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Objectives To quantify the heterogeneity of fibrosis boundaries in idiopathic pulmonary fibrosis (IPF) using the Gaussian curvature analysis for evaluating disease severity and predicting survival. Methods We retrospectively included 104 IPF patients and 52 controls who underwent baseline chest CT scans. Normal lungs below − 500 HU were segmented, and the boundary was three-dimensionally reconstructed using in-house software. Gaussian curvature analysis provided histogram features on the heterogeneity of the fibrosis boundary. We analyzed the correlations between histogram features and the gender-age-physiology (GAP) and CT fibrosis scores. We built a regression model to predict diffusing capacity of carbon monoxide (DLCO) using the histogram features and calculated the modified GAP (mGAP) score by replacing DLCO with the predicted DLCO. The performances of the GAP, CT-GAP, and mGAP scores were compared using 100 repeated random-split sets. Results Patients with moderate-to-severe IPF had more numerous Gaussian curvatures at the fibrosis boundary, lower uniformity, and lower 10th to 30th percentiles of Gaussian curvature than controls or patients with mild IPF (all p < 0.0033). The 20th percentile was most significantly correlated with the GAP score (r = − 0.357; p < 0.001) and the CT fibrosis score (r = − 0.343; p = 0.001). More numerous Gaussian curvatures, higher entropy, lower uniformity, and 10th to 30th percentiles (p < 0.001–0.041) were associated with mortality. The mGAP score was comparable to the GAP and CT-GAP scores for survival prediction (mean C-indices, 0.76 vs. 0.79 vs. 0.77, respectively). Conclusions Gaussian curvatures of fibrosis boundaries became more heterogeneous as the disease progressed, and heterogeneity was negatively associated with survival in IPF. Key Points • Gaussian curvature of the fibrotic lung boundary was more heterogeneous in patients with moderate-to-severe IPF than those with mild IPF or normal controls. • The 20th percentile of the Gaussian curvature of the fibrosis boundary was linearly correlated with the GAP score and the CT fibrosis score. • A modified GAP score that replaced the diffusing capacity of carbon monoxide with a composite measure using histogram features of the Gaussian curvature of the fibrosis boundary showed a comparable ability to predict survival to both the GAP and the CT-GAP score. Supplementary Information The online version contains supplementary material available at 10.1007/s00330-020-07594-y.

Adeno-associated virus (AAV)-induced dorsal root ganglia (DRG) toxicity has been observed in several nonclinical species, where lesions are characterized by neuronal degeneration/necrosis, nerve fiber degeneration, and mononuclear cell infiltration. As AAV vectors become an increasingly common platform for novel therapeutics, non-invasive biomarkers are needed to better characterize and manage the risk of DRG neurotoxicity in both nonclinical and clinical studies. Based on biological relevance, reagent availability, antibody cross-reactivity, DRG protein expression, and assay performance, neurofilament light chain (NF-L) emerged as a promising biomarker candidate. Dose- and time-dependent changes in NF-L were evaluated in male Wistar Han rats and cynomolgus monkeys following intravenous or intrathecal AAV injection, respectively. NF-L profiles were then compared against microscopic DRG lesions on Day 29 post-dosing. In animals exhibiting DRG toxicity, plasma/serum NF-L was strongly associated with the severity of neuronal degeneration/necrosis and nerve fiber degeneration, with elevations beginning as early as Day 8 in rats (≥5×1013 vg/kg) and Day 14 in monkeys (≥3.3×1013 vg/dose). Consistent with the unique positioning of DRGs outside the blood-brain barrier, NF-L in cerebrospinal fluid was only weakly associated with DRG findings. In summary, circulating NF-L is a promising biomarker of AAV-induced DRG toxicity in nonclinical species.

Meniscus segmentation from knee MR images is an essential step when analyzing the length, width, height, cross-sectional area, surface area for meniscus allograft transplantation using a 3D reconstruction model based on the patient’s normal meniscus. In this paper, we propose a two-stage DCNN that combines a 2D U-Net-based meniscus localization network with a conditional generative adversarial network-based segmentation network using an object-aware map. First, the 2D U-Net segments knee MR images into six classes including bone and cartilage with whole MR images at a resolution of 512 × 512 to localize the medial and lateral meniscus. Second, adversarial learning with a generator based on the 2D U-Net and a discriminator based on the 2D DCNN using an object-aware map segments the meniscus into localized regions-of-interest with a resolution of 64 × 64. The average Dice similarity coefficient of the meniscus was 85.18% at the medial meniscus and 84.33% at the lateral meniscus, these values were 10.79%p and 1.14%p, and 7.78%p and 1.12%p higher than the segmentation method without adversarial learning and without the use of an object-aware map with the Dice similarity coefficient at the medial meniscus and lateral meniscus, respectively. The proposed automatic meniscus localization through multi-class can prevent the class imbalance problem by focusing on local regions. The proposed adversarial learning using an object-aware map can prevent under-segmentation by repeatedly judging and improving the segmentation results, and over-segmentation by considering information only from the meniscus regions. Our method can be used to identify and analyze the shape of the meniscus for allograft transplantation using a 3D reconstruction model of the patient’s unruptured meniscus.

The 3D modeling of orbital bones in facial CT images is essential to provide a customized implant for reconstructions of orbit and related structures during surgery. However, 3D models of the orbital bone show an aliasing effect and disconnected thin bone in the inter-slice direction because the slice thickness is two to three times larger than the pixel spacing. To improve the inter-slice resolution of facial CT images, we propose a method based on a 2D convolutional neural network (CNN) that uses the spatial information on the sagittal and axial planes and the orbital bone edge-aware (OBE) loss. First, intermediate slices are generated on the sagittal plane. Second, the generated intermediate slices are transformed to an axial image, which is then compared with the original axial image. To generate intermediate slices with an accurate orbital bone structure, the OBE loss considering the orbital bone structure on the sagittal and axial planes is used. To improve the perceptual quality of the generated intermediate slices, the feature map difference loss is additionally used on the axial plane. In the experiment, the proposed method showed the best performance among bilinear and bicubic interpolations, 3D SRGAN, and a 2D CNN-based method. Experimental results confirmed that the proposed method can generate intermediate slices with clear edges of thin bones as well as cortical bones on both the sagittal and the axial plane.

This study offers timely empirical evidence of the magnitude of the language effect on the performance of different language user groups, namely English as a Foreign Language (EFL), English as a Second Language (ESL), and English as a Native Language (ENL) in an accounting program instructed in English, an area that has been under researched. Informed by Cognitive Load Theory (CLT), this study develops an innovative research methodology (crossover repeated measures design), drawing on a large data analysis (n = 2912) of students' academic results in six accounting specialisation subjects between 2007 and 2014 in an Australian university's undergraduate accounting program. Results show that while all language user groups perform worse in more conceptually (MC) oriented subjects compared to less conceptually (LC) oriented subjects, the relative performance between MC and LC is strongly related to English language user groups. For the first time the magnitude of the impact is derived. The study has implications for the instructional design of accounting programs in English-speaking universities and their offshore programs in non-English speaking countries.

Surgery in patients with craniosynostosis is a common treatment to correct the deformed skull shape, and it is necessary to verify the surgical effect of correction on the regional cranial bone. We propose a quantification method for evaluating surgical effects on regional cranial bones by comparing preoperative and postoperative skull shapes. To divide preoperative and postoperative skulls into two frontal bones, two parietal bones, and the occipital bone, and to estimate the shape deformation of regional cranial bones between the preoperative and postoperative skulls, an age-matched mean-normal skull surface model already divided into five bones is deformed into a preoperative skull, and a deformed mean-normal skull surface model is redeformed into a postoperative skull. To quantify the degree of the expansion and reduction of regional cranial bones after surgery, expansion and reduction indices of the five cranial bones are calculated using the deformable registration as deformation information. The proposed quantification method overcomes the quantification difficulty when using the traditional cephalic index(CI) by analyzing regional cranial bones and provides useful information for quantifying the surgical effects of craniosynostosis patients with symmetric and asymmetric deformities.

To evaluate diagnostic performance of a radiomics model for classifying hepatic cyst, hemangioma, and metastasis in patients with colorectal cancer (CRC) from portal-phase abdominopelvic CT images. This retrospective study included 502 CRC patients who underwent contrast-enhanced CT and contrast-enhanced liver MRI between January 2005 and December 2010. Portal-phase CT images of training (n = 386) and validation (n = 116) cohorts were used to develop a radiomics model for differentiating three classes of liver lesions. Among multiple handcrafted features, the feature selection was performed using ReliefF method, and random forest classifiers were used to train the selected features. Diagnostic performance of the developed model was compared with that of four radiologists. A subgroup analysis was conducted based on lesion size. The radiomics model demonstrated significantly lower overall and hemangioma- and metastasis-specific polytomous discrimination index (PDI) (overall, 0.8037; hemangioma-specific, 0.6653; metastasis-specific, 0.8027) than the radiologists (overall, 0.9622–0.9680; hemangioma-specific, 0.9452–0.9630; metastasis-specific, 0.9511–0.9869). For subgroup analysis, the PDI of the radiomics model was different according to the lesion size (< 10 mm, 0.6486; ≥ 10 mm, 0.8264) while that of the radiologists was relatively maintained. For classifying metastasis from benign lesions, the radiomics model showed excellent diagnostic performance, with an accuracy of 84.36% and an AUC of 0.9426. Albeit inferior to the radiologists, the radiomics model achieved substantial diagnostic performance when differentiating hepatic lesions from portal-phase CT images of CRC patients. This model was limited particularly to classifying hemangiomas and subcentimeter lesions. • Albeit inferior to the radiologists, the radiomics model could differentiate cyst, hemangioma, and metastasis with substantial diagnostic performance using portal-phase CT images of colorectal cancer patients. • The radiomics model demonstrated limitations especially in classifying hemangiomas and subcentimeter liver lesions.

This study provides insights from accounting practitioners on China's convergence with International Financial Reporting Standards (IFRS). Through a survey of 33 senior financial executives of Chinese listed companies in 2014, the study reports their perceptions on the following issues: first, the degree of convergence between IFRS and Chinese Accounting Standards (CAS); second, the choice between fair value and historical cost accounting, and the usefulness of fair value accounting for Chinese companies’ financial reporting; third, challenges in the process of China's harmonisation with IFRS; and finally, essential capabilities of Chinese accounting professionals in the process of China's harmonisation with IFRS. Multivariate regression was used for further analysis. The survey findings reveal that in general CAS have converged with IFRS, with a few exceptions that reflect the unique Chinese context. Historical cost accounting is the preferred measurement base to fair value accounting. Exercising professional judgement was identified as a challenge for China's full convergence with IFRS. Ownership structure and the expertise of accounting practitioners were found to affect respondents’ judgements on China's convergence with IFRS. This study has policy implications for international accounting standard setters and accounting educators to consider the contextual issues of implementing IFRS in an emerging economy.

This study aimed to evaluate inspiratory lung expansion in patients with interstitial lung disease (ILD) using histogram analyses based on advanced image registration between inspiratory and expiratory CT scans. We included 16 female ILD patients and eight age- and sex-matched normal controls who underwent full-inspiratory and expiratory CT scans. The CT scans were sequentially aligned based on the surface, landmarks, and attenuation of the lung parenchyma. Histogram analyses were performed on the degree of lung expansion (DLE) of each pixel between the aligned images in x-, y-, z-axes, and 3-dimensionally (3D). The overall mean registration error was 1.9 mm between the CT scans. The DLE

CRISPR/Cas9 is a programmable genome editing tool that has been widely used for biological applications. While engineered Cas9s have been reported to increase discrimination against off-target cleavage compared with wild type Streptococcus pyogenes (SpCas9) in vivo, the mechanism for enhanced specificity has not been extensively characterized. To understand the basis for improved discrimination against off-target DNA containing important mismatches at the distal end of the guide RNA, we performed kinetic analyses on the high-fidelity (Cas9-HF1) and hyper-accurate (HypaCas9) engineered Cas9 variants. While DNA unwinding is the rate-limiting step for on-target cleavage by SpCas9, we show that chemistry is seriously impaired by more than 100-fold for the high-fidelity variants. The high-fidelity variants improve discrimination by slowing the rate of chemistry without increasing the rate of DNA rewinding—the kinetic partitioning favors release rather than cleavage of a bound off-target substrate because chemistry is slow. Further improvement in discrimination may require engineering increased rates of dissociation of off-target DNA.

Bacterial adaptive immune systems employ clustered regularly interspaced short palindromic repeats (CRISPR) along with their CRISPR-associated genes (Cas) to form CRISPR RNA (crRNA)-guided surveillance complexes, which target foreign nucleic acids for destruction. Cas9 is unique in that it is composed of a single polypeptide that utilizes both a crRNA and a trans-activating crRNA (tracrRNA) or a single guide RNA to create double-stranded breaks in sequences complementary to the RNA via the HNH and RuvC nuclease domains. Cas9 has become a revolutionary tool for gene-editing applications. Here, we describe methods for studying the cleavage activities of Cas9. We describe protocols for rapid quench-flow and stopped-flow kinetics and interpretation of the results. The protocols detailed here will be paramount for understanding the mechanistic basis for specificity of this enzyme, especially in efforts to improve accuracy for clinical use.

[Background]: Circadian rhythms modulate growth and development in all organisms through interlocking transcriptional-translational feedback loops. The transcriptional loop involves chromatin modifications of central circadian oscillators in mammals and plants. However, the molecular basis for rhythmic epigenetic modifications and circadian regulation is poorly understood., [Results]: Here we report a feedback relationship between diurnal regulation of circadian clock genes and histone modifications in Arabidopsis. On one hand, the circadian oscillators CCA1 and LHY regulate diurnal expression of genes coding for the eraser (JMJ14) directly and writer (SDG2) indirectly for H3K4me3 modification, leading to rhythmic H3K4me3 changes in target genes. On the other hand, expression of circadian oscillator genes including CCA1 and LHY is associated with H3K4me3 levels and decreased in the sdg2 mutant but increased in the jmj14 mutant. At the genome-wide level, diurnal rhythms of H3K4me3 and another histone mark H3K9ac are associated with diurnal regulation of 20–30% of the expressed genes. While the majority (86%) of H3K4me3 and H3K9ac target genes overlap, only 13% of morning-phased and 22% of evening-phased genes had both H3K4me3 and H3K9ac peaks, suggesting specific roles of different histone modifications in diurnal gene expression., [Conclusions]: Circadian clock genes promote diurnal regulation of SDG2 and JMJ14 expression, which in turn regulate rhythmic histone modification dynamics for the clock and its output genes. This reciprocal regulatory module between chromatin modifiers and circadian clock oscillators orchestrates diurnal gene expression that governs plant growth and development., The research is supported by grants to Z.J.C. from the National Institute of General Medical Sciences (GM109076) and Samsung Electronics Co., Ltd. (UTA12-000733, 2012-2014).

Purpose This paper aims to investigate the extent international and domestic guidelines have influenced the content of corporate environmental reporting (CER) in the context of China’s radical institutional transition from bureaucratic secrecy to openness, marked by the first nationwide guidelines on Open Government Information (OGI) and Open Environment Information (OEI), effective in 2008. Design/methodology/approach The study develops a research instrument that captures international and Chinese national guidelines pertaining to environmental information disclosure. This instrument is used to analyse 471 reports of leading 100 listed Chinese companies for the critical period between 2006 and 2010. Chi-square test statistics are used to analyse the significance of differences in reporting items supported by Chinese guidelines versus those supported by international reporting guidelines only. Findings Partial convergence in climate-change reporting co-exists with divergent China specific interpretation of climate change. The coercive institutional influences of the Chinese government’s guidance in OGI and OEI led to the rapid growth of CER in 2008 compared to 2006, despite compliance being voluntary. Originality/value The study is innovative in explicitly measuring any changes in reporting relative to the potential for additional reporting. Such a method more accurately evaluates the effect of institutional influences on reporting. The study provides a fresh profile of the content and the reporting medium of CER, with a particular focus on climate change in the Chinese context. The findings highlight research into CER based on annual reports risks results being incomplete and misleading. Findings have practical implications for policy makers in other emerging economies.

This study aimed to evaluate inspiratory lung expansion in patients with interstitial lung disease (ILD) using histogram analyses based on advanced image registration between inspiratory and expiratory CT scans. We included 16 female ILD patients and eight age- and sex-matched normal controls who underwent full-inspiratory and expiratory CT scans. The CT scans were sequentially aligned based on the surface, landmarks, and attenuation of the lung parenchyma. Histogram analyses were performed on the degree of lung expansion (DLE) of each pixel between the aligned images in x-, y-, z-axes, and 3-dimensionally (3D). The overall mean registration error was 1.9 mm between the CT scans. The DLE3D in ILD patients was smaller than in the controls (mean, 17.6 mm vs. 26.9 mm; p = 0.023), and less heterogeneous in terms of standard deviation, entropy, and uniformity (p Z of the lower lungs. A forced vital capacity tended to be weakly correlated with mean (r2 = 0.210; p = 0.074), and histogram parameters (r2 = 0.194–0.251; p = 0.048–0.100) of the DLE3D in the lower lung in ILD patients. Our findings indicate that reduced and less heterogeneous inspiratory lung expansion in ILD patients can be identified by using advanced accurate image registration.

We propose an automatic vessel segmentation method of vertebral arteries in CT angiography using combined circular and cylindrical model fitting. First, to generate multi-segmented volumes, whole volume is automatically divided into four segments by anatomical properties of bone structures along z-axis of head and neck. To define an optimal volume circumscribing vertebral arteries, anterior-posterior bounding and side boundaries are defined as initial extracted vessel region. Second, the initial vessel candidates are tracked using circular model fitting. Since boundaries of the vertebral arteries are ambiguous in case the arteries pass through the transverse foramen in the cervical vertebra, the circle model is extended along z-axis to cylinder model for considering additional vessel information of neighboring slices. Finally, the boundaries of the vertebral arteries are detected using graph-cut optimization. From the experiments, the proposed method provides accurate results without bone artifacts and eroded vessels in the cervical vertebra.

Background The aim of this study was to evaluate the value of T1/T2-weighted imaging (T1/T2WI) registration to reduce the postbiopsy hemorrhage effect for prostate cancer localization on prostate magnetic resonance imaging (MRI). Methods Twenty-one men with pathology-proven prostate cancer who underwent preoperative MRI in a single institution were selected. The zonal anatomy was divided into 16 sections. T2WI, T1/T2-weighted registered imaging (T1/T2RI), T2WI combined with diffusion-weighted imaging (T2WI + DWI), and T1/T2RI combined with DWI (T1/T2RI + DWI) were scored for the likelihood of cancer by two radiology faculty members and two trainees, and were compared with histology results. Areas under the receiver operating characteristics curve (AUCs) were used to assess diagnostic accuracy. Results For the trainees (Reader 3 and Reader 4), the AUC values were significantly higher (P