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International treatment guidelines recommend tumor resection for patients with oligometastatic colorectal cancer (CRC). Despite this, recurrence occurs in ∼60% of patients post-surgery, indicating that the role and optimal type of perioperative systemic therapy has not been fully defined. In the COSMOS-oligo trials, comprising two studies, we are evaluating the potential role of circulating tumor DNA (ctDNA) analysis in clinical decision making and exploring adjuvant therapy strategies for patients with resectable metastatic CRC. The COSMOS-CRC-03 study aims to evaluate the prognostic value of post-operative minimal residual disease as detected by ctDNA and to explore the role of ctDNA in detecting disease recurrence. We plan to assess the predictive accuracy of ctDNA results for recurrence using blood collected 28 days post-surgery. We will additionally explore whether regular post-operative ctDNA test can detect recurrence earlier than standard imaging. Post-operative adjuvant therapy will not be administered to ctDNA-negative patients. The complementary AURORA trial is a randomized phase II study designed to test whether post-operative mFOLFOXIRI plus bevacizumab is superior to standard mFOLFOX6 for patients with metastatic CRC when the ctDNA status is positive after curative-intent surgery for patients enrolled in the COSMOS-CRC-03 study. Both studies will only include patients with resectable distant metastases of CRC. We designed these studies to stratify patients based on the results of a ctDNA assay and to determine the optimal treatment for patients at the highest risk for recurrence.

Theiler’s murine encephalomyelitis virus (TMEV) infection has been used as a mouse model for two virus-induced organ-specific immune-mediated diseases. TMEV-induced demyelinating disease (TMEV-IDD) in the central nervous system (CNS) is a chronic inflammatory disease with viral persistence and an animal model of multiple sclerosis (MS) in humans. TMEV infection can also cause acute myocarditis with viral replication and immune cell infiltration in the heart, leading to cardiac fibrosis. Since platelets have been reported to modulate immune responses, we aimed to determine the role of platelets in TMEV infection. In transcriptome analyses of platelets, distinct sets of immune-related genes, including major histocompatibility complex (MHC) class I, were up- or downregulated in TMEV-infected mice at different time points. We depleted platelets from TMEV-infected mice by injecting them with platelet-specific antibodies. The platelet-depleted mice had significantly fewer viral antigen-positive cells in the CNS. Platelet depletion reduced the severities of TMEV-IDD and myocarditis, although the pathology scores did not reach statistical significance. Immunologically, the platelet-depleted mice had an increase in interferon (IFN)-γ production with a higher anti-TMEV IgG2a/IgG1 ratio. Thus, platelets may play roles in TMEV infection, such as gene expression, viral clearance, and anti-viral antibody isotype responses.

A regulatory mechanism for SLC family transporters, critical transporters for sodium and glucose reabsorptions in renal tubule, is incompletely understood. Here, we report an important regulation of SLC family transporter by SETD2, a chromatin remodeling gene whose alterations have been found in a subset of kidney cancers. Kidney-specific inactivation of Setd2 resulted in hypovolemia with excessive urine excretion in mouse and interestingly, RNA-sequencing analysis of Setd2-deficient murine kidney exhibited decreased expressions of SLC family transporters, critical transporters for sodium and glucose reabsorptions in renal tubule. Importantly, inactivation of Setd2 in murine kidney displayed attenuated dapagliflozin-induced diuresis and glucose excretion, further supporting that SETD2 might regulate SLCfamily transporter-mediated sodium and glucose reabsorptions in renal tubule. These data uncover an important regulation of SLC family transporter by SETD2, which may illuminate a crosstalk between metabolism and epigenome in renal tubule., Competing Interests: Declaration of competing interest The authors declare neither competing interests nor conflict of financial interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Gene expression controllers are useful tools for microbial production of recombinant proteins and valued bio-based chemicals. Despite its usefulness, they have rarely been applied to the practical industrial bioprocess, due to the lack of systems that meets the three requirements: low cost, safety, and tight control, to the inducer molecules. Previously, we have developed the high-spec gene induction system controlled by safe and cheap inducer choline. However, the system requires relatively high concentration (~100 mM) of choline to fully induce the gene under control. In this work, we attempted to drastically improve the sensitivity of this induction system to further reduce the induction costs. To this end, we devised a simple circuit which couples gene induction system with positive-feedback loop (P-loop) of choline importer protein BetT. After the tuning of translation level of BetT (strength of the P-loop) and deletion of endogenous betI (noise sources), highly active yet stringent control of gene expression was achieved using about 100 times less amount of inducer molecules. The choline induction system developed in this study has the lowest basal expression, the lowest choline needed to be activated, and the highest amplitude of induction as the highest available promoter such as those known as P T5 system. With this system, one can tightly control the expression level of genes of interest with negligible cost for inducer molecule, which has been the bottleneck for the application to the large-scale industrial processes.

Damage to the peripheral nerves of trigeminal ganglion (TG) neurons leads to intractable orofacial neuropathic pain through the induction of neuroinflammation. However, the details of this process are not yet fully understood. Here, we found that fibroblast-derived interleukin (IL)-33 was required for the development of mechanical allodynia in whisker pad skin following infraorbital nerve injury (IONI). The amount of IL-33 in the TG increased after IONI when the mice exhibited mechanical allodynia. Neutralization of IL-33 in the TG inhibited the development of IONI-induced mechanical allodynia. Conversely, intra-TG administration of recombinant human IL-33 (rhIL-33) elicited mechanical allodynia in naïve mice. IL-33 and its receptor were exclusively expressed in fibroblasts and neurons, respectively, in the TG. Fibroblast ablation caused the loss of IL-33 in the TG and delayed the development of mechanical allodynia after IONI. rhIL-33 elicited an increase in intracellular Ca 2+ concentration and subsequent enhancement of Ca 2+ influx via transient receptor potential ankyrin 1 (TRPA1) in primary cultured TG neurons. Additionally, rhIL-33 facilitated membrane translocation of TRPA1 in the TG. Mechanical allodynia caused by intra-TG administration of rhIL-33 was significantly inhibited by pharmacological blockade or gene silencing of TRPA1 in the TG. Inhibition of protein kinase A abrogated TRPA1 membrane translocation and delayed mechanical allodynia after IONI. Substance P stimulation caused upregulation of IL-33 expression in primary cultured fibroblasts. Preemptive administration of a neurokinin-1 receptor antagonist in the TG attenuated mechanical allodynia and IL-33 expression following IONI. Taken together, these results indicate that fibroblast-derived IL-33 exacerbates TG neuronal excitability via suppression of tumorigenicity 2 (ST2)-TRPA1 signaling, ultimately leading to orofacial neuropathic pain., 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 Inc. All rights reserved.)

Sublingual immunotherapy (SLIT) has received considerable attention as a method for allergen immunotherapy (AIT). However, the mechanism of SLIT, especially its timing, has not been thoroughly investigated. We evaluated therapeutic and prophylactic SLIT in an allergic airway inflammation model and evaluated their efficacies. Mice were intranasally exposed to Dermatophagoides farinae (Der f) extract and received SLIT before (prophylactic model) and after (therapeutic model) intranasal exposure of Der f. We investigated airway responsiveness, airway inflammation, allergen-specific antibodies, lung histology and single-cell RNA sequencing (scRNA-seq) and T-cell receptor sequencing were also investigated. SLIT in the therapeutic model was effective; however, the effects of SLIT in the prophylactic model were stronger and immune tolerance was maintained for three months. ScRNA-seq of lung CD4 + CD25 + T cells revealed that the expansion of induced T regulatory (iTreg) cells was greater in the prophylactic model than that in the therapeutic model. Additionally, the TCR repertoire of iTregs from the prophylactic model was abundant, sharing many clones with the TCR repertoire of effector T cells. These data suggest that the prophylactic model of AIT is extremely effective and persistent, and may respond to allergen diversity, and provide evidence for the clinical recommendation of preventive AIT., (© 2024. The Author(s).)

Background/aim: The randomized phase II COMPASS trial revealed that neither the regimen nor the number of courses of preoperative neoadjuvant chemotherapy (NAC) for locally advanced gastric cancer (GC) significantly influence overall survival (OS). However, the impact of NAC regimens on OS may vary from patient to patient. The aim of this study was to identify biomarkers that can predict more appropriate individualized NAC regimens for improved prognosis using biopsy specimens from the COMPASS trial., Patients and Methods: RNA was extracted from endoscopic biopsy specimens of primary tumors obtained prior to NAC and real-time PCR analysis of 127 genes was conducted to identify those significantly affecting survival in the context of specific NAC regimens., Results: THBS1, MSI1, and IGF2BP3 were identified as significant factors for stratifying survival among different NAC regimens, with statistically significantly interaction p values. Immunohistochemical analysis confirmed that the protein levels of THBS1, MSI1, and IGF2BP3 strongly correlated with their gene expression levels, validating these proteins as reliable biomarkers., Conclusion: This study effectively identified THBS1, MSI1, and IGF2BP3 as promising biomarkers for personalizing NAC regimens in patients with locally advanced GC. By tailoring NAC based on these biomarkers, it is possible to enhance survival outcomes and advance personalized treatment strategies. The findings underscore the potential for incorporating biomarker-guided approaches into clinical trials, aiming to refine and optimize NAC regimens for improved patient-specific treatment efficacy., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Alpha-synuclein deposits in the brain have been suspected to cause Parkinson's disease and dementia with Lewy bodies (DLB). It was recently revealed that the glymphatic system is largely responsible for the removal of alpha-synuclein. We investigated changes in the glymphatic system's activity by determining the DTI‑ALPS (diffusion tensor image analysis along the perivascular space) index in DLB patients. Twenty-six patients with DLB and 43 healthy subjects underwent diffusion tensor imaging (DTI) scanning at our hospital during the period April 2013 to March 2023. We retrospectively computed each subject's DTI‑ALPS index to evaluate his/her glymphatic-system activity and then analyzed the relationships between the subjects' DTI‑ALPS index data and their DLB neuroimaging biomarker values. A significant reduction of the DTI‑ALPS index was observed in the patients with DLB compared to the healthy subjects. Significant positive correlations were also detected in the DLB group between the DTI‑ALPS index and the regional gray matter volume in the left insula and between the index and the specific binding ratio of 123 I-N-ω-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl)nortropane ([ 123 I]-FP-CIT). These results indicate that (i) the DTI‑ALPS index is a good biomarker of the progression of DLB, and (ii) this index might be effective to distinguish DLB from other neurocognitive disorders., 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.)

Background: The effect of differences in daily physical activity patterns on blood lipids has not been determined. This study examines the effects of the differences in free-living daily physical activity patterns (amount and intensity) on blood lipid levels in older adults., Methods: This cross-sectional study included 51 older participants (71.8 ± 0.6 years, men = 8, women = 43). A triaxial accelerometer was used to assess physical activity patterns. The time from awakening to bedtime for each participant was used for group classification based on the amount (number of steps) and intensity (moderate-to-vigorous physical activity, MVPA) of physical activity. The morning step group (M Step) was defined as those who took more steps in the morning, and the afternoon step group (A Step) was defined as those who took more steps in the afternoon. The same method was used for MVPA (morning MVPA: M MVPA; afternoon MVPA: A MVPA). Blood samples were collected at the start of the study to determine blood lipid levels., Results: Number of steps taken showed a trend toward lower low-density lipoprotein cholesterol (LDL-C) levels in the M Step group compared with the A Step group. The LDL/high-density lipoprotein (HDL) ratio was significantly lower in the M Step group than the A Step group (p < 0.05). The M MVPA group also had higher HDL-C levels and significantly lower LDL/HDL ratios than the A MVPA group (p < 0.05)., Conclusions: These results suggest that compared with afternoon physical activity, daily morning physical activity (amount and intensity) is more effective in improving blood lipid levels., (© 2024. The Author(s).)

Spectral variations of light-harvesting (LH) proteins of purple photosynthetic bacteria provide insight into the molecular mechanisms underlying spectral tuning of circular bacteriochlorophyll (BChl) arrays, which play crucial roles in photoenergy conversion in these organisms. Here we investigate spectral changes of the Q y band of B850 BChl a in LH2 protein from purple sulfur bacterium Thermochromatium tepidum (tepidum-LH2) by detergents and Ca 2+ . The tepidum-LH2 solubilized with lauryl dimethylamine N-oxide and n-octyl-β-D-glucoside (LH2 LDAO and LH2 OG , respectively) exhibited blue-shift of the B850 Q y band with hypochromism compared with the tepidum-LH2 solubilized with n-dodecyl-β-D-maltoside (LH2 DDM ), resulting in the LH3-like spectral features. Resonance Raman spectroscopy indicated that this blue-shift was ascribable to the loss of hydrogen-bonding between the C3-acetyl group in B850 BChl a and the LH2 polypeptides. Ca 2+ produced red-shift of the B850 Q y band in LH2 LDAO by forming hydrogen-bond for the C3-acetyl group in B850 BChl a, probably due to a change in the microenvironmental structure around B850. Ca 2+ -induced red-shift was also observed in LH2 OG although the B850 acetyl group is still free from hydrogen-bonding. Therefore, the Ca 2+ -induced B850 red-shift in LH2 OG would originate from an electrostatic effect of Ca 2+ . The current results suggest that the B850 Q y band in tepidum-LH2 is primarily tuned by two mechanisms, namely the hydrogen-bonding of the B850 acetyl group and the electrostatic effect., 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.)

Most predictive models that use alternatives to animal experiments divide judgements into two classes with a cutoff value for each model. However, if the results of alternative methods are close to the cutoff values, the true result may be ambiguous because of variability in the data. Therefore, the OECD GL497 uses a judgement method that establishes a borderline range (BR) around a cutoff value using a statistical method. However, because there is no detailed description of how the BR is calculated, we clarified two specific points. The scale-constant correction method was used to calculate the median absolute deviation (MAD) around the median. In addition, the bottom-raised transformation method was used when the data were "0" because calculation of the BR requires that all data are logarithmic. Indeed, the BRs for the amino acid derivative reactivity assay (ADRA), interleukin-8 reporter gene assay (IL-8 Luc), and epidermal sensitization assay (EpiSensA) were calculated using data from each validation study. The results showed that the BR for ADRA and IL-8 Luc ranged from 4.1 to 5.9 and 1.25 to 1.57, respectively. Furthermore, the BRs of four genes (ATF3, GCLM, DNAJB4, and IL-8) evaluated using EpiSensA ranged from 10.71 to 21.02, 1.64 to 2.45, 1.61 to 2.52, and 3.11 to 5.16, respectively. The difference (deviation) between the lower and upper BR limits and cutoff value for each alternative method were comparable to those of the alternative methods listed in the guidelines (DPRA, KerarinoSens, and h-CLAT) and thus were considered as adequate., (© 2024 John Wiley & Sons Ltd.)

Objectives: Physiologic knee kinematics are crucial for successful total knee arthroplasty (TKA) but are often not replicated. Using a medial stabilizing technique (MST) minimizes bone resection but results in lateral laxity. This study aimed to investigate the effects of lateral laxity on knee kinematics and symptoms after TKA., Methods: Mobile-bearing cruciate-retaining MST-TKA was performed on 40 knees using a navigation system. In the kinematic analysis, the anteroposterior (AP) translations of the medial femoral condyle (MFC) and lateral femoral condyle (LFC), femoral rotation angles, and medial and lateral component gaps were recorded every 0.1 s. These data were extracted from the software from 0° to 120° flexion in 10° increments. Kinematics were classified as the medial center of rotation (MCR) or non-MCR between 0° to 90° of flexion. Lateral laxity was calculated by subtracting the medial component gap from the lateral component gap. The final follow-up Knee Injury and Osteoarthritis Outcome Scores (KOOS) were evaluated. The relationships between the pre and postoperative kinematics and between postoperative lateral laxity and kinematics were assessed using Spearman's correlation coefficients. Finally, the correlation between postoperative lateral laxity and KOOS symptoms was evaluated using linear regression analysis., Results: Preoperative kinematics, including AP translation of the MFC and LFC and femoral rotation, correlated with postoperative kinematics (all P < 0.001). Additionally, postoperative lateral laxity correlated with postoperative AP translation of the MFC, LFC, and femoral rotation (all P < 0.001). Furthermore, the receiver operating characteristic analysis indicated a cutoff value of 0.9 mm on postoperative lateral laxity at 90° flexion for postoperative MCR (P < 0.001). Postoperative lateral laxity at 90° flexion was significantly correlated with KOOS symptoms (β = 0.465, P = 0.025)., Conclusion: Preoperative kinematics and postoperative lateral laxity correlated with postoperative kinematics after MST-TKA. Postoperative lateral laxity greater than 0.9mm at 90° flexion was associated with physiological kinematic motion, leading to fewer knee symptoms in the PROMs. The key to successful TKA was considered to be keeping the asymmetric gap balance with physiological lateral laxity, rather than the conventional symmetrical gap balance., Level of Evidence Level Iii: Retrospective study., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The high specificity of the human skin microbiome is expected to provide a new marker for personal identification. Metagenomic sequencing of clustered regularly interspaced short palindromic repeats (CRISPRs), which we call metaCRISPR typing, was shown to achieve personal identification accurately. However, the intra-individual variability observed in previous studies, which may be due to poor DNA yields from skin samples, has resulted in non-reproducible results. Furthermore, whether metaCRISPR typing can assist in the forensic human DNA analysis of low-biomass samples, from which the information obtained is insufficient, is unknown. In the present study, we sequenced serially diluted control streptococcal CRISPRs cloned into plasmids to determine the minimum copy number required to obtain reproducible results from metaCRISPR typing. We found that at least 10 2 copies of CRISPRs are necessary to obtain reproducible results. We then analyzed the skin swab samples using both metaCRISPR typing and human DNA typing. When the DNA extracted from the skin swabs was diluted, no information was obtained from six out of eight samples by human DNA typing. On the other hand, beta diversity indices of spacer sequences compared with reference samples were below 0.8 for three out of six samples, for which no information was obtained from human DNA analysis, indicating that the spacers observed in these samples were similar to those in the references. These results indicate that metaCRISPR typing may contribute to the identification of individuals from whom the samples were obtained, even in cases where human DNA yields are insufficient to perform human DNA analysis.IMPORTANCEPrevious studies have developed new personal identification methods utilizing personal differences in the skin microbiome. However, intra-individual diversity of skin microbiome may preclude the application of microbiome-based personal identification. Moreover, no study has compared microbiome-based personal identification and practical human DNA analysis. Here, we revealed that the results of metaCRISPR typing, a previously developed microbiome-based personal identification method, are stable if the copy number of the marker gene is sufficient. We then analyzed the skin swab samples using both metaCRISPR typing and human DNA analysis. Our results indicate that metaCRISPR typing may provide additional information for personal identification using low-biomass samples that cannot be used for conventional human DNA analysis.

Primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction (STEMI) is typically performed by experienced operators. Therefore, the safety of pPCI for STEMI performed by less experienced operators with the support of experienced operators remains unknown. We aimed to investigate the long-term outcomes of pPCI for STEMI performed by less experienced operators with the support of experienced operators. In total, 775 STEMI patients were enrolled and divided into groups according to operator experience in PCI: less experienced (n = 384) and experienced (n = 391) operator groups. Experienced operators were defined as those who had performed > 50 elective PCI procedures per year as the first operator or instructional assistant, whereas less experienced operators were defined as others. When less experienced operators performed the pPCI, experienced operators supported them. The primary endpoint was any cardiovascular event, defined as a composite of cardiovascular death, nonfatal myocardial infarction, and unplanned hospitalization for heart failure. In the propensity score-matched analysis, 324 patients were included in each group. The cumulative incidence of the primary endpoint over a median of 5 years in the less experienced operator group was similar to that in the experienced operator group (15% vs. 18%, P = 0.209). In the multivariate Cox proportional hazards model, there was no excess risk for patients operated upon by less experienced operators for the primary endpoint (adjusted hazard ratio, 0.85; 95% confidence interval, 0.58-1.25; P = 0.417). pPCI for STEMI by less experienced operators did not increase the risk of in-hospital mortality or 5-year long-term cardiovascular events if supported by experienced operators., (© 2024. The Author(s) under exclusive licence to Japanese Association of Cardiovascular Intervention and Therapeutics.)

Introduction: This study aimed to evaluate the efficacy of perioperative dysphagia rehabilitation in older adult patients diagnosed with gastric cancer who underwent gastrectomy., Materials and Methods: This retrospective study included 149 patients over 80 years who underwent gastrectomies between January 2000 and December 2020. The patients were divided into two groups based on the intervention of the dysphagia rehabilitation team (DRT group: n = 101) and the non-intervention control group (C group: n = 48). Inverse probability weighting (IPW) analysis was used to reduce bias caused by potential confounding., Results: The incidence of overall complications was significantly lower in the DRT group (odds ratio [OR]; 0.27[0.08-0.93]), among which the incidence of postoperative pneumonia (OR; 0.07[0.01-0.43]) and aspiration pneumonia (OR; 0.05[0.01-0.44] was significantly reduced. Ten patients developed postoperative pneumonia; seven were in the C group, and three were in DRT group. Sixty percent of these patients had preoperative comorbidities related to the respiratory system. Regarding the time of onset of aspiration pneumonia, two patterns were observed: onset within a short period after surgery and onset after the start of eating. In contrast, five patients underwent preoperative dysphagia rehabilitation in the DRT group. Among them, postoperative aspiration pneumonia was prevented in four patients, and the others were prevented from severe pneumonitis by the intervention of the dysphagia rehabilitation team., Discussion: Perioperative intervention in dysphagia rehabilitation is not only associated with reduced postoperative pneumonia but also creates awareness in the medical staff and promotes careful observation of swallowing in patients, thereby controlling the incidence of postoperative pneumonia. The perioperative intervention of the dysphagia rehabilitation team is useful for older adult patients with gastric cancer., Competing Interests: Declaration of Competing Interest Atsushi Yasuda, Yutaka Kimura, Takushi Yasuda, Yoko Hiraki, Takaomi Hagi, Hiroaki Kato, Osamu Shiraishi, Masayuki Shinkai, Motohiro Imano, and Haruhiko Imamoto declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Symptomatic heart failure (HF) negatively affects the quantity and quality of skeletal muscles. However, the association between asymptomatic HF and skeletal muscle function remains unclear. We aimed to use ultrasonography to elucidate the association between asymptomatic HF and skeletal muscle function in community-dwelling older adults., Methods: This cross-sectional study comprised community-dwelling older adults aged ≥ 60 years who could perform activities of daily living independently and had never had symptomatic HF (n = 52, 76.3 ± 6.1 years). The participants were classified into three groups namely, non-HF (n = 26), stage A (n = 19), and stage B (n = 7) according to the HF stage criteria of the American Heart Association /American College of Cardiology /Heart Failure Society of America guideline. Skeletal muscle quantity and quality were assessed using ultrasonography (thickness and echo intensity) of the rectus femoris (RF) and vastus intermedius (VI) muscles. The group effects on muscle thickness and echo intensity in each group were assessed using a multivariate analysis., Results: Both muscles consistently demonstrated significant group effects on the thickness and echo intensity. Thicknesses of the RF (p = 0.020) and VI (p = 0.035) were lower in the stage B group than that in the non-HF group. The echo intensities in the RF (p = 0.006) and VI (p = 0.009) were higher in the stage B group than that in the non-HF group., Conclusion: Asymptomatic HF negatively associated with the characteristics of skeletal muscle function, as assessed by ultrasonography in community-dwelling older adults. The stage B HF contributes to reduced skeletal muscle function as well as symptomatic HF., (© 2024. The Author(s).)

Although lenalidomide is an essential treatment for multiple myeloma (MM), skin rashes are a common adverse event. This retrospective study aimed to examine the association between skin rash development during lenalidomide treatment and the prognosis of relapsed/refractory MM. All patients who received lenalidomide at 10 hospitals between July 2009 and December 2015 were included in the study. The relationship of skin rash development with disease progression and survival was evaluated. Multivariate analysis was performed to identify factors affecting disease progression or survival, including skin rash. Of the 245 patients analyzed, 70 developed skin rashes. The median progression-free survival (PFS) of patients with skin rashes was 22.4 months, whereas the median PFS for patients who did not develop skin rashes was 10.5 months (p = 0.003). The median overall survival for patients with and without skin rash was 42.6 and 24.6 months, respectively (p = 0.013). Multivariate regression analysis showed that skin rash was an independent prognostic factor for PFS (p = 0.009). In this study, patients with skin rashes during lenalidomide treatment had significantly better PFS than those without such symptoms, indicating that lenalidomide-associated skin rashes may be a predictor of clinical outcomes in patients with MM., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The branchial epithelium is one of the main tissues in which histone H3K4 trimethylation (H3K4me3) occurs in the budding tunicate, Polyandrocarpa misakiensis. It contains proliferating and undifferentiated cell aggregates at the bottom of each pharyngeal cleft, providing the nest for the adult stem cell niche. We examined the sustainable mechanism enabling epigenetic histone methylation in adult stem cells., Results: Histone H3K4 demethylase (PmisKdm5) was not co-expressed in vivo with the transcription factor, signal transduction and activator of transcription (PmisStat) in the same cells. PmisStat mRNA, when electroporated into zooids, suppressed the gene expression of PmisKdm5 and facilitated the trimethylation of H3K4. A STAT5 inhibitor blocked the nuclear localization of PmisStat. It stimulated PmisKdm5 gene expression irrespective of PmisStat mRNA. The KDM5 inhibitor, CPI-455, stimulated H3K4me3 similarly to PmisStat mRNA. PmisStat mRNA and CPI-455 both induced the gene expression of PmisAp2 and PmisSp8, which were recently identified as budding/regeneration-related genes. When zooid tissues were treated with both CPI-455 and the STAT5 inhibitor, CPI-455 overwhelmed the effects of the STAT inhibitor on PmisAp2 and PmisSp8., Conclusion: PmisStat is involved in epigenetic histone methylation at H3K4 through the inhibition of PmisKdm5. H3K4me3 affects downstream gene expression more directly and strongly than PmisStat., (© 2024 American Association for Anatomy.)

Multiple sclerosis (MS) is an autoimmune-demyelinating disease with an inflammatory pathology formed by self-reactive lymphocytes with activated glial cells. Progressive MS, characterized by resistance to medications, significantly differs from the non-progressive form in gut microbiome profiles. After confirming an increased abundance of "Tyzzerella nexilis" in various cohorts of progressive MS, we identified a distinct cluster of T. nexilis strains enriched in progressive MS based on long-read metagenomics. The distinct T. nexilis cluster is characterized by a large number of mobile genetic elements (MGEs) and a lack of defense systems against MGEs. Microbial genes for sulfate reduction and flagella formation with pathogenic implications are specific to this cluster. Moreover, these flagellar genes are encoded on MGEs. Mono-colonization with MGE-enriched T. nexilis made germ-free mice more susceptible to experimental autoimmune encephalomyelitis. These results indicate that the progression of MS may be promoted by MGE-enriched T. nexilis with potentially pathogenic properties., Competing Interests: Declaration of interests T.Y. served on the scientific advisory board of Biogen Japan, Ltd., and received support for research and clinical trials from Sanofi K.K., Chugai Pharmaceutical, Co., Ltd., UCB Japan Co., Ltd., Biogen Japan, Ltd., Chiome Bioscience, Inc., Novartis Pharma K.K., and Mebix, Inc., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: The aim of this study is to directly compare the effects of SGLT2 inhibitors and DPP-4 inhibitors on β-cell function in patients with type 2 diabetes., Materials and Methods: We conducted a 26-week, randomized, open-label, parallel-group study, including a 1-2 week drug washout period, in patients with type 2 diabetes with HbA1c ≥7.0% and <9.0% and BMI ≥20 kg/m 2 despite treatment with a drug naïve or other than DPP-4 inhibitors or SGLT2 inhibitors. A total of 103 subjects were randomly assigned to receive once daily oral luseogliflozin (L) or teneligliptin (T). The primary endpoint was the effect of L vs. T on the change in logarithmus naturalis (Ln) disposition index (DI) (DI 0-120min ; combining measures of insulin secretion and sensitivity) from baseline to week 25-26 (post intervention), which was calculated by conducting an oral glucose tolerance test., Results: Ln DI 0-120min were improved in both groups: -0.46 ± 0.68 to -0.20 ± 0.59 ( p =0.03) in L group and -0.26 ± 0.60 to -0.05 ± 0.62 ( p =0.01) in T group. The change in Ln serum proinsulin/C-peptide ratio, a marker of β-cell dysfunction, was reduced in L group (1.63 ± 0.63 to 1.56 ± 0.68, p =0.16), but rather increased in T group (1.70 ± 0.75 to 1.90 ± 0.51, p =0.01), with significant difference between the two groups (-0.27; p =0.004)., Conclusions: Improvement of disposition index in subjects with obese type 2 diabetes was comparable between luseogliflozin and teneligliptin. On the other hand, it is likely that alleviation of β-cell dysfunction is more effective with luseogliflozin compared to tenegliptin., Clinical Trial Registration: https://rctportal.niph.go.jp/en, identifier jRCTs061190008., Competing Interests: HK has received honoraria for lectures and received scholarship grants from Sanofi, Novo Nordisk, Lilly, Boehringer Ingelheim, MSD, Takeda, Ono Pharma, Daiichi Sankyo, Sumitomo Pharma, Mitsubishi Tanabe Pharma, Pfizer, Kissei Pharma, AstraZeneca, Astellas, Novartis, Kowa, Chugai and Taisho Pharma. KKa has been an advisor to, received honoraria for lectures from, and received scholarship grants from Novo Nordisk Pharma, Sanwa Kagaku Kenkyusho, Takeda, Taisho Pharmaceutical Co., Ltd, MSD, Kowa, Sumitomo Pharma, Novartis, Mitsubishi Tanabe Pharma, AstraZeneca, Nippon Boehringer Ingelheim Co., Ltd, Chugai, Daiichi Sankyo, and Sanofi. TK has received honoraria for lectures from Sumitomo Pharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shimoda, Katakura, Mashiko, Iwamoto, Nakanishi, Anno, Kawasaki, Obata, Fushimi, Sanada, Kohara, Isobe, Iwamoto, Hirukawa, Tatsumi, Kimura, Kimura, Mune, Kaku and Kaneto.)

Background: Colorectal cancer is a major global health burden, with surgical resection being the standard treatment aimed at curative tumor removal. Oxidative stress plays a crucial role in colorectal cancer progression and prognosis. This study hypothesized that physical removal of colorectal cancer, a primary source of oxidative stress, would reduce blood levels of reactive oxygen metabolite derivatives (d-ROMs), a marker of oxidative stress, and biologic antioxidant potential (BAP) levels, a marker of antioxidant potential., Methods: This study included 123 patients who underwent radical resection for colorectal cancer. d-ROM and BAP levels were measured before and one month after surgery., Results: The clinicopathological analysis showed a correlation between preoperative d-ROM levels and tumor size ( p < 0.001). This study confirmed a significant reduction in d-ROM levels following tumor resection, indicating reduced systemic oxidative stress. The reduction was significant in stages II and III, but not in stage I. The d-ROM ratio before and after tumor resection was significantly higher in cases with positive lymph node metastasis and larger tumor size. BAP levels showed no significant changes post-surgery., Conclusions: These results suggest that d-ROMs could serve as a valuable biomarker for monitoring tumor burden and surgical efficacy in patients with colorectal cancer.

Purpose: The impact of untreated medial meniscus posterior root (MMPR) tear (MMPRT) during opening-wedge high tibial osteotomy (OWHTO) on patient-reported outcomes (PROs) remains poorly understood. This retrospective cohort study aimed to investigate the association between the presence of MMPRT and post-operative PROs in patients who underwent OWHTO., Methods: A total of 83 knees that underwent OWHTO that were followed up for 6.6 years were included. Post-operative PROs were assessed using the knee injury and osteoarthritis outcome score (KOOS) subscales. Medial meniscus extrusion (MME) was measured by magnetic resonance imaging (MRI). MMPRT was diagnosed based on preoperative MRI and intraoperative arthroscopy findings. The participants were categorized into the MMPRT and MMPR intact (MMPRI) groups, and their KOOS subscales were compared. Additionally, logistic regression analysis was conducted to explore the correlation between KOOS and MMPRT presence., Results: In total, 29 out of 80 (36.3%) knees were classified into the MMPRT group, while three knees underwent total knee arthroplasty. Preoperative MME was 3.5 ± 1.9 (range 0-8.9) mm, showing correlation with the presence of MMPRT ( p  = 0.004) by regression analysis. The post-operative KOOS subscales of the MMPRT group were lower than the MMPRI group for pain ( p  = 0.017), activities of daily living (ADLs) ( p  = 0.001), sports ( p  < 0.001) and quality of life (QOL) ( p  < 0.001). Additionally, regression analysis showed the presence of MMPRT was correlated with lower KOOS subscale scores for pain ( p  = 0.041), ADLs (p = 0.011), sports ( p  < 0.001) and QOL ( p  = 0.002)., Conclusion: Preoperative MMPRT correlated with a reduction in mid-term post-operative PROs, as assessed using the KOOS, among patients who underwent OWHTO. Surgeons should consider addressing an MMPRT at the time of OWHTO., Level of Evidence: Level IV., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Repeating X-ray computed tomography (CT) measurements over a short period of time allows for obtaining a spatiotemporal four-dimensional (4D) volume image. This study presents an interactive method for segmenting a 4DCT image by fitting a template model to a target organ. The template consists of a three-dimensional (3D) mesh model and free-form-deformation (FFD) cage enclosing the mesh. The user deforms the template by placing multiple curve constraints that specify the boundary shape of the template in 3D space. We also present curve constraints shared over all time frames and interpolated along the time axis to facilitate efficient curve specification. Our method formulates the template deformation using the FFD cage modification, allowing the user to switch between our curve-based method and traditional FFD at any time. To illustrate the feasibility of our method, we show segmentation results in which we could accurately segment three organs from a 4DCT image capturing a swallowing motion. To evaluate the usability of our method, we conducted a user study comparing our curve-based method with the cage-based FFD. We found that the participants finished segmentation in approximately 20% interaction time periods on average with our method., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Kimura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: We investigated the effectiveness of lenvatinib (LEN) after disease progression following first-line treatment with atezolizumab plus bevacizumab (Atez/Bev) in patients with unresectable hepatocellular carcinoma (HCC)., Methods: One hundred and ten HCC patients treated with Atez/Bev as first-line systemic chemotherapy were enrolled and underwent dynamic computerized tomography/magnetic resonance imaging to determine the treatment response. We evaluated the treatment efficacy and prognosis after second-line LEN treatment, especially in elderly patients., Results: Of the 110 study patients, 88 patients (80%) were determined to have progressive disease (PD) during the observation periods, and 40 patients received second-line LEN therapy. The 40 patients included 13 patients who were unable to continue LEN until the initial evaluation due to adverse events (AE). The 27 patients who were able to continue LEN therapy (Group A) were significantly younger at initiation of Atez/Bev than those who could not continue (71 vs. 77 years old, p = 0.013). Comparing the OS and PFS between Group A and 44 patients that included 13 patients who were unable to continue LEN and 31 patients did not receive the second-line treatment (Group B), the former had significantly better OS than Group B (31.1 vs. 17.8 months, p = 0.035)., Conclusions: The tolerability of second-line LEN therapy was lower in elderly patients, and the OS from the start of Atez/Bev therapy was different depending on the tolerability of second-line LEN therapy., (© 2024 S. Karger AG, Basel.)

Background: Precise skin phenotypic data are indispensable in accurately diagnosing atopic dermatitis (AD). Therefore, this study examined the interobserver concordance for AD and non-AD diagnoses between two dermatologists. AD prevalence determined by the self-reported physician diagnoses and the diagnoses determined from the United Kingdom (UK) diagnostic criteria were compared with the diagnoses made by the two dermatologists, using data from a skin health survey., Methods: This study included 1,638 children that participated in the skin health survey, which was part of the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. AD was assessed using dermatologist assessments, self-reported physician diagnoses, and the UK diagnostic criteria. The concordance for diagnoses was evaluated using kappa. The sensitivity and specificity of the self-reported physician diagnoses and the UK diagnostic criteria were calculated by comparing them with the two dermatologists' diagnoses., Results: Among the 1,638 children, 393 (24.0 %), 194 (11.9 %), and 597 (37.2 %) were diagnosed with AD by the two dermatologists, physicians, and the UK diagnostic criteria, respectively. The kappa (95 % CI) of the interobserver concordance for AD or non-AD diagnoses between the two dermatologists was 0.78 (0.75-0.81). The sensitivity and specificity of the self-reported physician diagnoses were 26.7 % and 94.1 %, respectively. The sensitivity and specificity of the UK diagnostic criteria were 85.0 % and 82.4 %, respectively., Conclusions: Interobserver concordance for AD or non-AD diagnoses between the two dermatologists was substantial. Self-reported physician diagnoses exhibited low sensitivity that potentially indicated underdiagnosis of AD, whereas the UK diagnostic criteria might overdiagnose AD., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

We developed phosphorylation reagents with a nitrobenzyl hydrophobic tag and used them for 5'-phosphorylation of chemically or transcriptionally synthesized RNA. The capability of hydrophobic tags to synthesize 5'-monophosphorylated RNA was evaluated based on the yield of the desired oligonucleotides, stability of protecting groups during cleavage/deprotection, separation ability in reverse-phase HPLC (RP-HPLC), and deprotection efficiency after RP-HPLC purification. The results showed that a nitrobenzyl derivative with a tert-butyl group at the benzyl position was most suitable for RNA 5'-phosphorylation. Using the developed phosphorylation reagent, we chemically synthesized 5'-phosphorylated RNA and confirmed that it could be purified by RP-HPLC and the following deprotection. In addition, we demonstrated complete chemical synthesis of minimal mRNA by chemical capping of 5'-monophosphorylated RNA. Ribonucleoside 5'-monophosphates with hydrophobic protecting groups have also been developed and used as substrates to transcriptionally synthesize 5'-phosphorylated RNA with >1000 bases. From the mixture of the by-products and the desired RNA, only 5'-monophosphorylated RNA could be effectively isolated by RP-HPLC. Furthermore, monophosphorylated RNA can be converted into circular mRNA via RNA ligase-mediated cyclization. Circular mRNA expression of nanoluciferase in cultured cells and mice. These techniques are important for the production of chemically synthesized mRNA and circular mRNA., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Up to seven doses of coronavirus disease 2019 (COVID-19) mRNA vaccines (BNT162b2) were administered to Japanese healthcare workers, until February 2024. The monovalent Omicron XBB.1.5 vaccine (hereafter called XBB.1.5 vaccine) was used for dose 7., Objective: Although the XBB.1.5 vaccine has been reported to induce a robust increase in neutralizing antibodies against the currently circulating Omicron variant BA.2.86, little is known about its serological effects in Japan, where the BNT162b2 mRNA vaccine is the most frequently administered in the world., Study Design: Twenty-five recipients of the XBB.1.5 vaccine, categorized as seronegative (n = 18) or seropositive (n = 7) based on their recent history of COVID-19, were analyzed. Neutralizing antibody titers against Omicron subvariants, receptor binding domain (RBD) IgG levels, IgG subclass distribution, and T-cell responses were assessed., Results: We found a significant increase in neutralizing antibody titers against XBB.1.5 and BA.2.86 variants following XBB.1.5 vaccination, particularly in seropositive individuals. No significant change in total RBD IgG levels was observed, indicating efficient induction of antibodies targeting regions outside the RBD by XBB.1.5 vaccination. IgG subclass analysis demonstrated no significant subclass switching after vaccination. T-cell responses against the virus were comparable between seropositive and seronegative groups., Conclusions: The study suggests that XBB.1.5 vaccination enhances humoral immunity against Omicron variants without significant IgG subclass switching. However, some individuals with low pre-vaccination IgG titers did not exhibit increased antibody levels post-vaccination, raising concerns about potential immune tolerance., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Therapeutic oligonucleotides, such as antisense DNA, show promise in treating previously untreatable diseases. However, their applications are still hindered by the poor membrane permeability of naked oligonucleotides. Therefore, it is necessary to develop efficient methods for intracellular oligonucleotide delivery. Previously, our group successfully developed disulfide-based Membrane Permeable Oligonucleotides (MPON), which achieved enhanced cellular uptake and gene silencing effects through an endocytosis-free uptake mechanism. Herein, we report a new molecular design for the next generation of MPON, called trimer MPON. The trimer MPON consists of a tri-branched backbone, three α-lipoic acid units, and a spacer linker between the oligonucleotides and tri-branched cyclic disulfide unit. We describe the design, synthesis, and functional evaluation of the trimer MPON, offering new insights into the molecular design for efficient oligonucleotide delivery., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Synaptic phenotypes in living patients with psychiatric disorders are poorly characterized. Excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a fundamental component for neurotransmission. We recently developed a positron emission tomography (PET) tracer for AMPAR, [ 11 C]K-2, the first technology to visualize and quantify AMPARs density in living human brain. In this study, we characterized patients with major psychiatric disorders with [ 11 C]K-2. One hundred forty-nine patients with psychiatric disorders (schizophrenia, n = 42; bipolar disorder, n = 37; depression, n = 35; and autism spectrum disorder, n = 35) and 70 healthy participants underwent a PET scan with [ 11 C]K-2 for measurement of AMPAR density. We detected brain regions that showed correlation between AMPAR density and symptomatology scores in each of four disorders. We also found brain areas with significant differences in AMPAR density between patients with each psychiatric disorder and healthy participants. Some of these areas were observed across diseases, indicating that these are commonly affected areas throughout psychiatric disorders. Schizophrenia, bipolar disorder, depression, and autism spectrum disorder are uniquely characterized by AMPAR distribution patterns. Our approach to psychiatric disorders using [ 11 C]K-2 can elucidate the biological mechanisms across diseases and pave the way to develop novel diagnostics and therapeutics based on the synapse physiology., (© 2024. The Author(s).)

In this study, we report the synthesis of 2'-formamidonucleoside phosphoramidite derivatives and their incorporation into siRNA strands to reduce seed-based off-target effects of small interfering RNAs (siRNAs). Formamido derivatives of all four nucleosides (A, G, C and U) were synthesized in 5-11 steps from commercial compounds. Introducing these derivatives into double-stranded RNA slightly reduced its thermodynamic stability, but X-ray crystallography and CD spectrum analysis confirmed that the RNA maintained its natural A-form structure. Although the introduction of the 2'-formamidonucleoside derivative at the 2nd position in the guide strand of the siRNA led to a slight decrease in the on-target RNAi activity, the siRNAs with different sequences incorporating 2'-formamidonucleoside with four kinds of nucleobases into any position other than 2nd position in the seed region revealed a significant suppression of off-target activity while maintaining on-target RNAi activity. This indicates that 2'-formamidonucleosides represent a promising approach for mitigating off-target effects in siRNA therapeutics., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Competing Interests: Disclosures The authors have no conflicts of interest to disclose.

The dried fruits of Cornus officinalis (Cornaceae) are used in Kampo medicine (e.g. Hachimigan and Goshajinkigan) to treat senile osteoporosis, diabetes, gastric atony, frequent urination, and diarrhea/constipation associated with aging. The present study investigated the effects of a C. officinalis fruit extract and morroniside, an iridoid compound from isolated these fruits, on the reduction in gastric emptying small intestinal motility caused by 5-hydroxytryptamine (5-HT) and 1-(3-chlorophenyl) biguanide (5-HT 3 receptor agonist), and gastric ulcers induced by 150 or 75 mM HCl/90 % EtOH (HCl-EtOH) and/or 5-HT in mice. C. officinalis extract (500 mg/kg) and morroniside (20 and 50 mg/kg) suppressed the reduction in gastric emptying induced by 5-HT- and 5-HT 3 agonist. C. officinalis extract, morroniside and 5-HT 3 receptor antagonist (ramosetron) attenuated 5-HT-induced diarrhea. Furthermore, morroniside (20 and 50 mg/kg) prevented EtOH/HCl-induced gastric ulcers and those caused by 5-HT. Morroniside (20 and 50 mg/kg) attenuated elevations in the plasma levels of corticosterone, corticotropin-releasing factor (CRF), and adrenocorticotropic hormone (ACTH) in 75 mM HCl/90 % EtOH- and 5-HT-treated mice. The results obtained herein suggest the potential of morroniside as an effective treatment for irritable bowel syndrome, such as diarrhea and functional dyspepsia (reductions in gastric emptying and small intestinal motility), caused by 5-HT. The present study suggests a role for morroniside in the regulation of elevations in CRF, ACTH, and corticosterone levels through hypothalamic-pituitary-adrenal axis activity induced by stress loading, such as a 5-HT treatment and/or HCl/EtOH stimulation., Competing Interests: Declaration of competing interest Authors declare that this research was conducted in the absence of any commercial of financial relationships that may be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Report writing in class provides basic training for academic writing. However, report writing education in medical schools in Japan has rarely been reported and no teaching strategy has been established for it., Methods: This study developed a report writing program using peer review for first-year medical students consisting of two 120-minute classes. The goal of being able to write reports appropriately was established and presented to students at the beginning of the program. In session 1, students decided on a topic, gathered information, and structured their report. In session 2, students' written reports were peer reviewed. The reports were improved based on the peer reviews. The responses of the pre- and post-program questionnaires were evaluated to determine the program's effectiveness. The other reports that were assigned one month after the program were used as comparison with the reports of students who did not participate. Furthermore, the long-term effects of the program were also evaluated by comparing the results of students from the previous year who did not participate in the program with those of program participants six months after the program., Results: A total of 106 students completed the questionnaire evaluation. The program was rated as being acceptable for the students. Self-assessment of report writing significantly improved after the program. The report scores of program participants (n = 99) were significantly higher overall and in all domains than were those of non-participants (n = 99). The self-assessment of students who participated (n = 96) was significantly higher than that of non-participants (n = 109). No difference was observed for students' sense of burden in report writing., Conclusions: The report writing skills of medical students can be improved by clearly establishing the goals of report writing and practicing the basic skills of report writing step-by-step. Moreover, the use of peer review may enhance the effectiveness of learning opportunities for report writing., (© 2024. The Author(s).)

Background: With the use of heated tobacco products (HTPs) becoming more widespread in Japan, interest in the health effects of HTP has grown. Since the majority of HTP users are former smokers, information about the user's smoking history and health status before HTP use is needed when assessing the health effects of HTP use. The limited epidemiological studies available did not consistently consider this information adequately, therefore we conducted a cross-sectional study investigating the association between HTP use and respiratory chronic diseases and symptoms., Methods: The questionnaires were sent to a research panel members in Japan via the Internet, and individuals who met the study criteria and were either current exclusive HTP users, current exclusive cigarette users or those had never used tobacco products were selected. Information about the participants' smoking history and health status before they used HTPs was obtained. The effects of participant smoking history before HTP use and the impacts on outcomes upon switching to HTP were assessed using a logistic regression model. The odds ratio (OR) for current exclusive HTP users relative to never tobacco users was calculated. The OR was calculated under two scenarios, one in which the smoking history was ignored or one in which the smoking history was considered., Results: Of the participants from whom responses to the questionnaires were obtained, 17,406 participants were included in the analysis. Almost all participating current exclusive HTP users had a history of long-term smoking (mean: 30.8 years), and the occurrence of outcomes both before and after the start using HTP was reported. The ORs, without adjustment and with adjustment for smoking history before HTP use were, 3.23 (95% CI: 1.37-7.61) and 1.85 (95% CI: 0.70-4.89) respectively in COPD, same as other outcomes., Conclusions: These results suggest that smoking history before HTP using affects the occurrence of outcomes, and underscore the importance of considering smoking history when assessing the health effect of HTP use. Since the duration of HTP use is considerably shorter than that of cigarette use at present, further research, such as follow-up surveys assessing the long-term respiratory effects of HTP use, will be necessary., (© 2024. The Author(s).)

Background and Purpose: Elevated intracranial pressure (ICP) resulting from severe head injury or stroke poses a risk of secondary brain injury that requires neurosurgical intervention. However, currently available noninvasive monitoring techniques for predicting ICP are not sufficiently advanced. We aimed to develop a minimally invasive ICP prediction model using simple CT images to prevent secondary brain injury caused by elevated ICP., Methods: We used the following three methods to determine the presence or absence of elevated ICP using midbrain-level CT images: (1) a deep learning model created using the Python (PY) programming language; (2) a model based on cistern narrowing and scaling of brainstem deformities and presence of hydrocephalus, analyzed using the statistical tool Prediction One (PO); and (3) identification of ICP by senior residents (SRs). We compared the accuracy of the validation and test data using fivefold cross-validation and visualized or quantified the areas of interest in the models., Results: The accuracy of the validation data for the PY, PO, and SR methods was 83.68% (83.42%-85.13%), 85.71% (73.81%-88.10%), and 66.67% (55.96%-72.62%), respectively. Significant differences in accuracy were observed between the PY and SR methods. Test data accuracy was 77.27% (70.45%-77.2%), 84.09% (75.00%-85.23%), and 61.36% (56.82%-68.18%), respectively., Conclusions: Overall, the outcomes suggest that these newly developed models may be valuable tools for the rapid and accurate detection of elevated ICP in clinical practice. These models can easily be applied to other sites, as a single CT image at the midbrain level can provide a highly accurate diagnosis., (© 2024 American Society of Neuroimaging.)

This study explores a novel therapeutic approach for peritoneal metastasis (PM) using AAV-mediated delivery of tumor suppressor microRNA-29b (miR-29b) to peritoneal mesothelial cells (PMC). AAV serotypes 2 and DJ demonstrate high transduction efficiency for human and murine PMC, respectively. In vitro analysis indicates that AAV vectors encoding miR-29b precursor successfully elevate miR-29b expression in PMC and their secreted small extracellular vesicle (sEV), thereby inhibiting mesothelial mesenchymal transition and reducing subsequent attachment of tumor cells. A single intraperitoneal (IP) administration of AAV-DJ-miR-29b demonstrates robust and sustained transgene expression, suppressing peritoneal fibrosis and inhibiting the development of PM from gastric and pancreatic cancers. Additionally, AAV-DJ-miR-29b enhances the efficacy of IP chemotherapy using paclitaxel, restraining the growth of established PM. While conventional gene therapy for cancer encounters challenges targeting tumor cells directly but delivering miRNA to the tumor stroma offers a straightforward and efficient means of altering the microenvironment, leading to substantial inhibition of tumor growth. AAV-mediated miR-29b delivery to peritoneum via IP route presents a simple, minimally invasive, and promising therapeutic strategy for refractory PM., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Computed tomography (CT)-guided lung biopsy is a widely used technique for the diagnosis of pulmonary lesions and with a high technical success rate and diagnostic accuracy. On the other hand, it is associated with a high risk of complications, especially pneumothorax. Various methods have been tried to reduce the incidence of pneumothorax, but no established method exists. The purpose of this study was to evaluate whether the combination of tract sealing with normal saline and rapid rollover can reduce the rate of pneumothorax and chest tube insertion after CT-guided lung biopsy., Methods: We reviewed all CT-guided lung biopsies performed at a single institution between October 2016 and December 2021. Before August 2019, no specific additional techniques were employed to mitigate complications (Group 1). In contrast, after September 2019, normal saline for tract sealing was injected during needle removal, and if pneumothorax was observed during the intervention, the patient was rolled over into the puncture-site down position immediately after needle removal (Group 2). The rate of complications was compared between the two groups., Results: 130 patients in Group 1 and 173 in Group 2 were evaluated. There was no significant difference in pneumothorax rate between the two groups (30.0% vs. 23.1%, P = .177). A chest tube was inserted in 10 of 130 patients in Group 1 and only in 1 of 173 in Group 2 (P = .001). There were no complications associated with this combinational technique., Conclusions: The combination of normal saline injection and rapid rollover significantly reduced the incidence of pneumothorax requiring chest tube insertion after CT-guided lung biopsy. Therefore, normal saline injection and rapid rollover can serve as a preventive method for severe pneumothorax in CT-guided lung biopsy., (© 2024. The Author(s).)

We investigated the effects of Clostridioides difficile toxin B (TcdB), a major virulence factor in C. difficile infection (CDI), on human neutrophils. TcdB inhibits neutrophil migration via loss of polarity of F-actin polymerization in response to interleukin-8. TcdB facilitates CDI by allowing C. difficile to avert the host immune system., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic pulmonary aspergillosis (CPA) has recently gained attention owing to its substantial health burden. However, the precise epidemiology and prognosis of the disease are still unclear due to the lack of a nationwide descriptive analysis. This study aimed to elucidate the epidemiology of patients with CPA and to investigate their prognosis., Methods: Using a national administrative database covering >99% of the population in Japan, we calculated the nationwide incidence and prevalence of CPA from 2016 to 2022. Additionally, we clarified the survival rate of patients diagnosed with CPA and identified independent prognostic factors using multivariate Cox proportional hazard analysis., Results: During the study period, while the prevalence of CPA remained stable at 9.0-9.5 per 100,000 persons, its incidence declined to 2.1 from 3.5 per 100,000 person-years. The 1-, 3-, and 5-year survival rates were 65%, 48%, and 41%, respectively. During the year of CPA onset, approximately 50% of patients received oral corticosteroids (OCS) at least once, while about 30% underwent frequent OCS treatment (≥4 times per year) within the same timeframe. Increased mortality was independently associated with older age (>65 years) (hazard ratio [HR], 2.65; 95% confidence interval (CI), 2.54-2.77), males (1.24; 1.20-1.29), a history of chronic obstructive pulmonary disease (1.05; 1.02-1.09), lung cancer (1.12; 1.06-1.18); and ILD (1.19; 1.14-1.24); and frequent OCS use (1.13; 1.09-1.17). Conversely, decreased mortality was associated with a history of tuberculosis (HR, 0.81; 95% CI, 0.76-0.86), non-tuberculous mycobacteria (0.91; 0.86-0.96), and other chronic pulmonary diseases (0.89; 0.85-0.92)., Conclusions: The incidence of CPA decreased over the past decade, although the prevalence was stable and much higher than that in European countries. Moreover, the patients' prognosis was poor. Physicians should be vigilant about CPA onset in patients with specific high-risk underlying pulmonary conditions., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background/aim: The function of the S-100 protein family member hornerin (HRNR) in gastric cancer (GC) tissues is largely unknown. We researched the clinical significance of HRNR expression in GC tissues of patients with pathological (p)Stage II/III GC after curative resection., Patients and Methods: We included patients with pStage II/III GC who underwent curative gastrectomy (n=253). Expression levels of HRNR in GC tissue and in the adjacent normal mucosa were determined using quantitative real-time polymerase chain reaction. Clinicopathological features and overall survival (OS) were compared in patients with different HRNR expression levels in GC tissue., Results: HRNR expression levels were significantly higher in GC tissues than in the adjacent normal mucosa. HRNR expression level in GC tissue showed sex differences. The 5-year OS rate in the high-HRNR expression group was significantly worse than that in the low-expression group (5-year survival 53.6% vs. 74.9%; p=0.004). Furthermore, on multivariate analysis, high-HRNR expression was an independent predictor of poor OS (hazard ratio=1.534; 95% confidence interval=1.130-2.618; p=0.011)., Conclusion: In patients with pStage II/III GC after curative gastrectomy, HRNR expression in GC tissue may be a useful prognostic marker., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Granzyme B (GZMB) is mainly produced by natural killer (NK) cells and activated CD8-positive T cells to induce tumor cell apoptosis. We analyzed the significance of GZMB expression in gastric cancer (GC) tissues from patients with pathological (p)Stage II/III GC after curative resection., Patients and Methods: Patients with pStage II/III GC who received curative resection (n=253) were included and the expression levels of GZMB in GC tissues and in the adjacent normal mucosa were measured using quantitative real-time polymerase chain reaction. The expression levels in GC tissues and clinicopathological features and overall survival (OS) were compared in these patients., Results: GZMB expression levels were significantly higher in GC tissues than in the adjacent normal mucosa. GZMB expression levels in GC tissues were not associated with any clinicopathological features. The 5-year OS rate in the high-GZMB expression group was significantly better than that in the low-expression group (5-year survival rate 72.0% vs. 55.7%; p=0.009). Furthermore, on multivariate analysis, high-GZMB expression was an independent factor for better OS (hazard ratio=0.652; 95% confidence interval=0.432-0.987; p=0.043)., Conclusion: In patients with locally advanced GC after curative resection, GZMB expression in GC tissue may be a useful prognostic marker., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Sarcopenic obesity is the co-existence of obesity and sarcopenia in individuals aged 40-75 years. The Japanese Working Group on Sarcopenic Obesity has developed diagnostic criteria tailored for the Japanese population, considering their unique characteristics compared with European populations. Our algorithm consists of two steps: screening and diagnosis. The screening of obesity mandates using waist circumference and/or body mass index (BMI) based on national standards, while screening for sarcopenia involves the "finger ring test" in addition to the Asian Working Group for Sarcopenia 2019 criteria. The final diagnosis of sarcopenia involves handgrip strength for low muscle strength, the five-times chair stand test for low physical function, and limb skeletal muscle mass (corrected for BMI) for low muscle mass. Obesity is assessed by visceral fat area or body fat percentage. Sarcopenic obesity is then categorized into Stage I, with muscle weakness/loss of function, loss of muscle mass, and obesity; or Stage II, which includes complications. Further clinical validation is needed to refine the consensus and age range. Geriatr Gerontol Int 2024; 24: 997-1000., (© 2024 The Author(s). Geriatrics & Gerontology International published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society.)

Background and Aim: Serum interleukin-6 (IL-6) before the administration of atezolizumab plus bevacizumab (Atez + Bev) is a prognostic biomarker in patients with hepatocellular carcinoma (HCC) treated with Atez + Bev. We previously revealed that the neutrophil-to-lymphocyte ratio and serum chemokine levels during treatment with Atez + Bev were more useful as prognostic biomarkers. Therefore, we examined the predictive ability of serum IL-6 for the efficacy of Atez + Bev in patients with HCC., Methods: We enrolled 94 patients with HCC who received treatment with Atez + Bev. Initial responses were assessed through dynamic computed tomography or magnetic resonance imaging. The levels of IL-6 in serum were measured before and at the initiation of the second course of Atez + Bev. Subsequently, the relationship of IL-6 levels with treatment efficacy was evaluated., Results: IL-6 levels at the initiation of the second course tended to be higher in patients with progressive disease versus those with non-progressive disease in the initial evaluation (P = 0.054). Moreover, the cutoff value (7.4 pg/mL) was useful in stratifying patients by overall survival (i.e. low vs high: not reached vs 21.4 months, respectively, P = 0.001) and progression-free survival (low vs high: 11.9 vs 5.2 months, respectively, P = 0.004). This result was reproduced in patients with HCC who received Atez + Bev as first-line therapy. In the multivariate analyses, IL-6 levels at the initiation of the second course were independent predictive factors for progression-free and overall survival., Conclusions: Serum levels of IL-6 at the initiation of the second course of treatment may predict Atez + Bev efficacy and prognosis in HCC., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Higher vegetable intake is being promoted as an initiative to prevent lifestyle-related diseases. Carotenoids are yellow or red pigment components and are widely present in vegetables. Since ingested carotenoids accumulate in the skin, skin carotenoid levels are a quantitative indicator of vegetable intake. Recently, noninvasive optical sensors for assessing skin carotenoid levels were developed. We here examined the association between skin carotenoid scores measured using optical sensors and the presence of metabolic syndrome., Methods: A total of 1618 individuals (604 men and 1014 women) aged ≥ 40 years (mean age 63.1 years) participated in the study. Skin carotenoid scores were determined using a noninvasive optical sensor based on multiple spatially resolved reflectance spectroscopy. Metabolic syndrome was defined based on the Joint Scientific Statement criteria developed by six international scientific societies. Multivariable-adjusted logistic regression models were used., Results: The prevalence of metabolic syndrome was 31.3% (n = 506). A remarkably strong association was found between higher skin carotenoid scores and lower prevalence of metabolic syndrome after adjusting for confounders. The multivariable-adjusted odds ratio for the presence of metabolic syndrome in individuals with the highest quartile of skin carotenoid scores was 0.39 (95% confidence interval, 0.28-0.55) compared to those with the lowest quartile., Conclusions: Our findings suggest that higher skin carotenoid scores measured by non-invasive optimal sensors are significantly associated with a lower likelihood of having metabolic syndrome in the general Japanese population., (© 2024. The Author(s).)

Background and Aims: Successful left atrial posterior wall isolation (LAPWI) using only the cryoballoon (CB) is technically challenging for the treatment of atrial fibrillation (AF). This study aimed to evaluate the efficacy of the cross-over technique, wherein an overlapped ablation is performed by placing the CB from both directions in contact with the LAPW., Methods: This was a single-center, retrospective, observational study of 194 consecutive patients with persistent atrial fibrillation (PerAF) who underwent a first-time procedure of pulmonary vein isolation (PVI) + PWI (108 patients) or PVI-only (86 patients) using the CB. The cross-over technique was applied in all LAPWI., Results: For ablation of the LA roof and bottom, respectively, a mean of 8.6 ± 1.0 (right to left [R→L] 4.3 ± 1.1 and left to right [L→R] 4.3 ± 1.1) and 9.1 ± 1.2 (R→L 4.6 ± 1.6 and L→R 4.5 ± 1.2) CB applications were delivered. LAPW was successfully isolated solely using the CB in 99.1% of patients. Although the PVI + PWI group had significantly longer procedure time, no severe adverse events were observed in either group. During a median follow-up of 19 months, freedom from recurrence of all atrial tachyarrhythmias was achieved in 93.5% of the PVI + PWI group and 72.9% of the PVI-only group (p = .011)., Conclusions: LAPWI performed solely with the CB using the cross-over technique is feasibly, safe, and was independently associated with a significantly higher freedom from recurrence of atrial tachyarrhythmias compared with PVI alone in patients with PerAF., (© 2024 The Author(s). Pacing and Clinical Electrophysiology published by Wiley Periodicals LLC.)

To our best knowledge, the formation of a pancreatico-renal fistula and the presence of pancreatic fluid collection in the renal subcapsular space have not been reported as autoimmune pancreatitis (AIP) complications. We describe a case of a pancreatico-renal fistula associated with type 1 AIP. The patient presented with abdominal and back pain accompanied by pancreatic cystic lesions during an untreated course of AIP. The diagnosis of pancreatico-renal fistula was based on the presence of a left renal subcapsular fluid collection containing pancreatic amylase, disappearance of pancreatic cysts, and a defect in the partial anterior renal fascia observed on imaging studies. Treatment with steroids and percutaneous drainage resulted in improvement. Pancreatic pseudocysts can affect other organs owing to their digestive action. Similar symptoms may occur in patients with AIP., (© 2024. Japanese Society of Gastroenterology.)

Halorhodospira (Hlr.) halochloris is a triply extremophilic phototrophic purple sulfur bacterium, as it is thermophilic, alkaliphilic, and extremely halophilic. The light-harvesting-reaction center (LH1-RC) core complex of this bacterium displays an LH1-Q y transition at 1,016 nm, which is the lowest-energy wavelength absorption among all known phototrophs. Here we report the cryo-EM structure of the LH1-RC at 2.42 Å resolution. The LH1 complex forms a tricyclic ring structure composed of 16 αβγ-polypeptides and one αβ-heterodimer around the RC. From the cryo-EM density map, two previously unrecognized integral membrane proteins, referred to as protein G and protein Q, were identified. Both of these proteins are single transmembrane-spanning helices located between the LH1 ring and the RC L-subunit and are absent from the LH1-RC complexes of all other purple bacteria of which the structures have been determined so far. Besides bacteriochlorophyll b molecules (B1020) located on the periplasmic side of the Hlr. halochloris membrane, there are also two arrays of bacteriochlorophyll b molecules (B800 and B820) located on the cytoplasmic side. Only a single copy of a carotenoid (lycopene) was resolved in the Hlr. halochloris LH1-α3β3 and this was positioned within the complex. The potential quinone channel should be the space between the LH1-α3β3 that accommodates the single lycopene but does not contain a γ-polypeptide, B800 and B820. Our results provide a structural explanation for the unusual Q y red shift and carotenoid absorption in the Hlr. halochloris spectrum and reveal new insights into photosynthetic mechanisms employed by a species that thrives under the harshest conditions of any phototrophic microorganism known., (© 2024 The Authors. Journal of Integrative Plant Biology published by John Wiley & Sons Australia, Ltd on behalf of Institute of Botany, Chinese Academy of Sciences.)

Background: The association between recurrence timing and prognosis in patients with locally advanced resectable esophageal cancer undergoing neoadjuvant chemotherapy (NAC) followed by esophagectomy remains unclear. This study aimed to clarify this association using multicenter prospective clinical trial data., Methods: Among 162 patients enrolled in a NAC phase II study comparing the efficacy of cisplatin and fluorouracil plus docetaxel with cisplatin and fluorouracil plus adriamycin, 64 patients with recurrence after R0 resection were included in this study. We evaluated the association between recurrence timing and overall survival after recurrence (OSr), along with clinicopathological factors associated with recurrence timing and OSr., Results: Among 64 patients, 46 (71.9%) and 59 (92.2%) experienced recurrence within 1 and 2 years after surgery, respectively. Groups based on recurrence timing, including ≤ 6, 6-12, and > 12 months, had median OSr of 3.6, 13.9, and 13.4 months, respectively. The prognosis was significantly poorer for patients with recurrence ≤ 6 months after surgery than for other patients (P < 0.001). Multivariate analysis revealed pathological lymph node staging as an independent factor associated with early recurrence (odds ratio: 3.46, 95% confidence interval: 1.47-8.02, P = 0.0045). On the other hand, multivariate analysis for factors associated with OSr revealed pT (hazard ratio [HR]: 1.91, 95%CI 1.26-2.88, P = 0.0022), early recurrence (HR: 6.88, 95%CI 2.68-17.6, P < 0.001), and treatment after recurrence, with both local treatment (HR: 0.47, 95%CI 0.22-0.98, P = 0.043) and chemotherapy (HR: 0.25, 95%CI 0.11-0.58, P = 0.0011) as independent prognostic factors., Conclusion: Patients with advanced esophageal cancer experiencing recurrence within 6 months after esophagectomy following NAC have an extremely poor prognosis, suggesting that an advanced pN stage is associated with early recurrence., (© 2024. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Introduction: Achieving an adequate surgical plane through optimal traction is crucial for liver parenchymal transection in minimally invasive liver surgery (MILS). MILS is more technically demanding than open liver surgery because of limited instrument mobility and the inability to use the surgeon's hand, potentially leading to iatrogenic injuries. The Pulley maneuver using barbed sutures has been used for laparoscopic hepatectomy; however, the sutures are single-use and may pass through the liver parenchyma, making it uneconomical and inflexible. To address this, we developed a modified pulley maneuver using a barbed with a nonabsorbable polymer clip and metal clip for parenchymal transection in MILS., Materials and Surgical Technique: Before liver transection, we prepared barbed sutures and attached nonabsorbable polymer and metal clips to the distal end. The metal clip prevented the nonabsorbable polymer clip from slipping, allowing one suture to be reused three times. Before liver transection, the suture was passed through the liver surface twice, with the clips to reduce iatrogenic damage. The sutures were anchored to the diaphragm or peritoneum for optimal liver traction. A laparoscopic or robotic grasper adjusted the suture tension for the appropriate transection plane. In open-pit-shaped resections, the liver is lifted ventrally for deeper access, whereas in wedge-shaped resections, it is elevated in the caudal view. The modified pulley maneuver provides stable liver traction., Discussion: The modified pulley maneuver is an economical, simple, and feasible method for enabling stable liver traction, thereby enhancing the versatility and safety of liver parenchymal transection in MILS., (© 2024 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Introduction and Hypothesis: Robot-assisted radical nephroureterectomy (RANU) has emerged as a valid alternative to open or laparoscopic nephroureterectomy in recent years. However, different types of robotic platforms can limit surgical maneuvers in various ways. This study aimed to describe the surgical procedure and demonstrate RANU's technical feasibility and safety using the Hugo robot-assisted surgery (RAS) system. Materials and Methods: Using the Hugo RAS system, we reported data from the first five consecutive patients who underwent RANU at Tottori University Hospital. We adjusted the docking angles of the four independent arm carts in each case and performed a complete RANU via a transperitoneal approach. We collected patients' sociodemographic and perioperative data, including complications, and compared them retrospectively with data obtained using the da Vinci surgical system. Results: Arms positions were modified after the first patient to be placed all at the back of the patient. Median overall operative time was 283 minutes (203-377) and the median time using the robotic system was 187 minutes (121-277). The median estimated blood loss was 20 mL (5-155). None of the patients required a blood transfusion and none suffered postoperative complications of Clavien-Dindo grade ≥3. These outcomes were similar to those obtained with the da Vinci Xi system. Conclusion: This series represents the first report of RANU executed using the novel Hugo RAS system. Our proposed arm-setup will assist other surgeons and help ensure safe implementation of RANU on the Hugo platform.