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Background: Airway stenting is an established procedure for treating oncological emergencies in patients with airway disorders. In patients with airway hemorrhage, respiratory conditions may worsen during stenting. Bronchial artery embolization (BAE) is useful to prevent bleeding from the bronchus. We aimed to evaluate the efficacy and safety of airway stenting after BAE in patients with malignant airway disorders., Methods: The medical records of all patients who underwent airway stenting following BAE at the National Hospital Organization Okayama Medical Center between 2016 and 2023 were retrospectively reviewed., Results: Thirteen procedures (11 silicone Y stents, one hybrid stent, and one self-expandable metallic stent) were performed. The median duration from BAE to airway stenting was one day (range: 1-5 days). Nine patients experienced tumor shrinkage, and none experienced severe bleeding after BAE during the stent procedure. No other major complications were associated with the stent placement. The median survival time after stenting was 169 days (range; 24-1086). No serious complications caused by BAE, such as spinal cord infarction, were observed., Conclusions: Airway stent placement was safely performed after BAE without severe bleeding or acute respiratory failure. BAE, followed by airway stenting, is useful., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Abstract: Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P < .001; 25.0% vs 89.5%; P < .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: To assess the utility of deep learning (DL)-based image reconstruction with the combination of compressed sensing (CS) denoising cycle by comparing images reconstructed by conventional CS-based method without DL in fat-suppressed (Fs)-contrast enhanced (CE) three-dimensional (3D) T1-weighted images (T1WIs) of the head and neck., Materials and Methods: We retrospectively analyzed the cases of 39 patients who had undergone head and neck Fs-CE 3D T1WI applying reconstructions based on conventional CS and CS augmented by DL, respectively. In the qualitative assessment, we evaluated overall image quality, visualization of anatomical structures, degree of artifacts, lesion conspicuity, and lesion edge sharpness based on a five-point system. In the quantitative assessment, we calculated the signal-to-noise ratios (SNRs) of the lesion and the posterior neck muscle and the contrast-to-noise ratio (CNR) between the lesion and the adjacent muscle., Results: For all items of the qualitative analysis, significantly higher scores were awarded to images with DL-based reconstruction (p < 0.001). In the quantitative analysis, DL-based reconstruction resulted in significantly higher values for both the SNR of lesions (p < 0.001) and posterior neck muscles (p < 0.001). Significantly higher CNRs were also observed in images with DL-based reconstruction (p < 0.001)., Conclusion: DL-based image reconstruction integrating into the CS-based denoising cycle offered superior image quality compared to the conventional CS method. This technique will be useful for the assessment of patients with head and neck disease., Competing Interests: Declaration of competing interest Kwon Jihun and Masami Yoneyama are currently employed by Philips Japan. The other authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare no competing of interest.

Visuospatial perception is often impaired in people with Alzheimer's disease (AD). Because visuospatial information is thought to be processed in the visual dorsal stream, it is believed that brain activities in the dorsal stream will be altered in AD patients. In this study, we investigated whether regional brain activity related to visuospatial perception were associated with AD progression markers. An optic-flow task, which activates the dorsal stream associated with visuospatial perception, was performed, and the brain activities evoked by the task were evaluated using magnetoencephalography (MEG). First, we evaluated the responses to optic-flow stimuli in 21 cognitively unimpaired participants and determined the regions of interest (ROIs) where optic-flow activities were activated. Task-related activations were observed in 14 cortical regions including the dorsal stream: the right and left medial ventral occipital cortex (MVOcC), lateral occipital cortex (LOcC), precuneus (Pcun), inferior parietal lobule (IPL), superior parietal lobule (SPL), posterior superior temporal sulcus (pSTS), and fusiform gyri (FuG). Next, we performed correlation analyses between task-related activity in each ROI and two AD progression markers, global amyloid burden and parahippocampal gyrus (PHG) volume, for 25 participants who underwent amyloid positron emission tomography (PET) scans. We found that the global amyloid burden was negatively correlated with task-related activity in the left MVOcC and right SPL [r = -0.488 (p = 0.013) and r = -0.421 (p = 0.038), respectively]. Furthermore, significant positive correlations were observed between PHG volume and task-related activity in both the left and right SPL [r = 0.500 (p = 0.011) and r = 0.549 (p = 0.005), respectively]. Since the SPL is known to be responsible for visuospatial perception, these results suggest that MEG neuronal activity of patients performing the optic-flow activity can detect changes in brain activity associated with visuospatial impairment related to AD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ST, KK, HM, YM and TA are employees of Ricoh Company, Ltd. The authors declare that no other competing interests exist. The other authors have no competing financial conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Organizing pneumonia (OP) is recognized as a nonspecific lung injury response characterized histopathologically by the presence of intra-alveolar buds of granulation tissue. Most OP patients show excellent responses to corticosteroids, but relapse is frequently seen when corticosteroids are tapered or discontinued. Although several factors associated with relapse have been reported in cryptogenic OP (COP), the clinical features and risk factors associated with relapse in connective tissue disease-associated OP (CTD-OP) have yet to be fully understood., Methods: We retrospectively reviewed data on 47 CTD-OP patients. We investigated the frequency of relapse and compared the clinical data between CTD-OP with and without relapse to clarify the risk factors for relapse., Results: Eleven (23.4%) CTD-OP patients had relapses of OP during the study. In the multivariate analysis, no CTD treatment at OP diagnosis [O.R. 11.920, p = 0.012] and partial remission after steroid treatment [O.R. 35.944, p = 0.045] were independent risk factors for relapse. Among rheumatoid arthritis-associated OP (RA-OP) patients, partial remission after steroid treatment [O.R. 16.151, p = 0.047] and age at OP diagnosis [O.R. 0.899, p = 0.045] were independent risk factors for relapse. Most of the relapsed OP patients who were on no medication at OP diagnosis later developed CTD., Conclusion: CTD-OP patients with residual disease on HRCT after treatment and who had OP diagnosis preceding CTD diagnosis were more likely to have an OP relapse. During the clinical course of relapsed OP patients, it is necessary to pay attention to the onset of CTD., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with regard to this work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: To develop a method for predicting amyloid positron emission tomography (PET) positivity based on multiple regression analysis of quantitative susceptibility mapping (QSM)., Materials and Methods: This prospective study included 39 patients with suspected dementia from four centers. QSM images were obtained through a 3-T, three-dimensional radiofrequency-spoiled gradient-echo sequence with multiple echoes. The cortical standard uptake value ratio (SUVR) was obtained using amyloid PET with 18 F-flutemetamol, and susceptibility in the brain regions was obtained using QSM. A multiple regression model to predict cortical SUVR was constructed based on susceptibilities in multiple brain regions, with the constraint that cortical SUVR and susceptibility were positively correlated. The discrimination performance of the Aβ-positive and Aβ-negative cohorts was evaluated based on the predicted SUVR using the area under the receiver operating characteristic curve (AUC) and Mann-Whitney U test., Results: The correlation coefficients between true and predicted SUVR were increased by incorporating the constraint, and the AUC to discriminate between the Aβ-positive and Aβ-negative cohorts reached to 0.79 (p < 0.01)., Conclusion: These preliminary results suggest that a QSM-based multiple regression model can predict amyloid PET positivity with fair accuracy., Competing Interests: Declaration of Competing Interest Tomoki Amemiya, Yasuo Kawata, Yoshitaka Bito, Toru Shirai, and Hisaaki Ochi are employees of FUJIFILM Healthcare Corporation. Kohsuke Kudo, Makoto Sasaki, and Masafumi Harada received research funding from FUJIFILM Healthcare Corporation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Twisted carotid bifurcation (TCB) is a well-known anatomical variation of the carotid bifurcation in patients undergoing carotid endarterectomy. However, few investigations of TCB have focused on patients without internal carotid artery (ICA) stenosis. This study was performed to analyze the characteristics of TCB in patients with ICA stenosis and other diverse pathologies., Methods: All conventional cerebral angiographies performed in our institute for any reason from January 2012 to December 2018 were reviewed. The patients were divided into two groups, the TCB group and the anatomically normal non-TCB group, and the basic characteristics of the groups were analyzed., Results: Both sides of the carotid bifurcation were clearly visualized in 457 patients. TCB was found in 89 of 457 patients (19.5%); among these 89 patients, 74 (83.1%) had TCB only on the right side, 8 (9.0%) only on the left side, and 7 (7.9%) bilaterally. TCB was found more frequently on the right than left [81 (17.7%) and 15 (3.3%), respectively, on each of the 457 sides (p < 0.0001)]. TCB was significantly more frequent in older patients (p = 0.02), female patients (p < 0.001), and patients with ICA stenosis or occlusion at the bifurcation (p = 0.005). The prevalence of TCB was 19.5%, and 84.4% of cases were on the right side in patients with diverse pathologies., Conclusions: Older patients, female patients, and patients with ICA stenosis or occlusion are more prone to have TCB., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Salmon nasal cartilage proteoglycan (PG) was orally administered to mice. The PG digest was recovered from the small intestine, and its sugar chain size and unsaturated disaccharide content were examined. The elution position of the PG digest following Sepharose CL-4B chromatography was consistent with that of actinase-digested PG prior to administration. The PG digest was incubated with chondroitinase ABC, which resulted in the elution pattern of the unsaturated disaccharides being identical to that of the degraded product of actinase-digested PG. The core protein of PG was digested in the mouse small intestine, but chondroitin sulfate, which is the sugar chain of PG, was not degraded at all. Then, the effects of chondroitin 4- and 6-sulfates on human colon cancer cells were examined. These chondroitin sulfates were found to suppress the expression of interleukin-6 induced by TNF-α. Overall, the chondroitin sulfate chain may act on the intestinal epithelium and suppress inflammation of the intestinal tract., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Acute exacerbation (AE) is a life-threatening clinical event that occurs during the clinical course of idiopathic pulmonary fibrosis (IPF). Several studies have reported that AE also occurs in interstitial lung disease (ILD) other than IPF. However, the incidence, clinical features, risk factors for AE, and major causes of death in antineutrophil cytoplasmic antibody (ANCA)-associated ILD (ANCA-ILD) patients have not been well established., Methods: We retrospectively reviewed the data of 54 ANCA-ILD patients and 304 IPF patients. We investigated the frequency of AE, post-AE prognoses, risk factors for AE, and major causes of death in ANCA-ILD patients. We also compared the data of ANCA-ILD with that of IPF., Results: Fourteen (25.9%) ANCA-ILD patients and 84 (27.6%) IPF patients developed AE. The median survival times (MSTs) after AE in ANCA-ILD and IPF patients were 35.5 and 60 days, respectively (p = 0.588, log-rank test). In a multivariate analysis, the percentage of predicted forced vital capacity (%FVC) [O.R. 0.750 (95% CI 0.570, 0.986), p < 0.01] and serum C-reactive protein (CRP) [O.R. 2.202 (95% CI 1.037, 4.674), p < 0.01] were independent risk factors for AE. AE was the most frequent cause of death in ANCA-ILD and IPF patients., Conclusion: ANCA-ILD patients could develop AE, and the frequency of AE in ANCA-ILD is similar to that in IPF. AE is the most frequent cause of death in ANCA-ILD patients. A low %FVC and a high serum CRP level were independent predictive factors for AE in ANCA-ILD. The prognosis after AE in ANCA-ILD was poor, as it was in IPF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: This study aims to identify and validate a gray matter volume network in patients with Alzheimer's disease (AD)., Methods: To identify a disease-related network, a principal component analysis-based algorithm, Scaled Subprofile Model, was applied to gray matter volume data derived from structural T1-weighted magnetic resonance imaging of the training sample that consisted of nine patients with AD (women, four; dementia, seven; mild cognitive impairment, two; age, 66.7 ± 8.8 [mean ± SD] years) with positive 18 F-flutemetamol amyloid positron emission tomography and eight age-matched healthy controls obtained on-site. The network expression scores were calculated by topographic profile rating in the validation sample obtained via the Open Access Series of Imaging Studies and comprised 12 patients with AD dementia (women, four; age, 70.0 ± 3.7 years) and 12 age-matched healthy controls., Results: A significant network from the training sample, for which subject expression differed between the groups (permutation test, P = 0.006; sensitivity and specificity, 100%; area under the curve, 1), was identified. This network was represented by the principal components 1, 2, and 3 and showed a relative decrease in the inferior parietal lobule including angular gyrus, inferior temporal gyrus, premotor cortex, amygdala, hippocampus, and precuneus. It significantly differed between the groups with a sensitivity, specificity, and area under the curve of 83%, 91%, and 0.85, respectively, in the validation sample (P = 0.003)., Conclusions: An AD-related gray matter volume network that captured relevant regions was identified in amyloid positron emission tomography-positive patients and validated in an independent sample., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Several studies have reported that acute exacerbation (AE), which occurs during the clinical course of idiopathic pulmonary fibrosis (IPF), also occurs in rheumatoid arthritis-associated interstitial lung disease (RA-ILD). However, the incidence, clinical features, and risk factors for AE, a major cause of death of RA-ILD patients, and the differences in clinical aspects of AE between RA-ILD and IPF have yet to be fully understood., Methods: We retrospectively reviewed data on 149 RA-ILD patients and 305 IPF patients. We investigated the frequency of AE and compared the clinical data between RA-ILD with and without AE to clarify the risk factor for AE. We also compared the post-AE prognosis and cause of death between RA-ILD and IPF patients., Results: Twenty-seven (18.1%) RA-ILD patients and 84 (27.5%) IPF patients developed AE. The median survival time (MST) after AE of RA-ILD and IPF was 277 days and 60 days, respectively (log rank, p = 0.038). In a multivariate analysis, hypoalbuminemia [odds ratio (O.R.) 0.090 (95%CI 0.011-0.733), p = 0.012] and % carbon monoxide diffusion capacity (%DL CO ) [O.R. 0.810 (95%CI 0.814-0.964), p < 0.01] were independent risk factors for AE. AE was the most frequent cause of death of RA-ILD and IPF., Conclusion: RA-ILD patients could develop AE, and AE was not uncommon in RA-ILD or IPF. %DL CO and hypoalbuminemia were predictive factors of AE in RA-ILD. The prognosis after AE of RA-ILD was significantly better than that of IPF. The most frequent cause of death in RA-ILD and IPF was AE., Competing Interests: Declaration of interest The authors declare no conflict of interest to this work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: Nonencapsulated Streptococcus pneumoniae (NESp) is emerging after the introduction of pneumococcal conjugate vaccines (PCVs). This study aimed to elucidate the genetic characteristics of penicillin-binding proteins (PBPs; PBP1a, 2b, and 2x) associated with penicillin nonsusceptibility in emergent NESp., Methods: A total of 71 NESp isolates that were identified in our previous study during the PCV era in Japan (2011-2019) were analyzed for their amino acid sequences of transpeptidase domain in PBP 1a, 2b, and 2x., Results: Overall, we identified 21 different PBP profiles (1a-2b-2x), all of which represent novel PBP profiles. The dominant PBP profiles were 13-16-ne1 (32.4%, n = 23), ne1-16-ne2 (14.1%, n = 10), and 13-7-ne4 (7.0%, n = 5) (novel PBP type was numbered with "ne" denoting "nonencapsulated"), accounting for 53.5% of all isolates. All isolates with the PBP profiles 13-16-ne1 and 13-7-ne4 and those having PBP1a type-13 and -131, PBP2b type-7, -ne1, and -ne2 showed nonsusceptibility to penicillin. A high degree of genetic diversity was found in PBP2x, with most of them (81.7%) being new types., Conclusions: Our current study identified the 21 novel PBP profiles and remarkable mutations in the PBPs, which may be potentially associated with penicillin nonsusceptibility in NESp., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: To assess the cervical magnetic resonance neurography (MRN) imaging quality obtained with compressed sensing and sensitivity-encoding (compressed SENSE; CS-SENSE) technique in comparison to that obtained with the conventional parallel imaging (i.e., SENSE) technique., Materials and Methods: Five healthy volunteers underwent a three-dimensional (3D) turbo spin-echo (TSE)-based cervical MRN examination using a 3.0 Tesla MR-unit. All MRN acquisitions were performed with CS-SENSE and conventional SENSE. We used four acceleration factors (4, 8, 16 and 32) in CS-SENSE. The image quality in MRN was evaluated by assessing the degree of cervical nerve depiction using the contrast ratio (CR) and contrast-noise ratio (CNR) between the cervical nerve and the background signal intensity and a visual scoring system (1: poor, 2: moderate, 3: good). In all of the CR, CNR and visual score, we calculated the ratio of the CS-SENSE-based MRN to that from SENSE-based MRN plus the 95% confidence intervals (CIs) of these ratios., Results: In the multiple comparison of MRN images with the control of conventional SENSE-based MRN, both the quantitative CR values and the visual score for the CS-SENSE factors of 16 and 32 were significantly lower, whereas the CS-SENSE factors of 4 and 8 showed a non-significant difference. In addition, the quantitative CNR values obtained with the CS-SENSE factors of 4 and 8 were significantly higher than that obtained with the conventional SENSE-based MRN while the CS-SENSE factor of 32 was significantly lower, in contrast, the CS-SENSE factors of 16 showed a non-significant difference. For CS-SENSE factors of 4 and 8, all ratios of the CS-SENSE-based MRN values for CR, CNR and visual scores to those from SENSE-based MRN were above 0.95., Conclusion: CS-SENSE-based MRN can accomplish fast scanning with sufficient image quality when using a high acceleration factor., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate the feasibility of kinetic analysis of cerebrospinal fluid (CSF) using 17 O-labeled water tracer. Four subjects (two idiopathic normal pressure hydrocephalus (iNPH) and two possible AD dementia patients) were prospectively included. Injectable formulation of 17 O-labeled water containing 10 mol% of H 2 17 O (PSO17), was intrathecally administered to the subjects with the lateral decubitus position between the 3rd and 4th lumbar vertebrae. MRI acquisitions were performed in four-time points, before PSO17 administration, 1, 8, and 24 h after PSO17 administration. The 3-dimensional fast spin echo sequence was used. After image registration for all four-time points data, polygonal regions of interest (ROIs) were set in the 14 regions to obtain the signal intensity of CSF. Each signal intensity within the ROI was converted to 17 O concentration [%]. The peak concentration at one hour after administration, the slope of concentration changes after PSO17 administration [%/s], and the root mean square error (RMSE) for evaluating the performance of a fitting were calculated. There was no significant difference in peak concentration between the iNPH and AD group. The slope in the AD group (-2.25 ± 1.62 × 10 -3 [%/h]) was significantly smaller than in the iNPH group (-1.21 ± 2.31 × 10 -3 [%/h]), which suggests the speed of CSF clearance in the iNPH group was slower than AD group. The RMSE indicating the fit to the concentration change in the AD group (4.86 ± 4.74 × 10 -3 ) was also significantly smaller than in the iNPH group (8.64 ± 7.56 × 10 -3 ). The kinetic evaluation of CSF using 17 O-labeled water was feasible, and this preliminary study suggests that the differentiation of iNPH and possible AD dementia can be achieved using this method., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cyanide is a powerful and rapidly acting poison. In Japan, cyanide poisoning is rare, and regular cyanide testing can be costly and time consuming. In contrast, alcohol analysis is routinely performed in most forensic laboratories. In this study, we attempted to develop a method for the simultaneous quantification of cyanide and alcohols in blood using headspace gas chromatography (HS-GC). As nitrogen-phosphorus detection (NPD) is more sensitive to hydrogen cyanide than mass spectrometry (MS), a Deans switch was used to switch the detectors during a single run. The separation provided by three analytical columns, PoraBOND Q, CP-Sil 5 CB, and HP-INNOWax, was investigated, and PoraBOND Q was selected. The use of HS-GC-MS/NPD with a Deans switch enabled the simple and simultaneous quantification of cyanide, ethanol, and 1-propanol. Eighteen other volatile compounds were detected in the SIM/scan mode of the MS., (Copyright © 2022 The Chartered Society of Forensic Sciences. Published by Elsevier B.V. All rights reserved.)

Background: End-diastolic opening of the pulmonary valve and subsequent antegrade diastolic pulmonary artery flow (ADPAF) reflect restrictive right ventricular (RV) physiology in children. However, this has attracted little attention in adults., Purpose: To clarify the clinical implications of ADPAF in adults., Methods and Results: The study population consisted of 23,049 consecutive adult patients who underwent echocardiography in our hospital between 2008 and 2015. ADPAF was found in 17 patients (0.07%). The simultaneous recording of RV and pulmonary artery pressures revealed marked elevation of RV diastolic pressure, which exceeded pulmonary artery pressure at the time of atrial contraction. These results suggested that ADPAF implies RV restriction. Based on the level of tricuspid annular plane systolic excursion (TAPSE), we classified these patients into two groups: reduced RV function (R-RVF) group (12 patients with TAPSE <17 mm) and preserved RV function (P-RVF) group (5 patients with TAPSE ≥17 mm). In the R-RVF group, four patients died, one patient underwent left ventricular assist device implantation, and two patients underwent unplanned hospitalization for heart failure during follow-up. The R-RVF group had poorer prognosis and higher mortality rate compared with the P-RVF group., Conclusions: ADPAF reflects RV restriction in adults. ADPAF suggests a less favorable prognosis in patients with R-RVF., (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: The emergence and spread of nonencapsulated Streptococcus pneumoniae (NESp) is a public health concern in the post-pneumococcal conjugate vaccine era. We analyzed the prevalence, molecular characteristics, and antimicrobial resistance of NESp responsible for noninvasive infections in northern Japan., Methods: NESp isolates were identified using molecular and phenotypical methods among 4463 S. pneumoniae isolates from noninvasive infection cases during 4 study periods between January 2011 and January 2019. NESp isolates were analyzed for antimicrobial susceptibility, genotype, and virulence-associated genes., Results: Seventy-one NESp isolates were identified (1.6% of total clinical isolates) and assigned to the null capsule clade (NCC)1 (pspK+) (94.4%) or NCC2 (aliC+/aliD+) (5.6%). The dominant sequence types (STs) were ST7502 (23.9%), ST4845 (19.7%), ST16214 (11.3%), ST11379 (9.9%), and ST7786 (7.0%). These 5 dominant STs and all 7 novel STs were related to the sporadic NESp lineage ST1106 or PMEN clone Denmark 14 -ST230. High non-susceptibility rates of NESp were observed for trimethoprim-sulfamethoxazole, erythromycin, and tetracycline (>92.9%), and multidrug resistance was observed in 88.7% of the NESp isolates, including all ST7502, ST4845, and ST11379 isolates., Conclusions: The study revealed that the dominant clonal groups of NESp were associated with a high prevalence of non-susceptibility to antimicrobials in northern Japan., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Since novel coronavirus disease (COVID-19) emerged, various clinical features of COVID-19 have been reported., Methods: We conducted a systematic review of published studies reporting the clinical features of COVID-19. Two investigators independently searched PubMed (December 2019-February 2020) for eligible articles. A meta-analysis was performed to measure the frequencies of clinical outcomes and symptoms of COVID-19. A stratified analysis was conducted according to the timeline of outbreak and exposure histories: Group I, most patients were exposed to the Hunan seafood wholesale market and lived in Wuhan, Hubei province; Group II, patients lived in Hubei province but were not directly exposed to the market; and Group III, patients lived outside Hubei., Results: Thirteen studies, all from China, were eligible. The estimated mortality rate among all studies was 2.12%, but that in Group I was 8.66%. The incidence of acute respiratory distress syndrome in Group I was 20.00%. Both fever and cough were major symptoms, and their frequencies were higher in Group I than in Groups II and III, while the frequency of diarrhea in Group I was lower than that in Group III. The estimated frequency of dyspnea in Group I was 37.18%, while those in Groups II and III were 16.95% and 7.03%, respectively., Conclusions: The trends in the clinical features of COVID-19 changed from December 2019 to February 2020. During this observation period, as the infection continued to spread, the clinical conditions for majority of patients became less severe with the changes in the route of transmission., Competing Interests: Conflict of Interest The authors have no conflicts of interest to declare., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate the utility of diffusion-weighted arterial spin labeling (DW-ASL) for detecting the progression of brain white matter lesions., Materials and Methods: A total of 492 regions of interest (ROIs) in 41 patients were prospectively analyzed. DW-ASL was performed using the diffusion gradient prepulse of five b-values (0, 25, 60, 102, and 189) before the ASL readout. We calculated the water exchange rate (K w ) with post-processing using the ASL signal information for each b-value. The cerebral blood flow (CBF) was also calculated using b0 images. Using the signal information in FLAIR (fluid-attenuated inversion recovery) images, we classified the severity of white matter lesions into three grades: non-lesion, moderate, and severe. In addition, the normal K w level was measured from DW-ASL data of 60 ROIs in five control subjects. The degree of variance of the K w values (K w-var ) was calculated by squaring the value of the difference between each K w value and the normal K w level. All patient's ROIs were divided into non-progressive and progressive white matter lesions by comparing the present FLAIR images with those obtained 2 years before this acquisition., Results: Compared to the non-progressive group, the progressive group had significantly lower CBF, significantly higher severity grades in FLAIR, and significantly greater K w-var values. In a receiver operator characteristic curve analysis, a high area under the curve (AUC) of 0.89 was obtained with the use of K w-var . In contrast, the AUCs of 0.59 for CBF and 0.72 for severity grades in FLAIR were obtained., Conclusions: The DW-ASL technique can be useful to detect the progression of brain white matter lesions. This technique will become a clinical tool for patients with various degrees of white matter lesions., Competing Interests: Declaration of competing interest The authors of this manuscript declare relationships with the following companies: “Masami Yoneyama “is currently employed by Philips Electronics Japan. The other authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Although increases in knee adduction moment (KAM) and angle (KAA) during gait are considered key pathologies that produce mechanical overload in the medial compartment of knee osteoarthritis (OA), it is unclear how these pathologies are related to subjective pain. The purpose of this study was to examine how subjective pain is related to such pathologies., Methods: Gait analysis was performed in 31 participants with medial knee OA. The knees were classified into three groups based on Kellgren-Lawrence (KL) grade: early (0 and 1), moderate (2), and severe (3 and 4). Subjective pain was evaluated by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index pain score. The knees were classified into low- and high-pain groups based on the pain score., Results: The WOMAC pain score did not correlate with either peak KAM or peak KAA. Although a positive correlation between static limb alignment and peak KAA was observed in the low-pain group, it was not observed in the high-pain group. Knee flexion angle at heel strike correlated negatively with the gap between static femorotibial angle and peak KAA in the high-pain group., Conclusions: Although a direct correlation between subjective pain and peak KAM or KAA was not observed, our results suggest a compensatory movement in the high-pain group of participants to reduce KAA increases in the early stance phase. Such movements would be one of the reasons why it is difficult to obtain a consistent relationship between subjective pain and load-related parameters., Competing Interests: Declaration of competing interest The author(s) declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. This study was financially supported by Teijin Limited., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Presence of unperfused regions containing cells under hypoxia and nutrient starvation; contributes to radioresistance in solid human tumors. We have previously reported that cultured cells; under nutrient starvation show resistance to ionizing radiation compare with cells under normal; condition, and that nutrient starvation increases ATM activity, which causes cellular resistance to; ionizing radiation (Murata et al., BBRC2018). For further investigation of molecular mechanisms; underlying radioresistance of cells under nutrient starvation, effects of nutrient starvation on activity; of DNA-PKcs have been investigated because both DNA-PKcs and ATM belong to the PIKK family; and are required for DNA DSBs repair. In addition to DNA-PKcs, effects of nutrient starvation on; activities of FoxO3a and its regulators Akt, MST1 and AMPK have been investigated because FoxO3a; mediates cellular responses to stress and is activated under nutrient starvation., Methods: A human glioblastoma cell line, T98G was used to examine the effects of nutrient starvation on activities and expression of DNA-PKcs, Akt, MST1, FoxO3a, NDR1, and AMPK. To elucidate; signal transduction pathways for FoxO3a activation under nutrient starvation, we examined effects of; specific inhibitors or siRNA for DNA-PKcs or Akt on activities and expression of MST1, FoxO3, NDR1, andAMPK., Results: Under nutrient starvation, phosphorylations of DNA-PKcs at Ser2056, Akt at Ser473, MST at Thr183, FoxO3a at Ser413, NDR1 at Ser281 and Thr282, and AMPK at Thr172 were increased, which suggests their activation. Nutrient starvation did not affect expression of DNA-PKcs, Akt, MST1, or NDR1, with decreased expression of FoxO3a and increased expression of AMPK. Inhibition; of DNA-PK suppressed phosphorylation of Akt under nutrient starvation. Inhibition of DNA-PK or; Akt suppressed phosphorylations of MST1, FoxO3a, and NDR1 under nutrient starvation, which; suggests DNA-PKcs and Akt activate MST1, FoxO3a, and NDR1. Inhibition of DNA-PK did not; suppress phosphorylation ofAMPK under nutrient starvation., Conclusion: Our data suggest that DN-PKcs is activated under nutrient starvation and activates AktMST1, FoxO3a, and NDR1., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Often, pleural effusion is noted at autopsy when the cause of death is drowning or diseases such as heart, renal and liver failure. Several studies have established a correlation between the concentrations of electrolytes in pleural effusion and the post-mortem interval (PMI) or those concentrations and drowning site. The present study aims to investigate the relationship between the amount of pleural effusion, concentrations of electrolytes and total protein in pleural effusion, by integrated interpretation using various factors such as the deceased's gender, age, cause of death, drowning site, PMI and body temperature. We included 40 cadavers (26 male, 14 female) with >20-mL pleural effusion, which were categorised into four groups as follows: freshwater drowning; brackish water drowning; seawater drowning (drowning group); and not drowning. An equation derived to assess the lung weight revealed that the drowning site affected the lung weight. An equation for the amount of pleural effusion in the drowning group for the first time revealed that the amount of pleural effusion was directly proportional to the PMI. Using an equation to assess the PMI, we could estimate the PMI within 13.0-13.2 h in cases with >20-mL pleural effusion. Despite a small number of cases in the present study, we attained exciting results from the integrated statistical analysis., (Copyright © 2019. Published by Elsevier Ltd.)

Background: The internal carotid artery is normally positioned posterolateral to the external carotid artery at the carotid bifurcation. An anatomic variation with the internal carotid artery positioned medial to the external carotid artery, the so-called twisted carotid bifurcation (TCB), is sometimes encountered in patients undergoing carotid endarterectomy (CEA). Little is known about the TCB or the implications for CEA., Objective: The present study investigated the demographics and surgical results of our patients with TCB who underwent CEA, and demonstrates the surgery in a video clip., Methods: Eleven of our series of 73 consecutive CEA patients (15.1%) had a TCB (TCB group). The basic surgical method was the same for both the TCB and non-TCB groups., Results: The patient demographics were almost identical between the 2 groups. No significant difference was observed in the degree of stenosis, the duration of operation, or the surgery-related complications between the 2 groups. However, 9 of 11 cases were right-sided in the TCB group; the only significant difference between the groups., Conclusions: CEA for TCB can be safely performed by extension of the normal procedure, but with more meticulous preoperative assessment and gentle maneuvers. The reason for the right-side dominance is still unknown. Further investigation is needed of this anatomic entity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We have developed a high-pressure electron spin resonance probe and successfully installed into the world's highest-field cryogen-free superconducting magnet having a maximum central field of 24.6 T. The high pressure of 2.5 GPa is achieved by the specially designed piston-cylinder pressure cell using THz-wave-transparent components. In the first application of this high-pressure high-field ESR system, we observed that the orthogonal dimer spin system SrCu 2 (BO 3 ) 2 undergoes a quantum phase transition from the dimer singlet ground to the plaquette singlet ground states., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The QuantiFERON-TB Gold Plus (QFT-Plus) was introduced in 2015 as a new generation of interferon-gamma release assays (IGRAs) designed to detect Mycobacterium tuberculosis infection (TB). Examination of its diagnostic accuracy is crucial before it is launched in Japan., Method: We examined 99 patients with laboratory-confirmed active TB (patients) and 117 healthy volunteers with no risk of TB infection (controls) at a medical center in Tokyo, Japan. Blood samples were collected from both the patients and controls and tested using three types of IGRAs: the QFT-Plus, the QuantiFERON-TB Gold In-Tube (QFT-GIT), and the T-SPOT.TB (T-SPOT). The sensitivity and specificity of each IGRA were examined and compared., Results: The sensitivity of the QFT-Plus was 98.9% (95% confidence interval [CI], 0.934-0.998) and similar to that of the QFT-GIT (97.9%; 95% CI, 0.929-0.998) and T-SPOT (96.9%; 95% CI, 0.914-0.994). The specificity of the QFT-Plus was the same as that of the QFT-GIT and T-SPOT (98.1%; 95% CI, 0.934-0.998). One patient with uncontrolled diabetes mellitus showed negative results on all three IGRAs., Conclusions: The QFT-Plus showed a high degree of agreement with the QFT-GIT and T-SPOT, with high sensitivity and specificity. Severe diabetes mellitus may influence the results of IGRAs. Larger studies are needed to validate the accuracy of the GFT-Plus and determine whether it can contribute as adjunctive method for the early diagnosis of active TB in Japan., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to identify baseline peripheral blood biomarkers associated with clinical outcome in patients with NSCLC treated with nivolumab., Methods: Univariable and multivariable analyses were performed retrospectively for 134 patients with advanced or recurrent NSCLC treated with nivolumab to evaluate the relationship between survival and peripheral blood parameters measured before treatment initiation, including absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count, and absolute eosinophil count (AEC), as well as serum C-reactive protein and lactate dehydrogenase levels. Progression-free survival, overall survival, and response rate were determined., Results: Among the variables selected by univariable analysis, a low ANC, high ALC, and high AEC were significantly and independently associated with both better progression-free survival (p = 0.001, p = 0.04, and p = 0.02, respectively) and better overall survival (p = 0.03, p = 0.03, and p = 0.003, respectively) in multivariable analysis. Categorization of patients according to the number of favorable factors revealed that those with only one factor had a significantly worse outcome than those with two or three factors. A similar trend was apparent for patients with a programmed death 1 ligand tumor proportion score less than 50%, whereas all patients with a score of 50% or higher had at least two favorable factors., Conclusions: A baseline signature of a low ANC, high ALC, and high AEC was associated with a better outcome of nivolumab treatment, with the number of favorable factors identifying subgroups of patients differing in survival and response rate., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: To establish an optimized sequence design for fast acceleration of arterial spin labeling (ASL)-based time-resolved magnetic resonance angiography (MRA) by acquisition of control and labeled images in the same shot (fast ACTRESS) and a scan time of <1min, for the evaluation of intracranial vessels., Materials and Methods: Ten healthy volunteers with no unilateral symptomatic arterial stenosis, who underwent 3-tesla MRI, were investigated. Imaging parameters for the fast ACTRESS sequence were set with an acquisition time of 45s. During post-processing, the first phase in the multi-phase readout, which was defined as the control image, was subtracted from each of the other phases. Thus, four-dimensional (4D)-MRA images of each phase were obtained. The maximum intensity projection was used for the reconstruction of 4D-MRA images and time-to-signal intensity curves (TIC) obtained for each vessel. The area under the curve (AUC), peak time, and maximum signal intensity were obtained from TIC. The different labeling types were broadly divided into six groups: L1, L2, L3, L4, L5, and L6 according to the actual number of labeling pulse., Results: A total of 5040 regions of interest were evaluated. The peak SI of L3, except for those in the A2 segment of the anterior cerebral artery, was significantly higher than that of L5. However, there were no significant differences between L4 and L5. Although the AUCs of L3 and L4 for anterior circulation were relatively higher than that of the other subgroups, the AUC of L3 was significantly higher than that of L4., Conclusion: The fast ACTRESS was optimized and indicated that the labeling type of L3 was the most appropriate for the well visualization of intracranial arteries. The fast ACTRESS sequence was useful to acquire well-delineated images of intracranial vessels in ˂1min., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Serotonin (5-hydroxytryptamine, 5-HT) plays an important role in milk volume homeostasis in the mammary gland during lactation; 5-HT in milk may also affect infant development. However, there are few reports on 5-HT concentrations in human breast milk. To address this issue, we developed a simple method based on high-performance liquid chromatography with fluorescence detection (HPLC-FD) for measuring 5-HT concentrations in human breast milk. Breast milk samples were provided by four healthy Japanese women. Calibration curves for 5-HT in each sample were prepared with the standard addition method between 5 and 1000 ng/ml, and all had correlation coefficients >0.999. The recovery of 5-HT was 96.1%-101.0%, with a coefficient of variation of 3.39%-8.62%. The range of 5-HT concentrations estimated from the calibration curves was 11.1-51.1 ng/ml. Thus, the HPLC-FD method described here can effectively extract 5-HT from human breast milk with high reproducibility., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: We assessed advanced fitting models of diffusion weighted imaging (DWI) in head/neck squamous cell carcinoma (HNSCC) patients to determine the best goodness of fit and correlations among diffusion parameters. We compared these results with those of dynamic contrast-enhanced (DCE) perfusion parameters., Materials and Methods: We retrospectively evaluated 32 HNSCC patients (12 sinonasal, 20 pharynx/oral cavity). The DWI acquisition used single-shot spin-echo echo-planar imaging (EPI) with 12 b-values (0-2000). We calculated 14 DWI parameters using mono-exponential, bi-exponential, and tri-exponential models, stretched exponential model (SEM) and diffusion kurtosis imaging (DKI) models. We compared each model's goodness of fit using the residual sum of squares (RSS), Akaike Information Criterion (AIC) and Bayesian information criterion (BIC) value. We determined the correlation between each pair of DWI parameters and between each DWI parameter and DCE perfusion parameter., Results: The tri-exponential fit's RSS, AIC and BIC values were significantly smaller than those for bi-exponential fit. The RSS, AIC and BIC values of the SEM fit and DKI fit were significantly smaller than mono-exponential model. Significant correlations were observed in 30 pairs (sinonasal cavity) and 31 (sinonasal cavity group) among 91 DWI parameter combinations. Significant correlations were also observed in nine pairs (both sinonasal cavity and pharynx/oral cavity group) among 64 DWI/DCE perfusion parameter pairs, in particular, high positive correlations between the tri-exponential model's intermediate diffusion fraction (f 2 ) and the volume of the extracellular extravascular space per unit volume of tissue (v e ) were observed in both patient groups., Conclusion: We identified several correlations between DWI parameters by advanced fitting models and correlations between DWI and DCE parameters. These will help determine HNSCC patients' detailed tissue structures., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Macrophages are key players in the innate immune response. Turnover of phosphoinositides (PI), particularly phosphatidylinositol 4,5 bisphosphate (PI(4,5)P2), has been implicated in macrophage functions such as toll-like receptor (TLR)-mediated cytokine production and phagocytosis. However, PI metabolizing enzymes responsible for macrophage functions are not well defined. The phospholipase C (PLC) family of enzymes is critical in PI(4,5)P2 turnover. In this study, we investigated the role of PLCδ1, a prototype PLC, in macrophages on the expression of inflammation-associated genes and phagocytosis. Lipopolysaccharides (LPS) signal through TLR4 to produce proinflammatory cytokines such as interleukin (IL)-1β. LPS stimulation of both RAW264.7 murine macrophages and murine bone marrow-derived macrophages resulted in lower PLCδ1 mRNA and protein expression levels, compared to that in the control. Using chemical inhibitor compounds, we demonstrated that the up-regulation of p38 MAPK activity led to down-regulation of PLCδ1 mRNA expression in macrophages. PLCδ1 reduction by RNAi or gene deletion resulted in greater LPS-induced IL-1β expression than that observed in the control siRNA-treated cells, without increasing TLR4 cell surface expression. PLCδ1 also negatively regulated LPS-induced cell spreading. Analysis of Fcγ receptor-mediated phagocytosis demonstrated an increased phagocytosis index after PLCδ1 knockdown in RAW264.7 cells. Conversely, overexpression of PLCδ1 reduced phagocytosis whereas catalytic inactive PLCδ1 had no effect. Altered levels of PLCδ1 affected the binding of opsonized latex beads with cells, rather than the phagocytic activity. Taken together, the data suggest that PLCδ1 negatively regulates LPS-induced production of IL-1β and Fcγ receptor-mediated phagocytosis in macrophages., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Serotonin (5-hydroxytriptamine, 5-HT) has an important role in milk volume homeostasis within the mammary gland during lactation. We have previously shown that the expression of β-casein, a differentiation marker in mammary epithelial cells, is suppressed via 5-HT-mediated inhibition of signal transduction and activator of transcription 5 (STAT5) phosphorylation in the human mammary epithelial MCF-12A cell line. In addition, the reduction of β-casein in turn was associated with 5-HT7 receptor expression in the cells. The objective of this study was to determine the mechanisms underlying the 5-HT-mediated suppression of β-casein and STAT5 phosphorylation. The β-casein level and phosphorylated STAT5 (pSTAT5)/STAT5 ratio in the cells co-treated with 5-HT and a protein kinase A (PKA) inhibitor (KT5720) were significantly higher than those of cells treated with 5-HT alone. Exposure to 100 μM db-cAMP for 6 h significantly decreased the protein levels of β-casein and pSTAT5 and the pSTAT5/STAT5 ratio, and significantly increased PTP1B protein levels. In the cells co-treated with 5-HT and an extracellular signal-regulated kinase1/2 (ERK) inhibitor (FR180294) or Akt inhibitor (124005), the β-casein level and pSTAT5/STAT5 ratio were equal to those of cells treated with 5-HT alone. Treatment with 5-HT significantly induced PTP1B protein levels, whereas its increase was inhibited by KT5720. In addition, the PTP1B inhibitor sc-222227 increased the expression levels of β-casein and the pSTAT5/STAT5 ratio. Our observations indicate that PTP1B directly regulates STAT5 phosphorylation and that its activation via the cAMP/PKA pathway downstream of the 5-HT7 receptor is involved in the suppression of β-casein expression in MCF-12A cells., (Copyright © 2016 Elsevier Inc. All rights reserved.)

During pregnancy, both ischemic reperfusion and bacterial agent LPS are known risk factors for fetal brain damage. However, there is a lack of evidence to explain whether vaginal LPS affects the fetus response to ischemic reperfusion. Here we reported that there was more than 2 folds higher vulnerability of fetal brain hemorrhage response to ischemic reperfusion when mother mouse was treated with vaginal LPS. As our previously reported, ischemic reperfusion induces P53-dependent fetal brain damage was based on a molecular mechanism: the transcriptional pattern was changed from HIF-1alpha-dependent to P53-dependent immediately. In the present work, only with vaginal LPS precondition, phosphorylation of activated transcriptional factor (ATF) 2 at Thr71 appeared in response to ischemic reperfusion. Moreover, this phosphorylation was completely blocked by pre-treatment with a P53 inhibitor, pifithrin-α. We concluded that vaginal LPS precondition trigged the p53-dependent phosphorylation of ATF2 in response to ischemic reperfusion, which played an important role of increasing vulnerability to hemorrhage in fetus., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Arterial spin labeling (ASL) methods have been widely used for evaluation of cerebral blood flow (CBF) by magnetic resonance imaging. However, ASL methods require setting of the post labeling delay (PLD) time for obtaining images. As the hemodynamic status cannot be estimated in each patient, the resultant quantitative values of blood flow may not be accurate. The multi-phase pseudo continuous arterial spin labeling (pCASL) method can be used to obtain images at various time-points. The purpose of this study was to create the transit-time maps for correcting the delayed blood flow and evaluate CBF using the transit-time maps obtained by the multi-phase pCASL method., Materials and Methods: Twelve patients who underwent both 3.0-tesla magnetic resonance imaging (MRI) and single photon emission computed tomography with iodine-123-N-isopropyl-p-iodoamphetamine (123I-IMP) were investigated. This study was approved by the institutional review board of our institution. MRI acquisitions included PLD time-fixed (1525ms) and multi-phase pCASL sequences. The transit-time maps were calculated from multi-phase pCASL images by software. The transit-time maps were applied to PLD-fixed pCASL images pixel by pixel, for calculating the CBF value corrected for peak blood transit time. Regions of interest were drawn on the brain. IMP-CBF, ASL-CBF (default and corrected) and transit time were measured for each segment., Results: Twelve patients and 264 segments were investigated. The mean IMP-CBF, ASL-CBF (default, corrected) and transit time were 28.4, 23.0, 29.6, [ml/min/100g] and 1977.5 [ms], respectively. There were no significant differences between IMP-CBF and ASL-CBF (corrected)., Conclusion: CBF values can be corrected by using the transit-time maps obtained using the multi-phase pCASL method., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Compared to two-dimensional (2D) monolayer cultures, three-dimensional (3D) tumor cell culture models are thought to be structurally more similar to the in vivo tumor microenvironment. We investigated the regulation of the expression of genes encoding the drug-metabolizing enzymes CYP1A1 and CYP1A2 in 3D spheroids comprised of cells of the human hepatocellular carcinoma cell JHH1, Huh7, and HepG2. Expression of CYP1A1 and CYP1A2 in the spheroids was higher than that in 2D cultured cells. Expression of CYP1A1 and CYP1A2 is regulated by aryl hydrocarbon receptor (AhR) in 2D cultured cells. Knockdown of AhR in spheroids suppressed CYP1A1 expression; however, CYP1A2 expression levels remained unchanged. Moreover, we found that pregnane X receptor (PXR) likely regulated CYP1A2 expression in JHH1, HepG2, and Huh7 spheroids and that CYP1A1 expression in JHH1 and Huh7 3D spheroids is regulated not only by AhR but also by PXR. It is well known that gene expression levels are different between 3D spheroids and 2D monolayer cultured cells, and our results indicate that the regulation of gene expression also varies between the two culture conditions. Taken together, these results underlie a novel finding regarding the regulation of drug-metabolizing enzyme expression in liver cancer cells growing as 3D spheroids., (Copyright © 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Background: The clinical implementation of genomic profiling for lung cancer with high-throughput, multiplex tests is warranted to allow prioritization of appropriate therapies for individual patients. We have now applied such testing to detect actionable mutations that may inform treatment recommendations in lung cancer., Patients and Methods: We prospectively applied amplicon sequencing panels that cover both mutational hotspots in 22 genes related to lung and colon tumorigenesis as well as 72 major variants of ALK, RET, ROS1, and NTRK1 fusion transcripts. We then determined the proportion of patients who received genotype-directed therapy and their overall survival (OS)., Results: Tumor specimens from 110 patients with lung cancer recruited between July 2013 and March 2015 were analyzed. The most common genetic alterations were TP53 mutations in 42 patients, followed by EGFR mutations in 25, STK11 mutations in 12, and KRAS mutations in 10. Potentially actionable mutations were identified in 44 patients including 50% of those with adenocarcinoma and 14% of those with squamous cell carcinoma. The OS of patients with advanced or recurrent cancer who had an actionable mutation and received targeted therapy (median OS not achieved) was significantly longer than that of those with no mutation (18.1 months, P = 0.041) or of those with a mutation not so treated (6.1 months, P = 0.0027)., Conclusions: Multiplex genomic testing was performed on formalin-fixed, paraffin-embedded tumor specimens with a success rate of ≥95%. Such testing can assist physicians in matching patients with approved or experimental targeted treatments., Clinical Trial Registration: The University Medical Hospital Information Network (UMIN) Clinical Trials Registry under the identifier UMIN000014782., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In Japan, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced to the nation's routine immunization program in April 2013 and was replaced by the 13-valent pneumococcal conjugate vaccine (PCV13) in November 2013. Distribution of serotypes and macrolide resistance genotypes was investigated for a total of 1097 (975 children, 122 adults) and 960 (873 children, 87 adults) clinical isolates of Streptococcus pneumoniae from noninvasive infections in Hokkaido (northern main island of Japan) in the routine immunization periods for PCV7 and PCV13 (April-October 2013 and November 2013-November 2014, respectively). Serotype was determined by sequential multiplex PCR and additional genetic analyses. Macrolide resistance genes erm(B) and mef(A/E) were detected by multiplex PCR. Although the most prevalent serotypes in children were 23A and 6C in the PCV7 period, after replacement with PCV13, 19A became the most common, followed by 6C, 15A and 23A. Among adults, serotype 3 was consistently the most frequent throughout the study periods. Compared with values from the pre-PCV7 routine immunization period, PCV7 serotypes decreased from 48.3 to 3.3% in the PCV13 period among children, while the rates of non-PCV13 serotypes (particularly 15A, 23A, 11A, 10A and 35B) increased from 39.7 to 75.1% (p < 0.001). In the PCV13 period, erm(B), mef(A/E) and both of these genes were detected in 75.8, 31.6 and 11.3% of all isolates, respectively. Serotype 19A accounted for 76.9% of the isolates with both the macrolide resistance genes, and emerging non-PCV13 serotypes 15A, 15C and 23A mostly harboured erm(B).

Purpose: To investigate the correlation between perfusion-related parameters obtained with intravoxel incoherent motion (IVIM) and classical perfusion parameters obtained with dynamic contrast-enhanced (DCE) magnetic resonance imaging in patients with head and neck squamous cell carcinoma (HNSCC), and to compare direct and asymptotic fitting, the pixel-by-pixel approach, and a region of interest (ROI)-based approach respectively for IVIM parameter calculation., Materials and Methods: Seventeen patients with HNSCC were included in this retrospective study. All magnetic resonance (MR) scanning was performed using a 3T MR unit. Acquisition of IVIM was performed using single-shot spin-echo echo-planar imaging with three orthogonal gradients with 12 b-values (0, 10, 20, 30, 50, 80, 100, 200, 400, 800, 1000, and 2000). Perfusion-related parameters of perfusion fraction 'f' and the pseudo-diffusion coefficient 'D*' were calculated from IVIM data by using least square fitting with the two fitting methods of direct and asymptotic fitting, respectively. DCE perfusion was performed in a total of 64 dynamic phases with a 3.2-s phase interval. The two-compartment exchange model was used for the quantification of tumor blood volume (TBV) and tumor blood flow (TBF). Each tumor was delineated with a polygonal ROI for the calculation of f, f∙D* performed using both the pixel-by-pixel approach and the ROI-based approach. In the pixel-by-pixel approach, after fitting each pixel to obtain f, f∙D* maps, the mean value in the delineated ROI on these maps was calculated. In the ROI-based approach, the mean value of signal intensity was calculated within the ROI for each b-value in IVIM images, and then fitting was performed using these values. Correlations between f in a total of four combinations (direct or asymptotic fitting and pixel-by-pixel or ROI-based approach) and TBV were respectively analyzed using Pearson's correlation coefficients. Correlations between f∙D* and TBF were also similarly analyzed., Results: In all combinations of f and TBV, f∙D* and TBF, there was a significant correlation. In the comparison of f and TBV, a moderate correlation was observed only between f obtained by direct fitting with the pixel-by-pixel approach, whereas a good correlation was observed in the comparisons using the other three combinations. In the comparison of f∙D* and TBF, a good correlation was observed only with f∙D* obtained by asymptotic fitting with the ROI-based approach. In contrast, moderate correlations were observed in the comparisons using the other three combinations., Conclusion: IVIM was found to be feasible for the analysis of perfusion-related parameters in patients with HNSCC. Especially, the combination of asymptotic fitting with the ROI-based approach was better correlated with DCE perfusion., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Human herpesvirus-6 (HHV-6) is a cause of exanthema subitum and, sometimes, of febrile seizures. However, the pathogenesis of febrile seizures associated with HHV-6 infection remains unclear. We investigated serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels in infants with HHV-6 infection. Serum levels of both MMP-9 and TIMP-1 were significantly higher in infants with HHV-6 infection than in controls. Serum TIMP-1 levels were significantly higher in infants with febrile seizures than in infants without febrile seizures. Serum MMP-9/TIMP-1 ratios were significantly lower in infants with febrile seizures than in infants without febrile seizures. In infants with HHV-6 infection, positive correlations were found between serum MMP-9 concentrations and the white blood cells (WBC) count, and between serum TIMP-1 concentrations and the WBC count. Positive correlations were also found between the amounts of HHV-6 DNA and the ratios of MMP-9/TIMP-1 in infants with HHV-6 infection. In conclusion, we suggest that high serum levels of MMP-9 and TIMP-1 in infants with HHV-6 infection may induce dysfunction of the blood-brain barrier, eventually causing febrile seizures., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection., Methods: We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling., Findings: We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each day's delay)., Interpretation: We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection., Funding: F Hoffmann-La Roche., (Copyright © 2014 Elsevier Ltd. All rights reserved.)