Ti3C2Tx MXene and examined its effects on morphological and electrophysiological properties of NSC-derived neurons. With a combination of immunostaining and patch-clamp recording, we found that Ti3C2Tx MXene promotes NSCs differentiation and neurite growth, increases voltage-gated current of Ca2+ but not Na+ or K+ in matured neurons, boosts their spiking without changing their passive membrane properties, and enhances synaptic transmission between them. CONCLUSIONS: These results expand our understanding of interaction between Ti3C2Tx MXene and NSCs and provide a critical line of evidence for using Ti3C2Tx MXene in neural interface or scaffold in stem cell therapy.

Deep learning-based automated segmentation of eight brain anatomical regions using head CT images in PET/CT.

OBJECTIVE: We aim to propose a deep learning-based method of automated segmentation of eight brain anatomical regions in head computed tomography (CT) images obtained during positron emission tomography/computed tomography (PET/CT) scans. The brain regions include basal ganglia, cerebellum, hemisphere, and hippocampus, all split into left and right. MATERIALS AND METHODS: We enrolled patients who underwent both PET/CT imaging (with an extra head CT scan) and magnetic resonance imaging (MRI). The segmentation of eight brain regions in CT was achieved by using convolutional neural networks (CNNs): DenseVNet and 3D U-Net. The same segmentation task in MRI was performed by using BrainSuite13, which was a public atlas label method. The mean Dice scores were used to assess the performance of the CNNs. Then, the agreement and correlation of the volumes of the eight segmented brain regions between CT and MRI methods were analyzed. RESULTS: 18 patients were enrolled. Four of the eight brain regions obtained high mean Dice scores (> 0.90): left (0.978) and right (0.912) basal ganglia and left (0.945) and right (0.960) hemisphere. Regarding the agreement and correlation of the brain region volumes between two methods, moderate agreements were observed on the left (ICC: 0.618, 95% CI 0.242, 0.835) and right (ICC: 0.654, 95% CI 0.298, 0.853) hemisphere. Poor agreements were observed on the other regions. A moderate correlation was observed on the right hemisphere (Spearman's rho 0.68, p = 0.0019). Lower correlations were observed on the other regions. CONCLUSIONS: The proposed deep learning-based method performed automated segmentation of eight brain anatomical regions on head CT imaging in PET/CT. Some regions obtained high mean Dice scores and the agreement and correlation results of the segmented region volumes between two methods were moderate to poor.

Three-dimensional magnetic resonance imaging assessment of levator ani in women progressing from full-term pregnancy to 10 months postpartum.

AIM: To identify the anatomical morphology of levator ani (LA) in primigravidae at term pregnancy and its natural process of changing after delivery. METHODS: Forty-one primigravidae (vaginal delivery: 29 women, cesarean delivery in the first stage of labor: 12 women) underwent magnetic resonance imaging (MRI) at full-term pregnancy, 6 weeks and 10 months postpartum. Three-dimensional (3-D) model of LA created from MRI data using Mimics v.21.0 software and source images were assessed to determine the morphology. LA volume (LVOL) was calculated and used as indicator of muscle atrophy. RESULTS: Decrease of levator hiatus length (LH-L) was shown in both groups since 6 weeks postpartum. In the vaginal delivery group, the differences in LVOL between time points were significant (p < 0.05), showing a persistent decreasing tendency. Puborectalis attachment width (PAW) on the left was the smallest at 6 weeks postpartum (p < 0.05). LA avulsion and significant 2-D morphological change after delivery were only observed in this group (p < 0.05); In the cesarean section group, smaller LVOL was found at 6 weeks postpartum comparing with full-term pregnancy (p < 0.05); Larger levator-symphysis gap (LSG) and levator hiatus width (LH-W), smaller PAW were observed in vaginal delivery group comparing with cesarean section group at 6 weeks postpartum (p < 0.05), but none of the values exhibited between-group differences (p > 0.05) at 10 months postpartum. No other comparisons were considered significant (p >0.05). CONCLUSIONS: Vaginal delivery, or even active labor itself may both lead to LA atrophy. And the morphology of LA is basically similar in different delivery modes at 10 months postpartum once the onset of labor has occurred, even though it changes more complicatedly after vaginal delivery.

Development of CRISPR-CAS9 based RNA drugs against Eimeria tenella infection.

Parasitic diseases are major trouble in many parts of the world. We consider that if a chemical can break a DNA barcode sequence, it might be used to develop a species-specific anti-parasitic agent. To examine this hypothesis, we constructed sgRNAs that target both the control (5.8S rDNA) and a DNA barcode (ITS) sequence in Eimeria tenella. In vitro experiment showed that Cas9 mRNA combined with sgRNAs could reduce the sporulation percentage of oocysts and the survival rate of sporulated oocysts and sporozoites. Quantitative real-time PCR showed that the DNAs of parasites exposed to Cas9 mRNA and sgRNAs were significantly affected, regardless of whether they were exposed to a combination of two sgRNAs or just a single sgRNA. The DNA sequencing also indicated that the experimental group exposed to two sgRNAs mixed with Cas9-induced deletion of large parts and a single sgRNA mixed with Cas9-induced mutation at sgRNA targeted fragments. In vivo trial, the effect of sgRNA and Cas9 RNA on the pathogenicity of E. tenella in chicken showed less lesion score and oocysts score (P < 0.05) in experimental groups than control groups. The results and concepts presented in this research can lead to discovering novel nucleic acid therapeutic drugs for Eimeriasis and other parasitic infections, which provide insights into the development of species-specific anti-parasitic agents.

Screening of dopamine in living cells and animal model via graphene quantum dots anchored 3D macroporous nonenzymatic sensor.

A series of three-dimensional copper oxide (CuO) inverse opals anchored with carboxylated graphene quantum dots (CuO/cGQDs) have been fabricated for non-enzymatic tracking of dopamine (DA). Heterostructures composed of various building blocks are promising to construct versatile biosensing platforms. The optimal CuO/cGQDs modified electrode demonstrates sensitivities of 243.45 µA mM-1 cm-2 (50 nM-1888.5 µM) with the practical detection limit as low as 0.5 nM in mimic physiological environment (at + 0.45 V vs. Ag/AgCl). The extraordinary tolerance to various interferents enables the practical detection of intracellular DA amount in human neural cells. On this basis, the proposed biosensor attains precise evaluation of antipsychotic drug effects on stimulated DA release. Particularly, it successfully spots fluctuation of DA in plasma and cerebrospinal fluid in murine model of Parkinson's disease, which serves as a crucial tool to understand neuropathology and symptomatology of DA-related diseases. This study developed a reliable sensing platform and is expected to be applied to physiological and pathological studies.

Simple Sensitivity Analysis for Differential Measurement Error.

Sensitivity analysis results are given for differential measurement error of either the exposure or outcome. In the case of differential measurement error of the outcome, it is shown that the true effect of the exposure on the outcome on the risk ratio scale must be at least as large as the observed association between the exposure and the mismeasured outcome divided by the maximum strength of differential measurement error. This maximum strength of differential measurement error is itself assessed as the risk ratio of the controlled direct effect of the exposure on the mismeasured outcome not through the true outcome. In the case of differential measurement error of the exposure, under certain assumptions concerning classification probabilities, the true effect on the odds ratio scale of the exposure on the outcome must be at least as large as the observed odds ratio between the mismeasured exposure and the outcome divided by the maximum odds ratio of the effect of the outcome on mismeasured exposure conditional on the true exposure. The results can be immediately used to indicate the minimum strength of differential measurement error that would be needed to explain away an observed association between an exposure measurement and an outcome measurement for this to be solely due to measurement error.

Impact of radical hysterectomy on the transobturator sling pathway: a retrospective three-dimensional magnetic resonance imaging study.

INTRODUCTION AND HYPOTHESIS: Morphological and functional anomalies of the urethra may cause stress urinary incontinence after radical hysterectomy (RH). We introduce a novel three-dimensional (3D) magnetic resonance imaging (MRI) technique to assess the impact of RH on the transobturator sling pathway. METHODS: 3D-MRI reconstruction models were retrospectively developed for the measurement of various parameters before and after RH, including puncture angle, orientation and distance from the midurethral puncture site to the obturator membrane (DUO), in 31 patients with cervical cancer. Additionally, the correlations between DUO and body height and interspinal diameter were evaluated. RESULTS: No significant differences were noted between the preoperative and postoperative inclination angle (-7.1 ± 33.5° vs. -0.68 ± 23.9°, ranges -62.4 to 46.8° vs. -54.1 to 42.2°, respectively) or between the preoperative and postoperative left and right mean rotation angles (left 69.0 ± 8.0° vs. 67.8 ± 9.2°; right 65.1 ± 8.38° vs. 64.3 ± 10.5°). Similarly, there were no statistically or clinically significant differences between the preoperative and postoperative DUO, although slight differences were noted between the two sides before and after RH (P = 0.018 and P = 0.023, respectively). None of the parameters differed significantly between the groups with and without postoperative urodynamic stress incontinence. Further, there was no clinically significant correlation between DUO and height or interspinal diameter. CONCLUSIONS: The sling procedure via the transobturator approach is technically safe from a 3D anatomical standpoint. However, wide variability in the anatomical parameters must be taken into account when planning the procedure.

Study on the cephalopelvic relationship with cephalic presentation in nulliparous full-term Chinese pregnant women by MRI with three-dimensional reconstruction.

PURPOSE: To analyze the relationship between fetal head size and maternal pelvis size using magnetic resonance imaging (MRI) with a 3-D reconstruction technique. METHODS: A total of 301 nulliparous full-term Chinese pregnant women with cephalic presentation were enrolled and received MRI examinations before labor onset. Data were collected and imported into Mimics software to reconstruct the maternal pelvis and fetus. RESULTS: Of 301 pregnant women, 212 underwent vaginal delivery and 32 received cesarean section. The body mass index (BMI) was significantly different between the vaginal delivery group and the suspected cephalopelvic disproportion (CPD) group; the larger the BMI, the higher was the risk of CPD. The transverse diameter of the pelvic inlet and the posterior sagittal diameter of the midpelvis were significantly larger in the vaginal delivery group, compared with the suspected CPD group. Fetal weight > 3.5 kg could be used as a diagnostic indicator for CPD. CONCLUSIONS: BMI is a risk factor for CPD, and fetal weight < 3.5 kg is an important diagnostic indicator for natural delivery in Chinese pregnant women.

Resistance Risk and Molecular Mechanism of Tomato Wilt Pathogen Fusarium oxysporum f. sp. lycopersici to Pyraclostrobin.

Tomato wilt disease caused by Fusarium oxysporum f. sp. lycopersici (Fol) results in a decrease in tomato yield and quality. Pyraclostrobin, a typical quinone outside inhibitor (QoI), inhibits the cytochrome bc1 complex to block energy transfer. However, there is currently limited research on the effectiveness of pyraclostrobin against Fol. In this study, we determined the activity of pyraclostrobin against Fol and found the EC50 values for pyraclostrobin against 100 Fol strains (which have never been exposed to QoIs before). The average EC50 value is 0.3739 ± 0.2413 µg/mL, indicating a strong antifungal activity of pyraclostrobin against Fol, as shown by unimodal curves of the EC50 values. Furthermore, we generated five resistant mutants through chemical taming and identified four mutants with high-level resistance due to the Cytb-G143S mutation and one mutant with medium-level resistance due to the Cytb-G137R mutation. The molecular docking results indicate that the Cytb-G143S or Cytb-G137R mutations of Fol lead to a change in the binding mode of Cytb to pyraclostrobin, resulting in a decrease in affinity. The resistant mutants exhibit reduced fitness in terms of mycelial growth (25 and 30 °C), virulence, and sporulation. Moreover, the mutants carrying the Cytb-G143S mutation suffer a more severe fitness penalty compared to those carrying the Cytb-G137R mutation. There is a positive correlation observed among azoxystrobin, picoxystrobin, fluoxastrobin, and pyraclostrobin for resistant mutants; however, no cross-resistance was detected between pyraclostrobin and pydiflumetofen, prochloraz, or cyazofamid. Thus, we conclude that the potential risk of resistance development in Fol toward pyraclostrobin can be categorized as ranging from low to moderate.