Clinical and Microbiological Characteristics of Bacteremia Caused by Carbapenemase-producing Enterobacterales in Minami Ibaraki Area, Japan.

Although recent propagation of carbapenemase-producing Enterobacterales (CPE) has become a problem worldwide, the picture of CPE infection in Japan has not fully been elucidated. In this study, we examined clinical and microbiological characteristics of invasive CPE infection occurring at 8 hospitals in Minami Ibaraki Area between July 2001 to June 2017. Of 7294 Enterobacterales strains isolated from independent cases of bacteremia and/or meningitis, 10 (0.14%) were CPE (8 Enterobacter cloacae-complex, 1 Escherichia coli, and 1 Edwardsiella tarda）, all of which had the blaIMP-1 gene and susceptible to gentamicin and trimethoprim/sulfamethoxazole. These strains were isolated from 7 adult and 2 infant bacteremia (1 infant patient developed CPE bacteremia twice) after 2007. The most common portal of entry was intravenous catheters. All of the adult patients were recovered, while the infant patients eventually died. Genomic analyses showed that the 8 E. cloacae-complex strains were classified into 5 groups, each of which was exclusively detected in specific facilities at intervals of up to 3 years, suggesting persistent colonization in the facilities. This study showed that invasive CPE infection in the area was rare, caused by IMP-1-type CPE having susceptibility to various antibiotics, and nonfatal among adult patients.

Deep learning study on the mechanism of edge artifacts in point spread function reconstruction for numerical brain images.

OBJECTIVE: Non-blinded image deblurring with deep learning was performed on blurred numerical brain images without point spread function (PSF) reconstruction to obtain edge artifacts (EA)-free images. This study uses numerical simulation to investigate the mechanism of EA in PSF reconstruction based on the spatial frequency characteristics of EA-free images. METHODS: In 256 × 256 matrix brain images, the signal values of gray matter (GM), white matter, and cerebrospinal fluid were set to 1, 0.25, and 0.05, respectively. We assumed ideal projection data of a two-dimensional (2D) parallel beam with no degradation factors other than detector response blur to precisely grasp EA using the PSF reconstruction algorithm from blurred projection data. The detector response was assumed to be a shift-invariant and one-dimensional (1D) Gaussian function with 2-5 mm full width at half maximum (FWHM). Images without PSF reconstruction (non-PSF), PSF reconstruction without regularization (PSF) and with regularization of relative difference function (PSF-RD) were generated by ordered subset expectation maximization (OSEM). For non-PSF, the image deblurring with a deep image prior (DIP) was applied using a 2D Gaussian function with 2-5 mm FWHM. The 1D object-specific modulation transfer function (1D-OMTF), which is the ratio of 1D amplitude spectrum of the original and reconstructed images, was used as the index of spatial frequency characteristics. RESULTS: When the detector response was greater than 3 mm FWHM, EA in PSF was observed in GM borders and narrow GM. No remarkable EA was observed in the DIP, and the FWHM estimated from the recovery coefficient for the deblurred image of non-PSF at 5 mm FWHM was reduced to 3 mm or less. PSF of 5 mm FWHM showed higher spatial frequency characteristics than that of DIP up to around 2.2 cycles/cm but was lower than the latter after 3 cycles/cm. PSF-RD showed almost the same spatial frequency characteristics as that of DIP above 3 cycles/cm but was inferior below 3 cycles/cm. PSF-RD has a lower spatial resolution than DIP. CONCLUSIONS: Unlike DIP, PSF lacks high-frequency components around the Nyquist frequency, generating EA. PSF-RD mitigates EA while simultaneously suppressing the signal, diminishing spatial resolution.

Diagnostic and prognostic biomarkers for progressive fibrosing interstitial lung disease.

No biomarkers have been identified in bronchoalveolar lavage fluid (BALF) for predicting fibrosis progression or prognosis in progressive fibrosing interstitial lung disease (PF-ILD). We investigated BALF biomarkers for PF-ILD diagnosis and prognosis assessment. Overall, 120 patients with interstitial pneumonia who could be diagnosed with PF-ILD or non PF-ILD were enrolled in this retrospective study. PF-ILD was diagnosed according to Cottin's definition. All patients underwent bronchoscopy and BALF collection. We evaluated blood and BALF parameters, high-resolution computed tomography (HRCT) patterns, and spirometry data to identify factors influencing PF-ILD diagnosis and prognosis. On univariate logistic analysis, age, sex, the BALF white blood cell fraction (neutrophil, lymphocyte, eosinophil, and neutrophil-to-lymphocyte ratio), BALF flow cytometric analysis (CD8), and an idiopathic pulmonary fibrosis/usual interstitial pneumonia pattern on HRCT were correlated with PF-ILD diagnosis. Multivariate logistic regression analysis revealed that sex (male), age (cut-off 62 years, area under the curve [AUC] 0.67; sensitivity 0.80; specificity 0.47), white blood cell fraction in BALF (NLR, neutrophil, and lymphocyte), and CD8 in BALF (cut-off 34.2; AUC 0.66; sensitivity, 0.74; specificity, 0.62) were independent diagnostic predictors for PF-ILD. In BALF, the NLR (cut-off 8.70, AUC 0.62; sensitivity 0.62; specificity 0.70), neutrophil count (cut-off 3.0, AUC 0.59; sensitivity 0.57; specificity 0.63), and lymphocyte count (cut-off 42.0, AUC 0.63; sensitivity 0.77; specificity 0.53) were independent diagnostic predictors. In PF-ILD patients (n = 77), lactate dehydrogenase (cut-off 275, AUC 0.69; sensitivity 0.57; specificity 0.78), Krebs von den Lungen-6 (cut-off 1,140, AUC 0.74; sensitivity 0.71; specificity 0.76), baseline forced vital capacity (FVC) (cut-off 1.75 L, AUC 0.71; sensitivity, 0.93; specificity, 0.46), and BALF neutrophil ratio (cut-off 6.0, AUC 0.72; sensitivity 0.79; specificity 0.80) correlated with death within 3 years. The BALF cellular ratio, particularly the neutrophil ratio, correlated with the diagnosis and prognosis of PF-ILD. These findings may be useful in the management of patients with interstitial pneumonia.

Conversion of triphenylphosphine oxide to organophosphorus via selective cleavage of C-P, O-P, and C-H bonds with sodium.

For over half a century, thousands of tons of triphenylphosphine oxide Ph3P(O) have been produced every year from the chemical industries as a useless chemical waste. Here we disclose efficient transformations of Ph3P(O) with cheap resource-abundant metallic sodium finely dispersed in paraffin oil. Ph3P(O) can be easily and selectively transformed to three reactive organophosphorus intermediates-sodium diphenylphosphinite, sodium 5H-benzo[b]phosphindol-5-olate and sodium benzo[b]phosphindol-5-ide-that efficiently give the corresponding functional organophosphorus compounds in good yields. These functional organophosphorus compounds are difficult to prepare but highly industrially useful compounds. This may allow Ph3P(O) to be used as a precious starting material for highly valuable phosphorus compounds.

[Incident Photon Number and Reconstructed Linear Attenuation Coefficients in Iterative CT Image Reconstruction].

[Purpose] The iterative CT image reconstruction (IR) method has been successfully incorporated into commercial CT scanners as a means to promote low-dose CT with high image quality. However, the algorithm of the IR method has not been made publicly available by scanner manufacturers. Kudo reviewed the fundamentals of IR methods on the basis of the articles published by the joint research group of each manufacture that were released before and during product development (Med Imag Tech 32: 239-248, 2014). According to this review, the object function of the IR method consists of the data fidelity term (likelihood) and the regularization term. The regularization term plays a significant role in the IR method; however, it has not been clarified whether or not the variance of projection data should be included into the likelihood to act the regularization term effectively. Our purpose in this study was to investigate the relationship of the incident photon number and the reconstructed linear attenuation coefficients of the IR method by numerical experiments.[Methods] We assumed the X-ray beam was a pencil beam, and the system matrix was given by the line integral of linear attenuation coefficients because we focused on the accuracy of the reconstructed linear attenuation coefficients in the ideal photon detection system equations given by Kudo. Total variation (TV) and the relative difference function were used for regularization of the IR method. Three kinds of numerical phantoms with 256×256 pixels were used as test images. Poisson noise was added to the projection data with 256 linear sampling and 256 views over 180°. The accuracy of reconstructed linear attenuation coefficients was evaluated by the mean reconstructed value within a region of interest (ROI) and the relative root mean square errors (%RMSEs) to the object image.[Results] The linear attenuation coefficients were reconstructed accurately by the IR method including the variance of projection data into the likelihood in comparison with the IR method without including the variance. When the incident photon number ranged from 100 to 2000 for the object having a mean linear attenuation coefficient of 0.067 to 0.087 cm-1, the reconstructed linear attenuation coefficients in ROI were close to the true values. However, when the incident photon number was 50, both the accuracy and the uniformity of reconstructed images decreased.[Discussion] From the viewpoint of the visual observation, the image quality of the IR method was superior to that of the filtered back-projection (FBP) image processed with the Gaussian filter of FWHM equal to 3 pixels. For the object with a high absorber, the FBP gives linear attenuation coefficients that were lower than the true values. This phenomenon was also observed in the IR method. The projection data of CT were given by the logarithm operation of the ratio between the incident photon and the transmitted photon numbers. If the transmitted photon number happened to be equal to 0 owing to the influence of noise, it was held to a value of 1 to avoid the logarithm of zero. This process caused an error of the linear attenuation coefficients.[Conclusion] The variance of projection data should be included into the likelihood to act the regularization term effectively in the IR method.

[An Error Evaluation of Iterative Image Reconstruction Methods Using Chi-Square (χ2) Statistic Minimization for Poisson-Distributed Projection Data].

[Purpose] Iterative image reconstruction (IR) methods using Neyman's chi-square statistic (χ2N) or Pearson's chi-square statistic (χ2P) have been investigated in nuclear medicine. However, these chi-square statistic-based image reconstructions have never been installed on clinical nuclear medicine instruments. Mighell developed another chi-square statistic (χ2M). Recently, Mighell's chi-square statistic has been incorporated into commercial SPECT instrument aiming at high accuracy in the iterative image reconstruction from low count projection data. However, the error evaluation for χ2M was not reported by the instrument manufacturer or the joint research group involved in the product development. Therefore, it is not certain to what extent χ2M is superior to χ2N or χ2P. In this study we investigated the accuracy of the chi-square statistic-based IR methods by computer simulation.[Methods] We used two kinds of numerical phantoms (256×256 pixels) for testing root mean square error (RMSE). Phantom A was a disk that was 18.4 cm in diameter and the count density was varied from 1 count/pixel to 10 counts/pixel at intervals of 1 count/pixel in each trial. Phantom B was a disk that was 18.4 cm in diameter and the count densities for the seven disk inserts (diameter 3 cm) which were investigated were 1, 2, 3, 4, 5, 6, and 7 counts/pixel. Poisson noise was added to the projection data with 256 linear samplings and 256 views over 180°. Projection data were assumed to be without attenuation and scatter effects, because we focused our evaluation on the noise propagation from projection data to the reconstructed image that was attributable to the mathematical equations of the different types of chi-square statistic. Minimization of the chi-square statistic-based IR methods was performed by conjugate gradient method.[Results] We found the noise was suppressed by including the variance of projection data in each chi-square statistic; however, it was not suppressed sufficiently by χ2P in comparison with χ2N and χ2M. For 1000 iterations, the RMSEs of Phantom A having the count density of 1 count/pixel were 21.46±2.75, 39.21±0.71, and 12.29±0.63, obtained by χ2N, χ2P, and χ2M in 20 trials, respectively. For 2 counts/pixel, RMSEs were 5.26±0.32, 19.89±1.29, and 4.23±0.08; and for 3 counts/pixel, they were 5.34±0.56, 10.27±0.38, and 4.03±0.07. With Phantom B, RMSEs of the 3 cm disk insert having the count density of 2 counts/pixel were 7.36±0.56, 21.21±1.52, and 6.79±0.54; for 3 counts/pixel it was 5.46±0.34, 14.43±1.08, and 4.84±0.32, for χ2N, χ2P, and χ2M, respectively.(View PDF for the rest of the abstract.).

[Implementation of Statistically-Based Image Reconstruction Algorithms for CT and Numerical Evaluation of Image Quality].

[Purpose] Statistically-based image reconstruction (SIR) methods that have been incorporated into commercial CT scanners have succeeded in promoting low-dose CT with high image quality in comparison with scanners using the filtered back-projection (FBP) method. Not only researchers but also medical doctors and technologists engaged in CT studies have an interest in the algorithms of the SIR methods, however, the algorithms have not been made available to users by the CT manufacturers. Kudo reviewed the fundamentals of SIR methods on the basis of the articles published by the joint research group of each manufacturer released before product development (Med Imag Tech 32: 239-248, 2014). He classified the SIR methods into true iterative reconstruction (true IR), hybrid IR, and image space denoising (ISD) methods. His review article has made a significant contribution to the CT community of users. However, the reconstructed images obtained by those methods have not been presented. Our purpose in this study is to implement the mathematical equations of three IR methods, one each of the true IR, hybrid IR and ISD methods, and evaluate their image quality.[Methods] The system matrix of IR methods used in commercial CT scanners uses a physical photon detection process based on the finite size of an X-ray focal spot, the beam width, and the X-ray detector. However, we assumed the X-ray beam was a pencil beam and the system matrix was then given by the line integral of linear attenuation coefficients because we focus on the image quality in the ideal photon detection system equations given by Kudo. Total variation (TV) was used for regularization of the true IR, hybrid IR and ISD methods. Four kinds of numerical phantoms with 256×256 pixels were used as test images. Gaussian noise of 15, 20, 25, and 30 dB was added to the projection data with 256 linear samplings and 256 views over 180°.[Results] Root mean square errors (RMSEs) of the true IR, hybrid IR, and ISD methods were 4.28-5.70, 15.87-16.47, and 16.94-17.17, respectively. RMSE of the FBP method ranged from 27.64-33.02 and that of the FBP method processed with a Gaussian filter of FWHM (full width at half maximum) of 3 pixels ranged from 8.14-17.28. The image quality of the true IR method was superior to that of the hybrid IR and ISD methods and the FBP method.[Discussion] The noise was slightly suppressed by including the variance of projection data; however, the regularization was inevitable even if the noise levels were in the range of 25-30 dB. The noise was not suppressed sufficiently by the hybrid IR and ISD methods because the noise due to the FBP image used as the initial image for these IR methods has a dominating effect in successive reconstruction or denoise processing. Mathematical equations of each IR method were easily realized by observing the intermediate images such as the regularization term of the iteration process. In addition to these equations, the reconstructed images by the SIR methods and their RMSEs presented in this study are useful in CT research.[Conclusions] The fundamental point of SIR methods is the regularization term used in minimizing the object function.

Undersampling patterns in k-space for compressed sensing MRI using two-dimensional Cartesian sampling.

In compressed sensing magnetic resonance imaging (CS-MRI), undersampling of k-space is performed to achieve faster imaging. For this process, it is important to acquire data randomly, and an optimal random undersampling pattern is required. However, random undersampling is difficult in two-dimensional (2D) Cartesian sampling. In this study, the effect of random undersampling patterns on image reconstruction was clarified using phantom and in vivo MRI, and a sampling pattern relevant for 2D Cartesian sampling in CS-MRI is suggested. The precision of image restoration was estimated with various acceleration factors and extents for the fully sampled central region of k-space. The root-mean-square error, structural similarity index, and modulation transfer function were measured, and visual assessments were also performed. The undersampling pattern was shown to influence the precision of image restoration, and an optimal undersampling pattern should be used to improve image quality; therefore, we suggest that the ideal undersampling pattern in CS-MRI for 2D Cartesian sampling is one with a high extent for the fully sampled central region of k-space.

[Evaluation of the Image Registration Program for Portal Images Using CR and DRR Images in Radiation Therapy].

In this study, computer simulations and experiments were used to verify the accuracy of a two-dimensional image registration program (program) for portal images that we previously developed. The program used a computed radiography cassette system and digitally reconstructed radiography images as planning images for external beam radiation therapy. Using this program, we also investigated the reason two-dimensional automatic image registration images experienced large misregistration in clinical practice using commercial image registration systems. Mutual information and normalized mutual information were used as the registration criteria. To investigate the influence of image background with or without a region of interest (ROI), results of image registrations were compared. Parameters of image registration were defined as translation in the horizontal and vertical directions (x and y, respectively) and rotation (θ) around the axis perpendicular to the x-y plane. There was no significant difference in image registration arising from the difference between mutual information and normalized mutual information. Image registration was improved with a ROI. Regardless of the registration criteria, errors in image registration with a ROI in the experimental study were ≤1.2 mm in directions x and y and ≤1.0 degree in rotation θ. We found that image registration required setting up as close to the planned position as possible.

A Novel Mutation in NKX2-1 Shows Dominant-Negative Effects Only in the Presence of PAX8.

To date, >100 mutations in NKX2-1 have been described. Most NKX2-1 mutations are assumed to result in brain-lung-thyroid syndrome through haploinsufficiency, and only five NKX2-1 mutations with dominant-negative effects have been reported so far. In this case report, an additional patient with brain-lung-thyroid syndrome is reported, carrying a novel heterozygous mutation, c.533G>C (p.R178P), in the homeobox of NKX2-1. This mutation has been proven to be a dominant-negative mutation by an in vitro functional assay. Of note, the dominant-negative effect of R178P-NKX2-1 was shown only in the presence of PAX8.

Furan- and Thiophene-2-Carbonyl Amino Acid Derivatives Activate Hypoxia-Inducible Factor via Inhibition of Factor Inhibiting Hypoxia-Inducible Factor-1.

Induction of a series of anti-hypoxic proteins protects cells during exposure to hypoxic conditions. Hypoxia-inducible factor-α (HIF-α) is a major transcription factor that orchestrates this protective effect. To activate HIF exogenously, without exposing cells to hypoxic conditions, many small-molecule inhibitors targeting prolyl hydroxylase domain-containing protein have been developed. In addition, suppression of factor inhibiting HIF-1 (FIH-1) has also been shown to have the potential to activate HIF-α. However, few small-molecule inhibitors of FIH-1 have been developed. In this study, we synthesized a series of furan- and thiophene-2-carbonyl amino acid derivatives having the potential to inhibit FIH-1. The inhibitory activities of these compounds were evaluated in SK-N-BE(2)c cells by measuring HIF response element (HRE) promoter activity. Several furan- and thiophene-2-carbonyl amino acid derivatives inhibited FIH-1 based on correlations among the docking score of the FIH-1 active site, the chemical structure of the compounds, and biological HIF-α/HRE transcriptional activity.

[Numerical and Visual Evaluation of Compressed Sensing MRI Using 3D Cartesian Sampling].

We performed numerical and visual evaluation of compressed sensing MRI (CS-MRI) using 3D Cartesian sampling by numerical simulation. Three brain anatomical ROIs (white matter, gray matter, cerebrospinal fluid) of a T1-weighted image (T1WI), a T2-weighted image (T2WI) and a proton density-weighted image (PDWI) were used for numerical evaluation. Sampling ratio of the Cartesian grid was 30%. Reconstruction was performed by the projection onto convex sets (POCS) method with soft thresholding, subject to data fidelity constraints. In the absence of noise, RMSE of 3D-T1WI was 1.50, ant that of the 2D-T1WI of the transverse plane was in the range of 1.06 to 1.54; anatomical ROIs was in the range of 0.75 to 2.80; those of T2WI were 3.20, 2.77 to 3.06, and 1.81 to 4.51; those of PDWI were 1.69, 1.33 to 1.49, and 1.08 to 1.86. Visual evaluation was performed by three radiologists on the basis of three categories: artifact, anatomical structure, and tissue contrast. Average score of the visual evaluation indicated that anatomical structure and tissue contrast of CS images were equal to those of the original image, although a few artifacts were visible. If noise level was assumed to be 20 dB or less, anatomical structure and tissue contrast were not significantly degraded compared to noise-free CS images.

Novel compound heterozygous mutations identified by whole exome sequencing in a Japanese patient with geroderma osteodysplastica.

Geroderma osteodysplastica (GO) is a subtype of cutis laxa syndrome characterized by congenital wrinkly skin, a prematurely aged face, extremely short stature, and osteoporosis leading to recurrent fractures. GO exhibits an autosomal recessive inheritance pattern and is caused by loss-of-function mutations in GORAB, which encodes a protein important for Golgi-related transport. Using whole exome sequencing, we identified novel compound heterozygous nonsense mutations in the GORAB in a GO patient. The patient was a 14-year-old Japanese boy. Wrinkled skin and joint laxity were present at birth. At 1 year of age, he was clinically diagnosed with cutis laxa syndrome based on recurrent long bone fractures and clinical features, including wrinkled skin, joint laxity, and a distinctive face. He did not show retarded gross motor and cognitive development. At 11 years of age, he was treated with oral bisphosphonate and vitamin D owing to recurrent multiple spontaneous fractures of the vertebral and extremity bones associated with a low bone mineral density (BMD). Bisphosphonate treatment improved his BMD and fracture rate. Whole exome sequencing revealed two novel compound heterozygous nonsense mutations in the GORAB gene (p.Arg60* and p.Gln124*), and the diagnosis of GO was established. GO is a rare connective tissue disorder. Approximately 60 cases have been described to date, and this is the first report of a patient from Japan. Few studies have reported the effects of bisphosphonate treatment in GO patients with recurrent spontaneous fractures. Based on this case study, we hypothesize that oral bisphosphonate and vitamin D are effective and safe treatment options for the management of recurrent fractures in GO patients. It is important to establish a precise diagnosis of GO to prevent recurrent fractures and optimize treatment plans.

[Numerical and Visual Evaluations of Compressed Sensing MRI Using 2D Radial Sampling].

Two-dimensional radial MRI using compressed sensing (2D radial CS) enables incoherence sampling in k space unlike conventional Cartesian MRI, however 2D radial CS has not been sufficiently investigated. Numerical and visual evaluations of 2D radial CS were performed in this paper. Three brain anatomical ROIs (white matter, gray matter, cerebrospinal fluid) of a T1-weigthted image (T1WI), a T2-weighted image (T2WI) and a proton density-weighted image (PDWI) were used for the numerical evaluation. The Brainweb MRI Data Base was used for test images. Projection of 80 spokes with linear sampling of 256 pixels was used. Reconstruction was performed by minimizing the L1 norm of a transformed image using wavelet transform and spatial finite-differences (total variation), subject to data fidelity constraint. In the absence of noise, the root mean square error (RMSE) of T1WI was in the range of 3.75 to 5.05; that of the anatomical region of interests (ROIs) was in the range of 1.54 to 10.24; those of T2WI were 8.75 to 11.65 and 4.31 to 6.99; and those of PDWI were 3.44 to 4.46 and 1.34 to 3.09. Visual evaluation was performed by three radiologists on the basis of three categories: artifact, anatomical structure, and tissue contrast. Average percent scores of the visual evaluation were 96% for T1WI, 74-81% for T2WI, and 81-89% for PDWI.

[Numerical and Visual Evaluations of Compressed Sensing MRI Using 2D Cartesian Sampling].

This paper describes numerical and visual evaluations of compressed sensing MRI (CS-MRI) using 2D Cartesian sampling by numerical simulation. The BrainWeb MRI Data Base was used for test images. Three brain anatomical ROIs (white matter, gray matter, cerebrospinal fluid) of a T1-weighted image (T1WI), a T2-weighted image (T2WI) and a proton density-weighted image (PDWI) were used for the numerical evaluation. Sampling ratio was 50%. Reconstruction was performed by minimizing the L1 norm of a transformed image using wavelet transform and total variation, subject to data fidelity constraints. The conjugate gradient method was used in the minimization of the object function. In the absence of noise, the root mean square error (RMSE) of T1WI was in the range of 2.99 to 3.57; that of the anatomical region of interests (ROIs) was in the range of 1.77 to 8.53; those of T2WI were 4.72 to 5.65 and 3.28 to 5.54; and those of PDWI were 1.91 to 2.36 and 1.32 to 2.09. Visual evaluation was performed by three radiologists on the basis of three categories: artifact, anatomical structure, tissue contrast. CS image quality was nearly equal to that of the original image, although a few artifacts were visible. If the noise level was assumed to be 30 dB or less, T1-CS image and PD-CS images were not significantly degraded compared to noise-free images.