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Fecal corticosterone metabolite (FCM) concentrations, which can be determined noninvasively, have recently been explored as a stress indicator in birds. In our study, we measured FCM concentrations in penguins under nonmolting or molting conditions, cool or hot season, diseased condition, and incubation period. These measurements were conducted in an aquarium that housed king penguins, gentoo penguins, and African penguins. This study aimed to investigate the validity of fecal matter as a stress indicator. Our findings revealed that FCM concentrations were significantly higher in molting individuals than in nonmolting individuals. Compared with the cool season, FCM concentrations were significantly higher in penguins housed outdoors during the hot season. However, no differences were observed in penguins housed indoors. Diseased individuals and an incubating individual showed notably higher FCM concentrations than healthy individuals. Interestingly, the FCM concentration in king penguin that underwent cataract surgery was extremely high before the surgery. However, 1 month postsurgery, it decreased to a level similar to that of healthy individuals. We observed increased FCM concentrations in penguins considered to be exposed to stressors. Notably, FCM concentration decreased after removing the stress factor. The FCM concentration was found to be consistent with the stress state of penguins, suggesting its usefulness as a stress indicator.

Brain-computer interface (BCI) technology has gained recognition in various fields, including clinical applications, assistive technology, and human-computer interaction research. BCI enables communication, control, and monitoring of the affective/cognitive states of users. Recently, BCI has also found applications in the artistic field, enabling real-time art composition using brain activity signals, and engaging performers, spectators, or an entire audience with brain activity-based artistic environments. Existing techniques use specific features of brain activity, such as the P300 wave and SSVEPs, to control drawing tools, rather than directly reflecting brain activity in the output image. In this study, we present a novel approach that uses a latent diffusion model, a type of deep neural network, to generate images directly from continuous brain activity. We demonstrate this technology using local field potentials from the neocortex of freely moving rats. This system continuously converted the recorded brain activity into images. Our end-to-end method for generating images from brain activity opens new possibilities for creative expression and experimentation. Notably, our results show that the generated images successfully reflect the dynamic and stochastic nature of the underlying neural activity, providing a unique procedure for visualization of brain function., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yamashiro et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Pathogenic variants in Gap junction protein beta 1 (GJB1), which encodes Connexin 32, are known to cause X-linked Charcot-Marie-Tooth disease (CMTX), the second most common form of CMT. CMTX presents with the following five central nervous systems (CNS) phenotypes: subclinical electrophysiological abnormalities, mild fixed abnormalities on neurological examination and/or imaging, transient CNS dysfunction, cognitive impairment, and persistent CNS manifestations., Case Presentation: A 40-year-old Japanese male showed CNS symptoms, including nystagmus, prominent spastic paraplegia, and mild cerebellar ataxia, accompanied by subclinical peripheral neuropathy. Brain magnetic resonance imaging revealed hyperintensities in diffusion-weighted images of the white matter, particularly along the pyramidal tract, which had persisted since childhood. Nerve conduction assessment showed a mild decrease in motor conduction velocity, and auditory brainstem responses beyond wave II were absent. Peripheral and central conduction times in somatosensory evoked potentials elicited by stimulation of the median nerve were prolonged. Genetic analysis identified a hemizygous GJB1 variant, NM_000166.6:c.520C > T p.Pro174Ser., Conclusions: The patient in the case described here, with a GJB1 p.Pro174Ser variant, presented with a unique CNS-dominant phenotype, characterized by spastic paraplegia and persistent extensive leukoencephalopathy, rather than CMTX. Similar phenotypes have also been observed in patients with GJC2 and CLCN2 variants, likely because of the common function of these genes in regulating ion and water balance, which is essential for maintaining white matter function. CMTX should be considered within the spectrum of GJB1-related disorders, which can include patients with predominant CNS symptoms, some of which can potentially be classified as a new type of spastic paraplegia., (© 2024. The Author(s).)

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide despite advances in cancer therapeutics. In several gynecological cancers, anti-Müllerian hormone receptor type 2 (AMHR2) mediates AMH-induced growth inhibition and is expressed at high levels. Furthermore, 5%-8% of NSCLCs exhibit high AMHR2 expression, suggesting that AMH may inhibit the progression of some lung cancers. However, the clinical relevance of AMHR2 expression and its role in lung cancer is not fully clarified., Methods: Immunostaining was performed on 79 surgical specimens of NSCLC. The Cancer Genome Atlas RNA-seq data for lung adenocarcinoma were analyzed, and gene ontology and gene set enrichment analyses were performed. In cellular experiments, AMHR2-overexpressing NSCLC cell lines were established, and the role of the AMH-AMHR2 pathway in cell proliferation with recombinant human AMH protein treatment was examined., Results: A total of 13 cases (16.5%) were positive for immunostaining in lung adenocarcinoma tissues; no positive signals were detected in lung squamous carcinoma tissues. Gene expression variation analysis using The Cancer Genome Atlas data showed that the expression of genes related to the cell cycle was downregulated in the AMHR2-high group. Cellular experiments showed that activation of the AMH-AMHR2 pathway suppressed cell proliferation., Conclusion: In lung adenocarcinoma tissues with high expression of AMHR2, activation of the AMH-AMHR2 pathway may suppress cell proliferation., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Fertility control has traditionally been applied in zoos to control captive populations, and reversible contraception is important. However, contraceptive methods for male bears have not been reported. We aimed to establish a reversible contraceptive for male brown bears by investigating the effects of a gonadotropin-releasing hormone (GnRH) vaccine (Improvac®) that was developed for the immune castration of pigs. We vaccinated six bears with two sequential doses of 400 (n = 2) or 600 μg Improvac® (n = 4) with a 1-month interval during the pre-breeding season (February to April). We compared the reproductive parameters (testosterone levels and semen parameters) of the six vaccinated and four non-vaccinated (control) bears once during the breeding season (May or June). To investigate whether the reproductive performance could be restored in the following year of contraception, we also compared the reproductive parameters once during the breeding season in two bears between the year with GnRH vaccination and the following year without vaccination. Vaccination treatments suppressed reproductive parameters in 5 bears, although vaccination with 400 μg of Improvac® was not effective in one bear. Testosterone levels and the rate of progressive sperm motility were significantly lower, and total sperm count and testis size tended to be lower in vaccinated bears, compared with the controls. Blood biochemical findings and direct observations after Improvac® vaccination did not reveal side effects. Moreover, testosterone levels and spermatogenic scores of two bears were restored in the following year. We confirmed that the Improvac® vaccine elicited a reversible contraceptive effect in male brown bears., (© 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Objective: Pharyngeal foreign bodies (PFBs) are a prevalent disease affected by food culture and dietary habits, with fish bones as the leading cause. Most studies were limited to specific regions, and a nationwide survey was not conducted in Japan. In this ecological study, we aimed to conduct a nationwide analysis of outpatient PFB cases in Japan over three years, focusing on seasonal trends, sex- and age-stratified cases, and regional differences., Methods: We used the National Database of Health Insurance Claims and Specific Health Checkups of Japan open data from April 2019 to March 2022. The case data were analyzed by month, age, sex, and prefecture. Additionally, we calculated the standardized claim ratios (SCRs) for each prefecture and investigated the association between dietary habits, food culture, and SCR of PFBs using a two-level linear regression model., Results: We analyzed a total of 164,337 outpatient PFB cases in Japan, revealing an average incidence rate of 45.6 per 100,000 persons. The seasonal trend revealed a peak in July each year from 2019 to 2021, confirming seasonality in PFB incidents. Children reported a higher incidence rate. Living west of Japan and expenditure on fish and shellfish had a strongly positive association with the SCR of PFBs., Conclusion: Our nationwide survey reveals that, even within Japan, there were regional variations influenced by food culture and dietary habits. The data showed that PFB incidence was higher among children, highlighting the need for preventive education., Level of Evidence: Level 3., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease caused by the expansion of GGC repeats in the 5'-untranslated region (5'-UTR) of NOTCH2NLC. Although increasing evidence suggests that NIID affects various organs, its association with renal involvement remains unclear. We studied the genetic background of a family with NIID, in which four of five members presented with proteinuria as the initial manifestation. The renal pathology of three patients was diagnosed as focal segmental glomerulosclerosis (FSGS) at a previous hospital. These patients also presented with tremors, retinal degeneration, and episodic neurological events. Finally, one patient exhibited reversible bilateral thalamic high-intensity signal changes on diffusion-weighted imaging during episodic neurological events., Methods: Exome sequencing (ES) and nanopore long-read whole-genome sequencing (LR-WGS) were performed on the index case, followed by nanopore target sequencing using Cas9-mediated PCR-free enrichment and methylation analysis., Results: ES revealed no candidate variants; however, nanopore LR-WGS in the index case revealed expansion of short tandem repeats (STR) in NOTCH2NLC. Subsequent nanopore target sequencing using Cas9-mediated PCR-free enrichment showed STR expansion of NOTCH2NLC in an affected sibling and asymptomatic father. Methylation analysis using nanopore data revealed hypermethylation of the expanded allele in the asymptomatic father and partial hypermethylation in a mildly symptomatic sibling, whereas the expanded allele was hypomethylated in the index case., Conclusions: This investigation expands the clinical spectrum of NIID, suggesting that STR expansion of NOTCH2NLC is a cause of renal diseases, including FSGS., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Carotid intima-media thickness (IMT) measurement is used to assess subclinical atherosclerosis. We aimed to examine the association between the maximum IMT by location and the occurrence of silent brain infarction (SBI)., Methods: Overall, 280 Japanese individuals (92 females, 52.6±5 years old) underwent a medical check-up at our hospital in Tokyo in 2015. Carotid IMT was measured at each site on ultrasound images (common carotid artery [CCA], internal carotid artery, or bifurcation). The risk factors for arterial dysfunction were evaluated. SBI was assessed using magnetic resonance imaging (MRI). The cross-sectional relationship between carotid maximum IMT and SBI was evaluated., Results: Of the 280 individuals, 18 (6.4%) were diagnosed with SBI on MRI. The mean age of the SBI(-) and SBI(+) groups was 51.9±10.6 and 63.6±18.6 years, respectively. The correlation coefficients between the carotid maximum IMT at each location were very weak (correlation coefficient range: 0.180-0.253). The percentage of participants with SBI increased significantly with increasing maximum CCA and bIMT values. After adjusting for confounders, SBI was found to be significantly associated with the maximum bIMT (per 0.1-mm increase) (adjusted odds ratio [aOR], 1.10; 95% confidence interval [CI]: 1.03-1.17). When bIMT was categorized according to three groups (＜1.0 mm, 1.0-＜2.0 mm, and ≥ 2.0 mm), a significant SBI risk was also observed with an increase by each category of bIMT (aOR: 3.96, 95% CI: 1.63-9.52, P=0.002)., Conclusion: The maximum bIMT was found to be the main determinant of SBI. A significant SBI risk was associated with an increase in each category of the maximum bIMT. Therefore, the maximum bIMT might be a useful predictor of future stroke in Japanese stroke-free medical check-up participants.

Background: Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. The overall survival has not improved significantly over the last decades because no major therapeutic breakthroughs have been achieved for over 15 years., Methods: We analyzed a genome-wide loss-of-function screening database to identify vulnerabilities in SCLC for the development of urgently needed novel therapies., Results: We identified SKP2 (encoding S-phase kinase-associated protein 2) and CKS1B (encoding CDC28 protein kinase regulatory subunit 1B) as the two most essential genes in that order in SCLC. Notably, SKP2 and CKS1B comprise the p27 binding pocket of the E3 ubiquitin ligase SCF SKP2 complex. Immunohistochemistry on tissue microarrays revealed that SKP2 was expressed in >95% of samples at substantially higher levels than that observed for commonly used neuroendocrine markers. As expected, SCLC cell lines were sensitive to SKP2 inhibition. Furthermore, SKP2 or CKS1B knockdown induced apoptosis in RB1 mutant cells, whereas it induced senescence in RB1 wild-type cells., Conclusion: Although the mechanism underlying SKP2 knockdown-induced growth inhibition differs between RB1-wild-type and -mutant SCLC, SKP2 can be considered a novel therapeutic target for patients with SCLC regardless of the RB1 mutation status. Our findings indicate that SKP2 is a potential novel clinical diagnostic marker and therapeutic target in SCLC., Competing Interests: Declaration of competing interest Ken Tajima received research funding from Novartis. Kazuhisa Takahashi received research funding from Chugai Pharm, MSD, Ono Pharm, and Bristol-Myers Squibb. Additionally, Kazuhisa Takahashi acknowledges donations from Eli Lilly Japan, Teijin Pharm, Chugai Pharm, Nippon Boehringer Ingelheim, Kyorin Pharm, Taiho Pharm, and Sanofi. The other authors have no conflicts of interest., (Copyright © 2024 [The Author]. Published by Elsevier B.V. All rights reserved.)

Rhythmic movement is the fundamental motion dynamics characterized by repetitive patterns. Precisely defining onsets in rhythmic movement is essential for a comprehensive analysis of motor functions. Our study introduces an automated method for detecting rat's forelimb foot-strike onsets using deep learning tools. This method demonstrates high accuracy of onset detection by combining two techniques using joint coordinates and behavioral confidence scale. The analysis extends to neural oscillatory responses in the rat's somatosensory cortex, validating the effectiveness of our combined approach. Our technique streamlines experimentation, demanding only a camera and GPU-accelerated computer. This approach is applicable across various contexts and promotes our understanding of brain functions during rhythmic movements., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Despite the emergence of SARS-CoV-2 variants and waning immunity after initial vaccination, data on antibody kinetics following booster doses, particularly those adapted to Omicron subvariants like XBB.1.5, remain limited. This study assesses the kinetics of anti-spike protein receptor-binding domain (S-RBD) IgG antibody titers post-booster vaccination in a Japanese population during the Omicron variant epidemic., Methods: A prospective cohort study was conducted in Bizen City, Japan, from November 2023 to January 2024. Participants included residents and workers aged ≥18 years, with at least three COVID-19 vaccinations. Antibody levels were measured from venous blood samples. The study analyzed 424 participants and 821 antibody measurements, adjusting for variables such as age, sex, underlying conditions, and prior infection status. Mixed-effects models were employed to describe the kinetics of log-transformed S-RBD antibody titers., Results: The study found that S-RBD antibody titers declined over time but increased with the number of booster vaccinations, particularly those adapted to Omicron and its subvariant XBB.1.5 (Pfizer-BioNTech Omicron-compatible: 0.156, 95%CI -0.032 to 0.344; Pfizer-BioNTech XBB-compatible: 0.226; 95%CI -0.051 to 0.504; Moderna Omicron-compatible: 0.279, 95%CI 0.012 to 0.546; and Moderna XBB-compatible: 0.338, 95%CI -0.052 to 0.728). Previously infected individuals maintained higher antibody titers, which declined more gradually compared to uninfected individuals (coefficient for interaction with time 0.006; 95%CI 0.001 to 0.011). Sensitivity analyses using Generalized Estimating Equations and interval-censored random intercept model confirmed the robustness of these findings., Conclusions: The study provides specific data on antibody kinetics post-booster vaccination, including the XBB.1.5-adapted vaccine, in a highly vaccinated Japanese population. The results highlight the importance of considering individual demographics and prior infection history in optimizing vaccination strategies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Takashi Yorifuji reports financial support was provided by Bizen city. If there are other authors, they 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 © 2024 Elsevier Ltd. All rights reserved.)

We report a case of severe Aicardi-Goutières syndrome caused by a novel homozygous RNASEH2B intronic variant, NC_000013.10(NM_024570.4):c.65-13G > A p.Glu22Valfs*5. The patient was born with pseudo-TORCH symptoms, including intracranial calcification, cataracts, and hepatosplenomegaly. Furthermore, the patient exhibited profound intellectual impairment and died at 14 months due to aspiration pneumonia accompanied by interstitial lung abnormalities. The severity of the patient's symptoms underscores the critical role of the C-terminal region of RNase H2B., (© 2024. The Author(s).)

Background: Although output-dependent QRS transition is a specific indicator that confirms left bundle branch (LBB) capture during left bundle branch area pacing (LBBAP), its durability remains unclear., Objective: To evaluate the presence of output-dependent QRS transition and capture thresholds of the LBB and left ventricular septal myocardium (LVS) immediately and up to 1 year after the LBBAP procedure., Methods: We enrolled 129 patients with successful LBBAP who were available for 1-year follow-up postoperatively. Threshold testing was performed immediately after LBBAP on postoperative day 0 (POD-0), after three days (POD-3), 6 months (POD-180), and 1 year (POD-360)., Results: Output-dependent QRS transition persisted in 64 (88%) patients on POD-360, from amongst the 73 patients with output-dependent QRS transition on POD-0. In contrast, 55 (98%) of 56 patients without QRS transition on POD-0 did not exhibit QRS transition thereafter. LBB thresholds were slightly elevated on POD-360, albeit without statistical significance, compared to those on POD-0 (1.22 ± 1.00 vs. 1.43 ± 1.29 V at 0.4 ms, p=0.26). The LBB thresholds increased by ≥1.5 V in 7 (11%) patients. However, in 93% of patients with an LBB threshold of ≤2.5 V on POD-0, LBB capture was maintained at 2.5 V on POD-360. LVS thresholds were similar on POD-0 and POD-360 (0.81 ± 0.36 vs. 0.83 ± 0.24 V, p=1.0), and did not increase by ≥1.5 V in any patient., Conclusion: Output-dependent QRS transitions were highly reproducible after implantation. Furthermore, LBB thresholds remained stable in most cases during the first postoperative year., (Copyright © 2024. Published by Elsevier Inc.)

Spontaneous activity refines neural connectivity prior to the onset of sensory experience, but it remains unclear how such activity instructs axonal connectivity with subcellular precision. We simultaneously measured spontaneous retinal waves and the activity of individual retinocollicular axons and tracked morphological changes in axonal arbors across hours in vivo in neonatal mice. We demonstrate that the correlation of an axon branch's activity with neighboring axons or postsynaptic neurons predicts whether the branch will be added, stabilized, or eliminated. Desynchronizing individual axons from their local networks, changing the pattern of correlated activity, or blocking N -methyl-d-aspartate receptors all significantly altered single-axon morphology. These observations provide the first direct evidence in vivo that endogenous patterns of correlated neuronal activity instruct fine-scale refinement of axonal processes.

Charcot-Marie-Tooth disease type 2Z is caused by MORC2 mutations and presents with axonal neuropathy. MORC2 mutations can also manifest as developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (DIGFAN). We report a patient exhibiting an intermediate phenotype between these diseases associated with a novel MORC2 variant. A literature review revealed that the genotype‒phenotype correlation in MORC2-related disorders is complex and that the same mutation can cause a variety of phenotypes., (© 2024. The Author(s).)

Objective: to report the first case series of Brazilian children diagnosed with Kleefstra syndrome, present a possible phenotype expansion to the syndrome and to raise physicians' awareness for this rare disease., Results: seven patients with confirmed KS were evaluated, including 5 males and 2 females. Abnormal prenatal findings were observed in 4 patients. Most patients were born at term, with normal birth measurements. All patients had neurodevelopmental delay and 6 evolved with intellectual disability. Hearing loss was present in 57.1% of patients and 28.7% had congenital heart disease. In males, cryptorchidism was present in 75%. Despite the facial dysmorphisms, only 2 out of 7 patients had a pre-test clinical suspicion of KS. One specific patient presented bilateral agenesis of the semicircular canals, a very rare ear manifestation in Kleefstra syndrome, representing a possible phenotype expansion of the syndrome., Conclusion: this report aims to promote awareness among physicians evaluating patients in a context of neurodevelopmental delay or congenital malformations, especially congenital heart defects. We also highlight a possible phenotype expansion of the syndrome, with a case of semicircular anomaly, not reported in this syndrome so far., Competing Interests: Declaration of competing interest nothing to declare., (Copyright © 2024. Published by Elsevier Masson SAS.)

We report a case of a patient with neck pain only who was diagnosed with spontaneous cerebrospinal fluid leak (SCFL) based on characteristic findings on cervical spine magnetic resonance imaging (MRI). The patient was a 47-year-old man who had been experiencing neck pain for 3 days. He experienced neck pain when he got up in the morning and could not keep standing. Cervical spine MRI showed significant dilatation of the anterolateral dural canal veins at the C2 level. Under the suspicion of SCFL, additional thoracic spine MRI was performed, which revealed epidural fluid collection in the lower thoracic spine. He underwent bed rest, but his symptoms returned. Epidural blood patch (EBP) was performed. The symptoms improved after EBP, and the venous dilatation disappeared on MRI. Venous dilatation in SCFL is considered an effect of epidural space enlargement due to dural sac shrinkage caused by cerebrospinal fluid loss. Therefore, venous dilatation in the cervical spine is an indirect finding of SCFL. It has been reported that images of epidural fluid collection and dural canal collapse on spinal MRI are useful as direct findings in the diagnosis of SCFL, and these findings are most noticeable at the thoracic level. Because SCFL with neck pain only also exists, dilated images of the epidural vein are valuable for diagnosing SCFL, and neurospine surgeons should be aware of this finding when encountering patients complaining of neck pain., Competing Interests: None, (© 2024 The Japan Neurosurgical Society.)

Background: Bleeding events are one of the major concerns in patients using oral anticoagulants (OACs). We aimed to evaluate the association between major bleeding and long-term clinical outcomes in atrial fibrillation (AF) patients taking OACs., Methods: We analyzed a database comprising two large-scale prospective registries of patients with documented AF: the RAFFINE and SAKURA registries. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE), defined as the composite of all-cause death, ischemic stroke, and myocardial infarction. Major bleeding was defined in accordance with the criteria of the International Society on Thrombosis and Hemostasis. Cox multivariate analysis was used to determine the impact of major bleeding on the incidence of MACCE., Results: The median follow-up period was 39.7 (interquartile range, 33.1-48.1) months. Among 6,633 patients with AF who were taking OAC, 298 (4.5%) had major bleeding and 737 (11.1%) had MACCE. The incidence of MACCE was higher in patients with bleeding than in those without (18.33 and 3.22, respectively, per 100 patient-years; log-rank p < 0.0001). Multivariate logistic regression analysis revealed older age, vitamin K antagonist use, and antiplatelet drug use as independent predictors of major bleeding. Median duration of MACCE occurrence after major bleeding was 41 (interquartile range, 3-300) days. Multivariate Cox hazard regression analysis showed that the risk of MACCE was significantly higher in patients with major bleeding compared to those without (hazard risk, 4.64; 95% confidence interval, 3.62-5.94; p < 0.0001)., Conclusions: Major bleeding was associated with long-term adverse cardiovascular events among AF patients taking OAC. Therefore, reducing the risk of bleeding is important for improving clinical outcomes in patients with AF., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

How frequently hybridisation and gene flow occur in the contact zones of diverging taxa is important for understanding the speciation process. Stigmaeopsis sabelisi and Stigmaeopsis miscanthi high-aggression form (hereafter, S. miscanthi HG) are haplodiploid, social spider mites that infest the Chinese silver grass, Miscanthus sinensis. These two species are closely related and parapatrically distributed in Japan. In mountainous areas, S. sabelisi and S. miscanthi HG are often found in the highlands and lowlands, respectively, suggesting that they are in contact at intermediate altitudes. It is estimated that they diverged from their common ancestors distributed in subtropical regions (south of Japan) during the last glacial period, expanded their distribution into the Japanese Archipelago, and came to have such a parapatric distribution (secondary contact). As their reproductive isolation is strong but incomplete, hybridisation and genetic introgression are expected at their distributional boundaries. In this study, we investigated their spatial distribution patterns along the elevation on Mt. Amagi using male morphological differences, and investigated their hybridisation status using single-nucleotide polymorphisms by MIG-seq. We found their contact zone at altitudes of 150-430 m, suggesting that their contact zone is prevalent in the parapatric area, which is in line with a previous study. Interspecific mating was predicted based on the sex ratio in the contact zone. No obvious hybrids were found, but genetic introgression was detected although it was extremely low., (© 2024. The Author(s), under exclusive licence to The Genetics Society.)

Aim: To examine cross-sectional associations between continuous glucose monitoring (CGM)-derived metrics and cerebral small vessel disease (SVD) in older adults with type 2 diabetes., Materials and Methods: In total, 80 patients with type 2 diabetes aged ≥70 years were analysed. Participants underwent CGM for 14 days. From the CGM data, we derived mean sensor glucose, percentage glucose coefficient of variation, mean amplitude of glucose excursion, time in range (TIR, 70-180 mg/dl), time above range (TAR) and time below range metrics, glycaemia risk index and high/low blood glucose index. The presence of cerebral SVD, including lacunes, microbleeds, enlarged perivascular spaces and white matter hyperintensities, was assessed, and the total number of these findings comprised the total cerebral SVD score (0-4). Ordinal logistic regression analyses were performed to examine the association of CGM-derived metrics with the total SVD score., Results: The median SVD score was 1 (interquartile range 0-2). Higher hyperglycaemic metrics, including mean sensor glucose, TAR >180 mg/dl, TAR >250 mg/dl, and high blood glucose index and glycaemia risk index, were associated with a higher total SVD score. In contrast, a higher TIR (per 10% increase) was associated with a lower total SVD score (odds ratio 0.73, 95% confidence interval 0.56-0.95). Glycated haemoglobin, percentage glucose coefficient of variation, mean amplitude of glucose excursions, time below range and low blood glucose index were not associated with total cerebral SVD scores., Conclusions: The hyperglycaemia metrics and TIR, derived from CGM, were associated with cerebral SVD in older adults with type 2 diabetes., (© 2024 John Wiley & Sons Ltd.)

Introduction: CAD (MIM*114010) encodes a large multifunctional protein with the enzymatic activity of the first three enzymes initiating and controlling the de novo pyrimidine biosynthesis pathway. Biallelic pathogenic variants in CAD cause the autosomal recessive developmental and epileptic encephalopathy 50 (MIM #616457) or CAD deficiency presenting with epilepsy, status epilepticus (SE), neurological deterioration and anemia with anisopoikilocytosis. Mortality is around 9% of patients, mainly related to the no use of its specific treatment with uridine. Majority of reported cases have an early onset during infancy, with some few starting later in childhood., Case Report: Here we report a deceased female patient with CAD deficiency whose epilepsy started at 14 years. She showed a rapid neurologic deterioration including cognitive decline, electroencephalographic background slowing which later evolved to a fatal refractory SE and supra and infratentorial atrophy on neuroimaging. Anemia developed after SE onset., Methods and Results: her post-mortem whole exome sequencing identified biallelic missense variants in CAD (NM&#95;004341.5): c.[2944G > A];[5366G > A] p.[(Asp982Asn)];[(Arg1789Gln)]. Our review of twenty-eight reported cases (2015-2023) revealed an epilepsy age onset from neonatal period to 7 years and the SE prevalence of 46 %., Discussion: With our case, we highlight the relevance of suspecting this treatable condition in older patients and in SE with no evident etiology., 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 © 2024 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Autobiographical memory specificity is known to contribute to better mental health, social problem-solving, and episodic future thinking. While numerous studies have addressed variables that affect autobiographical memory specificity, little is known regarding the meta-memory processes that underpin memory retrieval. In this study, we introduced two meta-memory constructs, ease of retrieval judgments and anticipation of negative emotion evoked, which potentially affect autobiographical memory specificity. Participants (N = 109) first rated the ease of retrieval and anticipated emotions for positive and negative words used in a subsequent autobiographical memory test. We used the Optional Instructions of the Autobiographical Memory Test, in which participants were instructed that "specific memories are better, but other memories are permissible," allowing them to adjust how much cognitive effort they spent on generative retrieval after a failure of direct retrieval. They also self-judged whether each retrieval was generative (using additional cues with cognitive effort) or direct (immediate recall without much cognitive effort). Results showed that for generative retrieval, ease of retrieval was associated with greater specific and general memories and fewer omissions. A more negative anticipated emotion was associated with fewer specific memories and greater omissions, but was not with general memories. These results suggest that low retrievability and anticipated negative emotion prevent individuals from devoting efforts to generative retrieval. The lack of association between anticipated negative emotion and general memory calls into question the functional avoidance hypothesis regarding autobiographical memory specificity. We discussed how participants judged these meta-memories and directions for future research., (© 2024. The Psychonomic Society, Inc.)

Objective: Pemphigus Vulgaris (PV) is a rare autoimmune disease that could cause laryngeal lesions; however, only a few studies have described the localization of the laryngeal lesions associated with this disease owing to its rarity. Therefore, this study aimed to determine the localization of laryngeal lesions in patients with PV., Methods: Fourteen patients with PV accompanied by laryngeal or pharyngeal lesions, who underwent flexible laryngeal endoscopy performed by laryngologists, were examined retrospectively., Results: The arytenoid area was the most frequently affected site in the larynx, followed by the epiglottis and aryepiglottic folds. Vocal folds and ventricular bands were the least affected., Conclusion: Lesions in the arytenoid area were observed more frequently in this study than in previous studies. This result suggests that a more careful inspection of arytenoid lesions in patients with PV is required under laryngeal fiber observation. Moreover, we proposed a novel classification system for laryngeal findings in patients with PV and a systematic observation method. This novel classification and method would be useful not only for determining the lesions but also for careful inspection in this field., Level of Evidence: 4 Laryngoscope, 134:3719-3725, 2024., (© 2024 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: To efficiently detect somatic UBA1 variants and establish a clinical scoring system predicting patients with pathogenic variants in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome., Methods: Eighty-nine Japanese patients with clinically suspected VEXAS syndrome were recruited [81 males and 8 females; median age of onset 69.3 years (interquartile range 62.1-77.6)]. Peptide nucleic acid-clamping PCR (PNA-PCR), regular PCR targeting exon 3 clustering UBA1 variants and subsequent Sanger sequencing were conducted for variant screening. Partitioning digital PCR or targeted amplicon deep sequencing was also performed to evaluate the variant allele frequency (VAF). We developed our clinical scoring system to predict UBA1 variant-positive and -negative patients and assessed the diagnostic value of our system using receiver operating characteristics (ROC) curve analysis., Results: Forty patients (44.9%) with reported pathogenic UBA1 variants were identified, including a case having a variant with VAF of 1.7%, using a highly sensitive method. Our clinical scoring system considering age >50 years, cutaneous lesions, lung involvement, chondritis and macrocytic anaemia efficiently predicted patients with UBA1 variants (the area under the curve for the scoring total was 0.908)., Conclusion: Genetic screening with the combination of regular PCR and PNA-PCR detected somatic UBA1 variants with high sensitivity and specificity. Our scoring system could efficiently predict patients with UBA1 variants., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Normal saline (NS) is recommended for the treatment of chloride-depletion alkalosis (CDA). However, its use in patients with drinking water restrictions or fluid volume deficiencies may lead to hypernatremia. We report the case of a 42-year-old Japanese man with ileus due to sigmoidal volvulus, who presented with CDA. After endoscopic decompression, NS was administered to treat the CDA. Despite the administration of NS, CDA persisted and hypernatremia developed. The infusion was then changed to high cation-gap amino acids (HCG-AA), which improved both metabolic alkalosis and hypernatremia. Thus, HCG-AA may be useful for the treatment of hypernatremia in patients with CDA., (© 2023. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype-phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Hereditary spastic paraplegia (HSP) is a heterogeneous group of neurological disorders that are characterized by progressive spasticity and weakness in the lower limbs. SPG26 is a complicated form of HSP, which includes not only weakness in the lower limbs, but also cognitive impairment, developmental delay, cerebellar ataxia, dysarthria, and peripheral neuropathy, and is caused by biallelic mutations in the B4GALNT1 (beta-1,4- N -acetylgalactosaminyltransferase 1) gene. The B4GALNT1 gene encodes ganglioside GM2/GD2 synthase (GM2S), which catalyzes the transfer of N -acetylgalactosamine to lactosylceramide, GM3, and GD3 to generate GA2, GM2, and GD2, respectively. The present study attempted to characterize a novel B4GALNT1 variant (NM&#95;001478.5:c.937G>A p.Asp313Asn) detected in a patient with progressive multi-system neurodegeneration as well as deleterious variants found in the general population in Japan. Peripheral blood T cells from our patient lacked the ability for activation-induced ganglioside expression assessed by cell surface cholera toxin binding. Structural predictions suggested that the amino acid substitution, p.Asp313Asn, impaired binding to the donor substrate UDP-GalNAc. An in vitro enzyme assay demonstrated that the variant protein did not exhibit GM2S activity, leading to the diagnosis of HSP26. This is the first case diagnosed with SPG26 in Japan. We then extracted 10 novel missense variants of B4GALNT1 from the whole-genome reference panel jMorp (8.3KJPN) of the Tohoku medical megabank organization, which were predicted to be deleterious by Polyphen-2 and SIFT programs. We performed a functional evaluation of these variants and demonstrated that many showed perturbed subcellular localization. Five of these variants exhibited no or significantly decreased GM2S activity with less than 10% activity of the wild-type protein, indicating that they are carrier variants for HSP26. These results provide the basis for molecular analyses of B4GALNT1 variants present in the Japanese population and will help improve the molecular diagnosis of patients suspected of having HSP., Competing Interests: The 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 Inamori, Nakamura, Shishido, Hsu, Nagafuku, Nitta, Ikeda, Yoshimura, Kodaira, Tsuchida, Matsumoto, Uemura, Ohno, Manabe, Yamaguchi, Togayachi, Aoki-Kinoshita, Nishihara, Furukawa, Kaname, Nakamura, Shimohata, Tadaka, Shirota, Kinoshita, Nakamura, Ohno, Sekijima and Inokuchi.)

Background: Otitis media (OM) is a prevalent respiratory disease in children and poses significant public health challenges due to its impact on child health and economic burdens. However, there have no nationwide epidemiological studies conducted in Japan. This study investigates the epidemiological trends of OM in Japan, taking into account the impact of the 7-valent pneumococcal conjugate vaccine (PCV7) introduction., Method: This study was retrospective cohort study using secondary data on the nationwide longitudinal birth cohort. This survey followed two cohorts born in 2001 (pre-PCV era) and 2010 (post-PCV era) until the age of 9. Every year, parents were surveyed about their children's health status, including occurrences of OM. The annual period prevalence and cumulative incidence of OM were assessed in this study, and the two cohorts were compared using a modified Poisson regression model adjusted environmental factors with the 2001 cohort as reference., Result: The study included 47,015 children from the 2001 cohort and 38,554 from the 2010 cohort. Peak annual period prevalence of OM varied by era. Cumulative incidence was 13.8 % for the 2001 cohort and 18.5 % for the 2010 cohort by 1.5 years of age and 28.9 % and 33.3 %, respectively, by 3.5 years of age. In particular, from the fourth survey onward, covering ages 2.5-3.5 years, a shift was observed from an increased risk to a decreased risk of OM., Conclusion: This nationwide longitudinal study emphasizes variations in OM epidemiology across Japan over time, with changes potentially influenced by the introduction of PCV7. In this study, due to the absence of individual PCV7 vaccination data, the effect of PCV7 was estimated based on the vaccination rate at the population level. The results suggest a notable decrease in the incidence of OM in later years, aligning with the increased uptake of PCV7., 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 © 2024. Published by Elsevier Ltd.)

Introduction: Many mouse models for autoimmune diseases also have lesions in non-target organs, which may make it difficult to determine whether the target organ lesion is primary or secondary. Hyposalivation has conventionally been studied using genetically modified mouse models for Sjogren's syndrome as well as spontaneous autoimmune mice with systemic lesions, none of which has salivary gland-specific injury., Methods: In this study, we established a salivary gland-specific injury mouse model using the TRECK system by gene modification with the transgene composed of the 5' untranslated region of human salivary mucin gene MUC7 (highly expressed specifically in human salivary gland) inserted at the upstream of hHB-EGF (diphtheria toxin receptor) in the TRECK vector., Results: In this transgenic mouse model, we confirmed salivary gland-specific expression of hHB-EGF gene, and hyposalivation after treatment with diphtheria toxin. Histological assessment of the salivary gland from these mice showed granular convoluted tubule epithelial cells destruction at the same position as a positivity in TUNEL assay., Conclusion: This transgenic mouse model may become a useful tool for elucidating the mechanisms involved in hyposalivation and for developing pharmaceuticals and tissue regenerative medical products for this condition., (S. Karger AG, Basel.)

Cardiofaciocutaneous syndrome (CFC) is a rare genetic disorder that presents with cardiac, craniofacial, and cutaneous symptoms, and is often accompanied by neurological abnormalities, including neurodevelopmental disorders and epilepsy. Regarding epilepsy in CFC, the onset of seizures commonly occurs in childhood. Since research data has mainly been collected from young patients with relatively short observation period, there is insufficient information regarding adult-onset epilepsy in CFC. Here, we report the long-term clinical course of epilepsy and other complications in a 45-year-old female with genetically confirmed CFC carrying a pathogenic de novo heterozygous variant of MAP2K1 , c.389 A>G (p.Tyr130Cys). The patient presented psychomotor delay from infancy and had severe intellectual disability with autistic features. At the age of 30, she first developed combined generalized and focal epilepsy that was resistant to anti-seizure medication. Her refractory epilepsy was fairly controlled with a combination of three anti-seizure medications, especially lacosamide, which effectively suppressed both generalized and focal seizures. The present case provides detailed information regarding the clinical course and treatment of adult-onset epilepsy, which may be useful for optimal treatment and prognostic prediction of CFC., Competing Interests: MK received contracts and honoraria from Otsuka Pharmaceutical Co., Ltd., Eisai Co., Ltd., Daiichi Sankyo Co., Ltd., and UCB Japan Co., Ltd. MK is an associate editor for BMC Neurology. The remaining authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2024 Tsuburaya-Suzuki, Ohori, Hamanaka, Fujita, Matsumoto and Kinoshita.)

Camurati-Engelmann disease (CED) is an autosomal dominant bone dysplasia characterized by progressive hyperostosis of the skull base and diaphyses of the long bones. CED is further divided into two subtypes, CED1 and CED2, according to the presence or absence of TGFB1 mutations, respectively. In this study, we used exome sequencing to investigate the genetic cause of CED2 in three pedigrees and identified two de novo heterozygous mutations in TGFB2 among the three patients. Both mutations were located in the region of the gene encoding the straitjacket subdomain of the latency-associated peptide (LAP) of pro-TGF-β2. Structural simulations of the mutant LAPs suggested that the mutations could cause significant conformational changes and lead to a reduction in TGF-β2 inactivation. An activity assay confirmed a significant increase in TGF-β2/SMAD signaling. In vitro osteogenic differentiation experiment using iPS cells from one of the CED2 patients showed significantly enhanced ossification, suggesting that the pathogenic mechanism of CED2 is increased activation of TGF-β2 by loss-of-function of the LAP. These results, in combination with the difference in hyperostosis patterns between CED1 and CED2, suggest distinct functions between TGFB1 and TGFB2 in human skeletal development and homeostasis., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Competing Interests: None

Technologies for detecting structural variation (SV) have advanced with the advent of long-read sequencing, which enables the validation of SV at a nucleotide level. Optical genome mapping (OGM), a technology based on physical mapping, can also provide comprehensive SVs analysis. We applied long-read whole genome sequencing (LRWGS) to accurately reconstruct breakpoint (BP) segments in a patient with complex chromosome 6q rearrangements that remained elusive by conventional karyotyping. Although all BPs were precisely identified by LRWGS, there were two possible ways to construct the BP segments in terms of their orders and orientations. Thus, we also used OGM analysis. Notably, OGM recognized entire inversions exceeding 500 kb in size, which LRWGS could not characterize. Consequently, here we successfully unveil the full genomic structure of this complex chromosomal 6q rearrangement and cryptic SVs through combined long-molecule genomic analyses, showcasing how LRWGS and OGM can complement each other in SV analysis., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Background: Status epilepticus, characterized by the temporal neurological deficits, often mimics acute ischemic stroke. We investigated the usefulness of magnetic resonance imaging for differentiation of status epilepticus from acute ischemic stroke., Methods: A retrospective case series of patients with status epilepticus who underwent brain magnetic resonance imaging. For comparative analysis, a series of patients with acute ischemic stroke caused by unilateral middle cerebral artery occlusion was used., Results: Ten patients (4 females and 6 males) with status epilepticus who underwent brain magnetic resonance imaging were included. The median age at diagnosis was 82 years (age range, 70-90 years). In all ten patients, hyperintensities in diffusion-weighted imaging with decreased apparent diffusion coefficient values, decreased venous intensity in susceptibility-weighted imaging, and hyperperfusion in arterial spin labeling perfusion were detected in the cortex of the affected side. Four patients showed an additional diffusion restriction in the thalamus. The apparent diffusion coefficient value of the lesional area was 13.1% less than the contralateral, which was less than one-third as acute ischemic stroke. Status epilepticus patients showed no change in medullary venous intensity of the affected area in susceptibility-weighted imaging, whereas acute ischemic stroke patients showed increased cortical and medullary venous intensity in affected hemisphere. Seven of eight patients with status epilepticus who underwent magnetic resonance angiography showed dilation of the cerebral arteries in the ipsilateral side., Conclusions: The combined use of diffusion-weighted imaging, susceptibility-weighted imaging, and arterial spin labeling perfusion may help accurate and prompt diagnosis of status epilepticus., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Tailored, preventive cancer care requires the identification of pathogenic germline variants (PGVs) among potentially at-risk blood relatives (BRs). Cascade testing is carried out for BRs of probands who are positive for PGVs of an inherited cancer but not for negative probands. This study was conducted to examine the prevalence of PGVs for BRs of PGV-negative probands., Methods: PGV prevalence was assessed for 682 BRs of 281 probands with BRCA1/BRCA2 wild-type hereditary breast and ovarian cancer (HBOC) syndrome., Results: PGVs were discovered in 22 (45.8%) of the 48 BRs of the PGV-positive probands and in 14 (2.2%) of 634 BRs of the PGV-negative probands. Eleven PGVs on high-risk BRCA1, BRCA2, and TP53 genes were present only in BRs and not in the probands (probands vs BRs in Fisher exact test; p = 0.0104; odds ratio [OR] = 0.000 [0.000-0.5489 of 95% confidence interval]), partly due to the nature of the selection criteria. The enrichment of high-risk PGVs among BRs was also significant as compared with a non-cancer East Asian population (p = 0.0016; OR = 3.0791 [1.5521-5.6694]). PGV prevalence, risk class of gene, and genotype concordance were unaffected by the cancer history among BRs., Conclusion: These findings imply the necessity to construct a novel testing scheme to complement cascade testing., (© 2024. The Author(s).)

Libman-Sacks endocarditis is an important cause of embolic stroke in systemic lupus erythematosus, although the detailed pathogenesis of stroke remains unclear. We herein report two cases of stroke with Libman-Sacks endocarditis in which the emboli were retrieved by mechanical thrombectomy. The embolus consisted of eosinophilic homogeneous acellular structures, whereas fibrin-platelet thrombi were hardly observed in the embolus. Immunohistochemistry showed immunoglobulin deposits in the embolus, suggesting that immunological mechanisms were involved in the growth of the embolus. A pathological analysis of the embolus retrieved by mechanical thrombectomy provided useful information on the etiology, leading to optimal treatment.

Metronomic chemotherapy (MC) is based on chronic administration of chemotherapeutic agents at minimally toxic doses without prolonged drug-free breaks, that inhibits tumor angiogenesis and induces tumor dormancy. This study aimed to determine the efficacy of MC for pediatric refractory solid tumors. We retrospectively analyzed the data of pediatric patients with relapsed/refractory solid tumors who received treatment, including low-dose continuous administration of anticancer drugs, at our institute. Of the 18 patients, the disease statuses at the initiation of MC were complete remission (n=2), partial remission/stable disease (n=5), and progressive disease (n=11). The overall survival rate was 61% at 12 months and 34% at 24 months, and the progression-free survival rate was 21% at 12 and 24 months. Although only 5 of the 18 patients showed certain tumor regression or maintained remission, tumors that stabilized, maintained remission/stable disease, and showed certain advantages in terms of overall survival rate, even if limited to progressive disease. Approximately half of the patients demonstrated temporal tumor stabilization and improved survival time. Overall, previous reports and the present study support the conclusion that MC has the potential to play an important role in pediatric cancer treatment during the advanced stage., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Treatment with regorafenib, which inhibits vascular endothelial growth factor (VEGF) receptor, frequently results in hand-foot skin reaction (HFSR), requiring treatment discontinuation or dose reduction. In our prospective study of regorafenib on patients with metastatic colorectal cancer, 17% of patients developed grade 3 HFSR. Herein, we retrospectively examined genetic polymorphisms associated with regorafenib-induced severe HFSR., Methods: To identify associated polymorphisms, exploratory whole-exome sequencing focusing on factors related to VEGF-mediated signaling pathways was first performed in seven patients each, with grade 3 HFSR and without HFSR. The identified HFSR-associated polymorphisms were analyzed in all the 40 patients., Results: The genotype frequency of rs3025009 G/A or A/A in the gene encoding VEGF-A (VEGFA) in patients with ≥ grade 2 HFSR was significantly higher than in other patients (P = 0.0257, Pc = 0.0771 [Bonferroni correction]). The frequency of C-C motif of chemokine ligand 4-like 2 (CCL4L2) rs3744596 A/T or T/T in patients with grade 3 HFSR was significantly lower than in others (P = 0.00894, Pc = 0.0268). The combination of the risk genotypes VEGFA rs3025009 G/A or A/A and CCL4L2 rs3744596 A/A was significantly associated with a higher incidence of grade 3 (P = 0.000614, Pc = 0.00246) and a longer median progression-free survival (P = 0.0234) than others., Conclusions: These VEGF-related polymorphisms were found to be associated with HFSR and the survival benefits of regorafenib treatment., Trial Registration Number and Date: UMIN000013939, registered on May 12, 2014, when 6 months after the approval by the Institutional Review Board of Showa University., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Many outbreaks of coronavirus disease 2019 have occurred in Japanese nursing homes in which residents and staff are in close daily contact. This study evaluated longitudinal changes in antibody titers in nursing homes in which clusters occurred and examined the association between antibody titer and the severe acute respiratory syndrome coronavirus 2 infection or severity., Methods: This cohort study included 171 participants who had provided at least one antibody titer test between June 2022 and March 2023. A descriptive analysis estimated the association between the risk of infection and antibody titer level., Results: The facility experienced 2 clusters during the study period that involved facility staff as the initial source of infection. Noninfected participants had less variation in antibody titer levels and a higher level of preinfection antibodies than infected participants. The risk of infection and severity was lower in participants with higher antibody titers than in those with lower titers., Conclusions: We showed the changes in antibody titers over time and the association between antibody titer and severe acute respiratory syndrome coronavirus 2 infection or severity. Vaccination schedules may need to be tailored to the dynamics of decreasing antibody titers over time and the occurrence of infectious diseases in facilities., (Copyright © 2024 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

This study investigated the association between housing type and clinical remission of infantile-onset allergic rhinitis (AR) in 53,575 children born in 2001 in Japan. Infantile-onset AR was defined as the presence of AR symptoms reported between ages 1.5 and 4.5 years, and remission was assessed between ages 10 and 12. The type of housing was categorized into detached houses and multi-unit residential buildings with 1-2, 3-5, or ≥6 floors. Among the 4,352 infantile-onset AR, 42.9% experienced remission. Notably, living in multi-unit residential buildings, particularly those with 1-2 and ≥6 floors, was positively associated with AR remission., (Copyright © 2023 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.)

Purpose: Identification of drainage vessels is useful for differential diagnosis of hepatic tumors. Direct drainage to the hepatic vein has been reported to occur in focal nodular hyperplasia (FNH), but studies evaluating the drainage veins of FNH are limited. We aimed to investigate the detection rate of the FNH drainage vein and the factors related to visualization of the drainage vein on contrast-enhanced ultrasound (CEUS)., Methods: Fifty consecutive patients with 50 FNH lesions were retrospectively evaluated in this study. We calculated and compared the detection rate of the FNH drainage vein on CEUS, contrast-enhanced magnetic resonance imaging (CEMRI), and contrast-enhanced computed tomography (CECT), and identified the factors correlated with visualization of the FNH drainage vein on CEUS by using multivariate logistic regression analyses., Results: Visualization of the drainage vein was confirmed in 31 of 50 lesions (62%) using CEUS, three of 44 lesions (6.8%) using CEMRI, and one of 18 lesions (5.6%) using CECT. The detection rate of the FNH drainage vein on CEUS was significantly higher than that on CEMRI and CECT (p < 0.001). Multivariate analysis identified lesion size (≥ 25 mm) and detection of the spoke-wheel pattern on Doppler US as independent factors for drainage vein detection in FNH., Conclusion: Our study showed that rapid FNH drainage to the hepatic vein was observed at a relatively high rate on CEUS, suggesting that CEUS focusing on detection of drainage veins is important for diagnosing FNH., (© 2024. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

We herein report a case with a novel homozygous variant in the kyphoscoliosis peptidase (KY) gene. A 58-year-old Japanese female was referred to our hospital with a gait disturbance that gradually worsened after the age of 50. She had bilateral equinus foot deformity since early childhood. Neurological examination revealed moderate weakness of the neck, trunk, femoral, and brachial muscles, mild respiratory failure, and areflexia. Whole-exome sequencing revealed a novel homozygous frameshift variant of the KY gene, NM&#95;178554.6:c.824del p.(Glu275Glyfs*53). Our case demonstrated that KY-associated neuromuscular disease can present with extremely slow progressive muscle weakness and respiratory failure over a long natural course., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Although wild bird rehabilitation facilities are important for the conservation of wild species, individuals may be kept within the facilities for long periods, consequently posing a risk for the bird to be infected with pathogens to which they are not naturally exposed. In turn, novel pathogens may be introduced through rescued migratory species. Avian malaria and West Nile fever are important avian diseases transmitted by mosquitoes. To understand the transmission dynamics of such diseases at rehabilitation facilities, the ecology of vector mosquitoes, including species composition, seasonality, and feeding behaviors, were explored. Mosquitoes were collected at a wild bird rehabilitation facility and wildlife sanctuary in Japan from 2019 to 2020 using mouth aspirators, sweep nets, and light traps. A total of 2,819 mosquitoes of 6 species were captured, all of which are potential vectors of avian diseases. Culex pipiens pallens and Cx. pipiens form molestus were the dominant species (82.9% of all collected mosquitoes). Density and seasonality differed between sampling locations, presumably because of differences in mosquito behaviors including feeding preferences and responses to climatic factors. Blood-fed Culex mosquitoes fed solely on birds, and many mosquito species are thought to have fed on birds within the facility. Particularly, Cx. pipiens group probably fed on both rescued and free-living birds. The rehabilitation facility may be an important site for the introduction and spread of pathogens because 1) numerous mosquitoes inhabit the hospital and its surroundings; 2) blood-fed mosquitoes are caught within the hospital; 3) there is direct contact between birds and mosquitoes; 4) both birds within the hospital and wild birds are fed upon. Furthermore, blood-fed Cx. pipiens form molestus were observed in the winter, suggesting that pathogens might be transmitted even during the winter when other mosquito species are inactive., (© Wildlife Disease Association 2024.)

Xenobiotic metabolic reactions in the hepatocyte endoplasmic reticulum (ER) including UDP-glucuronosyltransferase and carboxylesterase play central roles in the detoxification of medical agents with small- and medium-sized molecules. Although the catalytic sites of these enzymes exist inside of ER, the molecular mechanism for membrane permeation in the ER remains enigmatic. Here, we investigated that organic anion transporter 2 (OAT2) regulates the detoxification reactions of xenobiotic agents including anti-cancer capecitabine and antiviral zidovudine, via the permeation process across the ER membrane in the liver. Pharmacokinetic studies in patients with colorectal cancer revealed that the half-lives of capecitabine in rs2270860 (1324C > T) variants was 1.4 times higher than that in the C/C variants. Moreover, the hydrolysis of capecitabine to 5'-deoxy-5-fluorocytidine in primary cultured human hepatocytes was reduced by OAT2 inhibitor ketoprofen, whereas capecitabine hydrolysis directly assessed in human liver microsomes were not affected. The immunostaining of OAT2 was merged with ER marker calnexin in human liver periportal zone. These results suggested that OAT2 is involved in distribution of capecitabine into ER. Furthermore, we clarified that OAT2 plays an essential role in drug-drug interactions between zidovudine and valproic acid, leading to the alteration in zidovudine exposure to the body. Our findings contribute to mechanistically understanding medical agent detoxification, shedding light on the ER membrane permeation process as xenobiotic metabolic machinery to improve chemical changes in hydrophilic compounds., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: DYT-KMT2B, also known as DYT28, is a childhood-onset hereditary dystonia caused by KMT2B mutation. The pathogenesis of DYT-KMT2B involves haploinsufficiency of KMT2B, an enzyme that catalyzes specific histone methylation (H3K4me3). Dysmorphic features in patients with DYT-KMT2B suggest that KMT2B dysfunction may extend beyond the neuronal system. Therefore, valuable diagnostic insights may be obtained from readily available tissue samples., Objectives: To explore the altered H3K4me3 levels in non-neural tissue of DYT-KMT2B patients., Methods: A database analysis was performed to determine in which parts of the body and in which cells KMT2B is highly expressed. Twelve clinically and genetically diagnosed patients with DYT-KMT2B and 12 control subjects participated in this study. Oral mucosa-derived purified histone proteins were analyzed using Western blotting with anti-H3K4me3 and anti-H4 antibodies., Results: Higher expression of KMT2B was observed in oral keratinocytes and gingival fibroblasts, constituting the oral mucosa. In oral mucosa analyses, DYT-KMT2B cases exhibited markedly reduced H3K4me3 levels compared with the controls. Using a cutoff window of 0.90-0.98, the H3K4me3/H4 expression ratio was able to distinguish patient groups., Conclusions: Oral mucosa H3K4me3 analysis is currently not sufficient as a diagnostic tool for DYT-KMT2B, but has the advantage for screening test since it is a non-invasive means., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Naomichi Matsumoto reports financial support was provided by Takeda Science Foundation. If there are other authors, they 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 © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: We assessed microvessel flow within peripheral nerves using nerve sonography in patients with peripheral neuropathy., Methods: This study included consecutive patients with peripheral neuropathy who were admitted to our hospital. The patients were divided into two groups: inflammatory neuropathies for immune-mediated neuropathies, such as Guillain - Barré syndrome and chronic inflammatory demyelinating polyneuropathy, and the rest were defined as non-inflammatory neuropathies. We assessed nerve size and intraneural blood flow at four sites on each median and ulnar nerve. Blood flow was evaluated using color Doppler imaging, advanced dynamic flow (ADF), and superb microvascular imaging (SMI) techniques., Results: Thirty-nine patients (median age, 60.0 years; 20 male) were enrolled in this study. An increase in intraneural blood flow was observed in five patients when evaluated by color Doppler, five patients by ADF, and 13 patients by SMI. An overall analysis of the three methods showed that intraneural blood flow was significantly higher in patients with inflammatory neuropathy than in those with non-inflammatory neuropathy (54.2% vs. 0%, p = 0.0005)., Conclusions: Intraneural hypervascularization is more frequent in patients with inflammatory neuropathy than in those with non-inflammatory neuropathy., Significance: Evaluation of microvessel flow within peripheral nerves may contribute to the diagnosis of peripheral neuropathy., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective:  We aimed to examine the association between respiratory severity score (RSS; mean airway pressure × fraction of inspired oxygen) and neurodevelopmental outcomes in extremely preterm infants., Study Design:  This was a single-center, retrospective cohort study. We analyzed data from extremely preterm infants who were admitted to the neonatal intensive care unit at Okayama Medical Center between 2010 and 2019. Infants without invasive respiratory management during the first day of life were excluded. The exposure variable was the highest RSS during the first day of life. RSS was categorized into two groups: low (<3.5) and high (≥3.5) RSS. The primary outcome was death or neurodevelopmental impairment at age 3 years, defined as cognitive impairment (developmental quotient <70) or the presence of cerebral palsy. Secondary outcomes were the components of the primary outcome. We conducted robust Poisson regression analyses to investigate the association between RSS category and primary and secondary outcomes, adjusting for perinatal confounders., Results:  The cohort included 97 infants with neurodevelopmental data, of whom 34 and 63 infants were in the low- and high-RSS categories, respectively. The median (interquartile range) gestational age and birth weight were 26.0 (24.7-26.9) and 25.7 (24.6-26.7) weeks and 761 (584-866) and 806 (618-898) g for infants in the low- and high-RSS categories, respectively. Compared with infants in the low-RSS category, those in the high-RSS category had a greater risk of death or neurodevelopmental impairment at age 3 years (26.3 vs. 42.3%; adjusted risk ratio [RR], 2.0; 95% confidence interval [CI], 1.1-3.5) and neurodevelopmental impairment at age 3 years (17.6 vs. 28.6%; adjusted RR, 2.7; 95% CI, 1.3-5.9)., Conclusion:  High RSS (≥3.5) during the first day of life was associated with an increased risk of neurodevelopmental impairment at age 3 years in extremely preterm infants., Key Points: · RSS is a valuable tool for assessing respiratory failure.. · RSS = Mean airway pressure × fraction of inspired oxygen.. · RSS at age 1 day was associated with neurodevelopment.., Competing Interests: None declared., (Thieme. All rights reserved.)

Organic crystals are a promising class of materials for various optical applications. However, it has been challenging to make macroscopic organic crystals with bicontinuous porosity that are applicable to flow chemistry. In this study, a new class of porous materials, cm-scale crystalline organic monoliths (COMs) with bicontinuous porosity, are synthesized by replicating the porous structure of silica monolith templates. The COMs composed of p -terphenyl can take up more than 30 wt% of an aqueous solution, and the photophysical properties of the p -terphenyl crystals are well maintained in the COMs. The relatively high surface area of the COMs can be exploited for efficient Dexter energy transfer from triplet sensitizers on the pore surface. The resulting triplet excitons in the COMs encounter and annihilate, generating upconverted UV emission. The COMs would open a new avenue toward applications of organic crystals in flow photoreaction systems., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

OTULIN-related autoinflammatory syndrome (ORAS), a severe autoinflammatory disease, is caused by biallelic pathogenic variants of OTULIN, a linear ubiquitin-specific deubiquitinating enzyme. Loss of OTULIN attenuates linear ubiquitination by inhibiting the linear ubiquitin chain assembly complex (LUBAC). Here, we report a patient who harbors two rare heterozygous variants of OTULIN (p.P152L and p.R306Q). We demonstrated accumulation of linear ubiquitin chains upon TNF stimulation and augmented TNF-induced cell death in mesenchymal stem cells differentiated from patient-derived iPS cells, which confirms that the patient has ORAS. However, although the de novo p.R306Q variant exhibits attenuated deubiquitination activity without reducing the amount of OTULIN, the deubiquitination activity of the p.P152L variant inherited from the mother was equivalent to that of the wild-type. Patient-derived MSCs in which the p.P152L variant was replaced with wild-type also exhibited augmented TNF-induced cell death and accumulation of linear chains. The finding that ORAS can be caused by a dominant-negative p.R306Q variant of OTULIN furthers our understanding of disease pathogenesis., (© 2024 Takeda et al.)