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We develop a computational approach for ultrafast nano-optics based on first-principles time-dependent density functional theory. Solving Maxwell equations for light propagation and time-dependent Kohn-Sham equation for electron dynamics simultaneously, intense and ultrashort laser pulse interaction with a dielectric nano-structure is described taking full account of nonlinear effects. As an illustrative example, irradiation of a pulsed light on silicon nano-sphere system is presented.

Objectives: To develop a simple postoperative risk stratification based on histopathologic findings from radical prostatectomy specimens., Methods: This study included 3 cohorts of patients with a preoperative diagnosis of clinically localized prostate cancer: 1 derivation cohort (n = 432) and 2 validation cohorts (n = 506 and n = 720). First, a postoperative risk stratification model was developed in the derivation cohort using the factors extraprostatic extension, surgical margin status, seminal vesicle invasion, and lymph node involvement. Each of the first 3 factors was assigned 0 or 1 point for negative or positive results, respectively, and the sum of the points, ranging from 0 to 3, was scored. pN1 was not scored but was analyzed separately. Validation cohorts were then used to evaluate the predictive accuracy of the model. Additionally, we compared the model with the Cancer of the Prostate Risk Assessment (CAPRA) score., Results: Because the log-rank test showed no statistically significant differences between scores 1 vs 2 or score 3 vs pN1 in the derivation cohort, the following 3-level risk stratification was created: low risk (score 0), intermediate risk (score 1-2), and high risk (score 3 or pN1). There were statistically significant differences in recurrence-free survival between any of 2 groups of 3-level risk stratification. This model similarly worked in both validation cohorts. The C indexes for the model were higher than those for the CAPRA score., Conclusions: This simple postoperative risk stratification model, based on radical prostatectomy findings, has a prognostic impact that has been validated in a multicenter population., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

We describe a method for the synthesis of various 2-silyloxy-2-norbornen-7-ones by exploiting the specific reactivity of the 1,4-bis(silyloxy)-1,3-cyclopentadiene framework, which is generated by the silylation of a 2,2-disubstituted-1,3-cyclopentanedione bearing a picolinoyloxy group at the 2' position of its C-2 side chain. The release of the acyloxy group during the reaction generates carbocations that are then attacked by silyloxy-substituted carbons in the 1,4-bis(silyloxy)-1,3-cyclopentadiene moiety skeleton, forming a 4,5-cis-fused ring skeleton. Skeletal rearrangement of the bicyclic core results in the formation of the corresponding 2-silyloxy-2-norbornen-7-one. This novel transformation of 1,3-cyclopentanedione moieties can be used to synthesise other cyclopentenone-fused bicyclic frameworks., (© 2024 Wiley-VCH GmbH.)

Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Double somatic mutations in CTNNB1 and GNA11/Q have recently been identified in a small subset of aldosterone-producing adenomas (APAs). As a possible pathogenesis of APA due to these mutations, an association with pregnancy, menopause, or puberty has been proposed. However, because of its rarity, characteristics of APA with these mutations have not been well characterized. A 46-year-old Japanese woman presented with hypertension and hypokalemia. She had two pregnancies in the past but had no history of pregnancy-induced hypertension. She had regular menstrual cycle at presentation and was diagnosed as having primary aldosteronism after endocrinologic examinations. Computed tomography revealed a 2 cm right adrenal mass. Adrenal venous sampling demonstrated excess aldosterone production from the right adrenal gland. She underwent right laparoscopic adrenalectomy. The resected right adrenal tumor was histologically diagnosed as adrenocortical adenoma and subsequent immunohistochemistry (IHC) revealed diffuse immunoreactivity of aldosterone synthase (CYP11B2) and visinin like 1, a marker of the zona glomerulosa (ZG), whereas 11β-hydroxylase, a steroidogenic enzyme for cortisol biosynthesis, was mostly negative. CYP11B2 IHC-guided targeted next-generation sequencing identified somatic CTNNB1 (p.D32Y) and GNA11 (p.Q209H) mutations. Immunofluorescence staining of the tumor also revealed the presence of activated β-catenin, consistent with features of the normal ZG. The expression patterns of steroidogenic enzymes and related proteins indicated ZG features of the tumor cells. PA was clinically and biochemically cured after surgery. In conclusion, our study indicated that CTNNB1 and GNA11 -mutated APA has characteristics of the ZG. The disease could occur in adults with no clear association with pregnancy or menopause., Competing Interests: KN received a research grant from AstraZeneca, which is unrelated to the current work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nanba, Blinder, Udager, Hirokawa, Miura, Okuno, Moriyoshi, Yamazaki, Sasano, Yasoda, Satoh-Asahara, Rainey and Tagami.)

Radical cations of dimeric clusters of carbon dioxide/disulfide, [(CX 2 ) 2 ] +• (X = O and S), form strong intracluster bonds through charge resonance (CR) interactions. We herein performed electronic photodissociation spectroscopy of [(CX 2 ) 2 ] +• while regulating the temperature under ambient and cryogenic conditions using a quadrupole ion trap. Both ions exhibited broad band absorption in the near-infrared-visible light region; it is called the "CR band", as a measure of the strength of the CR interaction. Strikingly, this band underwent a noticeable blue shift upon cryogenic cooling for [(CS 2 ) 2 ] +• while not for [(CO 2 ) 2 ] +• . On the basis of quantum chemical calculations with a coupled cluster method, the band shift was attributed to the variations in the relative population of two energetically close conformers found for [(CS 2 ) 2 ] +• . This study highlights a strong correlation between CR interactions and conformation of the radical dimer cations, demonstrating the exceptional significance of cryogenic cooling in the chemistry of ionic molecular clusters.

Mutations in the tumor suppressor TP53 cause cancer and impart poor chemotherapeutic responses, reportedly through loss-of-function, dominant-negative effects and gain-of-function (GOF) activities. The relative contributions of these attributes is unknown. We found that removal of 12 different TP53 mutants with reported GOFs by CRISPR/Cas9 did not impact proliferation and response to chemotherapeutics of 15 human cancer cell lines and colon cancer-derived organoids in culture. Moreover, removal of mutant TP53/TRP53 did not impair growth or metastasis of human cancers in immune-deficient mice or growth of murine cancers in immune-competent mice. DepMap mining revealed that removal of 158 different TP53 mutants had no impact on the growth of 391 human cancer cell lines. In contrast, CRISPR-mediated restoration of wild-type TP53 extinguished the growth of human cancer cells in vitro. These findings demonstrate that LOF but not GOF effects of mutant TP53/TRP53 are critical to sustain expansion of many tumor types., Significance: This study provides evidence that removal of mutant TP53, thereby deleting its reported GOF activities, does not impact the survival, proliferation, metastasis, or chemotherapy responses of cancer cells. Thus, approaches that abrogate expression of mutant TP53 or target its reported GOF activities are unlikely to exert therapeutic impact in cancer. See related commentary by Lane, p. 211 . This article is featured in Selected Articles from This Issue, p. 201., (©2023 The Authors; Published by the American Association for Cancer Research.)

Spinal dural arteriovenous fistula (SDAVF) is among the most common arterial shunt diseases typically found in middle aged or older men. Herein, we aimed to clarify the reasons for misdiagnoses and delayed diagnoses of SDAVF, determine how these affect prognoses, and establish how they can be prevented. We conducted a PubMed/MEDLINE literature search using "spinal dural arteriovenous fistula", "delayed diagnosis", "late diagnosis", and "misdiagnosis" terms. We identified 18 articles, including 965 SDAVF cases. Patients were predominantly males (71.8-100.0%) (mean age: 53.5-71.0 years). Misdiagnoses rates varied (17.5-100.0%) and encompassed many conditions. The mean time between early manifestations and confirmed diagnosis was approximately 10-15 months and from the first radiologic image revealing dural arteriovenous fistula (DAVF) features to diagnosis was 9.2-20.7 months. Posttreatment outcomes showed a significant improvement in motor functions, gait, and micturition, particularly in patients exhibiting preoperative symptoms over a short period. SDAVF is frequently misdiagnosed or subject to delayed diagnosis, causing poor clinical outcomes. SDAVF symptoms including progressive lower-limb weakness, paresthesia, and vesicorectal dysfunction are indications for spinal magnetic resonance imaging with subsequent spinal angiography, wherein DAVF is evidenced by extensive T2 hyperintensity and flow-void abnormalities. We reported a representative case with delayed diagnosis.

Background: Adjustable shunt valves that have been developed for managing hydrocephalus rely on intrinsically magnetic components ; thus, artifacts with these valves on magnetic resonance imaging (MRI) are inevitable. No studies on valve-induced artifacts in lumboperitoneal shunt (LPS) surgery have been published. Therefore, this study aimed to evaluate valve-induced artifacts in LPS., Methods: We retrospectively reviewed all MRIs obtained between January 2023 and June 2023 in patients with an implanted Codman CERTAS Plus adjustable shunt valve (Integra Life Sciences, Princeton, New Jersey, USA). The valve was placed <1 cm subcutaneously on the paravertebral spinal muscle of the back, with its long axis perpendicular to the body axis. The scans were performed using a Toshiba Medical Systems 1.5 Tesla scanner. The in-plane artifact sizes were assessed as the maximum distance of the artifact from the expected region of the back., Results: All spinal structures or spinal cords can be recognized, even with valve-induced artifacts. The median maximum valve-induced artifact distance on T1-weighted axial imaging was 25.63 mm (mean, 25.98 mm ; range, 22.24-30.94 mm). The median maximum valve-induced artifact distance on T2-weighted axial imaging was 25.56 mm (mean, 26.27 mm ; range, 21.83-29.53 mm)., Conclusion: LPS surgery with adjustable valve implantation on paravertebral muscles did not cause valve-induced artifacts in the spine and spinal cord. We considered that LPS could simplify the postoperative care of these patients. J. Med. Invest. 71 : 154-157, February, 2024.

Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated impressive success in the treatment of patients with hematologic tumors yet achieved very limited efficacy for solid tumors due to hurdles unique to solid tumors. It is also noted that the tumor microenvironment composition varies between tumor type, which again imposes unique set of hurdles in each solid tumor. Therefore, elucidation of individual hurdles is key to achieving successful CAR-T therapy for solid tumors. In the present study, we employed an orthotopic human PDAC xenograft model, in which quantitative, spatial and functional dynamics of CAR-T cells in tumor tissues were analyzed to obtain insights into ways of overcoming PDAC related hurdles. Contrary to previous studies that demonstrated a limited persistency and infiltration of CAR-T cells in many solid tumors, they persist and accumulated in PDAC tumor tissues. Ex vivo analysis revealed that CAR-T cells that had been recovered at different time points from mice bearing an orthotopic PDAC tumor exhibited a gradual loss of tumor reactivity. This loss of tumor reactivity of CAR-T cells was associated with the increased expression of AMP-activated protein kinase and Mitofusin 1/ Dynamin-related protein 1 ratio., Competing Interests: Declaration of Competing Interest We confirm that this manuscript has not been published elsewhere and is not under consideration by another journal. All authors have approved the manuscript and agree with the submission. The authors have no conflicts of interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Insulinoma-associated protein 1 (INSM1) is a representative diagnostic marker of neuroendocrine neoplasms (NENs); however, it has not yet been used to diagnose pituitary neuroendocrine tumors (PitNETs), according to the 2022 World Health Organization (WHO) classification of pituitary tumors. This study aimed to examine the expression of INSM1 using immunohistochemistry, in the various cell lineages of PitNET classified by hormone secretion and transcription factor expression. INSM1 expression in PitNETs (different subtypes) and normal pituitary tissues was immunohistochemically assessed. The results were interpreted as scores of 0 (negative), 1 (focally positive), or 2 (frankly positive), depending on the proportion of cell staining. Twenty-eight of 35 PitNET cases (80%) showed INSM1 positivity in their nuclei. The staining in each histological subtype of PitNETs was as follows: somatotroph tumors, score 0 = 3/5, score 1 = 1/5, score 2 = 1/5; lactotroph tumors, score 0 = 2/5, score 1 = 1/5, score 2 = 2/5; thyrotroph tumors, score 2 = 5/5; corticotroph tumors: score 1 = 1/9, score 2 = 8/9; gonadotroph tumors, score 0 = 2/10, score 1 = 0/10, score 2 = 8/10; and unclassifiable tumor, score 1 = 1/1. INSM1 expression in most PitNETs was obtained, similar to that in the normal pituitary gland; thus, INSM1 may maintain the characteristics of anterior pituitary cells and pituitary tumors., Competing Interests: VThe authors declare that there are no conflicts of interest., (2023 The Japan Society of Histochemistry and Cytochemistry.)

Predictive drug testing of patient-derived tumor organoids (PDTOs) holds promise for personalizing treatment of metastatic colorectal cancer (mCRC), but prospective data are limited to chemotherapy regimens with conflicting results. We describe a unified framework for PDTO-based predictive testing across standard-of-care chemotherapy and biologic and targeted therapy options. In an Australian community cohort, PDTO predictions based on treatment-naive patients (n = 56) and response rates from first-line mCRC clinical trials achieve 83% accuracy for forecasting responses in patients receiving palliative treatments (18 patients, 29 treatments). Similar assay accuracy is achieved in a prospective study of third-line or later mCRC treatment, AGITG FORECAST-1 (n = 30 patients). "Resistant" predictions are associated with inferior progression-free survival; misclassification rates are similar by regimen. Liver metastases are the optimal site for sampling, with testing achievable within 7 weeks for 68.8% cases. Our findings indicate that PDTO drug panel testing can provide predictive information for multifarious standard-of-care therapies for mCRC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterized by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here, we used electron cryo-microscopy to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in three Kii cases and tau filaments with the corticobasal degeneration fold in one Kii case. We identified a new Type III CTE tau filament, where protofilaments pack against each other in an antiparallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Amyotrophic lateral sclerosis/Parkinsonism-dementia complex in Kii peninsula, Japan (Kii ALS/PDC), is an endemic neurodegenerative disease whose causes and pathogenesis remain unknown. However, astrocytes in autopsied cases of Kii ALS/PDC show characteristic lesions. In addition, relationships between extracellular vesicles (EVs) and neurodegenerative diseases are increasingly apparent. Therefore, we focused on proteins in EVs derived from Kii ALS/PDC astrocytes in the present study., Methods: Induced pluripotent stem cells (iPSCs) derived from three healthy controls (HCs) and three patients with Kii ALS/PDC were differentiated into astrocytes. EVs in the culture medium of astrocytes were collected and subjected to quantitative proteome analysis., Results: Our proteome analysis reveals that EV-containing proteins derived from astrocytes of patients with Kii ALS/PDC show distinctive patterns compared with those of HCs. Moreover, EVs derived from Kii ALS/PDC astrocytes display increased proteins related to proteostasis and decreased proteins related to anti-inflammation., Discussion: Proteins contained in EVs from astrocytes unveil protective support to neurons and may reflect the molecular pathomechanism of Kii ALS/PDC; accordingly, they may be potential biomarker candidates of Kii ALS/PDC., (© 2023. Fondazione Società Italiana di Neurologia.)

Purpose: The predictive value of 18 F-sodium fluoride ( 18 F-NaF) positron emission tomography (PET) in combination with coronary computed tomography (CT) angiography (CCTA) for future coronary events has attracted interest. We evaluated the potential of 18 F-NaF PET/CT following CCTA to predict major coronary events (MACE) during a 5-year follow-up period., Methods: Forty patients with coronary atherosclerotic lesions detected on CCTA underwent 18 F-NaF PET/CT examination. Each lesion was evaluated for luminal stenosis and high-risk plaque (HRP) with < 30 Hounsfield units and a > 1.1 remodeling index on CCTA. Focal 18 F-NaF uptake in each lesion was quantified using the maximum tissue-to-background ratio (TBR max ), and the maximum TBR max per patient (M-TBR max ) was determined. We followed MACE (cardiac death, acute coronary syndrome, and/or coronary revascularization > 6 months after 18 F-NaF PET/CT) for 5 years., Results: In total, 142 coronary lesions were analyzed. Eleven patients experienced any MACE. Patients with MACE showed a higher M-TBR max than those without (1.40 ± .19 vs. 1.18 ± .18, P = .0011), and the optimal M-TBR max cutoff to predict MACE was 1.29. Patients with M-TBR max of ≥ 1.29 had a higher risk of MACE than those with lower values (P = .012, log-rank test), whereas patients with obstructive stenosis and those with HRP did not. Multivariate Cox proportional analysis adjusted for age, sex, coronary risk factors, and CCTA findings showed that M-TBR max of ≥ 1.29 remained an independent predictor of 5-year MACE (hazard ratio, 5.4; 95% confidence interval, 1.1-25.4; P = .034)., Conclusion: 18 F-NaF PET/CT following CCTA provides useful strategies to predict 5-year MACE., (© 2023. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Background: Prostate cancer patients with pathological prognostic factors have a poor prognosis, but it is unclear whether pathological prognostic factors are associated with prognosis limited to low-risk patients with good prognosis according to NCCN guidelines. The present study examined whether prognosis is influenced by pathological prognostic factors using radical prostatectomy (RP) specimens from low-risk patients., Methods: We evaluated diagnostic accuracy by examining biochemical recurrence (BCR)-free survival with respect to clinical and pathological prognostic factors in 419 all-risk patients who underwent RP. Clinical prognostic factors included age, prostate-specific antigen (PSA) levels, PSA density, and risk stratification, while pathological prognostic factors included grade group, lymphovascular space invasion, extraprostatic extension, surgical margins, seminal vesicle invasion, intraductal carcinoma of the prostate (IDCP), and pT. In a subsequent analysis restricted to 104 low-risk patients, survival curves were estimated for pathological prognostic factors using the Kaplan-Meier method and compared using log-rank and generalized Wilcoxon tests., Results: In the overall risk analysis, the presence of pathological prognostic factors significantly shortened BCR-free survival (p < 0.05). Univariable analysis revealed that PSA density, risk categories, and pathological prognostic factors were significantly associated with BCR-free survival, although age and PSA were not. In multivariable analysis, age, risk categories, grade group, IDCP, and pT significantly predicted BCR-free survival (p < 0.05). Conversely, no statistically significant differences were found for any pathological prognostic factors in low-risk patients., Conclusions: In low-risk patients, pathological prognostic factors did not affect BCR-free survival, which suggests that additional treatment may be unnecessary even if pathological prognostic factors are observed in low-risk patients with RP., (© 2023. The Author(s).)

Introduction: In this study, we aimed to evaluate the feasibility, utility, and potential effects of LQ-M/D App, a smartphone application developed by Life Quest Inc., Tokyo, Japan, for patients with mild cognitive impairment (MCI) and mild dementia. The app incorporates cognitive and physical exercise training, lifestyle habit acquisition features, and a continuity improvement feature added in the post-update version to enhance user engagement. The continuity improvement feature includes the optimization of training content, and disease education, and enables family monitoring via a family app., Methods: A retrospective analysis was conducted on app usage, cognitive and exercise training implementation and interruptions, questionnaire response rates, and cognitive assessments in a single institution. A total of 20 patients used the app, with 10 patients using the pre-update version without the continuity improvement feature, and the other 10 patients using the post-update version with the continuity improvement feature., Results and Conclusion: The results demonstrated that the LQ-M/D App could be effectively used by the study population, and the continuity improvement feature positively influenced app usage in several aspects. Although a potential association between app usage and cognitive ability was suggested, the scatter in the data points warrants cautious interpretation. Limitations of the study included a small sample size, a single institution setting, and the retrospective nature of the study. In the future, a randomized controlled trial design using a larger sample size and multiple institutions to further evaluate the effectiveness of LQ-M/D App in managing MCI and mild dementia should be performed., Competing Interests: RH, YH, HT, NH, and SH hold executive or advisory positions within Life Quest Inc. EI is involved in development and research at Life Quest Inc., although not directly engaged in the development of the app analyzed in this study. RH, YH, HT, and SH own unlisted shares of the company. RS is the founder and a shareholder of Life Quest Inc. The remaining authors declare that the research was conducted in the absence of any commercial relationships that could be construed as potential conflict of interest., (© 2023 Hamaguchi, Hirokawa, Takahashi, Hachiya, Kawano, Isotani, Ito, Handa, Saito, Horie and Ide.)

Purpose: How coronary arterial 18 F-sodium fluoride ( 18 F-NaF) uptake on positron emission tomography changes over the long term and what clinical factors impact the changes remain unclear. We sought to investigate the topics in this study., Methods: We retrospectively studied 15 patients with ≥1 coronary atherosclerotic lesion/s detected on cardiac computed tomography who underwent baseline and follow-up (interval of >3 years) 18 F-NaF positron emission tomography/computed tomography scans. Focal 18 F-NaF uptake in each lesion was quantified using maximum tissue-to-background ratio (TBR max ). The temporal change in TBR max was assessed using a ratio of follow-up to baseline TBR max (R-TBR max )., Results: A total of 51 lesions were analyzed. Mean R-TBR max was 0.96 ± 0.21. CT-based lesion features (location, obstructive stenosis, plaque types, features of high-risk plaque) did not correlate with an increase in R-TBR max . In multivariate analysis, baseline TBR max significantly correlated with higher follow-up TBR max (β = 0.57, P < 0.0001), and the presence of diabetes mellitus significantly correlated with both higher follow-up TBR max (β = 0.34, P = 0.001) and elevated R-TBR max (β = 0.40, P = 0.003)., Conclusion: Higher coronary arterial 18 F-NaF uptake is likely to remain continuously high. Diabetes mellitus affects the long-term increase in coronary arterial 18 F-NaF uptake., (© 2022. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

During the coronavirus disease 2019 (COVID-19) pandemic, online-based learning has become mainstream in many countries, and its learning outcomes have been evaluated. However, various studies have shown that online-based learning needs to be optimized in the future, and the number of reports for this purpose is currently not sufficient. The purpose in this study was to determine the relationship between academic performance and attitudes toward face-to-face and remote formats among Japanese pharmacy students enrolled in a course designed for knowledge acquisition. A combination of face-to-face and remote formats was used in a practice course for sixth-year pharmacy students, designed to improve academic performance through knowledge acquisition. To evaluate learning outcomes, we used a questionnaire that was administered to the course participants and the results of examinations conducted before and after the course. Online-oriented and face-to-face-oriented groups differed in their attitudes toward the ease of asking questions of faculty and communicating with the faculty members and classmates in each format. In a knowledge acquisition course for Japanese pharmacy students, the study revealed that the same academic outcomes were achieved, regardless of the students' own perceptions of their aptitude for face-to-face or remote learning style.

A 74-year-old woman presented with vertigo, left-beating nystagmus, and auditory disturbance 4 months prior, in whom a former physician suspected Meniere's disease. Her signs and symptoms mildly improved with a moderate dose of glucocorticoids, which was eventually tapered. Fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) was performed 12 days prior to routine examination. Remarkable FDG uptake was observed in the surrounding areas of the bilateral Eustachian tubes and left middle ear, which was only partially detected on magnetic resonance imaging. The patient also tested positive for myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA). She was admitted to our hospital and diagnosed with otitis media with ANCA-associated vasculitis (OMAAV) based on the classification criteria. Four months after immunosuppressive therapy, the abnormal ear findings were not observed on follow-up FDG-PET/CT. The clinical course of this case suggests that FDG-PET/CT can detect occult ear involvement better than do other modalities in patients with OMAAV. In addition, FDG-PET/CT-positive ear lesions responded to immunosuppressive therapy. Therefore, FDG-PET/CT can help distinguish OMAAV from other ear diseases with non-inflammatory aetiologies and detect occult treatment-responsive OMAAV lesions in the clinical setting., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Thrombotic aneurysms at the nonbranching segment of the distal anterior cerebral artery (ACA) are extremely rare and difficult to differentiate from cavernous malformations by radiographic features alone., Observations: Computed tomography and magnetic resonance imaging of a 30-year-old female patient with a chronic headache complaint revealed a 22-mm frontal lobe mass. The mass showed heterogeneous mixed intensity and hemosiderin deposits on magnetic resonance images. It was not visualized by conventional angiography, indicating that the mass and ACA/other vessels were not connected. The patient was preoperatively diagnosed with a cavernous malformation. However, during resection, the mass surface was white and smooth, different from a cavernous malformation. Although the mass was adherent to the pericallosal artery branch, no luminal continuity was observed. After detachment, the mass was completely resected. Pathological and immunohistochemical findings indicated a vessel wall and interior thrombus. The patient was rediagnosed with a thrombotic aneurysm at the distal ACA nonbranching segment and discharged 10 days postsurgery without neurological deficits., Lessons: Because radiographic findings of thrombotic aneurysm and cavernous malformation are similar, mass lesions in contact with major arteries should be differentiated as thrombotic aneurysms, even when the artery lumen appears disconnected from the mass.

Rationale: Septic pulmonary embolism (SPE) and subsequent pneumothorax are rare but serious conditions. We report a case of SPE and pneumothorax caused by central venous port (CV port) infection., Patient Concerns: A 73-year-old woman, who underwent chemoradiotherapy for a head angiosarcoma and a CV port placement, presented with general malaise and myalgia., Diagnosis: A laboratory examination showed high levels of inflammatory markers. Chest computed tomography showed fluid collection around the CV port and multiple ground-glass opacities and nodular shadows in the bilateral lung field. She was admitted with a diagnosis of SPE due to CV port infection. The port was removed, and antibiotic administration was initiated; however, she was intubated because of refractory septic shock. Methicillin-susceptible Staphylococcus aureus was detected in the blood and pus around the port site., Interventions: Her respiratory status did not improve despite recovering from septic shock, and radiologic findings showed a left pneumothorax and exacerbation of SPE on day 9. Her condition was judged ineligible for surgery for pneumothorax, and chest tube thoracostomy was continued., Outcomes: Air leaks persisted after chest tube thoracostomy, and her respiratory status did not improve despite ventilator management and recruitment maneuvers. Moreover, a right pneumothorax developed on day 19. Her respiratory status gradually worsened, and she died on day 21. Autopsy showed multiple cavitary lesions in the bilateral lungs and emboli containing organization and inflammatory cells that obstructed the pulmonary arterioles., Lessons: This case indicates that CV port-related infections are infrequent and difficult to diagnose; understanding the clinical features of SPE is important because of its high mortality rate; and pneumothorax secondary to SPE is a rare but serious condition and is difficult to treat during ventilator management., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: A neuroendoscope is a technical advance that allows surgeons to visualize certain regions of the brain that was previously inaccessible through the use of a surgical microscope. Several neuroendoscope designs have been implemented by other neurosurgeons over the past 5 years. The advantage of a neuroendoscope is the addition of a flexible and narrow tip that allows for safe entry into intracranial structures for clinical observation. However, there are some limitations to this approach. Here, we report the use of a modified angioscope as a newly developed neuroendoscope to be employed in observing intracranial structures., Methods: We report the use of an angioscope that is 1.8 mm in diameter and has both a thin and flexible tip. In this study, the angioscope was inserted into the lumen of an aspirator tube, and the tip of the device was placed at the intracranial area of intended observation area. Image findings were evaluated using an established in vivo goat brain model., Results: The angioscope was light in weight and maneuverable and could be reached and observed in the blind spot using a surgical microscope. From the cerebellopontine angle, the lower cranial nerves and trigeminal nerve could be observed, and from the cisterna magna, the floor of the fourth ventricle and the aqueduct could be seen., Conclusion: The angioscope is a useful instrument to observe intracranial locations safely and effectively even within a limited surgical field. Further modifications will be required to use the angioscope in various craniotomy procedures., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Surgical Neurology International.)

Background: Novice neurosurgeons require neurosurgical technique training, but the current method is demanding and time consuming. Therefore, it is crucial to perform training using an appropriate and informative method. In this report, we describe our attempts to provide training in neurosurgical techniques using goat in vivo brain model and to demonstrate the effectiveness of this model., Methods: Under general anesthesia, the surgery was performed on a male goat in the prone position. A midline liner skin incision was made in the scalp, six burr holes were drilled, a craniectomy was performed, and the dura was incised in an arcuate fashion. We attempted the interhemispheric approach and a retrosigmoid approach., Results: It was confirmed that common neurosurgical approaches are achievable in this model. Furthermore, anatomical structures such as nerves and blood vessels were similar to those of humans. Moreover, the goat brain was similar in color and texture to that of humans., Conclusion: Unlike a cadaver brain, in vivo brain requires hemostasis and careful dissection, which provides the surgeons a realistic experience of actual neurosurgery., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Surgical Neurology International.)

Caspase-generated fragmented cytokeratin 18 (fCK18) is recognized as a useful noninvasive biomarker in the diagnosis of nonalcoholic fatty liver disease (NAFLD), particularly nonalcoholic steatohepatitis (NASH). However, fCK18 measurement is not applied clinically due to widely variable cut-off values under the current enzyme-linked immunosorbent assay platform. Therefore, we developed a highly sensitive chemiluminescent enzyme immunoassay using newly developed monoclonal antibodies against fCK18 and investigated its relevance in NASH diagnosis. Serum fCK18 levels were measured in the derivation and validation cohort. The correlation between serum fCK18 levels and NAFLD activity score (NAS), fibrosis stage, and liver function was examined. Serum fCK18 levels were significantly correlated with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase. Serum fCK18 levels were significantly associated with NAS, Brunt's grade/stage, Matteoni's classification, portal inflammation, and fat accumulation in the liver. Notably, hepatocyte ballooning was the only independent variable significantly associated with serum fCK18 in the multivariate linear regression analysis. Serum fCK18 levels were significantly elevated in patients with NAFLD and nonalcoholic fatty liver (NAFL) compared to healthy individuals. They were also significantly elevated in patients with NAFL compared to NASH defined by NAS or Matteoni's classification, with area under the curve values being 0.961 (NAFLD vs. healthy), 0.913 (NAFL vs. healthy), 0.763 (NASH vs. NAFL), and 0.796 (NASH type 3-4 vs. NAFL type 1-2). These results were confirmed by a validation cohort. Notably, changes over time in serum fCK18 levels were significantly correlated with changes in ALT, AST, and the fibrosis-4 index in 25 patients who underwent lifestyle modification. Serum fCK18 levels were significantly correlated with liver damage associated with NASH pathology. Serum fCK18 levels are accurate in distinguishing patients with NAFL or NASH from healthy individuals and may be useful to monitor NASH over time., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Purpose: In synthetic q-space learning (synQSL), which uses deep learning to infer the diffusional kurtosis (K), a bias that depends on the noise level added to the synthetic training data occurs. The purpose of this study was to evaluate K inference using synQSL and bias correction., Methods: Using the synthetic test data and the real image data, K was inferred by synQSL, and bias correction was performed. Then, those results were compared with K inferred by fitting by the least-squares fitting (LSF) method. At this time, the noise level of the training data was set to 3 types, the noise level of the synthesis test data was set to 5 types, and the number of excitation (NEX) of the real image data was set to 4 types. Robustness of inference was evaluated by the outlier rate, which is the ratio of K outliers to the whole brain. We also evaluated the root mean square error (RMSE) of the inferred K., Results: The outlier rate inferred by synQSL without correction was significantly lower in the test data of each noise level than that by the LSF method and was further reduced by correction. In addition, the RMSE of NEX 1 with NEX 4 as the correct answer based on the real image data had the smallest correction result of K by synQSL., Conclusion: Inferring K using synQSL and bias correction is a robust and small error method compared to that using the LSF method.

Microalgae are considered to be promising producers of bioactive chemicals, feeds and fuels from carbon dioxide by photosynthesis. Thus, the prediction of microalgal growth profiles is important for the planning of cost-effective and sustainable cultivation-harvest cycles. This paper proposes a mathematical model capable of predicting the effect of light flux into culture and medium concentration on the growth profiles of microalgae by incorporating these growth-limiting factors into a logistic equation. The specific form of the equation is derived based on the experimentally measured growth profiles of Monoraphidium sp., a microalgal strain isolated by the authors, under 16 conditions consisting of combinations of incident light fluxes into culture and initial medium concentrations. Using a cross-validation method, it is shown that the proposed model has the ability to predict necessary incident light flux into culture and initial medium concentration for harvesting target biomass at a target time. Finally, model-guided cultivation planning is performed and is evaluated by comparing the result with experimental data.

Systemic amyloidosis is recognized as a serious complication of rheumatoid arthritis or inflammatory bowel disease, but also of inflammatory skin disease. However, the detailed molecular mechanism of amyloidosis associated with cutaneous inflammation remains unclear, and therapeutic approaches are limited. Here, we investigated the pathophysiology of amyloidosis secondary to cutaneous inflammation and the therapeutic effects of Janus kinase (JAK) inhibitors by examining a mouse model of spontaneous dermatitis (KCASP1Tg mice). Moreover, KCASP1Tg mice were crossed with interleukin-17A (IL-17A) knockout mice to generate IL-17A-/KCASP1Tg and examine the role of IL-17A in amyloidosis under cutaneous inflammation. KCASP1Tg mice showed severe amyloid deposition in the liver and spleen. Increased serum-neutral fat levels and decreased lymphocyte production were observed in the spleen. Overproduction of amyloidosis was partially ameliorated by the administration of JAK inhibitors and was further improved in IL-17A-/KCASP1Tg mice. IL-17A-producing cells included CD4, gamma delta, and CD8 T cells. In summary, our results from the analysis of a mouse model of dermatitis revealed that skin-derived inflammatory cytokines can induce amyloid deposition in the liver and spleen, and that the administration of JAK inhibitors and, even more, IL-17A ablation, reduced amyloidosis. This study demonstrates that active control of skin inflammation is essential to prevent internal organ amyloidosis.

Three-dimensional culture of human normal colorectal epithelium and cancer tissue as organoids and tumoroids has transformed the study of diseases of the large intestine. A widely used strategy for generating patient-derived colorectal organoids and tumoroids involves embedding cells in domes of extracellular matrix (ECM). Despite its success, dome culture is not ideal for scalable expansion, experimentation, and high-throughput screening applications. Our group has developed a protocol for growing patient-derived colorectal organoids and tumoroids in low-viscosity matrix (LVM) suspension culture. Instead of embedding colonic crypts or tumor fragments in solid ECM, these are grown suspended in medium containing only a low percentage of ECM. Compared with dome cultures, LVM suspension culture reduces the labor and cost of establishing and passaging organoids and tumoroids, enables rapid expansion, and is readily adaptable for high-throughput screening. Graphic abstract: Generation of organoids and tumoroids from human large intestine using LVM suspension culture (Created with BioRender.com)., Competing Interests: Competing interestsThe authors declare no competing interests., (Copyright © 2022 The Authors; exclusive licensee Bio-protocol LLC.)

We report a case of eosinophilic fasciitis triggered by strenuous physical activity, which did not relapse during the follow-up period. We ascertained that interleukin-33 (IL-33) was released from the vascular endothelial cells after intense exercise, inducing type 2 innate lymphocytes (ILC2) and causing fasciitis. A healthy woman experienced itching on both limbs a few hours after a game of drumming. Her hand, knee joints, and legs gradually swelled up with groove signs along the superficial veins. White blood cell and eosinophil counts were significantly elevated. Magnetic resonance imaging revealed a high signal at the fascia on both lower limbs. Histopathological findings of the left lower limb tissue specimen showed edematous fascia with eosinophils. No relapse of eosinophilic fasciitis was observed after finishing treatment with prednisolone. Immunological staining for IL-4, IL-5, IL-33, tumor necrosis factor-α, and interferon-γ was performed on the fascial tissue. Both IL-4 and IL-5 were stained on the lymphocytes at the muscle and fascia levels; however, CD3 and CD4 were unstained in these cells, suggesting that those cells were ILC2. Tumor necrosis factor-α and interferon-γ were unstained. Vascular endothelial cells in the fascia strongly expressed IL-33. Eosinophilic fasciitis may be associated with type 2 immunity triggered by IL-33 in the current case., (© 2022 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Indocyanine green (ICG) videoangiography is rarely used during the surgical treatment of thoracic outlet syndrome (TOS)., Objective: To evaluate subclavian artery (SA) flow dynamics using the analytical ICG videoangiography during TOS surgeries., Methods: We examined patients with neurogenic TOS who received surgical treatment and whose SA blood flow at the interscalene space was evaluated using ICG videoangiography equipped with an analytical function (FLOW800). Anterior scalenectomy with or without middle scalenectomy and first rib resection were conducted for decompression of the brachial plexus. ICG videoangiography was performed before and after decompression of the brachial plexus. After acquisition of grayscale and color-coded maps, a region of interest was placed in the SA to obtain time-intensity diagrams. Maximum intensity (MI), rise time (RT), and blood flow index (BFi) were calculated from the diagram, in arbitrary intensity (AI) units. We compared values before and after decompression. Comparisons of the three parameters before and after decompression were assessed statistically using the paired t-tests and Wilcoxon signed-rank test., Results: We evaluated nine procedures in consecutively presenting patients. The observed mean values of MI, RT, and BFi before decompression were 174.1 ± 61.5 AI, 5.2 ± 1.1 s, and 35.2 ± 13.5 AI/s, respectively, and the observed mean values of MI, RT, and BFi after decompression were 299.3 ± 167.4 AI, 6.6 ± 0.8 s, and 44.6 ± 28.3 AI/s, respectively. These parameters showed higher values after decompression than before decompression, and the increase in MI and RT was statistically significant (P < .05)., Conclusion: ICG videoangiography allows semiquantitative evaluation of hemodynamic changes during TOS surgery. A marked decrease in the velocity of SA flow was observed after decompression., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)