Search

Human olfactory receptors are G protein-coupled receptors that detect odorants and initiate olfactory signaling. Analyzing the olfactory receptor is important to elucidate the mechanism of olfaction. However, the expression of most human olfactory receptors in heterologous cell systems is challenging because of their poor stability and poor trafficking to the cell surface, which makes it difficult to analyze them. Here, we report a case in which an odorant enhanced the cell surface expression of human olfactory receptors. Using OR1A1 as a model olfactory receptor, we screened odorants and identified ethyl 3-phenylglycidate, which significantly increased both the total and cell surface expression levels of OR1A1 in a dose-dependent manner. This increase leads to an enhanced OR1A1 response to the agonist. Functional assays confirmed that ethyl 3-phenylglycidate acts as an agonist for OR1A1. Ethyl 3-phenylglycidate also enhances the expression of other human olfactory receptors, such as OR11G2 and OR2W1, which recognize ethyl 3-phenylglycidat as an agonist, like OR1A1. These findings indicate that ethyl 3-phenylglycidate stabilizes human olfactory receptors by binding to its ligand-binding pocket. Here, we showed the examples that treating human olfactory receptor-expressing cells with an odorant during the induction of hOR expression significantly increases the expression levels of the human olfactory receptor. Our findings provide a novel strategy to enhance the functional expression of human olfactory receptors, which will contribute to understanding of the functions of olfactory receptors as well as the mechanisms underlying olfactory perception., 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 © 2025 Elsevier Inc. All rights reserved.)

Objectives: The objective of the current study is to elucidate the relationship between blood cadmium (Cd-B) levels and proximal tubular dysfunction using urinary β2-microglobulin (B2M-U) as an indicator among workers in nickel-cadmium battery plants in Japan., Methods: Medical check-up data from 338 workers exposed to cadmium at 2 plants were collected from 1997 through 2020. Workers with at least 2 check-ups were included, excluding those with other renal dysfunctions. Proximal tubular dysfunction was defined as a B2M-U of 300 μg/g creatinine or higher in 2 or more consecutive check-ups. A multivariable Cox proportional-hazards regression model with time-dependent covariates was performed to analyze the relationship between Cd-B levels and the time to onset of proximal tubular dysfunction, adjusting for age, sex, and smoking history., Results: Of the 338 workers, 238 met the study eligibility criteria for the analyses. The geometric mean of Cd-B was 1.97 μg/L. The Cox proportional hazards analysis demonstrated that higher time-dependent Cd-B levels were significantly associated with an increased risk of proximal tubular dysfunction, with a hazard ratio (HR) of 1.17 (95% confidence interval [CI]: 1.06-1.29)., Conclusions: Higher Cd-B levels are associated with an increased risk of proximal tubular dysfunction in workers exposed to cadmium, indicating an increased risk of renal disease under the current industrial health management in Japan. Continuous monitoring and improved management of cadmium exposure are necessary to protect workers' health even in developed countries such as Japan., (© The Author(s) [2025]. Published by Oxford University Press.)

Lysosomal stress due to the accumulation of nucleic acids (NAs) activates endosomal TLRs in macrophages. Here, we show that lysosomal RNA stress, caused by the lack of RNase T2, induces macrophage accumulation in multiple organs such as the spleen and liver through TLR13 activation by microbiota-derived ribosomal RNAs. TLR13 triggered emergency myelopoiesis, increasing the number of myeloid progenitors in the bone marrow and spleen. Splenic macrophages continued to proliferate and mature into macrophages expressing the anti-inflammatory cytokine IL-10. In the liver, TLR13 activated monocytes/macrophages to proliferate and mature into monocyte-derived KCs (moKCs), in which, the liver X receptor (LXR) was activated. In accumulated moKCs, tissue clearance genes such as MerTK, AXL, and apoptosis inhibitor of macrophage (AIM) were highly expressed, while TLR-dependent production of proinflammatory cytokines was impaired. Consequently, Rnaset2-/- mice were resistant to acute liver injuries elicited by acetaminophen (APAP) and LPS with D-galactosamine. These findings suggest that TLR13 activated by lysosomal RNA stress promotes the replenishment of tissue-protective Kupffer cells., (© 2025 Sato et al.)

N-Acylethanolamines (NAEs) are a class of lipid mediators that exhibit anti-inflammatory and appetite-suppressive activities. Among them, palmitoylethanolamide (PEA) and arachidonoylethanolamide (AEA) bind to peroxisomal proliferator-activated receptor (PPAR) α and cannabinoid receptor CB1, respectively. N-Acyl-phosphatidylethanolamine (NAPE) as a precursor of NAEs is biosynthesized from membrane phospholipids by N-acyltransferases, which consist of group IVE cytosolic phospholipase A 2 ε (cPLA 2 ε) and PLAAT (phospholipase A and acyltransferase) family enzymes. While cPLA 2 ε is responsible for the production of NAEs not only in specific tissues, including muscle, skin, and the stomach, but also under pathological conditions, such as psoriasis and brain ischemia, the involvement of the PLAAT family in vivo remains unclear. Considering the specific expression of PLAAT5 in testes, we investigated the potential role of PLAAT5 in the formation of NAEs in testes using PLAAT5-deficient (Plaat5 -/- ) mice. High-performance liquid chromatography coupled with tandem mass spectrometry showed that PLAAT5 deficiency decreased the total level of NAEs by 61 %, with PEA and AEA being reduced by 64 % and 87 %, respectively. Following a treatment with cadmium chloride, an environmental toxin that induces testicular inflammation, the expression of inflammatory genes (Il6, Tnf, and Nos2) in testes was markedly higher in Plaat5 -/- mice than in Plaat5 +/+ mice, and their expression was attenuated by the administration of PEA and AEA. Furthermore, these anti-inflammatory effects were canceled by a co-treatment with the antagonists of PPARα or CB1. These results suggest that PLAAT5 is responsible for the biosynthesis of anti-inflammatory NAEs in testes., 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 Elsevier B.V. All rights reserved.)

Plasmacytoid dendritic cells produce large amounts of type-I interferon (IFN-I) upon sensing nucleic acid components of pathogens by Toll-like receptors (TLR7 and TLR9). The transcription factor Spi-B has the DNA-binding Ets domain, and transactivates the Ifna4 promoter co-operatively with IFN regulatory factor-7 (IRF-7) for TLR7/TLR9-induced IFN-I production. Spi-B associates with IRF-7, and activates transcription by binding to the 5'-AGAA-3' sequence, being different from 5'-GGAA-3', known as the Ets domain recognition sequence. To understand the molecular mechanism for the co-operative transactivation of the Ifna4 promoter by Spi-B and IRF-7, we performed X-ray structural determination of the Spi-B Ets domain in complex with target DNAs, including 5'-AGAA-3' and 5'-GGAA-3' sequences. Furthermore, we conducted a modeling study of the complex of the Spi-B and IRF-7 with Ifna4 promoter DNA. X-ray structures showed that the binding of the Spi-B Ets domain induces a kink in DNA at the recognition sequence, and a more kinked DNA structure was observed in 5'-AGAA-3' than 5'-GGAA-3'. A modeling study showed that the Spi-B-induced kinked DNA structure in 5'-AGAA-3' is favorable for Spi-B and IRF-7 to approach each other for association on DNA., 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 © 2025 Elsevier Inc. All rights reserved.)

Aims: The variant in SCN5A with the loss of function (LOF) effect in the cardiac Na+ channel (Nav1.5) is the definitive cause for Brugada syndrome (BrS), and the functional analysis data revealed that LOF variants are associated with poor prognosis. However, which variant types (e.g. missense or non-missense) affect the prognoses of those variant carriers remain unelucidated., Methods and Results: We defined SCN5A LOF variants as all non-missense and missense variants that produce peak INa < 65% of wild-type previously confirmed by patch-clamp studies. The study population consisted of 76 Japanese BrS patients (74% patients were male and the median age [IQR] at diagnosis was 28 [14-45] years) with LOF type of SCN5A variants: 40 with missense and 36 with non-missense variants. Non-missense variant carriers presented significantly more severe cardiac conduction disorder compared to the missense variant carriers. During follow-up periods of 9.0 [5.0-14.0] years, compared to missense variants, non-missense variants were significant risk factors of lifetime lethal arrhythmia events (LAEs) (P = 0.023). When focusing only on the missense variants that produce no peak INa, these missense variant carriers exhibited the same clinical outcomes as those with non-missense (log-rank P = 0.325). After diagnosis, however, both variant types were comparable in risk of LAEs (P = 0.155)., Conclusion: We identified, for the first time, that SCN5A non-missense variants were associated with higher probability of LAE than missense variants in BrS patients though it did not change significantly after diagnosis., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: To evaluate post-operative semicircular canal function in patients with non-vestibular schwannoma (VS) cerebellopontine angle (CPA) tumors by video Head Impulse Test (vHIT)., Methods: Fourteen patients with non-VS CPA tumors who underwent surgery. The gain in vestibulo-ocular reflex (VOR) was examined pre- and post-operatively for the semicircular canals in patients with non-VS CPA tumors., Results: Ten of 14 patients showed semicircular canal dysfunction in one or more of the semicircular canals pre-operatively and VOR gain was significantly correlated with hearing function. Two patients showed improvement in one or more semicircular canals at 1 month after surgery compared to the pre-operative results. Significant improvements in VOR gain were observed when comparing VOR gain at 1 month and 6 months after surgery., Conclusions: Detailed evaluation of semicircular canal function was achieved by using vHIT in patients with non-VS CPA tumors. The good prognosis for vestibular function as evaluated by vHIT post-operatively was confirmed in patients with non-VS CPA tumors when compared to those in patients with VS. As improvement may occur post-operatively, surgical approaches that preserve the vestibular nerves and semicircular canals should be chosen for patients with non-VS CPA tumors, regardless of preoperative vestibular function. Even if vestibular function deteriorates immediately after surgery, it may improve over time if the nerve is preserved., (Copyright © 2024. Published by Elsevier B.V.)

Competing Interests: Declaration of competing interest None.

Background: The risk of mortality due to serious complications associated with hepatectomy for biliary tract cancer remains high. We aimed to investigate the significance of preoperative functional liver volume in predicting and preventing serious morbidity following hepatectomy with bile duct resection (BDR)., Methods: Seventy-one patients who underwent hepatectomy with BDR for biliary tract cancer were included. Functional future remnant liver volume (fFRLV) was calculated using future liver remnant (FLR) volume and functional score measured using EOB-MRI. Patients with unsatisfactory fFRLV values underwent portal or sequential portal/hepatic vein embolization (PVE/HVE). We assessed relationship between variables for liver-related morbidity (LRM), including posthepatectomy liver failure, bile leakage, and persistent ascites. Additionally, we assessed Clavien-Dindo grade IV complications (CD ≥ IV) as indicators of serious morbidity., Results: LRM and CD ≥ IV occurred in 20 (28.2 %) and 6 (8.5 %) cases, respectively. Preoperative FLR volume (p = 0.021), FLR ratio (p = 0.004), fFRLV (p = 0.008), and ICGK-F (p = 0.023) were associated with LRM. fFRLV (p = 0.017) was predictive for LRM but not independent (AUC:0.704). Preoperative FLR volume (p = 0.005), FLR ratio (p = 0.008), and fFRLV (p < 0.001) were associated with CD ≥ IV. fFRLV (p = 0.017) was an independent predictive factor for CD ≥ IV(AUC:0.914), showing greater predictive power compared to other factors., Conclusion: fFRLV predicts CD ≥ IV in patients undergoing hepatectomy with BDR. A sufficient fFRLV, enhanced by PVE/HVE if necessary, may prevent serious morbidity and mortality., Competing Interests: Conflicts of interest None declared., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Plasma exchange (PE) removes high-molecular-weight substances and is sometimes used for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) with alveolar hemorrhage. Hypotension during PE is rare, except in allergic cases. We report a case of shock likely caused by increased pulmonary vascular resistance (PVR) during PE., Case Presentation: A 66-year-old man with pulmonary hypertension (PH) and glomerulonephritis was admitted with dyspnea. He had discontinued sildenafil prior to admission. Alveolar hemorrhage associated with AAV was suspected, and PE was performed. Soon after, he developed circulatory failure and hyperlactatemia. Echocardiography revealed right ventricular dilation, suggesting increased PVR. Inhaled nitric oxide (iNO) was administered, rapidly improving hyperlactatemia and oxygenation. The shock observed during PE was attributed to multiple factors, including the potential removal of sildenafil, which may have led to an increase in PVR., Conclusions: The shock was attributable to acute right heart failure caused by an exacerbation of PH, possibly due to sildenafil removal via PE, although other contributing factors could not be excluded., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Written informed consent was obtained from the patient for publication of this case report and accompanying images. Competing interests: The authors declare that they have no competing interests., (© 2025. The Author(s).)

The Mecanum-wheeled robot has four special wheels. It can control four wheels independently and has seven turning axes. The robot can translate in all directions and travel in curves without changing its direction by means of the control commands for turning ratio, speed, and direction of travel. However, no model has been proposed that can accurately simulate the output of the actual machine for the three types of inputs, even when the characteristics of the motor and motor driver are unknown. In this study, we synthesized and simplified transfer functions and estimated the undetermined coefficients that minimize the sum of squared errors to construct a model of the robot that can output the position and posture equivalent to those of the actual robot for the input commands for turning ratio, speed, and the direction of travel. We modeled a Mecanum-wheeled robot using the proposed modeling method and parameter determination method and compared the outputs of the real robot to the step and ramp inputs. The results showed that the errors between the two outputs were very small and accurate enough to simulate AI learning, such as reinforcement learning, using the model of the robot.

Background: Despite increasing awareness in general practice, heart failure with preserved ejection fraction (HFpEF) remains under-diagnosed in the community due to diagnostic difficulties. Dedicated dyspnea clinics are responsible for diagnosing HFpEF and efficient referral from primary care physicians is the key to enhance its role., Methods: This retrospective analysis was performed to assess the effectiveness of a one-year collaborative project between our dyspnea clinic and the Maebashi Medical Association. Primary care physicians were encouraged to screen patients at risk for HFpEF and refer them to the dyspnea clinic, where exercise stress echocardiography was utilized to enhance the identification of HFpEF. To evaluate the clinical value of the project, the data obtained were compared with data from the previous year without collaboration., Results: The collaborative project was conducted between May 2023 and May 2024. The rate of patients referred from the city increased from 47 % during the previous year to 87 % during the collaborative period (p < 0.0001). Most of the patients were referred by non-cardiologists (77 %). The prevalence of HFpEF diagnosis tended to increase from 32 % to 39 % after the collaborative project, while pulmonary causes of dyspnea tended to decrease from 21 % to 12 %. After a thorough evaluation at the dyspnea clinic, 98 % of referred patients were referred back to their referring physicians for further treatment and follow-up., Conclusions: These data suggest the effectiveness of our approach to identify HFpEF in the community through collaboration between the dedicated dyspnea clinic and primary care physicians., Competing Interests: Declaration of competing interest Dr. Obokata received speaker honoraria from Novartis, Otsuka Pharmaceutical, AstraZeneca, Eli Lilly, and Nippon Boehringer-Ingelheim. Dr. Ishii received lecture fees from AstraZeneca Inc., Bayer Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan, Bristol-Myers Squibb Inc., Daiichi-Sankyo Pharma Inc., MSD K. K., Mitsubishi Tanabe Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., Novartis Japan, and Pfizer Japan Inc., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

The gold standard of microfluidic fabrication techniques, SU-8 patterning, requires photolithography equipment and facilities and is not suitable for 3D microfluidics. A 3D printer is more convenient and may achieve high resolutions comparable to conventional photolithography, but only with select materials. Alternatively, 5-axis computer numerical control (CNC) micro-milling machines can efficiently prototype structures with high resolutions, high aspect ratios, and non-planar geometries from a variety of materials. These machines, however, have not been catered for laboratory-based, small-batch microfluidics development and are largely inaccessible to researchers. In this paper, we present a new 5-axis CNC micro-milling machine specifically designed for prototyping 3D microfluidic channels, made affordable for research and laboratories. The machine is assembled from commercially available products and custom-build parts, occupying 0.72 cubic meters, and operating entirely from computer aided design (CAD) and manufacturing (CAM) software. The 5-axis CNC micro-milling machine achieves sub-μm bidirectional repeatability (≤0.23 μm), machinable features <20 μm, and a work volume of 50 × 50 × 68 mm. The tool compatibility and milling parameters were designed to enable fabrication of virtually any mill-able material including metals like aluminum, brass, stainless steel, and titanium alloys. To demonstrate milling high resolution and high aspect ratios, we milled a thin wall from 360 brass with a width of 18.1 μm and an aspect ratio of ∼50 : 1. We also demonstrated fabricating molds from 360 brass with non-planar geometries to create polydimethylsiloxane (PDMS) microfluidic channels. These included a channel on a 90° edge and a channel on a rounded edge with a 250 μm radius of curvature. Our 5-axis CNC micro-milling machine offers the most versatility in prototyping microfluidics by enabling high resolutions, geometric complexity, a large work volume, and broad material compatibility, all within a user-friendly benchtop system.

Semiconducting single-walled carbon nanotubes (SWCNTs) are significantly attractive for thermoelectric generators (TEGs), which convert thermal energy into electricity via the Seebeck effect. This is because the characteristics of semiconducting SWCNTs are perfectly suited for TEGs as self-contained power sources for sensors on the Internet of Things (IoT). However, the thermoelectric performances of the SWCNTs should be further improved by using the power sources. The ideal SWCNTs have a high electrical conductivity and Seebeck coefficient while having a low thermal conductivity, but it is challenging to balance everything. In this study, to improve the thermoelectric performance, we combined two types of SWCNTs: one with a high electrical conductivity (Tuball 01RW03, OCSiAl) and the other with a high Seebeck coefficient and low thermal conductivity (ZEONANO SG101, ZEON). The SWCNT inks were prepared by mixing two types of SWCNTs using ultrasonic dispersion while varying the mixing ratios, and p -type SWCNT films were prepared using vacuum filtration. The highest dimensionless figure-of-merit of 1.1 × 10 -3 was exhibited at approximately 300 K when the SWCNT film contained the SWCNT 75% of SWCNT (ZEONANO SG101) and 25% of SWCNT (Tuball 01RW03). This simple process will contribute to the prevalent use of SWCNT-TEG as a power source for IoT sensors.

To report a rare case of recurrent ectopic pregnancy in an ipsilateral fallopian tube remnant after left salpingectomy for tubal pregnancy. A 33-year-old patient presented with suspected ectopic pregnancy. The patient had previously undergone a left salpingectomy for a tubal pregnancy. Laparoscopy revealed ruptured swelling and bleeding from the left fallopian tube remnant. We diagnosed intra-abdominal hemorrhage due to ectopic pregnancy occurring in the fallopian tube remnant following a previous ipsilateral salpingectomy. Most ectopic pregnancies occur in the ampulla of the fallopian tube, but the occurrence of spontaneous ectopic pregnancy in a remnant tube is rare. There are several mechanisms underlying this phenomenon. In this study, we consider both the prevention and treatment of this rare form of ectopic pregnancy.

Background: The Wolff-Parkinson-White pattern is a delta wave frequently detected in school-based cardiovascular screening programs in Japan. Although most children with Wolff-Parkinson-White pattern are asymptomatic, initial symptoms may include syncope or sudden death, necessitating accurate diagnosis and management. Delta waves can also indicate a fasciculoventricular pathway, which poses no risk and does not require management., Methods: We reviewed the medical records of patients referred to our hospital between April 2008 and March 2022 to evaluate the electrocardiographic signs of the Wolff-Parkinson-White pattern. The existence of Wolff-Parkinson-White syndrome and fasciculoventricular pathway were determined based on atrioventricular block and QRS waveform changes after adenosine administration during sinus rhythm., Results: The study cohort included 127 children (65 males; median age: 12.8 years, resting heart rate: 75 beats/min, PR interval: 109 ms, and QRS duration: 101 ms). The adenosine administration test revealed a fasciculoventricular pathway, Wolff-Parkinson-White syndrome, and indeterminate findings in 64, 54, and 9 children, respectively. More than 60% of children with a QRS duration ≤ 120 ms had a fasciculoventricular pathway. Age ≤ 12 years, QRS duration >120 ms, and type A category (children with R/S ratios >1 in lead V1) were identified as independent risk factors for Wolff-Parkinson-White syndrome. No adverse events were observed in any child., Conclusions: The adenosine administration test is safe and feasible for differentiating Wolff-Parkinson-White syndrome from fasciculoventricular pathways and can reduce the unnecessary management of children with fasciculoventricular pathways.

Background: A recent conditional recommendation suggests considering live-attenuated vaccines for solid organ transplant recipients, yet the conditions of their safe and effective administration remain unclear., Methods: This prospective study was conducted at Keio University Hospital from 2002 to August 2023. We gave a live-attenuated vaccine to liver transplant (LT) recipients fulfilling criteria for live-attenuated vaccines, including criteria for humoral and cell-mediated immunity. Patient background information, immunization date, vaccine strain, immunosuppressive agents at the time of vaccination, and antibody titers were collected. Factors related to primary and secondary vaccine failure were evaluated to enhance the effectiveness of the live-attenuated vaccine program after LT., Results: Among 67 LT recipients, 54, 55, 47, and 55 received at least one dose of live-attenuated vaccine for measles, rubella, varicella, and mumps, respectively. The difference in vaccine strains, but not the use of two or more immunosuppressive agents, was associated with a lower risk of vaccine failures. Measles vaccine with the AIK-C strain exhibited significantly lower primary and secondary failure rates than the CAM-70 strain (1/38 vs. 4/16, odds ratio: 0.08, 95 % confidence interval [CI]: 0.01-0.80, p = 0.02, and hazard ratio: 0.54, 95 % CI: 0.34-0.85, p = 0.01, respectively). No primary failures were observed with the TO-336 strain of rubella, whereas 4 of 10 LT recipients with the Matsuura strain of rubella did not seroconvert. For mumps, the Hoshino strain showed lower primary failure rates than the Torii strain (15/52 vs. 3/3, p = 0.03)., Conclusion: According to a 20-year long-term study, vaccine strains are the most critical factor influencing primary and secondary vaccine failure in post-transplant live-attenuated vaccination., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Masayoshi Shinjoh reports a relationship with Meiji Seika Pharma Co Ltd. that includes: speaking and lecture fees. Masayoshi Shinjoh reports a relationship with Shionogi and Co Ltd. that includes: speaking and lecture fees. Masayoshi Shinjoh reports a relationship with MSD KK that includes: speaking and lecture fees. Masayoshi Shinjoh reports a relationship with FUJIREBIO Inc. that includes: speaking and lecture fees. Masayoshi Shinjoh reports a relationship with Mitsubishi Tanabe Pharma Corporation that includes: speaking and lecture fees. Masayoshi Shinjoh reports a relationship with Taisho 10 Pharmaceutical Co., Ltd. that includes: speaking and lecture fees. Masayoshi Shinjoh reports a relationship with Fujifilm Toyama Chemical Co Ltd. that includes: speaking and lecture fees. Masayoshi Shinjoh reports a relationship with The Mainichi Newspapers Co that includes: speaking and lecture fees. Masayoshi Shinjoh reports a relationship with Maruho Co Ltd. that includes: speaking and lecture fees. Masayoshi Shinjoh reports a relationship with Astellas Pharma Inc. that includes: speaking and lecture fees. Masayoshi Shinjoh reports a relationship with Sumitomo Pharma Co Ltd. that includes: speaking and lecture fees. Masayoshi Shinjoh reports a relationship with Daiichi Sankyo Co Ltd. Tokyo Office that includes: speaking and lecture fees. Masayoshi Shinjoh reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Masayoshi Shinjoh reports a relationship with Japan Vaccine that includes: speaking and lecture fees. Masayoshi Shinjoh reports a relationship with Pfizer Japan Inc. that includes: consulting or advisory. Tetsuo Nakayama reports a relationship with Eiken Chemical Co Ltd. that includes: funding grants. Tetsuo Nakayama reports a relationship with Daiichi Sankyo Inc. that includes: funding grants. Tetsuo Nakayama reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. 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.)

Recently, live-attenuated measles, rubella, varicella, and mumps vaccines have been administered to carefully selected post-liver transplant patients. Although attention has been focused on post-vaccination antibody titers and adverse events, the real-life clinical benefits remain unclear. A comprehensive analysis of breakthrough infections and natural boosters (asymptomatic cases with significant elevation in virus antibody titers) following immunization post-liver transplantation was conducted from 2002-2023, exploring the timing, frequency, correlation with domestic outbreaks, and degree of antibody elevation. During the median 10-year observation period among 68 post-liver transplant patients, breakthrough infections occurred only in chickenpox, with 7 mild cases (1 episode/64 person-years). A total of 59 natural booster episodes (1, 5, 20, and 33 for measles, rubella, chickenpox, and mumps, respectively) were observed, with incidence rates of 1 per 569, 110, 22, and 17 person-years, respectively. The timing of natural boosters closely correlated with domestic outbreaks (P < .05 in chickenpox and mumps), influenced by local vaccine coverage. The degree of antibody elevation was significantly higher in individuals with breakthrough infections than in those with natural boosters (P < .05). These findings suggest that immunization with live-attenuated vaccines for post-liver transplant patients has demonstrated clinical benefits. Furthermore, mass vaccination has a positive impact on post-transplant patient outcomes., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose, as described by the American Journal of Transplantation. M. Shinjoh has received speaking honoraria from Meiji Seika Pharma Co, Ltd, Shionogi & Co, Ltd, MSD K.K., FUJIREBIO Inc, Mitsubishi Tanabe Pharma Corporation, Taisho Pharmaceutical Co, Ltd, FUJIFILM Toyama Chemical Co, Ltd, The Mainichi Newspapers Co, Ltd, Maruho Co, Ltd, Astellas Pharma Inc, Sumitomo Pharma Co, Ltd, Daiichi Sankyo Co, Ltd, Takeda Pharmaceutical Co, Ltd, Japan Vaccine, a consultation fee from Pfizer Japan Inc, and grant support from JSPS KAKENHI, Japan (Grant Number JP20K10546, 2020-2023), none of which were in connection with the work presented here (all were less than JPY 500,000 USD370 per year). T. Nakayama received research funds from EIKEN Chemicals and Daiichi Sankyo, and lecture fees from Takeda Pharmaceuticals. The other authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

While screening for antibiotics in a marine sample, we discovered a berninamycin C-producing actinomycete, designated YSPA8 T , isolated from a sponge. A polyphasic approach was used to determine the taxonomic position of the strain. Strain YSPA8 T formed sympodially branched aerial mycelia that ultimately segment into chains of spores. Comparative and phylogenetic analyses of the 16S rRNA gene sequence showed that strain YSPA8 T were closely related to Streptomyces clavuligerus ATCC 27064 T (99.66%), Streptomyces amakusaensis NRRL B-3351 T (98.69%), Streptomyces inusitatus NBRC 13601 T (98.48%), and 'Streptomyces jumonjinensis' JCM 4947 (98.41%). The phylogenetic tree using the 16S rRNA gene sequences, and both phylogenomic trees suggested that the closest relative of strain YSPA8 T was S. clavuligerus ATCC 27064 T . The average nucleotide identity, digital DNA-DNA hybridization, and average amino acid identity values between strain YSPA8 T and S. clavuligerus ATCC 27064 T were 84.1%, 28.9%, and 82.5%, respectively, which were below the thresholds of 95%, 70%, and 95% for a prokaryotic conspecific assignment. The G + C of the strain YSPA8 T was 72.6%. Whole-cell hydrolysates of strain YSPA8 T contained LL-diaminopimelic acid. The predominant menaquinones were MK-9(H 6 ) (49%) and MK-9(H 8 ) (48%), and the major fatty acids were C 16:0 (26.8%), C 16:1 ω7c/ω6c (17.2%), iso-C 16:0 (16.0%), and iso-C 15:0 (12.5%). The major phospholipids were diphosphatidylglycerol, phosphatidylethanolamine, and other unidentified phospholipids. Based on the phenotypic, phylogenetic, genomic, and chemotaxonomic data, strain YSPA8 T represents a novel species of the genus Streptomyces, and the proposed name for this species is Streptomyces yaizuensis sp. nov. The type strain is YSPA8 T (=NBRC 115866 T  = TBRC 17196 T )., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

When encountering severe hypoxemia that does not respond to oxygen supplementation, it is essential to consider underlying right-to-left shunting. Among various diagnostic approaches, the microbubble test via transthoracic echocardiography (TTE) is a simple, noninvasive method for detecting pulmonary arteriovenous shunts, particularly in hepatopulmonary syndrome (HPS). Although microbubbles are usually administered peripherally, using a Swan-Ganz (SG) catheter to inject microbubbles directly into the pulmonary artery may provide even more definitive diagnostic information. We report a case of a woman in her 60s who was admitted in cardiac arrest after several months of progressive dyspnea and one month of poor appetite. While resuscitation was successful, severe hypoxemia persisted despite intubation, mechanical ventilation, and oxygen therapy. Immediately after resuscitation, TTE revealed no intracardiac shunt but did show microbubbles in both heart chambers. The patient exhibited refractory hypoxemia, high-output status, and pulmonary hypertension. Based on a history of severe dietary irregularities, beriberi heart disease was suspected, and empirical thiamine administration improved pulmonary hypertension and high-output state; however, the hypoxemia remained unresolved. Since microbubbles had been observed in the left heart without an intracardiac shunt, a pulmonary arteriovenous shunt was suspected. Peripheral microbubble testing showed Grade 4 opacification of the left heart three to four heartbeats subsequent to the filling of the right heart. Concerns regarding hemodynamic instability and timing prompted a microbubble test via the already-placed SG catheter. Injection of microbubbles directly into the pulmonary artery again demonstrated Grade 4 opacification in the left heart alone, confirming a pulmonary arteriovenous shunt independent of intracardiac pathways. The patient later died on day six due to irreversible brain damage. The autopsy revealed cirrhosis with histopathological features of autoimmune hepatitis and pulmonary changes suggestive of a pulmonary arteriovenous shunt. Postmortem evaluations indicated low vitamin B1 levels, consistent with beriberi heart disease, and the presence of autoimmune markers suggesting Sjögren's syndrome. In beriberi heart disease, high output is associated with reduced vascular resistance and increased metabolic demand. In liver disease, excessive nitric oxide and carbon monoxide production may worsen these hemodynamic conditions, promoting pulmonary vasodilation and pulmonary arteriovenous shunt formation. Using the SG catheter for the microbubble test proved practical and effective, especially when standard peripheral methods are complicated by hemodynamic instability, difficulty visualizing the right heart, the potential presence of intracardiac shunts, or contraindications to transesophageal echocardiography (TEE). This technique, relying on commonly available cardiovascular equipment, may facilitate earlier diagnosis of shunt-related diseases in complex clinical scenarios., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Hoshino et al.)

During pediatric cardiac surgery with cardiopulmonary bypass (CPB) for congenital heart disease, systemic hemodynamics dramatically change, which also causes changes in the cerebral hemodynamics. One of the representative methods in bedside monitoring for the estimation of cerebral hemodynamics during pediatric cardiac surgery is transcranial Doppler ultrasonography (TCD). However, there seem to be few reports on the changes in TCD findings in such operations, especially in cyanotic children. Accordingly, we examined the changes in TCD indices during these procedures in cyanotic children as well as non-cyanotic children. In the post hoc analysis of a previous prospective observational study, TCD indices of the middle cerebral artery at the start and end of surgery in patients aged 6 years or less were compared. The cerebral oxygenation (rSO 2 ) values were also compared. For this study, 47 cyanotic children and 49 non-cyanotic children were evaluated. At the end of surgery, cerebral blood flow velocities decreased and cerebrovascular resistance increased significantly compared to the start of surgery in both the cyanotic and non-cyanotic patients. This finding was almost constant regardless of age differences, although cerebral blood flow velocities and the rSO 2 increased until around 20 months after birth. The rSO 2 values did not change between the start and end of surgery. Thus, the changes in cerebral hemodynamics during pediatric surgery with CPB in cyanotic children were not so different from those in non-cyanotic children. The significance of monitoring of cerebral hemodynamics by TCD and rSO 2 should be evaluated further., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests. Ethical Approval: This was a retrospective observational study approved by the Institutional Review Board of our University Hospital (IRB #022–0040) in accordance with the ethical principles outlined in 1964 Declaration of Helsinki and Good Clinical Practice., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: This study investigated the significance of the Global Leadership Initiative on Malnutrition (GLIM) for patients with resected biliary tract cancers., Methods: The subjects of this retrospective analysis were 114 patients who underwent radical surgery for cholangiocarcinoma between 2018 and 2023. We analyzed both handgrip force and skeletal muscle area and classified patients as having GLIM malnutrition or modified GLIM malcondition. We also evaluated clinicopathological factors, short-term outcomes, and prognoses., Results: The GLIM criteria identified 47 patients (41.2%) with malnutrition and 13 patients (11.4%) with modified GLIM malcondition. Overall survival (P = 0.009) and recurrence-free survival (P = 0.016) were significantly different between the well-nourished and malnourished patients according to the GLIM criteria. Furthermore, modified GLIM criteria malcondition was a significant prognostic factor for both recurrence-free and overall survival (P = 0.002 and P < 0.001, respectively). Multivariate analysis identified a higher carcinoembryonic antigen level and modified GLIM malcondition as predictors of overall and recurrence-free survival. Pathological stage ≥ III was also a predictor of recurrence-free survival. On comparing the prognoses of modified GLIM malcondition and GLIM malnutrition using the Akaike Information Criteria, the modified GLIM malcondition was identified as a stronger prognostic factor., Conclusion: A modified GLIM malcondition can be a highly useful prognostic marker for patients with resected biliary tract cancer., Competing Interests: Declarations. Conflict of interest: We have no conflicts of interest to disclose for this research. Ethical approval: This research was approved by the Ethics Committee of Gunma University (HS2023-174), and it conforms to the rules of the Declaration of Helsinki. Informed consent for inclusion in this study was acquired from patients using an opt-out method., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

A 67-year-old woman underwent emergency sigmoid resection for perforated sigmoid cancer with synchronous liver metastasis(pT4aN0M1a, pStage Ⅳa). The patient was administered 7 courses of SOX plus bevacizumab and 7 courses of FOLFIRI plus bevacizumab as adjuvant chemotherapy. Fourteen months post-surgery, PET-CT and EOB-MRI revealed a nodule in segment 8 of the liver. Based on the diagnosis of hepatic metastasis, a partial hepatectomy was performed. Two months after hepatectomy, a recurrent lesion was observed in segment 4 of the liver, and radiofrequency ablation(RFA)was performed. Nine months after RFA, chest CT revealed a solitary nodule in segment 9 of the left lung. Six months later, the size of the pulmonary nodule had increased. A diagnosis of pulmonary metastasis was established, and thoracoscopic partial pulmonary resection was performed. Histopathological examination of the hepatic and pulmonary resection confirmed metastasis from sigmoid cancer. The patient has remained recurrence-free for 5 years following the final surgery. Herein, we report a case of long-term survival in a patient with perforated sigmoid cancer and simultaneous liver metastasis after multidisciplinary treatment.

The perception of verticality is formed through the integration of multisensory gravitational information, including somatosensory, visual, and vestibular inputs. Older adults exhibit visual dependency (VD) as they rely more on visual information to compensate for reduced somatosensory and vertical perception. Increased VD is associated with falls, and the dynamic subjective visual vertical (SVV) is used to assess VD. However, the measurement reliability of dynamic SVV and VD using virtual reality (VR), which has garnered considerable attention in recent years, remains unclear. Therefore, our purpose in this study was to assess the test-retest reliability of dynamic SVVs and VDs using a VR method. We evaluated static and dynamic SVV of 40 older adults using a smartphone-based VR system (SVR-SVV). Dynamic SVV consisted of numerous spheres on the background rotating clockwise (CW-SVV) or counterclockwise (CCW-SVV). Each SVV measurement consisted of one set of 10 trials. VD was calculated as the mean value of dynamic SVV minus the mean values of static SVV. A re-test was conducted after one week. Reliability was analyzed using Bland-Altman plots and intraclass correlation coefficients (ICC 2, k) for each SVV measure. We observed no systematic bias in any of the SVV values, which were 0.1° ( SD = 2.8°), 13.3° ( SD = 8.3°), -12.8° ( SD = 6.9°), and 15.7° ( SD = 8.1°) for static SVV, CW-SVV, CCW-SVV, and VD, respectively. Test-retest reliability was good for static SVV (ICC = .817, p < .001), CW-SVV (ICC = .896, p < .001) and excellent for CCW-SVV (ICC = .914, p < .001), VD (ICC = .937, p < .001). The dynamic SVV and VD measurements using SVR-SVV demonstrated good test-retest reliability. Moreover, the SVR-SVV is more portable than conventional methods, making it highly useful in clinical practice., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The transposition of the great arteries (TGA) associated with a complete atrioventricular septal defect is a rare and serious congenital cardiac anomaly. In this report, we describe the successful biventricular repair of a TGA with a complete atrioventricular septal defect in an infant. Due to the low body weight of the patient and a complex coronary pattern anomaly, an arterial switch operation was executed, with the Mee procedure and pulmonary arterial banding as initial palliative measures when the infant was 22 days old and weighed 2.5 kg. Subsequently, atrioventricular septal defect repair using the modified one-patch method was performed when the patient was 1.3 years old and weighed 8.8 kg. Remarkably, the postoperative course of the patient demonstrated no notable incidents. To our knowledge, this is the first time a two-stage strategy was applied to repair these complex defects, presenting a promising approach for managing similar cases in future medical practice., (© 2023. The Author(s).)

Erythritol is a latent heat storage material suitable for the utilization of unused heat in the medium temperature range of 100-250 °C. However, the supercooling characteristic of sugar alcohols reduces the energy utilization efficiency. In this study, erythritol and its fluorine analogues are mixed to suppress supercooling. Erythritol mixed with 2,3-difluorobutane-1,4-diol at a weight ratio of 1% is determined to be effective in suppressing supercooling. This indicates the possibility of utilizing energy more efficiently., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Flexible thermoelectric generators (TEGs) with pn-junction single-walled carbon nanotube (SWCNT) films on a polyimide substrate have attracted considerable attention for energy harvesting. This is because they generate electricity through the photo-thermoelectric effect by self-generated temperature gradient under uniform sunlight irradiation. To increase the performance and durability of the pn-junction TEGs, n-type films need to be improved as a priority. In this study, bismuth telluride (Bi 2 Te 3 ) nanoplates synthesized by the solvothermal method were added to the n-type SWCNT films, including a cationic surfactant to form the nanocomposite films because Bi 2 Te 3 has high n-type thermoelectric properties and high durability. The performances of the pn-junction TEGs were investigated by varying the heat treatment times. When the artificial sunlight was uniformly irradiated to the pn-junction TEGs, a stable output voltage of 0.47 mV was observed in the TEG with nanocomposite films heat-treated at 1 h. The output voltage decreased with increasing heat treatment time due to the decrease in the p-type region. The output voltage of TEG at 1 h is higher than that of the TEGs without Bi 2 Te 3 nanoplates under the same conditions. Therefore, the addition of Bi 2 Te 3 nanoplates was found to improve the performance of the pn-junction TEGs. These findings may aid in the development of facile and flexible optical devices, including photodetectors and hybrid devices integrating solar cells.

Aims: This study aimed to determine the value of the drainage fluid volume and direct bilirubin level for predicting significant bile leakage (BL) after hepatectomy and establish novel criteria for early drain removal., Methods: Data from 351 patients who underwent hepatic resection at Gunma University in Japan between October 2018 and March 2022 were retrospectively analyzed. Clinical characteristics and surgical outcomes of patients with and without significant BL were compared. Criteria for early drain removal were determined and verified., Results: Bile leakage occurred in 27 (7.1%) patients; 8 (2.3%) had grade A leakage and 19 (5.4%) had grade B leakage. The optimal cut-off value for the drainage fluid direct bilirubin level on postoperative day (POD) 2 was 0.16 mg/dL, which had the highest area under the curve and negative predictive value (NPV). Patients with BL had significantly larger drainage volumes on POD 2. The best cut-off value was 125 mL because it had the greatest NPV. Patients in both the primary and validation (n = 90) cohorts with bilirubin levels less than 0.16 mg/dL and drainage volumes less than 125 mL did not experience leakage., Conclusions: A drainage fluid volume less than 125 mL and direct bilirubin level less than 0.16 mg/dL on POD 2 are criteria for safe early drain removal after hepatectomy., (© 2024 Japan Society of Hepatology.)

Tumor microscopic structure is crucial for determining properties such as cancer type, disease state (key for early diagnosis), and novel therapeutic strategies. Magnetic particle imaging is an early cancer diagnostic tool using magnetic nanoparticles as a tracer, which actualizes cancer theranostics in combination with hyperthermia treatment using the abilities of magnetic nanoparticles as a heat source. This study focuses on the microscopic structures associated with cancer cell distribution, the stromal compartment, and vascularization in different kinds of living tumors by analyzing the intratumor magnetic relaxation response of magnetic nanoparticles injected into the tumors. Furthermore, this study describes a sequential system for the measurement of magnetic relaxation time and analysis of the intratumor structure using nonbiological samples such as viscous fluids and solidified magnetic nanoparticles. Particularly, the fine discriminability achieved by reconstructing a distribution map representing the relationship between magnetic relaxation time and viscosity of medium is demonstrated, based on experimental data with a limited condition number. Observing tumor microscopic structure through the dynamic magnetization response of intratumor magnetic nanoparticles is a low-invasive tool for analyzing tumor tissue without dissection. It holds promise for the advancement of biomedical applications, such as early cancer theranostics, using magnetic nanoparticles., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

Objective: To evaluate semicircular canal function using video head impulse test (vHIT) in relapsing polychondritis (RP) patients presenting with dizziness and sensorineural hearing loss., Study Design: Retrospective case review., Setting: Tertiary referral center., Patients: Three patients with RP underwent vHIT and hearing tests., Intervention: Diagnostic., Main Outcome Measures: The gain in vestibulo-ocular reflex (VOR) and the presence of catch-up saccade were examined, and the correlation between semicircular canal dysfunction and hearing loss was investigated., Results: Of the six ears, five exhibited semicircular canal dysfunction. Among these, one ear showed dysfunction in two semicircular canals, while the remaining four ears demonstrated dysfunction in all three semicircular canals. Sensorineural hearing loss, ranging from moderate to profound, was detected by pure-tone audiometry in all six ears. Furthermore, a significant correlation was observed between VOR gain in the horizontal semicircular canal (HSC) and hearing level., Conclusions: This study demonstrated semicircular canal dysfunction in RP patients presenting with dizziness and hearing loss using vHIT. Moreover, a significant correlation was found between HSC dysfunction and the severity of hearing loss. While inner ear involvement is a key clinical symptom included in the diagnostic criteria for RP, there have been few reports evaluating vestibular dysfunction, and this is the first report on the evaluation of several cases using vHIT. Accurate assessment of vestibular function by vHIT may facilitate early diagnosis and intervention in RP, potentially improving patient outcomes., Competing Interests: Conflicts of interest and source of funding: The authors disclose no conflicts of interest and sources of funding., (Copyright © 2024, Otology & Neurotology, Inc.)

Ovulation is critical for sexual reproduction and consists of the process of liberating fertilizable oocytes from their somatic follicle capsules, also known as follicle rupture. The mechanical force for oocyte expulsion is largely unknown in many species. Our previous work demonstrated that Drosophila ovulation, as in mammals, requires the proteolytic degradation of the posterior follicle wall and follicle rupture to release the mature oocyte from a layer of somatic follicle cells. Here, we identified actomyosin contraction in somatic follicle cells as the major mechanical force for follicle rupture. Filamentous actin (F-actin) and nonmuscle myosin II (NMII) are highly enriched in the cortex of follicle cells upon stimulation with octopamine (OA), a monoamine critical for Drosophila ovulation. Pharmacological disruption of F-actin polymerization prevented follicle rupture without interfering with the follicle wall breakdown. In addition, we demonstrated that OA induces Rho1 guanosine triphosphate (GTP)ase activation in the follicle cell cortex, which activates Ras homolog (Rho) kinase to promote actomyosin contraction and follicle rupture. All these results led us to conclude that OA signaling induces actomyosin cortex enrichment and contractility, which generates the mechanical force for follicle rupture during Drosophila ovulation. Due to the conserved nature of actomyosin contraction, this work could shed light on the mechanical force required for follicle rupture in other species including humans., Competing Interests: Competing interests statement:The authors declare no competing interest.

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&#95;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).)

Introduction: Herlyn-Werner-Wunderlich syndrome (HWWS) is characterized by uterine didelphys, unilateral cervical obstruction, and ipsilateral renal defects. Owing to its rarity, no standard surgical approach exists., Presentation of Case: An 11-year-old girl with severe dysmenorrhea had a duplicated uterus, a right cervical hemorrhagic cyst, and right ipsilateral kidney agenesis, indicative of HWWS. As transvaginal surgery was challenging, we turned to laparoscopic surgery for abdominal cavity inspection and surgical assistance. A longitudinal incision was made on the right uterus, followed by inserting a catheter tube fixed to an intrauterine device (IUD) into the right cervical canal from the anterior wall of the right uterine horn. Subsequently, the right external cervical os was inverted to prevent restenosis. Postoperatively, the hemorrhagic cyst at the right cervix disappeared. The patient had no symptom recurrence 24 months after the surgery., Discussion: The preoperative diagnosis for female genital malformations is complicated, and transvaginal manipulation is often difficult in adolescent girls. Laparoscopy is a valuable tool for evaluating female genital malformations, allowing for a thorough diagnosis and safe surgical treatment. In cases of female genital malformation with cervical obstruction, as in this case, reconstruction of the uterine cervix is important to prevent restenosis after surgery., Conclusion: In female genital malformations, laparoscopy provides a comprehensive evaluation of the malformation, assisting in a precise diagnosis and safe surgical treatment. Insertion of the catheter tube with IUD into the uterus and reconstruction of the cervix contribute to preventing restenosis., Competing Interests: Conflict of interest statement The authors have no potential conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Microvascular invasion (MVI) is a risk factor for postoperative recurrence of hepatocellular carcinoma (HCC), even in early-stage HCC. In small HCC ≤ 3 cm, treatment options include anatomical resection or non-anatomical resection, and MVI has a major effect on treatment decisions. We aimed to identify the predictors of MVI in small HCC ≤ 3 cm., Methods: We retrospectively studied 129 patients with very early or early-stage HCC ≤ 3 cm who had undergone 18 F-fluorodeoxyglucose positron emission tomography/computed tomography and subsequent hepatic resection from January 2016 to August 2023. These patients were divided into the derivation cohort (n = 86) and validation cohort (n = 43). We examined the risk factors for MVI using logistic regression analysis, and established a predictive scoring system in the derivation cohort. We evaluated the accuracy of our scoring system in the validation cohort., Results: In the derivation cohort, a Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3), prothrombin induced by vitamin K deficiency or antagonist-II (PIVKA-II), and metabolic tumor volume (MTV) were independent predictors of MVI. We established the scoring system using these three factors. In the validation test, there were no MVI-positive cases with a score of 0 and 1, and all cases were MVI-positive with a score of 4. Moreover, with a score ≥ 2, the sensitivity, specificity, and accuracy of our scoring system were 100%, 71.4%, and 81.4%, respectively., Conclusions: Our scoring system can accurately predict MVI in small HCC ≤ 3 cm, and could contribute to establishing an appropriate treatment strategy., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Thrombocytopenia frequently occurs in patients with sepsis. Disseminated intravascular coagulation (DIC) may be a possible cause of thrombocytopenia owing to its high prevalence and association with poor outcomes; however, it is important to keep the presence of other diseases in mind in sepsis practice. Thrombotic microangiopathy (TMA), which is characterized by thrombotic thrombocytopenic purpura, Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (HUS), and complement-mediated HUS, is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ damage. TMA has become widely recognized in recent years because of the development of specific treatments. Previous studies have reported a remarkably lower prevalence of TMA than DIC; however, its epidemiology is not well defined, and there may be cases in which TMA is not correctly diagnosed, resulting in poor outcomes. Therefore, it is important to differentiate DIC from TMA. Nevertheless, differentiating between DIC and TMA remains a challenge as indicated by previous reports that most patients with TMA can be diagnosed as DIC using the universal coagulation scoring system. Several algorithms to differentiate sepsis-related DIC from TMA have been suggested, contributing to improving the care of septic patients with thrombocytopenia; however, it may be difficult to apply these algorithms to patients with coexisting DIC and TMA, which has recently been reported. This review describes the disease characteristics, including epidemiology, pathophysiology, and treatment, of DIC, TMA, and other diseases with thrombocytopenia and proposes a novel practical approach flow, which is characterized by the initiation of the diagnosis of TMA in parallel with the diagnosis of DIC. This practical flow also refers to the longitudinal diagnosis and treatment flow with TMA in mind and real clinical timeframes. In conclusion, we aim to widely disseminate the results of this review that emphasize the importance of incorporating consideration of TMA in the management of septic DIC. We anticipate that this practical new approach for the diagnostic and treatment flow will lead to the appropriate diagnosis and treatment of complex cases, improve patient outcomes, and generate new epidemiological evidence regarding TMA., (© 2024. The Author(s).)

Eosinophilic otitis media (EOM) is a rare, intractable, and chronic form of otitis media. The associated hearing loss often progresses to deafness, necessitating cochlear implantation (CI). EOM is associated with type 2 inflammatory conditions such as asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Dupilumab, a monoclonal antibody targeting the IL4Rα subunit, has shown efficacy in mitigating type 2 inflammatory diseases, including asthma and CRSwNP. Recent studies also suggest its effectiveness in treating EOM. We report a unique case of CI for EOM, in which the post-implant hearing threshold improved after the introduction of dupilumab. The patient was a 63-year-old man with a history of asthma and multiple nasal polypectomies. Eosinophils were detected in otorrhea samples from both ears, leading to an EOM diagnosis four years prior. Despite local corticosteroid therapy, his hearing gradually deteriorated. One month ago, he experienced sudden bilateral deafness and was referred to our hospital. The right tympanic membrane had a pinhole perforation but no otorrhea. CT showed a small amount of soft tissue density in the right middle ear, while the left side displayed cochlear osteolysis with soft tissue density. A right CI and myringoplasty were performed one and a half months after his visit. The cochleostomy revealed no perilymph leakage, confirming that the scala tympani was filled with granulation tissue. The electrode was inserted successfully despite the granulation, and all electrodes were placed correctly. Six months after CI, his hearing threshold with the cochlear implant remained poor at 67.5 dB. However, upon starting dupilumab therapy seven months postoperatively, his hearing threshold with the cochlear implant rapidly improved to 31.3 dB. Intraoperative findings suggested that the scala tympani was filled with granulation tissue, indicating significant cochlear inflammation due to EOM. The subsequent hearing improvement after introducing dupilumab may be attributed to the reduction or disappearance of granulation in the cochlea, allowing for effective electrical stimulation from the electrodes to the spiral ganglion. This case suggests the potential for improved postoperative hearing outcomes in CI for EOM when inflammation is effectively controlled with dupilumab., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Fukuda et al.)

Background: Sarcopenia is a poor prognostic factor in cancer patients. In recent years, there have been reports that serum creatinine and cystatin C (Cr/CysC) ratio is associated with sarcopenia. However, the prognostic value of the Cr/CysC ratio in biliary tract cancer is unclear. We evaluated the impact of the Cr/CysC ratio on sarcopenia and prognosis in biliary tract cancer., Methods: We retrospectively reviewed the records of 190 patients with biliary tract cancer who had undergone surgical resection from January 2017 to March 2023. Frozen serum samples collected at the time of surgery were used to measure CysC. We calculated the Cr/CysC ratio and investigated the relationship with sarcopenia and the prognostic significance., Results: We calculated the cutoff value of the Cr/CysC ratio for low skeletal muscle index (SMI) (< 42 cm 2 /m 2 for males and < 38 cm 2 /m 2 for females). The optimal cutoff value of the Cr/CysC ratio was 0.848. The low Cr/CysC ratio group was significantly associated with higher preoperative CRP and lower albumin, lower SMI, lower handgrip strength, and higher intramuscular adipose tissue content. In multivariate analysis, patients with a low Cr/CysC ratio showed poorer overall survival (hazard ratio 2.60, 95% confidence interval 1.07-6.29, p = 0.033), which was significantly worse than in those with a high Cr/CysC ratio., Conclusions: In patients with biliary tract cancer, the Cr/CysC ratio showed weak correlation with sarcopenic indicators. However, the Cr/CysC ratio could be strong prognostic factor in biliary tract cancer., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Endothelial Notch signaling is critical for tumor angiogenesis. Notch1 blockade can interfere with tumor vessel function but causes tissue hypoxia and gastrointestinal toxicity. Notch4 is primarily expressed in endothelial cells, where it may promote angiogenesis; however, effective therapeutic targeting of Notch4 has not been successful. We developed highly specific Notch4-blocking antibodies, 6-3-A6 and humanized E7011, allowing therapeutic targeting of Notch4 to be assessed in tumor models. Notch4 was expressed in tumor endothelial cells in multiple cancer models, and endothelial expression was associated with response to E7011/6-3-A6. Anti-Notch4 treatment significantly delayed tumor growth in mouse models of breast, skin, and lung cancers. Enhanced tumor inhibition occurred when anti-Notch4 treatment was used in combination with chemotherapeutics. Endothelial transcriptomic analysis of murine breast tumors treated with 6-3-A6 identified significant changes in pathways of vascular function but caused only modest change in canonical Notch signaling. Analysis of early and late treatment timepoints revealed significant differences in vessel area and perfusion in response to anti-Notch4 treatment. We conclude that targeting Notch4 improves tumor growth control through endothelial intrinsic mechanisms., Significance: A first-in-class anti-Notch4 agent, E7011, demonstrates strong antitumor effects in murine tumor models including breast carcinoma. Endothelial Notch4 blockade reduces perfusion and vessel area., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objectives This study aims to evaluate semicircular canal function using video head impulse test (vHIT) in patients with peripheral vestibular disorders without nystagmus. Methods Patients who underwent vHIT were enrolled in this study, and the proportion of abnormal findings on vHIT in patients without nystagmus was investigated. In addition, the results of vestibular testing were investigated in cases in which both vHIT and caloric testing were performed in patients without nystagmus. Results Forty-six patients (23.4%) of 197 patients who had no abnormal findings on the nystagmus tests, including the gaze nystagmus test, positional nystagmus test, and positioning nystagmus test, showed dysfunction in at least one semicircular canal on vHIT. The most frequent diagnosis was vestibular schwannoma (14/46, 30.4%), and cases with bilateral vestibular dysfunction were also included (12/46, 26.1%). A disorganized pattern of catch-up saccade was observed more frequently in patients with subjective symptoms of dizziness/vertigo compared to those without subjective symptoms. Although the sensitivity of vHIT was low compared to caloric testing, vHIT could detect isolated vertical canal dysfunction not detected by caloric testing. Conclusions vHIT is considered to be a useful test for patients without nystagmus, as vHIT could detect abnormalities in approximately one-quarter of patients without nystagmus. vHIT is considered to be one of the first tests to be performed following nystagmus testing, including the gaze nystagmus test, the positional nystagmus test, and the positioning nystagmus test. On the other hand, there are some cases in which vHIT shows no abnormality while caloric testing shows canal paresis. It is necessary to perform vHIT, bearing in mind that there are abnormalities that cannot be detected by vHIT alone., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board of Hokkaido University Hospital issued approval 023-0163. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Fujiwara et al.)

Objectives: To evaluate pre- and post-operative semicircular canal function in patients with vestibular schwannoma (VS) by the video Head Impulse Test (vHIT)., Methods: Nineteen patients with VS who underwent surgery were enrolled in this study. The gain in vestibulo-ocular reflex (VOR) and the degree of scatter in catch-up saccades were examined pre- and post-operatively for the semicircular canals in VS patients., Results: Ten of 19 cases (52.6 %) with VS were defined as demonstrating both superior vestibular nerve (SVN) and inferior vestibular nerve (IVN) impairment from the results of pre-operative vHIT. Hearing level and subjective vestibular symptoms showed significant correlations with pre-operative semicircular canal function. Compared to pre-operative vHIT results, VOR gains within 1 month after surgery were significantly reduced in all three canals; however, significant differences had disappeared in the anterior and posterior semicircular canals at 6 months after surgery. Cases of unknown origin had a significantly greater reduction in posterior semicircular canal function after surgery compared with those with disease of IVN origin., Conclusions: As vHIT could evaluate pre-operative vestibular nerve impairment, post-operative VOR gain reduction and the degree of vestibular compensation, semicircular canal function evaluated by vHIT provides a good deal of useful information regarding VS patients undergoing surgery compared to caloric testing, and vHIT should be performed pre- and post-operatively for patients with VS., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: The quality of life (QOL) for patients with resolved facial nerve palsy has not been evaluated adequately. The objective of this study is to investigate QOL for patients with resolved facial nerve palsy., Methods: Forty-seven patients with resolved facial nerve palsy were included and the patients' QOL was evaluated using the Facial Clinimetric Evaluation Scale (FaCE Scale)., Results: Twenty-two of the 47 patients (46.8%) with resolved facial nerve palsy showed impaired QOL, especially in terms of facial comfort and eye comfort. In 10 cases followed-up after the condition was judged to be resolved, the median scores for the FaCE scale at the time the condition was judged to be resolved and at the last visit were 65.5 and 72, respectively. The mean durations from the onset of the palsy to diagnosis of cure and to the last visit were 2.4 ± 1.6 and 4.3 ± 2.2 months, respectively. There was a significant improvement in QOL after the condition was judged to be resolved., Conclusion: There were discrepancies between QOL and facial movement as evaluated by physicians in patients in whom facial nerve palsy was resolved as in patients with non-cured facial nerve palsy. Patients' QOL continued to improve even after physicians judged the condition to be resolved and this result indicated that there were cases where improvement in QOL was delayed in comparison to improvement in facial movement., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Japanese Society of Otorhinolaryngology-Head and Neck Surgery, Inc. Published by Elsevier B.V. All rights reserved.)

Purpose: Chyle leakage (CL) is a common complication in pancreatic surgery. Lymphangiography is a therapeutic option for CL in cases of conservative treatment failure. This study investigated the effect of lymphangiography on the healing time of CL., Methods: We retrospectively evaluated 283 patients who underwent pancreatic resection between January 2016 and June 2022. The risk factors for CL and the treatment period were evaluated according to whether or not lymphangiography was performed., Results: Of the 29 patients (10.2%) that had CL, lymphangiography was performed in 6. Malignant disease, the number of harvested lymph nodes, and drain fluid volume on postoperative day 2 were identified as independent risk factors for CL. Lymphangiography was associated with the cumulative healing rate of CL, and patients who underwent lymphangiography had a significantly shorter treatment period. No lymphangiography-related adverse events were observed., Conclusion: Lymphangiography is a feasible and safe treatment option for CL. The CL treatment period after pancreatic surgery was significantly shorter in patients who underwent lymphangiography than in those who did not. Our results suggest that lymphangiography may contribute to early improvement of persistent CL., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Alterations in the experience-dependent and autonomous elaboration of neural circuits are assumed to underlie autism spectrum disorder (ASD), though it is unclear what synaptic traits are responsible. Here, utilizing a valproic acid-induced ASD marmoset model, which shares common molecular features with idiopathic ASD, we investigate changes in the structural dynamics of tuft dendrites of upper-layer pyramidal neurons and adjacent axons in the dorsomedial prefrontal cortex through two-photon microscopy. In model marmosets, dendritic spine turnover is upregulated, and spines are generated in clusters and survived more often than in control marmosets. Presynaptic boutons in local axons, but not in commissural long-range axons, demonstrate hyperdynamic turnover in model marmosets, suggesting alterations in projection-specific plasticity. Intriguingly, nasal oxytocin administration attenuates clustered spine emergence in model marmosets. Enhanced clustered spine generation, possibly unique to certain presynaptic partners, may be associated with ASD and be a potential therapeutic target., (© 2024. The Author(s).)

Cytokine release syndrome (CRS) is a systemic inflammatory condition caused by an excessive immune response and cytokine overproduction. CRS is a life-threatening condition that is often associated with chimeric antigen receptor T-cell therapy. Despite the increased use of immune checkpoint inhibitors (ICIs), ICI-induced CRS remains rare. The present study describes a case of CRS that occurred after the administration of ICIs for recurrent adenocarcinoma of the uterine cervix. A 49-year-old woman received paclitaxel, carboplatin and pembrolizumab for recurrent cervical adenocarcinoma. On day 27 of the third cycle, the patient was admitted with a fever and suspected pyelonephritis. The following day, hypotension, upper respiratory symptoms and myalgia of the extremities were noted, and the left ventricular ejection fraction (LVEF) was decreased to 20%. Multiorgan failure (MOF) occurred, and the patient received ventilator support and continuous hemodiafiltration. Rhabdomyolysis, pancreatitis, erythema multiforme and enteritis were observed. CRS was diagnosed based on elevated ferritin and IL-6 levels. Steroid pulse therapy was administered; however, the MOF did not improve and the anti-IL-6-receptor monoclonal antibody tocilizumab (TOC) was administered. Subsequently, the LVEF improved to 50%, and the patient was removed from the ventilator on day 4 and from the continuous hemodiafiltration unit on day 6 after TOC administration. The patient was discharged on day 21. In conclusion, considering that ICI-induced CRS is a rare but severe complication, fever and other systemic conditions following ICI administration should be monitored., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Sekimata et al.)

Neurofibromatosis type 1 (NF1) is an autosomal dominant nevus disease characterized by multiple manifestations, primarily café-au-lait macules and neurofibromas. Here, we present the case of an NF1 patient with 47,XYY mosaicism whose diagnosis was prompted by café-au-lait macules on the skin and mandibular neurofibromas. Targeted next-generation sequencing of the patient's blood sample revealed a novel frameshift mutation in NF1 (NM&#95;000267.3:c.6832dupA:p.Thr2278Asnfs*8) that is considered a pathogenic variant., (© 2024. The Author(s).)

Background: Transcanal endoscopic ear surgery (TEES) reportedly requires a long learning curve and may be associated with more complications and longer operative times than microscopic ear surgery (MES). In this study, we aimed to examine the usefulness and validity of TEES for ossicular chain disruption in the early stages of its introduction in our institution., Methods: TEES was performed on 11 ears (10 with congenital ossicular chain discontinuity and 1 with traumatic ossicular chain dislocation), and MES was performed with a retroauricular incision on 18 ears (6 with congenital ossicular chain discontinuity and 12 with traumatic ossicular chain dislocation) in a tertiary referral center. Postoperative hearing results, operative times, and postoperative hospital length of stay were retrospectively reviewed. The Mann-Whitney U test and Fisher's exact test was performed to compare variables between the TEES and MES groups. Pre- and postoperative air- and bone-conduction thresholds and the air-bone gap of each group were compared using the Wilcoxon signed-rank test. The Mann-Whitney U test and Wilcoxon signed-rank was performed to compare the pre- and postoperative air-bone gaps between the diagnoses., Results: No significant differences in the postoperative air-conduction thresholds, bone-conduction thresholds, air-bone gaps, or incidence of air-bone gap ≤ 20 dB were observed between the TEES and MES groups. The air-conduction thresholds and air-bone gaps of the TEES group significantly improved postoperatively. The air-conduction thresholds and air-bone gaps of the MES group also significantly improved postoperatively. No significant difference was observed in the operative times between the groups (TEES group: median, 80 min; MES group: median, 85.5 min). The TEES group had a significantly shorter postoperative hospital stay (median, 2 days) than the MES group (median, 7.5 days)., Conclusions: TEES was considered appropriate for the treatment of ossicular chain disruption, even immediately after its introduction at our institution. For expert microscopic ear surgeons, ossicular chain disruption may be considered a suitable indication for the introduction of TEES., (© 2024. The Author(s).)

Most common cytometry methods, including flow cytometry, observe suspended or fixed cells and cannot evaluate their structural roles in 3D tissues. However, cellular physical interactions are critical in physiological, developmental, and pathological processes. Here, we present a novel optical visco-elastography that characterizes single-cellular physical interactions by applying in-situ micro-mechanical perturbation to live microtissues under 3D lightsheet microscopy. The 4D digital image correlation (DIC) analysis of ~20,000 nodes tracked the compressive deformation of 3D tissues containing ~500 cells. The computational 3D image segmentation allowed cell-by-cell qualitative observation and statistical analysis, directly correlating multi-channel fluorescence and viscoelasticity. To represent epithelia-stroma interactions, we used a 3D organoid model of maternal-fetal interface and visualized solid-like, well-aligned displacement and liquid-like random motion between individual cells. The statistical analysis through our unique cytometry confirmed that endometrial stromal fibroblasts stiffen in response to decidualization. Moreover, we demonstrated in the 3D model that interaction with placental extravillous trophoblasts partially reverses the attained stiffness, which was supported by the gene expression analysis. Placentation shares critical cellular and molecular significance with various fundamental biological events such as cancer metastasis, wound healing, and gastrulation. Our analysis confirmed existing beliefs and discovered new insights, proving the broad applicability of our method.

As power sources for Internet-of-Things sensors, thermoelectric generators must exhibit compactness, flexibility, and low manufacturing costs. Stretchable and flexible painted thermoelectric generators were fabricated on Japanese paper using inks with dispersed p- and n-type single-walled carbon nanotubes (SWCNTs). The p- and n-type SWCNT inks were dispersed using the anionic surfactant of sodium dodecylbenzene sulfonate and the cationic surfactant of dimethyldioctadecylammonium chloride, respectively. The bundle diameters of the p- and n-type SWCNT layers painted on Japanese paper differed significantly; however, the crystallinities of both types of layers were almost the same. The thermoelectric properties of both types of layers exhibited mostly the same values at 30 °C; however, the properties, particularly the electrical conductivity, of the n-type layer increased linearly, and of the p-type layer decreased as the temperature increased. The p- and n-type SWCNT inks were used to paint striped patterns on Japanese paper. By folding at the boundaries of the patterns, painted generators can shrink and expand, even on curved surfaces. The painted generator (length: 145 mm, height: 13 mm) exhibited an output voltage of 10.4 mV and a maximum power of 0.21 μW with a temperature difference of 64 K at 120 °C on the hot side.

Cholera toxin (CT), a bacterial exotoxin composed of one A subunit (CTA) and five B subunits (CTB), functions as an immune adjuvant. CTB can induce production of interleukin-1β (IL-1β), a proinflammatory cytokine, in synergy with a lipopolysaccharide (LPS), from resident peritoneal macrophages (RPMs) through the pyrin and NLRP3 inflammasomes. However, how CTB or CT activates these inflammasomes in the macrophages has been unclear. Here, we clarify the roles of inositol-requiring enzyme 1 alpha (IRE1α), an endoplasmic reticulum (ER) stress sensor, in CT-induced IL-1β production in RPMs. In RPMs, CTB is incorporated into the ER and induces ER stress responses, depending on GM1, a cell membrane ganglioside. IRE1α-deficient RPMs show a significant impairment of CT- or CTB-induced IL-1β production, indicating that IRE1α is required for CT- or CTB-induced IL-1β production in RPMs. This study demonstrates the critical roles of IRE1α in activation of both NLRP3 and pyrin inflammasomes in tissue-resident macrophages., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)