Search

Abstract IgA pemphigus is an autoimmune bullous disease caused by anti‐keratinocyte cell surface IgA autoantibodies. Mucous membrane involvement is rare in IgA pemphigus. We report a case of IgA pemphigus with oral mucosal lesions, in which acantholysis was pathologically confirmed. A 31‐year‐old woman presented with skin erythema with small pustules and oral mucosal erosions. Histopathological examination of the erosions on her oral mucosa and papules on her back revealed acantholysis and intraepidermal infiltration of neutrophils. Direct immunofluorescence tests showed intercellular deposition of IgA, but not IgG, mainly in the lower, but not entire, layer of the epidermis. C3 was linearly present in the basement membrane zone (BMZ), but not in the intercellular space. Enzyme‐linked immunosorbent assay revealed that both anti‐desmoglein (Dsg) 3 IgA and IgG were positive. Neither IgA nor IgG against desmocollin 1–3 were detected. This case was clinically and histologically compatible with IgA pemphigus, but immunologically anti‐BMZ autoimmunity was additionally observed. IgA pemphigus is classified into two major types: subcorneal pustular dermatosis type and intraepidermal neutrophilic dermatosis type. This case was not typical in terms of rarely observed oral lesions and predominant deposition of IgA in the lower layer of the epidermis. Instead, this case could be considered a rare subtype of IgA pemphigus, IgA‐pemphigus vulgaris. Oral lesions in IgA pemphigus may be clinical clue of having anti‐Dsg3 IgA that cannot be routinely examined.

Abstract The N-terminal fragment of apolipoprotein A-I (apoA-I), comprising residues 1–83, contains three segments prone to aggregation: residues 14–22, 53–58, and 67–72. We previously demonstrated that residues 14–22 are critical in apoA-I fibril formation while residues 53–58 entropically drove the nucleation process. Here, we investigated the impact of amyloidogenic mutations (Δ60–71/VT, Δ70–72, and F71Y) located around residues 67–72 on fibril formation by the apoA-I 1–83 fragment. Thioflavin T fluorescence assay demonstrated that the Δ60–71/VT mutation significantly enhances both nucleation and fibril elongation rates, whereas the Δ70–72 and F71Y mutations had minimal effects. Circular dichroism measurements and microscopic observations revealed that all variant fragments formed straight fibrils, transitioning from random coils to β-sheet structures. Kinetic analysis demonstrated that primary nucleation is the dominant step in fibril formation, with fibril elongation reaching saturation at high protein concentrations. Thermodynamically, both nucleation and fibril elongation were enthalpically and entropically unfavorable in all apoA-I 1–83 variants, in which the entropic barrier of nucleation was almost eliminated for the Δ60–71/VT variant. Taken together, our results suggest the presence of new aggregation-prone segment in the Δ60–71/VT variant that promotes nucleation through entropic effects.

Background/Aims The necessity for pharyngeal anesthesia during upper gastrointestinal endoscopy is controversial. This study aimed to compare the observation ability with and without pharyngeal anesthesia under midazolam sedation. Methods This prospective, single-blinded, randomized study included 500 patients who underwent transoral upper gastrointestinal endoscopy under intravenous midazolam sedation. Patients were randomly allocated to pharyngeal anesthesia: PA+ or PA– groups (250 patients/group). The endoscopists obtained 10 images of the oropharynx and hypopharynx. The primary outcome was the non-inferiority of the PA– group in terms of the pharyngeal observation success rate. Results The pharyngeal observation success rates in the pharyngeal anesthesia with and without (PA+ and PA–) groups were 84.0% and 72.0%, respectively. The PA– group was inferior (p=0.707, non-inferiority) to the PA+ group in terms of observable parts (8.33 vs. 8.86, p=0.006), time (67.2 vs. 58.2 seconds, p=0.001), and pain (1.21±2.37 vs. 0.68±1.78, p=0.004, 0–10 point visual analog scale). Suitable quality images of the posterior wall of the oropharynx, vocal fold, and pyriform sinus were inferior in the PA– group. Subgroup analysis showed a higher sedation level (Ramsay score ≥5) with almost no differences in the pharyngeal observation success rate between the groups. Conclusions Non-pharyngeal anesthesia showed no non-inferiority in pharyngeal observation ability. Pharyngeal anesthesia may improve pharyngeal observation ability in the hypopharynx and reduce pain. However, deeper anesthesia may reduce this difference.

Unequivocal functional assessment of candidate genomic regulatory regions, such as transcriptional response elements, requires genetic alteration at their native chromosomal loci. Targeted DNA cleavage by Cas9 or other programmable nucleases enables analysis at virtually any genomic region, and diverse alleles generated by editing can be defined by deep sequencing for functional analysis. Interpretation of disrupted response elements, however, presents a special challenge, as these regions typically comprise clustered DNA binding motifs for multiple transcriptional regulatory factors (TFs); DNA sequence differences, natural or engineered, that affect binding by one TF can confer loss or gain of binding sites for other TFs. To address these and other analytical complexities, we created three computational tools that together integrate, in a single experiment, allele definition and TF binding motif evaluation for up to 9216 clones isolated, sequenced and propagated from Cas9-treated cell populations. We demonstrate 1) the capacity to functionally assess edited TF binding sites to query response element function, and 2) the efficacy and utility of these tools, by analyzing cell populations targeted by Cas9 for disruption of example glucocorticoid receptor (GR) binding motifs near FKBP5, a GR-regulated gene in the human adenocarcinoma cell line A549.

Abstract Aim The purpose of this study is to evaluate the safety and pharmacokinetics of the novel morpholino oligomer NS‐089/NCNP‐02 which can induce exon 44 skipping, in patients with DMD. Additionally, we aimed to identify markers predictive of therapeutic efficacy and determine the optimal dosing for future studies. Methods This is an open‐label, dose‐escalation, two‐center phase I/II trial in ambulant patients with DMD, presence of an out‐of‐frame deletion, and a mutation amenable to exon 44 skipping. Part 1 is a stepwise dose‐finding stage (4 weeks) during which NS‐089/NCNP‐02 will be administered intravenously at four dose levels once weekly (1.62, 10, 40, and 80 mg/kg); Part 2 is a 24‐week evaluation period based on the dosages determined during Part 1. The primary (safety) endpoints are the results of physical examinations, vital signs, 12‐lead electrocardiogram and echocardiography tests, and adverse event reporting. Secondary endpoints include expression of dystrophin protein, motor function assessment, exon 44 skipping efficiency, plasma and urinary NS‐089/NCNP‐02 concentrations, and changes in blood creatine kinase levels. Discussion Exon‐skipping therapy using ASOs shows promise in selected patients, and this first‐in‐human study is expected to provide critical information for subsequent clinical development of NS‐089/NCNP‐02.

Abstract Various autoimmune responses increase with age, but the underlying mechanism is not clear. In this study, we used CD4+ T cells expressing a transgenic T cell receptor specific for desmoglein 3 (Dsg3), which is the target antigen of the autoimmune bullous disease pemphigus vulgaris, to examine how peripheral immunological tolerance against pathogenic autoreactive CD4+ T cells changes with age. Dsg3-specific T cells were deleted within 14 days after adoptive transfer into young mice (8 weeks old), while they escaped deletion when transferred into older mice over 42 weeks old. Dsg3-specific T cells produced higher levels of the proinflammatory cytokine IFN-γ in aged mice than in young mice. In addition, the expression levels of both OX40 and Birc5, which are important for cell survival in T cell clonal proliferation, were higher in aged than in young mice. The dysfunction in suppressing proinflammatory cytokine secretion and Birc5 upregulation in Dsg3-specific autoreactive T cells may reflect an aspect of the preliminary steps in autoimmune disease development in the aged population. Understanding this mechanism may lead to better risk evaluation of autoimmune disease development and to onset prevention.

Key Clinical Message We report a case of leukemia cutis showing annular erythema during the course of Philadelphia chromosome‐positive acute B‐lymphoblastic leukemia. The annular appearance may be developed by immunomodulatory effects of blinatumomab.

Objectives To assess 52-week safety and efficacy of bimekizumab in patients with active psoriatic arthritis (PsA) and prior inadequate response/intolerance to tumour necrosis factor inhibitors.Methods Patients completing the 16-week phase III double-blind, placebo-controlled BE COMPLETE (NCT03896581) study entered the open-label extension, BE VITAL (NCT04009499). All patients in BE VITAL received 160 mg bimekizumab every 4 weeks. Safety and efficacy are reported to week 52.Results A total of 347/400 (86.8%) patients completed week 52. To week 52, the exposure-adjusted incidence rate/100 patient-years for ≥1 treatment-emergent adverse event (TEAE) was 126.0, and was 7.0 for serious TEAEs. The most frequent TEAEs were SARS-CoV-2 (COVID-19), oral candidiasis, nasopharyngitis and urinary tract infection. All fungal infections were mild or moderate in severity and localised; two patients discontinued the study due to oral candidiasis. No cases of active tuberculosis, uveitis or inflammatory bowel disease were reported. One sudden death occurred. Sustained efficacy was observed with bimekizumab from week 16 to ‍52 across clinical and patient-reported outcomes. At week 52, 51.7% bimekizumab-randomised and 40.6% placebo/bimekizumab patients (receiving bimekizumab from week 16 to 52) had ≥50% improvement in the American College of Rheumatology criteria. Complete skin clearance (Psoriasis Area and Severity Index 100) was achieved by 65.9% bimekizumab and 60.2% placebo/bimekizumab patients at week 52. Minimal disease activity was achieved by 47.2% bimekizumab and 33.1% placebo/bimekizumab patients at week 52.Conclusions Bimekizumab demonstrated a safety profile consistent with previous reports; no new safety signals were identified. Sustained efficacy was observed from week 16 to 52.

We have discovered analytical expressions for the probability density function (PDF) of photons that are multiply scattered in relativistic flows, under the assumption of isotropic and inelastic scattering. These expressions characterize the collective dynamics of these photons, ranging from free-streaming to diffusion regions. The PDF, defined within the light cone to ensure the preservation of causality, is expressed in a three-dimensional space at a constant time surface. This expression is achieved by summing the PDFs of photons that have been scattered n times within four-dimensional space-time. We have confirmed that this formulation accurately reproduces the results of relativistic Monte Carlo simulations. We found that the PDF in three-dimensional space at a constant time surface can be represented in a separable variable form. We demonstrate the behavior of the PDF in the laboratory frame across a wide range of Lorentz factors for the relativistic flow. When the Lorentz factor of the fluid is low, the behavior of scattered photons evolves sequentially from free propagation to diffusion, and then to dynamic diffusion, where the mean effective velocity of the photons equates to that of the fluid. On the other hand, when the Lorentz factor is large, the behavior evolves from anisotropic ballistic motion, characterized by a mean effective velocity approaching the speed of light, to dynamic diffusion.

Background/aimAntiviral hepatitis and systemic therapies for hepatocellular carcinoma (HCC) remarkably progressed in the recent 10 years. This study aimed to reveal the actual transition and changes in the prognosis and background liver disease in non-advanced HCC in the past 20 years.MethodsThis retrospectively recruited 566 patients who were diagnosed with non-advanced HCC from February 2002 to February 2022. The prognosis was analyzed by subdividing according to the diagnosis date (period I: February 2002-April 2009 and period Ⅱ: May 2009-February 2022).ResultsPatients in period II (n = 351) were significantly older, with lower albumin-bilirubin (ALBI) scores and alpha-fetoprotein (AFP) and more anti-viral therapy, systemic therapy, and hepatic arterial infusion chemotherapy as compared with those in period I (n = 215). The etiology ratio of the background liver disease revealed decreased hepatitis C virus from 70.6% to 49.0% and increased non-B, non-C from 17.7% to 39.9% from periods I to Ⅱ. The multivariate analysis revealed older age and higher ALBI score in Barcelona Clinic Liver Cancer (BCLC) 0/A stage, AFP of >20 ng/mL, and higher ALBI score in BCLC B stage as independent prognosis factors. Fine-Gray competing risk model analysis revealed that liver-related deaths significantly decreased in period II as compared to period I, especially for BCLC stage 0/A (HR: 0.656; 95%CI: 0.442-0.972, P = 0.036).ConclusionThe characteristics of patients with non-advanced HCC have changed over time. Appropriate background liver management led to better liver-related prognoses in BCLC 0/A.

Immune checkpoint inhibitors have drastically improved cancer treatment. However, they may induce immune-related adverse events (irAEs). Here, we report a case of significantly delayed rheumatic irAEs (Rh-irAEs) with prior possible temporary neutropenic irAEs in a patient with atezolizumab-treated non-small-cell lung cancer and its management. A man in his sixties received atezolizumab monotherapy as the sixth-line treatment. He experienced an infusion-related reaction (fever) during the first cycle. On day 22 of cycle 2, grade 4 neutropenia suddenly appeared, but it disappeared on the next day. Cycle 3 was initiated after seven days; the patient did not exhibit any symptoms for approximately 500 days. However, on day 534 (day 1 of cycle 21), the patient complained of pain in the shoulders, back, and wrists. On day 644, the shoulder and back pain worsened with obvious swelling of the fingers. We thus suspended treatment and consulted a rheumatologist. A diagnosis of polyarthritis with active tenosynovitis was made based on joint ultrasound and laboratory tests. Prednisolone 15 mg attenuated the symptoms, allowing suspension of analgesics; however, dose reduction from 15 mg/day was difficult because of symptom flares. Finally, iguratimod 25 mg twice daily was initiated on day 764; prednisolone was reduced to 10 mg without flares, and its dosage was slowly reduced to 5 mg/day. Although irAEs exhibit multisystem features, delayed development of polyarthritis with active tenosynovitis after possible temporary neutropenic irAEs is rare. Thus, irAEs need to be monitored for a long time in patients with suspected irAE development even if it appears transiently.

Key Clinical Message We encountered an immunocompromised patient with severe respiratory disease immediately after the onset of varicella. Varicella zoster virus infection may be associated with more severe immunosuppressive condition.

The interior noise characteristics of railway vehicles vary depending on the position of the cabin. In general, interior noises are louder in the area directly above bogies (ends of the cabin) than in the center of the cabin. It has been known that structure-borne sounds from bogies contribute greatly to the interior noises directly above bogies. This paper describes, using measured data obtained with the rolling stock test plant at Railway Technical Research Institute (RTRI), the application of the operational transfer path analysis (OTPA) to determine the contribution ratio of each transmission path of vibration from bogies to cabin floors. It is considered that structure-borne sounds from bogies propagate mainly through the parts connecting the bogie and car body such as single-link-type traction devices (traction links), yaw dampers, and air springs. As a result of applying the OTPA and determining the contribution ratios, it has been confirmed that the contribution ratios varied depending on the position of the floor and the frequency band. In addition, the validity of the contribution has been verified by examining the linearity of input/output data and the correlations of input data using multiple coherence functions and partial coherence functions. Although a bogie vibrates rigidly in the low frequency range with the very high correlation between the vibrations of the bogie and the parts connecting the bogie and car body, the correlation becomes low in the high frequency region. Therefore, it is expected that the contribution of each transfer path can be well estimated by applying the OTPA in the high frequency range for structure-borne sounds from bogies.

BackgroundMultiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes myelin sheath damage and axonal degeneration. The glycolipid (2S, 3S, 4R)-1-O-(α-d-galactosyl)-2-tetracosanoylamino-1,3,4-nonaetriol (OCH-NCNP1 or OCH) exerts an immunoregulatory action that suppresses T helper (Th)1 cell–mediated immune responses through natural killer T cell activation, selective interleukin-4 production, and Th2 bias induction in human CD4-positive natural killer T cells. ObjectiveThis trial aims to investigate the efficacy and safety of the immunomodulator OCH in patients with relapsing MS through 24-week repeated administration. MethodsThis protocol describes a double-blind, multicenter, placebo-controlled, randomized phase II clinical trial that was initiated in September 2019. The participants were randomly assigned to either a placebo control group or an OCH-NCNP1 group and the investigational drug (3.0 mg) was orally administered once weekly for the 24-week duration. Major inclusion criteria are as follows: patients had been diagnosed with relapsing MS (relapsing-remitting and/or secondary progressive MS) based on the revised McDonald criteria or were diagnosed with MS by an attending physician as noted in their medical records; patients with at least two medically confirmed clinical exacerbations within 24 months prior to consent or one exacerbation within 12 months prior to consent; patients with at least one lesion suspected to be MS on screening magnetic resonance imaging (MRI); and patients with 7 points or less in the Expanded Disability Status Scale during screening. Major exclusion criteria are as follows: diagnosis of neuromyelitis optica and one of optic neuritis, acute myelitis, and satisfying at least two of the following three items: (1) spinal cord MRI lesion extending across at least three vertebral bodies, (2) no brain MRI lesions during onset (at least four cerebral white matter lesions or three lesions, one of which is around the lateral ventricle), and (3) neuromyelitis optica–immunoglobulin G or antiaquaporin-4 antibody-positive. Outcome measures include the primary outcome of MRI changes (the percentage of subjects with new or newly expanded lesions at 24 weeks on T2-weighted MRI) and the secondary outcomes annual relapse rate (number of recurrences per year), relapse-free period (time to recurrence), sustained reduction in disability (SRD) occurrence rate, period until SRD (time to SRD occurrence), no evidence of disease activity, and exploratory biomarkers from phase I trials (such as gene expression, cell frequency, and intestinal and oral microbiome). ResultsWe plan to enroll 30 patients in the full analysis set. Enrollment was closed in June 2021 and the study analysis was completed in March 2023. ConclusionsThis randomized controlled trial will determine whether OCH-NCNP1 is effective and safe in patients with MS as well as provide evidence for the potential of OCH-NCNP1 as a therapeutic agent for MS. Trial RegistrationClinicalTrials.gov NCT04211740; https://clinicaltrials.gov/study/NCT04211740 International Registered Report Identifier (IRRID)DERR1-10.2196/46709

Facial skin blood flow (SkBF) has attracted attention as an autonomic indicator because it influences facial colour, which informs others of emotional states, and facial temperature related to social anxiety. Previous studies have examined the facial SkBF in people experiencing emotions; however, facial SkBF changes in the observers of emotions are poorly understood. Our study clarified facial SkBF changes related to observing others’ emotions by comparing the changes with other physiological indices. Thirty healthy participants (24 females; mean age: 22.17) observed six types of facial expressions (neutral, angry, and embarrassed expressions with and without facial blushing) and rated the emotional intensity of the other person. We measured their facial SkBF, finger SkBF, and cardiac RR interval as they made their observations. Facial SkBF generally decreased in relation to observing emotional faces (angry and embarrassed faces) and significantly decreased for angry expressions with blushing. None of the participants noticed blushing of facial stimuli. For the RR interval and finger SkBF, there was no variation depending on the observed facial expressions, although there was a general increase related to observation. These results indicated that facial SkBF is sensitive and reactive to emotional faces—especially angry faces with blushing— compared with other autonomic indices. The facial SkBF changes were not related to either RR interval changes or the intensity rating, suggesting that facial SkBF changes may be caused by vasoconstriction and have potential functions for our emotions. The decrease in facial SkBF may have a role in calming observers by preventing them from adopting the same emotional state as a person with intense anger. These findings clarify daily facial SkBF fluctuations and their relationship with our emotional processing in interpersonal situations.

Abstract Purpose Immune‐checkpoint inhibitors (ICIs) are effective against advanced non‐small cell lung cancer (NSCLC). However, whether the efficacy and safety of ICI treatment in elderly patients are similar to those in younger patients is unclear. This study was designed to address this question. Methods We enrolled patients who received ICI monotherapy in Japan between December 2015 and December 2017; those ≥75 years of age comprised the elderly group. We compared the efficacy and safety of ICI monotherapy in elderly patients with those in younger patients and explored prognostic factors in elderly patients. Results We enrolled 676 patients; 137 (20.3%) were assigned to the elderly group. The median age of the elderly and younger groups was 78 (range, 75–85) and 66 (range, 34–74) years. The median progression‐free survival (4.8 months vs. 3.3 months, p = 0.1589) and median overall survival (12.3 months vs. 13.0 months, p = 0.5587) were similar between the elderly and younger groups. Multivariate analysis revealed that a significantly better OS in the elderly group was associated with better responses to first‐ or second‐line ICI treatment (p = 0.011) and more immune‐related adverse events (irAEs) (p = 0.02). IrAEs that led to ICI discontinuation occurred in 34 of 137 patients (24.8%) in the elderly group, and their survival was significantly higher than that in those who did not have irAEs. Conclusion ICI is also effective in elderly NSCLC patients, and treatment discontinuation due to irAEs may be a good prognostic marker.

Here, we describe a case of temporary severe neutropenia after atezolizumab monotherapy and its treatment course. Atezolizumab monotherapy was introduced as a 6th-line treatment for a man in his late 60s, who was diagnosed with stage Ⅳ lung adenocarcinoma. The first treatment cycle was administered during hospitalization, and the patient presented with a fever of 37.8°C on the first day. The fever resolved after the administration of acetaminophen and naproxen, and the white blood cell count, neutrophil count, and other white blood cell fractions were normal. However, grade 3 leukopenia and grade 4 neutropenia appeared at the beginning of the third cycle, and treatment was discontinued. After treatment, monocyte count in the leukocyte fraction increased from approximately 10% to 25.6%. Lenograstim 100 μg subcutaneous injection and oral levofloxacin 500 mg once daily were started of onset of neutropenia, and he was hospitalized the next day. Laboratory findings upon admission showed a significant improvement to 5,300/µL for leukocytes and 3,376/µL for neutrophils. Lenograstim was discontinued, with no further decrease in the neutrophil count. Atezolizumab therapy was resumed, and there was no further reduction in leukocyte, neutrophil, or leukocyte fractions over about a 2-year period. Concomitant drugs were maintained during the atezolizumab treatment, suggesting that they did not induce neutropenia. In conclusion, we observed temporary severe neutropenia during atezolizumab monotherapy. Neutrophil recovery with cautious monitoring has enabled longer efficacy. We should consider temporary symptom occurrence in cases of haematological immune-related adverse events.

Background: Schnitzler syndrome is a rare disorder with chronic urticaria, and there is no report summarizing the current status in Japan. Methods: A nationwide survey of major dermatology departments in Japan was conducted in 2019. We further performed a systematic search of PubMed and Ichushi-Web, using the keywords “Schnitzler syndrome” and “Japan” then contacted the corresponding authors or physicians for further information. Results: Excluding duplicates, a total of 36 clinically diagnosed cases were identified from 1994 through the spring of 2022, with a male to female ratio of 1:1. The median age of onset was 56.5 years. It took 3.3 years from the first symptom, mostly urticaria, to reach the final diagnosis. The current status of 30 cases was ascertained; two patients developed B-cell lymphoma. SchS treatment was generally effective with high doses of corticosteroids, but symptoms sometimes recurred after tapering. Colchicine was administered in 17 cases and was effective in 8, but showed no effect in the others. Tocilizumab, used in six cases, improved laboratory abnormalities and symptoms, but lost its efficacy after several years. Rituximab, used in five cases, was effective in reducing serum IgM levels or lymphoma mass, but not in inflammatory symptoms. Four cases were treated with IL-1 targeting therapy, either anakinra or canakinumab, and achieved complete remission, except one case with diffuse large B-cell lymphoma. Conclusions: Since Schnitzler syndrome is a rare disease, the continuous collection and long-term follow-up of clinical information is essential for its appropriate treatment and further understanding of its pathophysiology.

An educational augmented reality auscultation system (EARS) is proposed to enhance the reality of auscultation training using a simulated patient. The conventional EARS cannot accurately reproduce breath sounds according to the breathing of a simulated patient because the system instructs the breathing rhythm. In this study, we propose breath measurement methods that can be integrated into the chest piece of a stethoscope. We investigate methods using the thoracic variations and frequency characteristics of breath sounds. An accelerometer, a magnetic sensor, a gyro sensor, a pressure sensor, and a microphone were selected as the sensors. For measurement with the magnetic sensor, we proposed a method by detecting the breathing waveform in terms of changes in the magnetic field accompanying the surface deformation of the stethoscope based on thoracic variations using a magnet. During breath sound measurement, the frequency spectra of the breath sounds acquired by the built-in microphone were calculated. The breathing waveforms were obtained from the difference in characteristics between the breath sounds during exhalation and inhalation. The result showed the average value of the correlation coefficient with the reference value reached 0.45, indicating the effectiveness of this method as a breath measurement method. And the evaluations suggest more accurate breathing waveforms can be obtained by selecting the measurement method according to breathing method and measurement point.

BackgroundGenerative artificial intelligence (GAI), represented by large language models, have the potential to transform health care and medical education. In particular, GAI’s impact on higher education has the potential to change students’ learning experience as well as faculty’s teaching. However, concerns have been raised about ethical consideration and decreased reliability of the existing examinations. Furthermore, in medical education, curriculum reform is required to adapt to the revolutionary changes brought about by the integration of GAI into medical practice and research. ObjectiveThis study analyzes the impact of GAI on medical education curricula and explores strategies for adaptation. MethodsThe study was conducted in the context of faculty development at a medical school in Japan. A workshop involving faculty and students was organized, and participants were divided into groups to address two research questions: (1) How does GAI affect undergraduate medical education curricula? and (2) How should medical school curricula be reformed to address the impact of GAI? The strength, weakness, opportunity, and threat (SWOT) framework was used, and cross-SWOT matrix analysis was used to devise strategies. Further, 4 researchers conducted content analysis on the data generated during the workshop discussions. ResultsThe data were collected from 8 groups comprising 55 participants. Further, 5 themes about the impact of GAI on medical education curricula emerged: improvement of teaching and learning, improved access to information, inhibition of existing learning processes, problems in GAI, and changes in physicians’ professionality. Positive impacts included enhanced teaching and learning efficiency and improved access to information, whereas negative impacts included concerns about reduced independent thinking and the adaptability of existing assessment methods. Further, GAI was perceived to change the nature of physicians’ expertise. Three themes emerged from the cross-SWOT analysis for curriculum reform: (1) learning about GAI, (2) learning with GAI, and (3) learning aside from GAI. Participants recommended incorporating GAI literacy, ethical considerations, and compliance into the curriculum. Learning with GAI involved improving learning efficiency, supporting information gathering and dissemination, and facilitating patient involvement. Learning aside from GAI emphasized maintaining GAI-free learning processes, fostering higher cognitive domains of learning, and introducing more communication exercises. ConclusionsThis study highlights the profound impact of GAI on medical education curricula and provides insights into curriculum reform strategies. Participants recognized the need for GAI literacy, ethical education, and adaptive learning. Further, GAI was recognized as a tool that can enhance efficiency and involve patients in education. The study also suggests that medical education should focus on competencies that GAI hardly replaces, such as clinical experience and communication. Notably, involving both faculty and students in curriculum reform discussions fosters a sense of ownership and ensures broader perspectives are encompassed.

Despite treatment, hepatitis B surface antigen (HBsAg) persists in patients with chronic hepatitis B (CHB), suggesting the likely presence of the virus in the body. CD8+ T cell responses are essential for managing viral replication, but their effect on HBsAg levels remains unclear. We studied the traits of activated CD8+ T cells and HBV-specific CD8+ T cells in the blood of CHB patients undergoing nucleos(t)ide analog (NUC) therapy. For the transcriptome profiling of activated CD8+ T cells in peripheral blood mononuclear cells (PBMCs), CD69+ CD8+ T cells were sorted from six donors, and single-cell RNA sequencing (scRNA-seq) analysis was performed. To detect HBV-specific CD8+ T cells, we stimulated PBMCs from 26 donors with overlapping peptides covering the HBs, HBcore, and HBpol regions of genotype A/B/C viruses, cultured for 10 days, and analyzed via multicolor flow cytometry. scRNA-seq data revealed that CD8+ T cell clusters harboring the transcripts involved in the cytolytic functions were frequently observed in donors with high HBsAg levels. Polyfunctional analysis of HBV-specific CD8+ T cells utilized by IFN-γ/TNFα/CD107A/CD137 revealed that HBcore-specific cells exhibited greater polyfunctionality, suggesting that the quality of HBV-specific CD8+ T cells varies among antigens. Moreover, a subset of HBcore-specific CD8+ T cells with lower cytolytic potential was inversely correlated with HBsAg level. Our results revealed a stimulant-dependent qualitative difference in HBV-specific CD8+ T cells in patients with CHB undergoing NUC therapy. Hence, the induction of HBcore-specific CD8+ T cells with lower cytolytic potential could be a new target for reducing HBsAg levels.

Atopic dermatitis itch may cause sleep disturbance and impair quality of life. For patients finding topical therapy difficult to continue, it is important to control itch and reduce scratching. This study developed algorithms to measure nocturnal sleep and scratch, using an actigraph device worn on the back of the hand, and assessed smartphone application feedback to improve adherence with therapy. In the first trial, actigraph measurements in 5 participants who wore the device were highly correlated with measurements by a sleep-monitoring device beneath the mattress. Total actigraph-measured scratching duration for each hour of sleep was highly correlated with measurements by a person rating infrared video-recording of the sleepers. In the second trial, 40 patients with atopic dermatitis were randomly allocated into an intervention group that used the actigraph and smartphone application, and a control group that did not. Both groups were instructed to use the same moisturizer. Dermatology Life Quality Index scores decreased significantly from baseline and were lower than those in the control group at week 8. It is suggested that the device and associated smartphone application reinforced therapy adherence, moisturizer use, and contributed to improved quality of life in patients with atopic dermatitis.

Objective: Tube feeders are prone to membranous substance formation on the palate, and those with membranous substances have a risk of fever, with the probable involvement of their oral bacteria. However, the palatal microbiota of those with membranous substances has not been elucidated. Therefore, we evaluated the differences in palatal microbiota between tube-fed individuals with and without membranous substances to clarify the microbiota. Materials and methods: This study included 19 participants aged 65 years who required tube feeding. The participants’ characteristics were collected from nursing records and oral examinations. If membranous materials were found on the palate, a specimen was collected. Membranous substances were defined as keratotic degeneration observed under a microscope. Additionally, we performed a comprehensive microbiome analysis by extracting DNA from the samples and performing 16 S rRNA gene sequencing. Finally, we compared the participant demographics and oral microbiota between patients with and without membranous substances. Results: A total of 11 participants had membranous substances associated with “mouth dryness” (p

Abstract Suppressor of mek1 (Dictyostelium) homolog 2 (Smek2), was identified as one of the responsible genes for diet-induced hypercholesterolemia (DIHC) of exogenously hypercholesterolemic (ExHC) rats. A deletion mutation in Smek2 leads to DIHC via impaired glycolysis in the livers of ExHC rats. The intracellular role of Smek2 remains obscure. We used microarrays to investigate Smek2 functions with ExHC and ExHC.BN-Dihc2 BN congenic rats that harbor a non-pathological Smek2 allele from Brown-Norway rats on an ExHC background. Microarray analysis revealed that Smek2 dysfunction leads to extremely low sarcosine dehydrogenase (Sardh) expression in the liver of ExHC rats. Sarcosine dehydrogenase demethylates sarcosine, a byproduct of homocysteine metabolism. The ExHC rats with dysfunctional Sardh developed hypersarcosinemia and homocysteinemia, a risk factor for atherosclerosis, with or without dietary cholesterol. The mRNA expression of Bhmt, a homocysteine metabolic enzyme and the hepatic content of betaine (trimethylglycine), a methyl donor for homocysteine methylation were low in ExHC rats. Results suggest that homocysteine metabolism rendered fragile by a shortage of betaine results in homocysteinemia, and that Smek2 dysfunction causes abnormalities in sarcosine and homocysteine metabolism.

Abstract Introduction Bimekizumab treatment resulted in improved clinical outcomes in patients with moderate-to-severe plaque psoriasis in BE VIVID, a 52-week, phase 3, randomized, ustekinumab and placebo-controlled study. We present data from the BE VIVID Japan patient subpopulation. Methods Globally, patients were randomized to receive bimekizumab 320 mg every 4 weeks (Q4W), ustekinumab (45/90 mg weight-based at baseline and week 4, then every 12 weeks), or placebo (Q4W through week 16, then bimekizumab 320 mg Q4W). Efficacy endpoints included week 16 Psoriasis Area and Severity Index (PASI) 90 and Investigator’s Global Assessment (IGA) 0/1, and other outcomes [PASI 100, PASI 75, IGA 0, Dermatology Life Quality Index (DLQI) 0/1, absolute PASI, scalp IGA, Psoriasis Symptoms and Impacts Measure (P-SIM) responses]. Safety analyses were conducted. Results There were 108 Japanese randomized patients (bimekizumab: 62; ustekinumab: 29; placebo: 17). At week 16, bimekizumab-treated patients had a higher clinical response versus ustekinumab and placebo (PASI 90: 85.5% versus 51.7% and 5.9%; IGA 0/1: 82.3% versus 48.3% and 0.0%). Over 52 weeks, improved clinical response was maintained with bimekizumab, including patients switching from placebo at week 16. Overall, the safety profile in Japanese patients was consistent with that observed in the global population. Conclusion Bimekizumab resulted in improved clinical response versus ustekinumab and placebo, and was well-tolerated in Japanese patients. Trial registration NCT03370133. Graphical Abstract

Abstract Background Little is known about the epidemic status of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in cats in Japan due to insufficiently reliable seroepidemiological analysis methods that are easy to use in cats. Results We developed a protein-A/G-based enzyme-linked immunosorbent assay (ELISA) to detect antibodies against SARS-CoV-2 in cats. The assay was standardized using positive rabbit antibodies against SARS-CoV-2. The ELISA results were consistent with those of a conventional anti-feline-immunoglobulin-G (IgG)-based ELISA. To test the protein-A/G-based ELISA, we collected blood samples from 1,969 cats that had been taken to veterinary clinics in Japan from June to July 2020 and determined the presence of anti-SARS-CoV-2 antibodies. Nine cats were found to have SARS-CoV-2 S1-specific IgG, of which 4 had recombinant receptor-binding domain-specific IgG. Of those 9 samples, one showed neutralizing activity. Based on these findings, we estimated that the prevalence of SARS-CoV-2 neutralizing antibodies in cats in Japan was 0.05% (1/1,969 samples). This prevalence was consistent with the prevalence of neutralizing antibodies against SARS-CoV-2 in humans in Japan according to research conducted at that time. Conclusions Protein-A/G-based ELISA has the potential to be a standardized method for measuring anti-SARS-CoV-2 antibodies in cats. The infection status of SARS-CoV-2 in cats in Japan might be linked to that in humans.

Abstract Background Endobronchial ultrasound (EBUS)-guided transbronchial biopsy (TBB) facilitates the diagnosis of various respiratory diseases. The safety of performing EBUS-guided TBB in patients with a finding of pulmonary hypertension (PH) is controversial. Little is known about the relationship between the risk of bleeding associated with EBUS-guided TBB in the presence of PH suspected on echocardiography or chest CT. Methods To assess the risk of bleeding associated with EBUS-guided TBB in patients with presumed PH per echocardiography or chest CT, we retrospectively reviewed the medical records of 314 consecutive patients who underwent EBUS-guided TBB using a guide sheath (GS), as well as echocardiography and chest CT. Bleeding complication was defined as over one minute of suctioning; repeated wedging of the bronchoscope; instillation of cold saline, diluted vasoactive substances, or thrombin due to persistent bleeding. Findings of suspected PH were defined as peak tricuspid regurgitation velocity (TRV) > 2.8 m/s on echocardiography or pulmonary artery to aorta ratio (PA:A ratio) > 0.9 on chest CT. Results In total, 35 (11.1%) patients developed bleeding, and all cases were managed safely. Furthermore, 17 (5.4%) and 59 (18.8%) patients were suspected to have PH based on echocardiography and chest CT, respectively. Among the patients suspected to have PH on echocardiography, five (5/17 = 29.4%) patients developed bleeding. Among the patients suspected to have PH on chest CT, 11 (11/59 = 18.6%) patients developed bleeding. Univariate analysis revealed that long diameter (≥ 30 mm) of the lesion, lesion location (the biopsy site was inner than the segmental bronchus), bronchoscopic diagnosis of malignancy, and additional biopsy were potential predictive factors for bleeding. The finding of suspected PH on echocardiography correlated significantly with bleeding (p = 0.03). On multivariate analysis, long diameter (≥ 30 mm) of the lesion (p = .021) and findings of suspected PH on echocardiography (p = .049) were significantly associated with bleeding. Conclusion All cases of bleeding in the present study were managed safely. The risk of bleeding is moderately elevated when PH is suspected by echocardiography in patients undergoing EBUS-guided TBB using a GS.

Abstract Background Streptococcus canis causes deep pyoderma in canines, which raises concerns about the risk of isolates from lesions acquiring an antibiotic-resistant phenotype. It is necessary to identify effective antibiotics and the characteristics of the pathogenic cluster for S. canis-associated deep pyoderma. Results The signalment, molecular typing, and antibiotic-resistant status of S. canis isolated from deep pyoderma lesions (27 strains) and oral cavities (26 strains) were analyzed. Older dogs tended to have S. canis-associated deep pyoderma (15 of 27 dogs over 10 years old). Veterinarians chose quinolones for 10/16 cases (63%), even though the rate of quinolone-resistant strains of S. canis is 38–59%. Although 70% of the strains showed resistance to three or more antibiotic classes (37/53), 94% (50/53) strains showed sensitivity for penicillins. We also identified β-lactamase activity among penicillin-resistant strains of S. canis. Clonal complex 13 (CC13) was detected only in lesions and formed independent clusters in the phylogenetic tree. One strain of CC13 was resistant to the anti-methicillin-resistant Staphylococcus aureus drugs, vancomycin and linezolid. Conclusion Although antibiotic-resistant strains of S. canis are isolated at a high rate, they can currently be treated with β-lactamase-inhibiting penicillins. CC13 may be a pathogenic cluster with high levels of antibiotics resistance.