With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations
. However, whether such clonal expansion exists in the non-neoplastic intestine remains ...unknown. Here, using whole-exome sequencing data from 76 clonal human colon organoids, we identify a unique pattern of somatic mutagenesis in the inflamed epithelium of patients with ulcerative colitis. The affected epithelium accumulates somatic mutations in multiple genes that are related to IL-17 signalling-including NFKBIZ, ZC3H12A and PIGR, which are genes that are rarely affected in colon cancer. Targeted sequencing validates the pervasive spread of mutations that are related to IL-17 signalling. Unbiased CRISPR-based knockout screening in colon organoids reveals that the mutations confer resistance to the pro-apoptotic response that is induced by IL-17A. Some of these genetic mutations are known to exacerbate experimental colitis in mice
, and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Our findings highlight a genetic landscape that adapts to a hostile microenvironment, and demonstrate its potential contribution to the pathogenesis of ulcerative colitis.
The adaptive seamless design combining phases II and III into a single trial has been shown growing interest for improving the efficiency of drug development, becoming the most frequent adaptive ...design type. It typically consists of two stages, the trial objectives being often different in each stage. The primary objectives are to select optimal experimental treatment group(s) in the first stage and compare the efficacy between the selected treatment and control groups in the second stage. In this article, we focus on a two‐stage adaptive seamless design, for which treatment selection is based on the short‐term binary endpoint and treatment comparison is based on the long‐term binary endpoint. We thus propose an exact conditional test as a final analysis, based on the bivariate binomial distribution and given the selected treatment with the most promising short‐term endpoint response rate from an interim analysis. Additionally, the mid‐p$$ p $$ approach is incorporated to improve conservativeness for an exact test. Simulation studies were conducted to compare the proposed methods with a method based on the combination test. The proposed exact method controlled for type I error rate at the nominal level, regardless of the number of initial treatments or the correlation between short‐ and long‐term endpoints. In terms of the treatment comparison power, the proposed methods are more powerful than that based on the combination test in the scenarios, with only one treatment being effective.
To elucidate the microscopic origin of the thermal droop, a blue-emitting indium gallium nitride (InGaN) quantum well grown on epitaxially laterally overgrown gallium nitride was investigated using ...temperature-dependent microphotoluminescence spectroscopy. Below 300 K, the sample exhibited a well-known dislocation-tolerant luminescence behavior. However, as temperature increases from 300 K to 500 K, the near band-edge emission at the wing region (with lower threading dislocation densities) was stronger than that at the seed region (with higher threading dislocation densities), indicating that threading dislocations are the microscopic origin of the thermal droop. Considering the carrier diffusion length, edge-type threading dislocations should play a major role in the thermal droop of heteroepitaxially grown InGaN-based LEDs.
Objectives
To investigate the clinical utility of the Vesical Imaging-Reporting and Data System (VI-RADS) by comparing its diagnostic performance for muscle-invasive bladder cancer (MIBC) between ...radiologists and urologists based on multiparametric MRI, including three-dimensional (3D) fast spin-echo (FSE) T2-weighted acquisitions.
Methods
This study included 66 treatment-naïve patients (60 men, 6 women; mean age 74.0 years) with pathologically proven bladder cancer who underwent multiparametric MRI, including 3D FSE T2-weighted imaging, before transurethral bladder tumour resection between January 2010 and November 2018. The MRI scans were categorised according to the five-point VI-RADS score by four independent readers (two board-certified radiologists and board-certified urologists each), blinded to the histopathological findings. The VI-RADS scores were compared with the postoperative histopathological diagnosis. Interobserver agreement was assessed using weighted kappa coefficients. ROC analysis and generalised estimating equations were used to evaluate the diagnostic performance.
Results
Forty-nine (74.2%) and 17 (25.8%) tumours were confirmed to be non-MIBC and MIBC, respectively, based on pathological examination. The interobserver agreement was good-to-excellent between all pairs of readers (range, 0.73–0.91). The urologists’ sensitivity/specificity values for DCE-MRI VI-RADS scores were significantly lower than those of radiologists. No significant differences were observed for the overall VI-RADS score. The AUC for the overall VI-RADS score was 0.94, 0.92, 0.89, and 0.87 for radiologists 1 and 2 and urologists 1 and 2, respectively.
Conclusions
The VI-RADS score, based on multiparametric MRI including 3D FSE T2-weighted acquisitions, can be useful for radiologists and urologists to determine the bladder cancer muscle invasion status preoperatively.
Key Points
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VI-RADS (using multiparametric MRI including 3D FSE T2-weighted acquisitions) achieves good to excellent interobserver agreement and has similar diagnostic performance for detecting muscle invasion by both radiologists and urologists.
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The diagnostic performance of the overall VI-RADS score is high for both radiologists and urologists, particularly due to the dominant effect of diffusion-weighted imaging on the overall VI-RADS score.
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The sensitivity and specificity values of the T2WI VI-RADS scores for four readers in our study (using 3D FSE T2-weighted acquisitions) were similar (with slightly higher specificity values) to previously published results (using 2D FSE T2-weighted acquisitions).
Theoretically, the maximum likelihood estimator has the sandwich-type asymptotic variance-covariance matrix under model misspecification. Its empirical estimator, that is called the robust variance ...estimator, is consistent. Thus, the estimator is asymptotically valid even under model misspecification. In practice, the robust variance estimator is used for computation of standard errors in longitudinal data analysis. Recently, Golden et al. (
2019
Econometrics, 7, 1-27) showed that the maximum likelihood estimator retains a sandwich-type asymptotic variance-covariance matrix in the presence of missing data even when the missing-data mechanism is missing not at random. Although they revealed the asymptotic validity of the robust variance estimator in the simultaneous presence of both model misspecification and missing data, its finite-sample performance did not be investigated. In this article, we evaluated the finite-sample performance via simulation studies and clarify its small-sample problems. In addition, we illustrated the robust variance estimator using longitudinal CD4 count data from a randomized double-blind study.
A retrospective cohort study OBJECTIVE: To establish a logarithmic model to predict functional independence after spinal cord injury.
The National Hospital Organization, Murayama Medical Center, ...Japan.
Thirty-one adults with a traumatic spinal cord injury (SCI) were enrolled. The Spinal Cord Independence Measure (SCIM) III scores obtained at month 1 and 3 after admission were used to construct a simple logarithmic model to predict SCIM III scores. The validity of the predicted scores was evaluated using a linear mixed model, and agreement between the predicted and measured scores were assessed using the Bland-Altman analysis.
In the linear mixed model, the fixed effect slope 95% CI and the intercept 95% CI were 1.18 0.78, 1.58 and -1.75 -10.3, 6.83, respectively. The scatter plot showed non-linear correlation between the predicted and actual SCIM III scores. This non-linearity became inconspicuous when Sphincter Management scores were omitted. The fixed effect slope and the intercept were 1.12 0.89, 1.36 and -1.64 -4.95, 1.68, respectively. A significant fixed or proportional bias was not identified on the Bland-Altman analysis of the total SCIM III score, with most scores lying between an upper limit of +15.3 and a lower limit of -19.3.
The logarithmic model provided an accurate prediction of the functional independence score of individuals with SCI in our cohort which included various neurological levels and severity of the injury. Along with its simplicity, our prediction model could be useful in daily practice.
The aims of this study were to evaluate the feasibility of quantitative synthetic magnetic resonance imaging (SyMRI) for characterizing bone lesions in prostate cancer and to discriminate viable ...progressive osteoblastic bone metastasis from nonviable bone metastases with treatment-induced sclerosis during the treatment course.
This institutional review board-approved prospective study included 96 consecutive prostate cancer patients who underwent whole-body MRI including diffusion-weighted imaging at the time of staging at diagnosis or starting a new line of anticancer treatment. Additional synthetic MRI of the lumbosacral spine, pelvis, and proximal femurs was performed. A region of interest of 1.0 cm in diameter was set in each bone lesion by 2 independent readers who were blinded to bone lesions' diagnosis. Differences in SyMRI variables between the different bone lesions were compared with the Wilcoxon rank sum test, and associations of SyMRI variables with active disease were analyzed with logistic regression analysis. Performance of T1, T2, and proton density (PD) for diagnosing active disease was assessed using the area under the receiver operating characteristic curve.
Ninety-three bone lesions were eligible for analysis. The PD values of active (viable) bone metastatic lesions were significantly higher than those of inactive (nonviable) bone metastatic lesions without sclerosis and those of red bone marrow (P < 0.001 for both readers). The PD values of inactive bone metastatic lesions with sclerosis were significantly lower than those of inactive bone metastatic lesions without sclerosis and red bone marrow (P < 0.001 for both readers). The PD value proved to be an independent significant indicator (P < 0.001) for differentiating bone lesions. The areas under the curve of T1/T2/PD for identifying active disease were 0.81/0.69/0.93 for reader 1 and 0.78/0.70/0.92 for reader 2, respectively.
Signal quantification on SyMRI provides objective assessment of bone lesions in the lower trunk. The PD value can be useful to determine the viability of bone metastases in prostate cancer.
Temperature-dependent electroluminescence measurements are performed for 265-nm AlGaN-based deep-ultraviolet (DUV) light-emitting diodes (LEDs) grown on AlN substrates. The external quantum ...efficiency (EQE) increases as the temperature decreases from 293 K to 6 K. Using two assumptions, the internal quantum efficiency (IQE) and current injection efficiency (CIE) are unity at the peak EQE at 6 K and the light extraction efficiency is independent of current and temperature, the current and temperature dependences of the product (IQE × CIE) are derived. The temperature dependence of the EQE cannot be simply explained by the Auger recombination processes. This observation enables the CIE and IQE to be separately extracted by rate equation analysis. The room-temperature EQE of the AlGaN-based DUV LEDs is limited by the CIE and not the IQE. We propose that the relatively low CIE may originate from the nonradiative recombination process outside quantum-well layers.
The impact of a face-to-face annealed sputtered AlN/sapphire (FFA Sp-AlN) template with threading-dislocation densities (TDDs) of 2 × 108 cm−2 and an n-type AlGaN (n-AlGaN) underlayer on optical ...properties of AlGaN multiple quantum wells (MQWs) with an ultraviolet C (UVC) emission is investigated comprehensively. For comparison of the FFA Sp-AlN template with low TDDs, a conventional MOVPE (metalorganic vapor phase epitaxially)-grown AlN/sapphire (MOVPE-AlN) template with TDDs of 1 × 109 cm−2 was prepared. Consequently, cathodoluminescence (CL), temperature-dependent photoluminescence (PL), and time-resolved PL (TR-PL) measurements verified that both the FFA Sp-AlN template and n-AlGaN underlayer are indispensable for obtaining MQWs with high internal quantum efficiencies, which decrease the TDDs and point defect (PD) densities. Our results revealed that 10-period quantum wells (10QWs)/n-AlGaN/AlN grown on the FFA Sp-AlN template exhibit a lower dark spot density in CL panchromatic intensity maps, a higher integrated emission intensity ratio from the temperature-dependent PL (from 15 to 300 K), and a longer nonradiative lifetime from the TR-PL measurements at 300 K compared with those grown on the MOVPE-AlN template. Moreover, we found that the optical properties of 10QWs/AlN in FFA Sp-AlN and MOVPE-AlN templates do not exhibit a significant difference because of the existence of numerous PDs. Our experimental results demonstrate the favorable impact of the FFA Sp-AlN template for low-TDDs and the n-AlGaN underlayer for low-PDs, which holds promise for highly efficient AlGaN deep-ultraviolet light-emitting devices.
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