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Citriculture is facing challenges due to the spread of various diseases, among which the most threatening, with worldwide occurrence, is Huanglongbing (HLB), caused by the bacteria Candidatus Liberibacter spp., vectored by psyllids. In orchards, HLB-infected plants are identified by visual observation of symptoms. For laboratory diagnosis, the gold standard is the polymerase chain reaction (PCR), requiring expertise and specific equipment, and with high financial cost. In this work, a selective impedimetric immunosensor was developed for the detection and determination of Ca. L. asiaticus (CLas) in citrus samples. An anti-HLB antibody against the outer membrane protein (OMP) sequence of CLas was obtained and immobilized on previously synthesized and characterized magnetic nanoparticles. The immobilized antibody was presented to various citrus leaf sample extracts. After the affinity reaction with the antigen, a washing step was performed to minimize matrix effects. The affinity reaction was monitored by electrochemical impedance spectroscopy, using a glassy carbon working electrode containing a neodymium magnet. The developed device was able to distinguish HLB-positive samples from HLB-negative samples and those with other infections. The results obtained with the proposed methodology were in good agreement with quantitative PCR (qPCR)., Competing Interests: Declaration of competing interest The authors declared than not exist conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Adipose tissue engineering requires effective strategies for regenerating adipose tissue, with adipose-derived stem cells (ASCs) being favored due to their robust self-renewal capacity and multipotent differentiation potential. In this study, the efficacy of poly-L-lactic acid (PLLA) mesh containing collagen sponge (CS), seeded with ASCs to promote adipose tissue formation, was investigated. PLLA-CS implants seeded with GFP-positive ASCs were inserted at high concentration (1 × 10 6 cells/implant, H-ASC) and low concentration (1 × 10 5 cells/implant, L-ASC), as were unseeded controls. Adipogenesis was evaluated at 3, 6, and 12 months using a rat inguinal model. At 3 months, the weight and volume of newly formed tissues in the H-ASC group were significantly higher than those in the control group. Histological assessment revealed that the area of all newly formed tissue, including the adipose tissue inside the implants in the H-ASC group, was larger at 6 and 12 months compared with that of the control and L-ASC groups, with the adipose percentage at 12 months being higher in the H-ASC group than in the control group. GFP-positive ASCs in both the L-ASC and H-ASC groups adhered to the CS scaffolds and survived for up to 12 months postimplantation, with spontaneous differentiation into adipocytes observed exclusively in the H-ASC group. Double immunofluorescence confirmed the presence of GFP-positive adipocytes. In summary, this study demonstrated that ASCs coimplanted with PLLA-CS implants could enhance adipose tissue formation within the implants. Uninduced ASCs were capable of spontaneously differentiating into adipocytes within the PLLA-CS implants, with differentiation correlating with the number of implanted cells.

Objectives: Urate-lowering efficacy and safety of febuxostat was evaluated in paediatric patients with hyperuricaemia including gout., Methods: A Phase 2 study of febuxostat in paediatric patients aged 6-18 years with hyperuricaemia including gout was conducted. We evaluated the proportion of patients achieving serum uric acid (sUA) level ≤6.0 mg/dl at Week 26, and long-term safety and efficacy at Week 52. We also considered efficacy stratified by renal function., Results: Thirty patients (10 at <40 kg and 20 at ≥40 kg) were enrolled. Twenty-four were males, 29 had asymptomatic hyperuricaemia, and 1 had gout. Age was 8 to 18 years. Of these, 63.3% (95% confidence interval 43.9-80.1%) achieved a sUA level of ≤6.0 mg/dl at Week 26. sUA level (mean ± standard deviation) was 5.55 ± 0.87 mg/dl, reduced from 9.01 ± 1.23 mg/dl at baseline. Febuxostat efficacy appeared similar for mild to moderate renal dysfunction and with normal renal function. There were no major safety issues., Conclusions: In paediatric patients with hyperuricaemia including gout, febuxostat showed long-term, well-controlled urate-lowering efficacy with no major safety issues. Findings suggest that no dose adjustment is required for paediatric patients with mild to moderate renal dysfunction., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Objectives: We investigated the long-term effectiveness, safety, and factors affecting Japanese Health Assessment Questionnaire (J-HAQ) improvement during abatacept treatment in Japanese rheumatoid arthritis (RA) patients., Methods: The Orencia® Registry in Geographically Assembled Multicenter Investigation (ORIGAMI) study is an ongoing observational study of biologic-naïve RA patients with moderate disease activity treated with subcutaneous abatacept (125 mg, once weekly). Patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) were extracted from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) registry as a historical, weighted control group. The primary end point for this interim analysis was the proportion of patients with J-HAQ remission (score ≤0.5) at 3 years., Results: Among 279 abatacept-treated and 220 csDMARD-treated patients, J-HAQ remission was achieved at 3 years in 40.5% [95% confidence interval (CI) 34.7-46.2%] and 28.9% (95% CI 9.9-47.8%), respectively. Age, RA duration <1 year, baseline J-HAQ score, and Simplified Disease Activity Index remission at 6 months were associated with 3-year J-HAQ remission in the abatacept group. Overall, 24/298 patients (8.1%; safety analysis set) experienced serious adverse drug reactions with an incidence of 5.3 per 100 person-years., Conclusions: This study confirmed the 3-year effectiveness and safety and revealed potential factors associated with J-HAQ remission in biologic-naïve RA patients treated with abatacept in real-world clinical practice., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Objectives: To compare treatment outcomes in patients with late-onset rheumatoid arthritis (LORA) and younger-onset rheumatoid arthritis (YORA)., Methods: We analyzed patients diagnosed with early rheumatoid arthritis (disease duration < 2 years) between 2000 and 2016 in the IORRA cohort. Patients were categorized into LORA (onset at ≥ 65 years) and YORA (onset at < 65 years). The primary outcomes were changes in Clinical Disease Activity Index (CDAI) and Japanese version of the Health Assessment Questionnaire (J-HAQ) at Year 5. The secondary outcomes included the incidence of prespecified adverse events., Results: Methotrexate, biological disease-modifying anti-rheumatic drugs, and glucocorticoids were used in 70.6%, 8.4%, and 38.0% of the LORA group (n = 813, median age: 71 years), and 81.6%, 19.4%, and 32.0% of the YORA group (n = 2,457, median age: 51 years). Both groups exhibited significant initial improvements in CDAI and J-HAQ scores. At Year 5, mean CDAI scores were 4.39 and 4.03 for the LORA and YORA groups, respectively. J-HAQ score for YORA remained stable below 0.5 after Year 2, whereas that for LORA worsened progressively. At Year 5, mean J-HAQ scores were 0.56 for LORA and 0.33 for YORA. Patients with LORA had a higher incidence of adverse events, with adjusted hazard ratios of 4.70 for death and 2.58 for malignancy., Conclusions: Patients with LORA and YORA exhibited similar improvements in disease activity over 5 years; however, those with LORA demonstrated a more pronounced decline in physical function., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: We characterised early changes in laboratory parameters in Japanese patients with rheumatoid arthritis (RA) and assessed whether these changes at Month (M)1 were predictive of tofacitinib efficacy at M3., Methods: This post hoc analysis included data from Japanese patients with RA receiving tofacitinib or placebo pooled from two Phase (P)2 studies in Japan (NCT00603512; NCT00687193) and one global P3 study (NCT00847613). Outcomes: changes from baseline in laboratory parameters (Week 2 and M1/3); efficacy endpoints (Disease Activity Score in 28 joints, based on C-reactive protein [DAS28-4(CRP)], DAS28-4, based on erythrocyte sedimentation rate [DAS28-4(ESR)], and American College of Rheumatology-N index) at M3. Univariate/multivariable analyses assessed whether changes in laboratory parameters at M1 were predictive of efficacy outcomes at M3., Results: Overall, 467 patients receiving tofacitinib and 104 receiving placebo were included. Tofacitinib treatment was associated with decreases from baseline in CRP, ESR, neutrophils, and platelets, and increases in lymphocytes, haemoglobin, and lipids up to M3. Decreased platelet count and increased low-density lipoprotein cholesterol and haemoglobin at M1 were predictive of changes in efficacy outcomes at M3., Conclusions: Changes in laboratory parameters at M1 could potentially be used to assess whether tofacitinib therapy will be effective at M3; further investigation is needed., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Purpose: Whole-prostate dose escalation in stereotactic body radiotherapy (SBRT) for localized prostate cancer (PCa) can improve oncological outcomes, albeit at the cost of increased toxicity. A focal boost to the dominant intraprostatic lesion (DIL) is gaining interest as an alternative approach. Herein, we investigate the safety and efficacy of this approach., Methods: This retrospective study enrolled patients with localized PCa who underwent five-fraction SBRT with a focal boost to the DIL at our institution between May 2016 and August 2021. The prescription doses to the whole prostate were 35 and 36.25 Gy for low- to favorable intermediate-risk PCa and unfavorable intermediate- to high-risk PCa, respectively. The focal boost to the DIL was up to 115-140% of the prescribed dose. None of the patients underwent pretreatment fiducial or perirectal hydrogel spacer placement. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities and oncological outcomes were assessed., Results: Among the 520 patients, 44% were categorized as patients with high-risk PCa. The median follow-up period was 42.9 months. No acute or late grade ≥3 toxicities were observed. Acute and late grade 2 GU toxicities were observed in 22.3 and 6.1%, respectively, while GI toxicities were observed in 2.1 and 0.8% of the patients. The 4‑year relapse-free survival rate was 94.8% among all patients., Conclusion: Our results indicate that SBRT with a focal boost without fiducials or perirectal hydrogel spacer for localized PCa has a promising toxicity profile and oncological outcomes. Longer follow-up studies are necessary to adequately evaluate late toxicities and efficacy., Competing Interests: Conflict of interest: Y. Tsurugai, A. Takeda, N. Sanuki, Y. Aoki, Y. Kimura, Y. Oku, T. Eriguchi, H. Yamanaka, M. Machida, T. Matsushita, and S. Saito declare that they have no competing interests., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Anticipating the onset, location and severity of radiation dermatitis before radiotherapy can aid in dermatological care. This study developed a method for creation of a prediction diagram for dermatitis and conducted a comparative verification between the prediction diagram and actual patient condition. The prediction diagram involved converting skin doses into 2 Gy fractionated equivalent doses using α/β of 10.0, defining regions of interest (ROIs) from 20-50 Gy at 10 Gy intervals. Overlaps between these ROIs at each dose level and the skin (external) was sequentially color-coded as blue, yellow, red, and purple. The study included four patients: two underwent head and neck treatment and two received neck and chest treatment. This approach involved a visual assessment comparing the prediction diagram with skin photographs captured at the end of treatment. Nurses marked skin sites corresponding to grades 1 and 2 on photographs, assessing their correlation with the predicted range. Visual assessment results were largely positive, although one patient exhibited slightly lower scores. Results revealed a correlation between grade 1 skin reactions and the 20 Gy regions. Grade 2 reactions were observed in regions near 30 and 40 Gy. Although discrepancies between prediction diagram and actual skin symptoms were observed in patients, a broad agreement was evident. The prediction diagram cannot accurately predict radiation dermatitis, as it does not account for skin symptoms unrelated to the dose. However, the diagram is significant as it provides physicians, nurses, and patients with concise and visually comprehensible information regarding the location of dermatitis., Competing Interests: 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., (© 2024 The Author(s).)

Plant diseases caused by soil-borne fungi and oomycetes significantly reduce yield and quality of many crops in the agricultural systems and are difficult to control. We herein examine Pseudomonas rhodesiae HAI-0804, a bacterial biological control agent that was originally developed for control of bacterial diseases on the surface of vegetables, and assessed its efficacy at controlling soil-borne diseases caused by oomycetes. Strain HAI-0804 did not exhibit detectable antibiotic activity toward Pythium ultimum , a causal agent of damping-off and root rot; however, it effectively protected against Pythium damping-off and root rot in cucumber. Exogenous glutamate enhanced the efficacy of biocontrol, the production of siderophore pyoverdine, root colonization in cucumber plants, and the ratio of biofilm formation to planktonic cells. The epiphytic fitness of strain HAI-0804 appears to contribute to plant protection efficacy against a broad spectrum of pathogens for both above-ground plant parts and the rhizosphere., Competing Interests: KN, CN, YO, RM, HY, and TO were employed by Nippon Soda Co., Ltd. MM was employed by Nisso Field Service Co., Ltd. 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 Takeuchi, Ogiso, Ota, Nishimura, Nishino, Omori, Maeda, Mizui, Yamanaka, Ogino and Seo.)

Objective: There is no consensus on whether platinum doublet chemotherapy or lenvatinib and pembrolizumab (LEN/PEM) is superior for advanced or recurrent endometrial cancer. Thus, this study aimed to compare the prognosis and adverse events in patients with advanced or recurrent endometrial cancer treated with platinum doublet chemotherapy or LEN/PEM., Methods: We retrospectively reviewed the medical records of patients who received platinum doublet chemotherapy or LEN/PEM at our institution for advanced or recurrent endometrial cancer and had a history of platinum-based chemotherapy between January 2013 and August 2023., Results: During the study period, 11 regimens were identified in the platinum doublet chemotherapy group, and 11 regimens were identified in the LEN/PEM group. The objective response rates of the platinum doublet chemotherapy and LEN/ PEM groups were 36.4% and 54.5% (P=0.67), respectively. The 6-month progression-free survival (PFS) rates of the platinum doublet chemotherapy and LEN/PEM groups were 27.3% (95% confidence interval [CI], 13.8%-40.7%) and 70.0% (95% CI, 55.5%-84.5%), respectively. The differences were significant between the two groups. Multivariate analyses of histology, prior lines of chemotherapy, platinum-free intervals, and regimens revealed that the LEN/PEM group had significantly better PFS rates., Conclusion: Treatment with LEN/PEM resulted in significantly longer PFS than that of treatment with platinum doublet chemotherapy in patients with advanced and recurrent endometrial cancer. However, further large-scale studies are required to validate these findings.

Background: Congenital melanocytic nevus (CMN) is a benign skin lesion present from birth, which may present with a risk of malignant transformation if extensive. Curettage, a treatment method involving the removal of the superficial layer of the nevus, is often used in the early stages of life. However, recurrence of the nevus and postoperative scarring may present as problems. Additional treatments, such as resection and/or laser treatment, are regularly required after curettage, particularly in the craniofacial region. However, no systematic treatment strategy has been reported. This study investigated additional treatments used after curettage to treat CMN in the craniofacial region and compared the frequency of treatments with respect to specific sites., Methods: CMN cases involving curettage as an initial treatment were retrospectively reviewed at Kyoto University Hospital between May 2019 and April 2022., Results: This study comprised 23 cases. Curettage was performed at a mean of 3.8 (1-10) months of age. No additional treatments were provided for 80% of head CMN. Additional treatments were performed in all cases, including the forehead and cheek. Laser treatment was performed in 86% of eyelid CMN and 75% of nasal CMN. Tissue expansion and flap closure were used in 33% of forehead CMN and 33% of cheek CMN., Conclusions: Additional treatments used for CMN in the craniofacial region varied in accordance with the lesion site., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Introduction: Patients with rheumatoid arthritis (RA) may have an increased malignancy risk versus the general population, potentially elevated by biological disease-modifying antirheumatic drug (bDMARD) use. Using patient registry data, we determined malignancy risk, stratified by bDMARD use, among Japanese patients with RA versus the Japanese general population and investigated whether bDMARD use is a time-dependent risk factor for the development of malignancy., Methods: Patients aged ≥ 18 years with ≥ 2 data entries of RA in the IORRA (Institute of Rheumatology, Rheumatoid Arthritis) patient registry, enrolled from January 2013-December 2018, were identified ('All RA' cohort). Patients were stratified into bDMARD (≥ 1 bDMARD received) or non-bDMARD (no history of bDMARDs) sub-cohorts. Malignancy incidence rates and standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) versus the Japanese general population were calculated. Risk of RA medication use was analyzed using a time-dependent Cox proportional hazards model, after adjusting for covariates., Results: A total of 8020 patients were identified for the All RA cohort; 2187 and 5833 for the bDMARD and non-bDMARD sub-cohorts, respectively. For all three cohorts, incidence of overall malignancies was similar versus the Japanese general population. Incidence of specific malignancies was also similar, but incidence of lymphoma was higher for all three cohorts (SIRs [95% CIs] 3.72 [2.71-4.93], 5.97 [3.34-9.59], and 2.79 [1.82-4.02], respectively). In the bDMARD sub-cohort, no increase in SIRs was observed for other site-specific malignancies. In the All RA cohort, use of methotrexate, tacrolimus, glucocorticoids, non-steroidal anti-inflammatory drugs, and bDMARDs were not associated with the risk of overall malignancy; the hazard ratio (95% CI) was 1.36 (0.96-1.93) for bDMARD use. Increased disease activity was a time-dependent risk factor of overall malignancy with a hazard ratio (95% CI) of 1.35 (1.15-1.59)., Conclusions: The use of bDMARDs was not a time-dependent risk factor for malignancy., (© 2024. The Author(s).)

Introduction: The evolution of disease-modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA) has improved patient prognosis. However, more real-world safety/effectiveness data comparing methotrexate (MTX), tofacitinib, tumor necrosis factor inhibitors (TNFi), and non-TNFi biologic DMARDs (bDMARDs) are warranted., Methods: The CorEvitas RA Japan registry was used to identify patients with rheumatologist-diagnosed RA who initiated MTX/tofacitinib/TNFi/non-TNFi bDMARDs. Safety outcomes included incidence of major adverse cardiovascular events (MACE), total cardiovascular disease, total serious infections, total herpes zoster, and total malignancies (excluding non-melanoma skin cancer). Effectiveness outcomes included change from baseline (Δ) in Clinical Disease Activity Index (CDAI) and proportion of patients achieving a minimum clinically important difference (MCID) in CDAI at month 6. Adjusted regression models were fit; marginal means were estimated., Results: Overall, 1972 patients were included in the safety cohort: MTX (N = 298); tofacitinib (N = 253); TNFi (N = 663); non-TNFi (N = 758). Mean follow-up time was 3.8, 2.9, 3.0, and 2.9 years for MTX, tofacitinib, TNFi, and non-TNFi, respectively. Adjusted incidence rates (IRs, patients with events/100 patient-years [95% confidence intervals]) for MACE and total cardiovascular disease, respectively, were numerically lower for MTX (0.34 [0, 0.83]; 0.42 [0, 0.92]) and TNFi (0.09 [0, 0.27]; 0.61 [0.15, 1.07]) versus tofacitinib (0.48 [0, 1.20]; 2.30 [0.38, 4.22]) and non-TNFi (0.77 [0.35, 1.19]; 1.28 [0.73, 1.82]). Serious infections were numerically higher for non-TNFi (4.47 [3.38, 5.56]); herpes zoster was higher for tofacitinib (7.41 [4.52, 10.29]), versus other groups. IRs for malignancies were comparable between groups. Mean ΔCDAI and rates of achieving MCID in CDAI at month 6 were generally greater with tofacitinib versus other groups., Conclusion: Some variations in incidence of safety outcomes were observed between treatments, while certain effectiveness outcomes favored tofacitinib. Sample size variation between groups and low number of safety events limited the analysis. Further studies are warranted to investigate observed differences., Clinicaltrials: GOV: NCT05572567., (© 2024. The Author(s).)

Carinoplasty can be divided into the one-stoma method, the montage method, the double-barrel method, and the Miyamoto method. The one-stoma method is usually performed with right upper sleeve lobectomy, and with an anastomosis of the intermediate trunk to a carina. On the other hand, in the montage method, the double-barrel method or the Miyamoto method, carina is completely resected and the trachea, left main bronchus and right bronchus are divided into three pieces. In the montage method, a side hole is created in the trachea, left main bronchus, or right bronchus, and an end-to-side anastomosis is added. In the double-barrel method, a crista is created by suturing the left and right bronchi with their medial walls side by side, and these two side-by-side bronchi are anastomosed to the trachea. The Miyamoto method was initially reported as a variant of the double-barrel method, but it is rather a variant of the montage method, characterized by the creation of a new lateral hole at the anastomosis line between the trachea and the left main bronchus.

Abstract: The free fibular flap has been elevated by a "lateral approach" from the posterior edge of the peroneal muscle for more than 40 years. However, in this approach, the surgical view is limited because flap elevation in mandibular reconstruction is performed simultaneously with tumor resection in the supine position, even when using positioning pillows. We herein propose an "anterior approach" as a new surgical method. We retrospectively investigated free fibular flap surgeries performed using the anterior approach, which consists of three anterior approaches, over a seven-year period. First, to avoid the course of the superficial peroneal nerve, the crural fascia was incised 1-2 cm posterior to the anterior edge of the peroneal muscle. The anterior edge of the peroneus muscle is detached from the anterior intermuscular septum. After performing osteotomies distal and proximal to the fibula, the interosseous membrane was incised from the anterior view. Pulling out the fibula to the anterior space between the anterior intermuscular septum and the peroneal muscle made the surgical field shallow. No postoperative superficial or deep peroneal nerve palsies were found in the 55 patients. Only one tourniquet was used in 31 of the 55 cases (56.4%), with an average of 95 min. Twenty-four patients (43.6%) required a second tourniquet 38 min after an interval. Only one tourniquet was used in 25 of the 30 (83.3%) cases in the last 3 years. Moreover, double flaps were used in 21 cases (38.2%), all of which involved ipsilateral ALT flaps. In 18 cases, double-flap elevation and prefabrication were successfully finished before the completion of tumor resection by otorhinolaryngologists., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Giant somatosensory evoked potentials (SEPs) are observed in patients with cortical myoclonus. Short-latency components (SLC), are regarded as evoked epileptic activities or paroxysmal depolarization shifts (PDSs). This study aimed to reveal the electrophysiological significance of the middle-latency component (MLC) P50 of the SEPs., Methods: Twenty-two patients with cortical myoclonus having giant SEPs (patient group) and 15 healthy controls were included in this study. Waveform changes in SEPs before and after perampanel (PER) treatment were evaluated in the patient group. The wide range, time-frequency properties underlying the waveforms were compared between the groups., Results: After PER treatment, SLC was prolonged and positively correlated with PER concentration, whereas MLC showed no correlation with PER concentration. Time-frequency analysis showed a power increase (156 Hz in all patients, 624 Hz in benign adult familial myoclonus epilepsy patients) underlying SLC and a power decrease (156 Hz, 624 Hz) underlying MLC in the patient group., Conclusions: The high-frequency power increase in SLCs and decrease in MLCs clearly reflected PDS and subsequent hyperpolarization, respectively. This relationship was similar to that of interictal epileptiform discharges, suggesting that giant SEPs evoke epileptic complexes of excitatory and inhibitory components., Significance: MLCs of giant SEPs reflected inhibitory components., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: To address improvements in quality of life, we analysed the relative contributions of factors to EuroQol 5 Dimensions (EQ-5D) in abatacept-treated rheumatoid arthritis patients in the Orencia® Registry in Geographically Assembled Multicenter Investigation (ORIGAMI) study., Methods: Patients who were evaluable for disease activity through to  Week 52 in the ORIGAMI study were divided into those achieving Simplified Disease Activity Index-remission/low disease activity (remission/LDA; n = 178) and patients with moderate disease activity/high disease activity (MDA/HDA; n = 99). We compared the changes in EQ-5D and other outcomes through to Week 52. Focusing on the remission/LDA group, the contribution of each factor to the variance of EQ-5D at baseline and Week 52 was examined using analysis of variance., Results: The remission/LDA group showed greater improvements than the MDA/HDA group in EQ-5D, Japanese Health Assessment Questionnaire, visual analogue scale for pain (Pain VAS), and patient's global assessment (PtGA). In the remission/LDA group, factors significantly contributing to EQ-5D were sex, C-reactive protein, and Pain VAS at baseline, and PtGA and age at Week 52., Conclusions: In rheumatoid arthritis patients who achieved remission/LDA during abatacept treatment, PtGA and age at Week 52 contribute to the variance of EQ-5D, suggesting that the identification of factors associated with PtGA may be important to address improvements in quality of life., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Objectives: This article aims to examine the ability of the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) risk score to predict the occurrence of serious infections in Japanese patients with rheumatoid arthritis (RA), after initiating their first biologic disease-modifying antirheumatic drug (bDMARD)., Methods: We used data from the Institute of Rheumatology, Rheumatoid Arthritis cohort from 2008 to 2020. Patients with RA who were started on their first bDMARDs were included. Those with missing data required to calculate the score were excluded. A receiver operating characteristic curve was used to evaluate the discriminatory ability of the RABBIT score., Results: A total of 1081 patients were enrolled. During the 1-year observational period, 23 (1.7%) patients had serious infections; the most frequent one was bacterial pneumonia (n = 11, 44%). The median RABBIT score in the serious infection group was significantly higher than that in the non-serious infection group [2.3 (1.5-5.4) vs 1.6 (1.2-2.5), P < .001]. The area under the receiver operating characteristic curve for the occurrence of serious infections was 0.67 (95% confidence interval 0.52-0.79), suggesting that the score had low accuracy., Conclusions: Our present study revealed that the RABBIT risk score did not have sufficient discriminatory ability for predicting the development of severe infections in Japanese patients with RA after initiating their first bDMARD., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The endosomal-lysosomal system represents a crucial degradation pathway for various extracellular substances, and its dysfunction is linked to cardiovascular and neurodegenerative diseases. This degradation process involves multiple steps: (1) the uptake of extracellular molecules, (2) transport of cargos to lysosomes, and (3) digestion by lysosomal enzymes. While cellular uptake and lysosomal function are reportedly regulated by the mTORC1-TFEB axis, the key regulatory signal for cargo transport remains unclear. Notably, our previous study discovered that isorhamnetin, a dietary flavonoid, enhances endosomal-lysosomal proteolysis in the J774.1 cell line independently of the mTORC1-TFEB axis. This finding suggests the involvement of another signal in the mechanism of isorhamnetin. This study analyzes the molecular mechanism of isorhamnetin using transcriptome analysis and reveals that the transcription factor GATA3 plays a critical role in enhanced endosomal-lysosomal degradation. Our data also demonstrate that mTORC2 regulates GATA3 nuclear translocation, and the mTORC2-GATA3 axis alters endosomal formation and maturation, facilitating the efficient transport of cargos to lysosomes. This study suggests that the mTORC2-GATA3 axis might be a novel target for the degradation of abnormal substances., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2024 JCBN.)

Midfacial reconstruction for extensive defects of the hard nasal structures and bilateral maxillae is challenging. Postoperative radiotherapy causes skin contracture, making secondary reconstruction extremely difficult. A 57-year-old man underwent resection of the nasal bone, nasal cartilage, and hard palate for cancer of the nasal cavity. Postoperative radiotherapy (70 Gy) resulted in bilateral osteoradionecrosis. Severe depression deformity of the midface causes a disorder in closing the mouth, resulting in difficulty in conversation and oral intake. We performed simultaneous reconstruction of the bilateral maxillary and nasal hard structures using double free flaps (fibular osteocutaneous and anterolateral thigh flaps). A 16-cm right fibular osteocutaneous flap was elevated, and an 8-cm proximal bone was resected to obtain the length of the peroneal vessels. The distal 8 cm was cut into three pieces while maintaining the blood flow. The removed nonvascularized fibula was processed into two pieces of cortex: nasal bridge and columella. All areas of the skin island were de-epithelialized to bilaterally fill the maxillary sinuses. Next, the ipsilateral anterolateral thigh flap was elevated with the central 6-cm part for closure of the palate and the proximal area to fill the nasal cavity. The distal area consisted of a fascial flap to cover the reconstructed nasal structure. The chimeric double flap allowed for oral intake, conversation, and nasomaxillary prominence. Computed tomography performed 8 months postoperatively showed maintained bony structures. We used the extra fibula as a nonvascularized cortex piece to prevent infection and exposure, which enabled simultaneous reconstruction of the bilateral maxillae and hard nasal structure., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Reconstruction of extended total maxillectomy is challenging. This study aimed to isolate the skull base from the nasal cavity to avoid intracranial infection, cerebrospinal fluid fistula, and palate closure to maintain feeding and conversation. However, facial appearance and symmetry are important for quality of life. We report primary multiple buttress reconstruction using a removed nonvascularized fibula that reduced the risk of infection and exposure. A 74-year-old woman experienced a local recurrence of right maxillary sinus cancer after subtotal maxillectomy and postoperative radiotherapy (60 Gy). We performed extended total maxillectomy, including the right eyeball, orbit, temporal bone, palate, and zygomatic arch. Primary reconstruction was performed using fibular and anterolateral thigh free flaps. The proximal fibula bone was resected to obtain the length of the peroneal vessels, and the distal 9 cm of the fibula was made into two pieces while keeping the peroneal vessels attached. The nonvascularized 5-cm fibula was split sagittally with an L-shaped section to maintain the strength of the fragments. An anterolateral thigh flap was elevated from the ipsilateral thigh attached to the partial vastus lateralis muscle, which was divided into proximal (to the cheek skin and prosthetic eye bed) and distal (to the nasal cavity and palate) skin islands. Two nonvascularized bone fragments were fixed at the lateral and infraorbital rims. The dead space around the built-up pillar made of transferred bone was filled with vastus lateralis muscle to prevent infection and depression. This approach allowed for one-stage multiple buttress reconstruction for extended total maxillectomy., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

The transcription factor SRY-related HMG box 9 (Sox9) is essential for chondrogenesis. Mutations in and around SOX9 cause campomelic dysplasia (CD) characterized by skeletal malformations. Although the function of Sox9 in this context is well studied, the mechanisms that regulate Sox9 expression in chondrocytes remain to be elucidated. Here, we have used genome-wide profiling to identify 2 Sox9 enhancers located in a proximal breakpoint cluster responsible for CD. Enhancer activity of E308 (located 308 kb 5' upstream) and E160 (located 160 kb 5' upstream) correlated with Sox9 expression levels, and both enhancers showed a synergistic effect in vitro. While single deletions in mice had no apparent effect, simultaneous deletion of both E308 and E160 caused a dwarf phenotype, concomitant with a reduction of Sox9 expression in chondrocytes. Moreover, bone morphogenetic protein 2-dependent chondrocyte differentiation of limb bud mesenchymal cells was severely attenuated in E308/E160 deletion mice. Finally, we found that an open chromatin region upstream of the Sox9 gene was reorganized in the E308/E160 deletion mice to partially compensate for the loss of E308 and E160. In conclusion, our findings reveal a mechanism of Sox9 gene regulation in chondrocytes that might aid in our understanding of the pathophysiology of skeletal disorders.

Background: This phase 2b/3, randomized, placebo-controlled trial explored the efficacy and evaluated the safety of ensitrelvir. This trial involved individuals with asymptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patients with mild symptoms of coronavirus disease 2019 (COVID-19)., Methods: The trial was conducted at 57 medical institutions in Japan, South Korea, and Vietnam (study period: January 6-August 14, 2022). Eligible participants were randomized (1:1:1) to the ensitrelvir 125-mg, ensitrelvir 250-mg, or placebo group, received the allocated intervention orally, and were followed up until Day 28. Participants self-rated the severity of 14 typical COVID-19 symptoms and recorded the data in an electronic diary., Results: In total, 572 participants (194, 189, and 189 in the ensitrelvir 125-mg, ensitrelvir 250-mg, and placebo groups, respectively) were included in the intention-to-treat population. Ensitrelvir 125-mg group observed a 77% reduction in the risk of developing any of the 14 COVID-19 symptoms or fever and a 29% reduction in the risk of worsening of such symptoms or fever versus placebo (statistically nonsignificant). The viral RNA, viral titer, and time to infectious viral clearance observed a statistically significant decrease versus placebo. Most treatment-related adverse events (TEAEs) were mild to moderate in severity, and the most common TEAE observed across groups was a decrease in high-density lipoprotein., Conclusions: Our exploratory results suggest a potential reduction in the risk of development or worsening of COVID-19 symptoms with ensitrelvir. Ensitrelvir showed antiviral efficacy and was well tolerated., Trial Registration: Japan Registry of Clinical Trials identifier: jRCT2031210350., (© 2024 The Author(s). Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Patients with 21trisomy often develop congenital or acquired gastrointestinal diseases, such as duodenal or anal atresia, celiac disease, intussusception, and constipation. In these patients, it is often challenging to diagnose gastrointestinal diseases because most patients have difficulty explaining their complaints in detail. Furthermore, these patients also possess immunological disorders, such as increased type I interferon activation, innate immune hypersensitivity, and polarization to autoimmune. Here, we present a girl with 21trisomy and constipation who developed severe anemia, occult blood and elevated levels of calprotectin in stool, and chronic ileum obstruction confirmed by computed tomography. The patient underwent surgical resection of the ileum and recovered without complications. Pathological examination demonstrated intussusception, ischemia, ulceration, inflammatory granulation, and massive IgG4-positive plasma cell infiltration. After the surgery, her fecal calprotectin levels were normalized. We assumed that the ileum inflammation caused by ileum dilation generated ulcers and granulation, which could be associated with immunological, gastrointestinal, and intellectual disorders in patients with 21trisomy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Yamanaka et al.)

Study Question: To what extent and via what mechanism does the concomitant administration of rapamycin (a follicle activation pathway inhibitor and antitumour agent) and cyclophosphamide (a highly toxic ovarian anticancer agent) prevent cyclophosphamide-induced ovarian reserve loss and inhibit tumour proliferation in a breast cancer xenograft mouse model?, Summary Answer: Daily concomitant administration of rapamycin and a cyclic regimen of cyclophosphamide, which has sufficient antitumour effects as a single agent, suppressed cyclophosphamide-induced primordial follicle loss by inhibiting primordial follicle activation in a breast cancer xenograft mouse model, suggesting the potential of an additive inhibitory effect against tumour proliferation., What Is Known Already: Cyclophosphamide stimulates primordial follicles by activating the mammalian target of the rapamycin (mTOR) pathway, resulting in the accumulation of primary follicles, most of which undergo apoptosis. Rapamycin, an mTOR inhibitor, regulates primordial follicle activation and exhibits potential inhibitory effects against breast cancer cell proliferation., Study Design, Size, Duration: To assess ovarian follicular apoptosis, 3 weeks after administering breast cancer cells, 8-week-old mice were randomized into three treatment groups: control, cyclophosphamide, and cyclophosphamide + rapamycin (Cy + Rap) (n = 5 or 6 mice/group). Mice were treated with rapamycin or vehicle control for 1 week, followed by a single dose of cyclophosphamide or vehicle control. Subsequently, the ovaries were resected 24 h after cyclophosphamide administration (short-term treatment groups). To evaluate follicle abundance and the mTOR pathway in ovaries, as well as the antitumour effects and impact on the mTOR pathway in tumours, 8-week-old xenograft breast cancer transplanted mice were randomized into three treatment groups: vehicle control, Cy, and Cy + Rap (n = 6 or 7 mice/group). Rapamycin (5 mg/kg) or the vehicle was administered daily for 29 days. Cyclophosphamide (120 mg/kg) or the vehicle was administered thrice weekly (long-term treatment groups). The tumour diameter was measured weekly. Seven days after the last cyclophosphamide treatment, the ovaries were harvested, fixed, and sectioned (for follicle counting) or frozen (for further analysis). Similarly, the tumours were resected and fixed or frozen., Participants/materials, Setting, Methods: Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) was performed to examine ovarian follicular apoptosis in the short-term treatment groups. All subsequent experiments were conducted in the long-term treatment groups. Tumour growth was evaluated using the tumour volume index. The tumour volume index indicates the relative volume, compared to the volume 3 weeks after tumour cell injection (at treatment initiation) set to 100%. Tumour cell proliferation was evaluated by Ki-67 immunostaining. Activation of the mTOR pathway in tumours was assessed using the protein extracts from tumours and analysed by western blotting. Haematoxylin and eosin staining of ovaries was used to perform differential follicle counts for primordial, primary, secondary, antral, and atretic follicles. Activation of the mTOR pathway in ovaries was assessed using protein extracts from whole ovaries and analysed by western blotting. Localization of mTOR pathway activation within ovaries was assessed by performing anti-phospho-S6 kinase (downstream of mTOR pathway) immunohistochemistry., Main Results and the Role of Chance: Ovaries of the short-term treatment groups were resected 24 h after cyclophosphamide administration and subjected to TUNEL staining of apoptotic cells. No TUNEL-positive primordial follicles were detected in the control, Cy, and Cy + Rap groups. Conversely, many granulosa cells of growing follicles were TUNEL positive in the Cy group but negative in the control and Cy + Rap groups. All subsequent experimental results were obtained from the long-term treatment groups. The tumour volume index stabilized at a mean of 160-200% in the Cy group and 130% in the Cy + Rap group throughout the treatment period. In contrast, tumours in the vehicle control group grew continuously with a mean tumour volume index of 600%, significantly greater than that of the two treatment groups. Based on the western blot analysis of tumours, the mTOR pathway was activated in the vehicle control group and downregulated in the Cy + Rap group when compared with the control and Cy groups. Ki-67 immunostaining of tumours showed significant inhibition of cell proliferation in the Cy + Rap group when compared with that in the control and Cy groups. The ovarian follicle count revealed that the Cy group had significantly fewer primordial follicles (P < 0.001) than the control group, whereas the Cy + Rap group had significantly higher number of primordial follicles (P < 0.001, 2.5 times) than the Cy group. The ratio of primary to primordial follicles was twice as high in the Cy group than in the control group; however, no significant difference was observed between the control group and the Cy + Rap group. Western blot analysis of ovaries revealed that the mTOR pathway was activated by cyclophosphamide and inhibited by rapamycin. The phospho-S6 kinase (pS6K)-positive primordial follicle rate was 2.7 times higher in the Cy group than in the control group. However, this effect was suppressed to a level similar to the control group in the Cy + Rap group., Large Scale Data: None., Limitations, Reasons for Caution: The combinatorial treatment of breast cancer tumours with rapamycin and cyclophosphamide elicited inhibitory effects on cell proliferative potential compared to cyclophosphamide monotherapy. However, no statistically significant additive effect was observed on tumour volume. Thus, the beneficial antitumour effect afforded by rapamycin administration on breast cancer could not be definitively proven. Although rapamycin has ovarian-protective effects, it does not fully counteract the ovarian toxicity of cyclophosphamide. Nevertheless, rapamycin is advantageous as an ovarian protective agent as it can be used in combination with other ovarian protective agents, such as hormonal therapy. Hence, in combination with other agents, mTOR inhibitors may be sufficiently ovario-protective against high-dose and cyclic cyclophosphamide regimens., Wider Implications of the Findings: Compared with a cyclic cyclophosphamide regimen that replicates human clinical practice under breast cancer-bearing conditions, the combination with rapamycin mitigates the ovarian follicle loss of cyclophosphamide without interfering with the anticipated antitumour effects. Hence, rapamycin may represent a new non-invasive treatment option for cyclophosphamide-induced ovarian dysfunction in breast cancer patients., Study Funding/competing Interest(s): This work was not financially supported. The authors declare that they have no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Gelatin hydrogel nonwoven fabrics (Genocel) are three-dimensional gelatin scaffolds that provide cells with space for proliferation, migration, and differentiation. They are expected to be an effective wound healing modality to treat intractable wounds, such as diabetic foot ulcers, because they enhance early neovascularization when used as a skin substitute. In this study, we explored the healing process of Genocel applied to skin defects in diabetic mice and compared it with that of a conventional skin substitute, Pelnac., Methods: Genocel and Pelnac sheets were used to treat skin defects on the backs of diabetic mice. On days 7 and 14, the remaining wound area was evaluated and specimens were harvested for HE, Azan, anti-CD31, CD68, and CD163 staining to assess neoepithelialization, granulation tissue formation, capillary formation, and macrophage infiltration., Results: Wounds treated with Genocel showed a wound healing process comparable to that of wounds treated with Pelnac. No significant differences were observed in the remaining wound area, neoepithelial length, granulation formation, number of pan-macrophages, or M2 ratio on days 7 and 14. The only significant difference was the number of induced M2 macrophages, which was higher in Pelnac group than in the Genocel group on day 7 (p < 0.05)., Conclusions: Genocel showed similar healing effects in diabetic wounds as Pelnac and is considered an effective wound management modality for diabetic ulcers., Competing Interests: All authors declare no conflict of interest in association with the present study., (© 2024 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Background: Tissue expanders represent one of the main surgical options for skin reconstruction in cases of tumors, traumalike burn injury, scar contracture, and alopecia. However, the tissue expander device is also associated with complications such as infection and extrusion. The aim of this study was to analyze risk factors for major complications of use of tissue expanders in pediatric patients using multivariate analysis., Methods: A retrospective, single-center observational study was performed over 10 years in pediatric patients who were treated with tissue expanders for tumors, nevus, scars, burn reconstruction, and alopecia from April 2012 to March 2022. The primary outcome was overall complications per operation and expander, including infection and extrusion. Ten predictor variables were included as risk factors based on previous studies and as new factors considered important from clinical experience. Univariate and multivariate logistic regression analyses were performed to identify risk factors for major complications such as expander infection or extrusion., Results: The study included 44 patients who underwent 92 operations using 238 tissue expanders. The overall complication rate per expander was 14.3%. Univariate logistic regression analysis identified associations of younger age, number of expanders used per operation, history of infection, and tissue expander locations with a higher complication rate. In multivariate logistic regression analysis, younger age (odds ratio, 1.14; P = 0.043) was associated with a high likelihood of expander complications., Conclusions: Younger age is an independent risk factor for tissue expander complications in pediatric patients. This factor should be considered in preoperative planning and discussions with the patient's family., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

We must take special care when treating postoperative fluid accumulation around breast implants (BIs) to exclude any serious complications, including BI-associated anaplastic large cell lymphoma. However, most late-onset fluid accumulation is caused by other conditions, such as traumatic hematoma and residual postoperative seroma. Surgeons must choose whether to conservatively observe or remove such BIs, while also determining whether to perform partial capsulectomy or total capsulectomy to solve the problem of fluid accumulation. We treated a 72-year-old woman who noticed swelling in her right breast 4 years after undergoing bilateral BI reconstruction. Before she was referred to our hospital, the fluid had been drained by needle aspiration five times, but the swelling returned to a similar size within a month. No malignant findings were observed by needle-aspirated cytology or flow cytometry. The patient requested the simultaneous removal of the left BI. Therefore, we performed both BI removal with total capsulectomy on the right side and partial capsulectomy of the superficial layer on the left side. A pathological examination of the capsule on the right side indicated a chronic expanding hematoma and synovial metaplasia characterized by papillary projections rich in CD68-positive cells, thus indicating reactive synovial cells. In contrast, the left superficial capsule was much thinner and showed less synovial metaplasia. Our findings indicate the advantages of total capsulectomy to solve the problem of repeated serous fluid accumulation around BIs, according to histological changes in the capsule., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

DNA analysis of large herbivore feces samples collected from seagrass beds at two distant sites (Irabu Island in Miyako Islands and Kushi in Okinawa Island) in the Ryukyu Islands proved that some of these feces were from dugongs, which had been treated in recent studies as extinct in this region since the last stranding of a deceased individual in 2019. In addition, local knowledge of sightings of animals thought to be dugongs and confirmed cases of dugong feeding trails since 2010 were compiled to estimate its recent distribution. This is the first scientific report on the presence of this mammal in the Ryukyu Islands within the last four years, and particularly in the Miyako Islands within the last half-century. As the Ryukyu Islands are known to be the northern limit of the dugong's fragmented distribution in East Asia, conservation efforts are therefore needed., (© 2024. The Author(s).)

Environmental DNA and RNA (eDNA and eRNA; collectively eNA) analyses have the potential for non-invasive and cost-efficient biomonitoring compared with traditional capture-based surveys. Although various types of eNA particles, including not only mitochondrial eDNA but also nuclear eDNA and their transcripts, are present in the water, performances of eNA detection and quantification have not yet been evaluated sufficiently across multiple mitochondrial and nuclear genes. We conducted a tank experiment with ayu (Plecoglossus altivelis) to compare the detection sensitivity, yields per water sample, and quantification variability between replicates of each type of eNAs. The assay targeting the multi-copy nuclear gene exhibited a higher sensitivity than the assay targeting the mitochondrial gene, and both the target eDNA and eRNA concentrations per water sample were higher for the nuclear gene. On the contrary, variation in eRNA quantifications per sample does not necessarily correspond to that in eDNA, and the intra-sample quantification variability (represented as the CVs between PCR replicates) tended to be larger for eRNA than eDNA. Our results suggested that, even if suitable to the sensitive detection of species occurrence, the use of eRNA particularly derived from multi-copy nuclear gene may not be necessarily appropriate for the reliable assessment of species abundance. The findings in this study would help optimize eNA analyses for making biomonitoring and stock assessment in aquatic environments more efficient and reliable., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Glycosyltransferases (GTs), crucial enzymes in plants, alter natural substances through glycosylation, a process with extensive applications in pharmaceuticals, food, and cosmetics. This study narrows its focus to GT family 1, specifically UDP-glycosyltransferases (UGTs), which are known for glycosylating small phenolic compounds, especially hydroxybenzoates. We delve into the workings of Raphanus sativus glucosyltransferase (Rs89B1), a homolog of Arabidopsis thaliana UGT89B1, and its mutant to explore their glycosyltransferase activities toward hydroxybenzoates. Our findings reveal that Rs89B1 glycosylates primarily the para-position of mono-, di-, trihydroxy benzoic acids, and its substrate affinity is swayed by the presence and position of the hydroxyl group on the benzene ring of hydroxybenzoate. Moreover, mutations in the loop region of Rs89B1 impact both substrate affinity and catalytic activity. The study demonstrates that insertional/deletional mutations in non-conserved regions, which are distant from the UGT's recognition site, can have an effect on the UGT's substrate recognition site, which in turn affects acceptor substrate selectivity and glycosyltransferase activity. This research uncovers new insights suggesting that mutations in the loop region could potentially fine-tune enzyme properties and enhance its catalytic activity. These findings not only have significant implications for enzyme engineering in biotechnological applications but also contribute to a more profound understanding of this field., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ohashi 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.)

Objectives: The aim of the article is to investigate the associations of disease duration and anti-cyclic citrullinated peptide antibody (ACPA) status with the effectiveness of abatacept in biologic-naïve patients with rheumatoid arthritis (RA)., Methods: We performed post hoc analyses of the Orencia® Registry in Geographically Assembled Multicenter Investigation (ORIGAMI) study of biologic-naïve RA patients aged ≥20 years with moderate disease activity who were prescribed abatacept. Changes in the Simplified Disease Activity Index (SDAI) and Japanese Health Assessment Questionnaire (J-HAQ) at 4, 24, and 52 weeks of treatment were analysed in patients divided according to ACPA serostatus (positive/negative), disease duration (<1/≥1 year), or both., Results: SDAI scores decreased from baseline in all groups. SDAI scores tended to decrease more in the ACPA-positive group and disease duration <1-year group than in the ACPA-negative group and disease duration ≥1-year group, respectively. In the disease duration <1-year group, SDAI tended to decrease more in the ACPA-positive group than in the ACPA-negative group. Disease duration was independently associated with the change in SDAI and SDAI remission at Week 52 in multivariable regression models., Conclusions: These results suggest that starting abatacept within 1 year of diagnosis was associated with greater effectiveness of abatacept in biologic-naïve patients with RA and moderate disease activity., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Objectives: The aim of this article is to investigate the mortality rate of patients with early rheumatoid arthritis (RA) over the past 17 years., Methods: Japanese patients with early RA enrolled in the Institute of Rheumatology, Rheumatoid Arthritis cohort from 2001 to 2012 were classified into Groups A (2001-06) and B (2007-12). The standardized mortality ratio (SMR) and 5-year survival rate were calculated., Results: Groups A and B had 1609 and 1608 patients, of which 167 and 178 patients were lost during follow-up and 47 and 45 deaths were confirmed, respectively. The SMR (95% confidence intervals) for Groups A and B were 0.81 (0.59-1.08) and 0.78 (0.57-1.04), respectively, with the condition that all untraceable patients were alive. Assuming that the mortality rate of untraceable patients was twice as high as that of the general population, the SMR was 0.90 (0.68-1.19) for Group A and 0.92 (0.68-1.23) for Group B. The 5-year survival rates were 96.9% and 97.0% for Groups A and B, respectively., Conclusions: The 5-year mortality of patients with early RA has been comparable to that of the general Japanese population. The 5-year survival rate has been stable over the past 17 years., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background Context: Elucidating the mechanism of neuropathic pain (NeP) is crucial as it can result in motor dysfunction and negatively impact quality of life in patients with spinal cord injury (SCI). Although it has been reported that cyclooxygenase 2 (COX2) is involved in NeP in rat models of peripheral nerve injury and that COX2 inhibitors can alleviate NeP, these mechanisms after SCI have not been fully investigated., Purpose: The purpose is to investigate whether the thoracic SCI affects the expression of mRNAs for COX1 and COX2 in the lumbar spinal cord, and the effect of COX2 inhibitor on its behavior., Study Design: Male Sprague-Dawley (SD) rats underwent thoracic (T10) spinal cord contusion injury using an Infinite Horizon (IH) impactor device. SCI rats received COX2 inhibitors (50 μg/day) on days 5 and 6 after SCI., Methods: Male SD rats underwent T10 laminectomy under mixed anesthesia, and IH impactors were applied to the same site to create a rat SCI model. Rats that underwent only laminectomy were designated as sham. Lumbar spinal cord at the L4-5 level was harvested at 3, 5, 7, 14, and 28 days after SCI, and COX2 and COX1 were quantified by reverse-transcription PCR (RT-PCR). COX2 expression, expression site, and expression time were determined by immunohistochemistry (IHC) and in situ hybridization histochemistry (ISHH) at the same time points. The expression site and time of COX2 expression were also examined at the same time point by ISHH. On 5th and 6th day after SCI, saline and COX2 inhibitor (50 μg/day) were administered into the subarachnoid space as a single dose, and the two groups were compared in terms of mechanical withdrawal latency using the dynamic plantar esthesiometer, which is an automated von Frey-type system., Results: COX2 was significantly increased at 5 and 7 days after SCI, but no significant difference in COX1 was observed after SCI by RT-PCR. ISHH targeting COX2 showed clear expression of COX2 in spinal cord vascular endothelial cells at 5 and 7 days after SCI. COX2 expression was almost abolished at day 14 and 28. Behavioral experiments showed that pain was significantly improved from day 2 after COX2 inhibitor administration compared to the saline group, with improvement up to day 14 after SCI, but no significant difference was observed after day 21., Conclusions: The present findings suggest that thoracic SCI increased COX2 in vascular endothelial cells in the lumbar spinal cord and that the administration of COX2 inhibitor significantly alleviated mechanical hypersensitivity of the hind-paw following the thoracic SCI. Therefore, endothelial cell derived COX2 in the lumbar spinal cord may be involved in the induction of neuropathic pain in the SCI model rats., Clinical Significance: The findings in the present study regarding the induction of endothelial COX2 and the effect of its inhibitor on the mechanical hypersensitivity suggest that endothelial cell-derived COX2 is one of the focuses for the treatment for neuropathic pain in the acute phase of SCI., 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.)

A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.

Tumor tissues consist of heterogeneous cells that originate from stem cells; however, their cell fate determination program remains incompletely understood. Using patient-derived organoids established from patients with advanced colorectal cancer (CRC), we evaluated the potential of olfactomedin 4 (OLFM4) + stem cells to produce a bifurcated lineage of progenies with absorptive and secretory properties. In the early phases of organoid reconstruction, OLFM4 + cells preferentially gave rise to secretory cells. Additionally, we found that Paneth-like cells, which do not exist in the normal colon, were induced in response to Notch signaling inhibition. Video recordings of single OLFM4 + cells revealed that organoids containing Paneth-like cells were effectively propagated and that their selective ablation led to organoid collapse. In tumor tissues, Paneth-like cells were identified only in the region where tumor cells lost cell adhesion. These findings indicate that Paneth-like cells are directly produced by OLFM4 + stem cells and that their interaction contributes to tumor formation by providing niche factors. This study reveals the importance of the cell fate specification program for building a complete tumor cellular ecosystem, which might be targeted with novel therapeutics., (© 2024. The Author(s).)

Dietary Reference Intakes for Japanese provide target values for proteins, fats, and carbohydrates. However, they do not provide information on reference values for amino acids (AAs) and fatty acids (FAs), which determine the quality of foods in detail. Therefore, we evaluated AAs and FAs using the Food Exchange Lists-Dietary Guidance for Persons with Diabetes (in Japanese) Utilization, Second Edition Sample Menus and Practice (FELD) as an ideal Japanese diet. Based on FELD, 15 different daily meal patterns were employed with combinations of three levels of carbohydrates %energy (high carbohydrate [HC], 60%; middle carbohydrate [MC], 55%; and low carbohydrate [LC], 50%) and five levels of energy (1,200-2,000 kcal). Using the Japanese Food Composition Table 2020 adjusted for 1,000 kcal, 18 AAs, 49 FAs, and calorie densities (CDs, kcal/g) were calculated and compared among the three groups. Dietary AA was rich in glutamic acid, aspartic acid, and leucine; in order, no significant differences were observed among HC, MC, and LC for 18 AAs. Dietary FA was higher for 18:1 total, 16:0, and 18:2 n-6. Moreover, 16:0, 20:0, and 18:1 total in LC and 22:0 and 18:3 n-3 in MC were significantly higher than those in HC. The HC, MC, and LC CD was low at 0.82, 0.84, and 0.93 kcal/g, respectively. No significant differences in 18 AAs and CD were noted among HC, MC, and LC in FELD; however, significant differences were observed in the FA profiles. This study suggests the importance of evaluating diet using AA and FA units.

Macaques are useful animal models for studying the pathogenesis of rheumatoid arthritis (RA) and the development of anti-rheumatic drugs. The purpose of this study was to identify the major histocompatibility complex (MHC) polymorphisms associated with the pathology of collagen-induced arthritis (CIA) and anti-collagen IgG induction in a cynomolgus macaque model, as MHC polymorphisms affect the onset of CIA in other animal models. Nine female Filipino cynomolgus macaques were immunized with bovine type II collagen (b-CII) to induce CIA, which was diagnosed clinically by scoring the symptoms of joint swelling over 9 weeks. MHC polymorphisms and anti-b-CII antibody titers were compared between symptomatic and asymptomatic macaques. Four of 9 (44%) macaques were defined as the CIA-affected group. Anti-b-CII IgG in the affected group increased in titer approximately 3 weeks earlier compared with the asymptomatic group. The mean plasma IgG1 titer in the CIA-affected group was significantly higher (p < 0.05) than that of the asymptomatic group. Furthermore, the cynomolgus macaque MHC (Mafa)-DRB1*10:05 or Mafa-DRB1*10:07 alleles, which contain the well-documented RA-susceptibility five amino acid sequence known as the shared epitope (SE) in positions 70 to 74, with valine at position 11 (Val11, V11) and phenylalanine at position 13 (Phe13, F13), were detected in the affected group. In contrast, no MHC polymorphisms specific to the asymptomatic group were identified. In conclusion, the presence of V11 and F13 along with SE in the MHC-DRB1 alleles seems essential for the production of IgG1 and the rapid induction of severe CIA in female Filipino cynomolgus macaques., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

To investigate the prevalence of and factors associated with sarcopenia in Japanese patients with rheumatoid arthritis (RA). We analyzed a cross-section of patients with RA participating in the Institute of Rheumatology Rheumatoid Arthritis cohort survey in 2021. Participants completed self-administered questionnaires, including a 5-item sarcopenia screening index (SARC-F). Patients with a SARC-F score of 4 or higher were categorized as having sarcopenia. Among 2416 Japanese patients with RA (2113 women and 303 men; mean age 63.9 years), 341 (14.1%) patients were categorized as having sarcopenia. In a multivariable analysis of patients of all ages, age, body mass index (BMI), disease duration, history of fracture, patient pain on a visual analog scale (VAS), patient or physician global assessments based on VAS, and use of nonsteroidal anti-inflammatory drugs (NSAIDs), biologic disease-modifying antirheumatic drugs (bDMARDs), and corticosteroids were significantly (P < 0.05) associated with sarcopenia. Disease duration, patient global assessments based on VAS, and use of NSAIDs and bDMARDs were significantly associated with sarcopenia among the patients aged < 65 years, whereas age, female sex, BMI, disease duration, history of fracture, patient pain VAS and global assessments based on VAS, and use of bDMARDs and corticosteroids were significantly associated with sarcopenia in patients aged ≥ 65 years. In Japanese patients with RA, age, BMI, disease duration, history of fracture, patient pain VAS and global assessments based on VAS, and use of NSAIDs, bDMARDs, and corticosteroids were associated with sarcopenia. Among older patients with RA, female sex was additionally associated with sarcopenia. Key Points • To our knowledge, this is the first report showing factors associated with sarcopenia in Japanese patients with rheumatoid arthritis using a large cohort database. • Age, BMI, disease duration, history of fracture, patient pain on a visual analog scale, and use of nonsteroidal anti-inflammatory drugs, biologic disease-modifying antirheumatic drugs, and corticosteroids were associated with sarcopenia in Japanese patients with rheumatoid arthritis. Limited to elderly patients, female sex was also associated with sarcopenia., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

The development of calibration models using Raman spectra data has long been challenged owing to the substantial time and cost required for robust data acquisition. To reduce the number of experiments involving actual incubation, a calibration model development method was investigated by measuring artificially mixed samples. In this method, calibration datasets were prepared using spectra from artificially mixed samples with adjusted concentrations based on design of experiments. The precision of these calibration models was validated using the actual cell culture sample. The results showed that when the culture conditions were unchanged, the root mean square error of prediction (RMSEP) of glucose, lactate, and antibody concentrations was 0.34, 0.33, and 0.25 g/L, respectively. Even when variables such as cell line or culture media were changed, the RMSEPs of glucose, lactate, and antibody concentrations remained within acceptable limits, demonstrating the robustness of the calibration models with artificially mixed samples. To further improve accuracy, a model training method for small datasets was also investigated. The spectral pretreatment conditions were optimized using error heat maps based on the first batch of each cell culture condition and applied these settings to the second and third batches. The RMSEPs improved for glucose, lactate, and antibody concentration, with values of 0.44, 0.19, and 0.18 g/L under constant culture conditions, 0.37, 0.12, and 0.12 g/L for different cell lines, and 0.26, 0.40, and 0.12 g/L when the culture media was changed. These results indicated the efficacy of calibration modeling with artificially mixed samples for actual incubations under various conditions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Background: Hyaline fibromatosis syndrome (HFS) is a congenital disorder characterized by subcutaneous skin nodules, congenital multiple arthrogryposis, gingival hyperplasia, and chronic pain. The intellectual ability of patients with HFS is generally normal. This syndrome arises from variants of ANTXR2. Thus far, about 100 cases have been reported but few of these were reported from Japan., Methods: This study reports five additional Japanese patients with genetically confirmed HFS, from unrelatd families, and discusses the clinical course and quality of life of these patients., Results: At our last visit the ages of the patients were 3-19 years (the median age was 5 years). All the patients had arthrogryposis, skin nodules, and gingival hyperplasia, and four patients had chronic pain, all of which are distinctive, clinical characteristics of HFS. Four of the patients (80%) had pruritic skin nodules, and three experienced sleep disruptions due to pruritis. The visceral complications are an index of HFS severity. One patient in the present cohort had a mucosal abnormality without any gastrointestinal symptoms., Conclusion: Preventive and routine management of pruritis caused by skin nodules should be shared with the patient's family. Even asymptomatic patients might have endoscopic finding, which would be a soft marker that could predict the development of protein losing enteropathy., (© 2024 Japan Pediatric Society.)

Objectives: We evaluate the socioeconomic impact of treatment with biological and targeted synthetic disease-modifying antirheumatic drugs in Japanese patients with rheumatoid arthritis., Methods: We analysed data retrospectively from the prospective observational CorEvitas RA Japan Registry (March 2016-February 2020). Patients were categorised into paid workers (PWs) and home workers (HWs) and further based on drug classes. We assessed medication persistence, treatment outcomes, health care resource utilisation, and socioeconomic impact over 12 months, including direct (drugs and health care resource utilisation) and indirect (loss of productivity) costs., Results: Overall, 187 PWs and 114 HWs were identified. Over 12 months, medication persistence was high, treatment outcomes improved, and outpatient visits reduced in both groups. Following treatment initiation, direct costs increased, whereas indirect (loss of productivity) costs decreased in both groups. The unadjusted socioeconomic impact [Japanese yen (JPY)] increased across all drug classes in PWs (range: 29,700-151,700) and HWs (range: -28,700 to 83,000). Adjusted change in monthly socioeconomic impact was JPY 29,700-138,900 for PWs and JPY -28,000 to 92,800 for HWs., Conclusions: In this study of Japanese patients with rheumatoid arthritis, the socioeconomic burden increased across patient groups and drug classes. The decrease in indirect (loss of productivity) costs partially offset the increase in direct costs., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Objectives: To evaluate the long-term safety and efficacy of E6011, a humanized anti-fractalkine monoclonal antibody, in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX)., Methods: Active RA patients with an inadequate response to MTX were randomly assigned to the E6011 or placebo group and received the study drug subcutaneously every 2 weeks during a 24-week double-blind study period. Subjects who completed evaluations at Week 24 were rolled over into the extension phase and received open-label E6011 (200 or 400 mg) every 2 weeks until Week 102. The safety analysis was conducted up to Week 104, and the efficacy analysis was conducted up to Week 84., Results: A total of 169 subjects completed the double-blind treatment phase and were rolled over into the extension phase. In total, 167 (98.8%) subjects experienced any adverse events, and the incidence of treatment-related adverse events was 56.2%. The American College of Rheumatology 20 response rates were observed between 40 and 70% during the extension phase., Conclusions: E6011 was safe and well tolerated with no notable safety concerns up to 102 weeks in RA patients with an inadequate response to MTX., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The objective of the study is to evaluate the long-term safety and efficacy of E6011, a humanized anti-fractalkine monoclonal antibody, in patients with rheumatoid arthritis with an inadequate response to biological disease-modifying antirheumatic drugs., Methods: In the double-blind treatment phase (24 weeks), placebo or E6011 400 mg was administered until Week 10. Thereafter, E6011 200 mg or 400 mg was administered to Week 22. Subjects who completed the evaluation at Week 24 of the treatment phase were rolled over into the extension phase. The extension phase lasted until Week 104, and all subjects received E6011 400 mg or 200 mg every 2 weeks in an open-label manner until Week 102., Results: A total of 47 subjects completed the double-blind treatment phase and were rolled over into the extension phase. In total, 46 (97.9%) subjects experienced any adverse events, and the incidence of treatment-related adverse events was 57.4%. No clear efficacy trend in the American College of Rheumatology 20% response rates was observed., Conclusions: E6011 was well tolerated in active rheumatoid arthritis patients who had shown an inadequate response to biologic disease-modifying antirheumatic drugs, but no clear benefit in the American College of Rheumatology 20% response rates was observed. Further studies are needed to clarify the clinical benefit of E6011., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The prognosis for stage Ⅳ lung cancer is generally poor. However, there have been reports that local treatment of metastatic disease(that is oligometastatic disease), may improve prognosis. The standard treatment for stage Ⅳ non-small cell lung cancer with distant metastases is chemotherapy, and the efficacy of local therapy for primary tumors and metastases is controversial. In recent years, the efficacy of concomitant use of immune checkpoint inhibitor has also been reported, and it is possible that some evidence-based guidelines will be provided in the future. In this report, we describe a case of stage Ⅳ lung cancer with intra-abdominal lymph node metastasis that was treated with thoracoscopic and laparoscopic surgery, local radiation therapy, and chemotherapy. There have been no sign of recurrence for 1 year.

Disorder of phosphate metabolism is a common pathological condition in chronic kidney disease patients. Excessive intake of dietary phosphate deteriorates chronic kidney disease and various complications including cardiovascular and infectious diseases. Recent reports have demonstrated that gut microbiome disturbance is associated with both the etiology and progression of chronic kidney disease. However, the relationship between dietary phosphate and gut microbiome remains unknown. Here, we examined the effects of excessive intake of phosphate on gut microbiome. Five-week-old male C57BL/6J mice were fed either control diet or high phosphate diet for eight weeks. Analysis of the gut microbiota was carried out using MiSeq next generation sequencer, and short-chain fatty acids were determined with GC-MS. In analysis of gut microbiota, significantly increased in Erysipelotrichaceae and decreased in Ruminococcaceae were observed in high phosphate diet group. Furthermore, high phosphate diet induced reduction of microbial diversity and decreased mRNA levels of colonic tight junction markers. These results suggest that the excessive intake of dietary phosphate disturbs gut microbiota and affects intestinal barrier function., Competing Interests: YT received grant from Bayer Yakuhin, Ltd. The other authors have no conflicts of interest., (Copyright © 2023 JCBN.)

Objectives: During musculoskeletal development, the vitamin D endocrine system is crucial, because vitamin D-dependent calcium absorption is a major regulator of bone growth. Because exercise regimens depend on bone mass, the direct action of active vitamin D (1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ]) on musculoskeletal performance should be determined., Methods: To evaluate the effect of 1,25(OH) 2 D 3 on muscle tissue, the vitamin D receptor (Vdr) gene was genetically inactivated in mouse skeletal muscle and the role of 1,25(OH) 2 D 3 -VDR signaling on locomotor function was assessed. The direct action of 1,25(OH) 2 D 3 on muscle development was determined using cultured C2C12 cells with myogenic differentiation., Results: The lack of Vdr activity in skeletal muscle decreased spontaneous locomotor activity, suggesting that the skeletal muscle performance depended on 1,25(OH) 2 D 3 -VDR signaling. Bone phenotypes, reduced femoral bone mineral density, and accelerated osteoclast bone resorption were confirmed in mice lacking skeletal muscle Vdr activity. In vitro study revealed that the treatment with 1,25(OH) 2 D 3 decreased the cellular adenosine triphosphate (ATP)-to-adenosine monophosphate ratio without reducing ATP production. Remarkably, protein expressions of connexin 43, an ATP releaser to extracellular space, and ATP metabolizing enzyme ectonucleotide pyrophosphatase phosphodiesterase 1 were increased responding to 1,25(OH) 2 D 3 treatment. Furthermore, the concentration of pyrophosphate in the culture medium, which inhibits tissue calcification, was increased with 1,25(OH) 2 D 3 treatment. In the presence of 1,25(OH) 2 D 3 -VDR signaling, calcium accumulation was suppressed in both muscle samples isolated from mice and in cultured C2C12 cells., Conclusions: This study dissected the physiological functions of 1,25(OH) 2 D 3 -VDR signaling in muscle and revealed that regulation of ATP dynamics is involved in sustaining locomotor function., 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 © 2023 Elsevier Inc. All rights reserved.)

Surgical intervention for alveolar bone formation is important in patients with alveolar cleft; however, the treatment methods and materials are still controversial. A precise evaluation method for postoperative bone formation is important for comparing outcomes and establishing the best treatment protocol. The purpose of this study is to establish a new method of evaluating surgical outcomes for patients with alveolar cleft. Computed tomography datasets from 20 patients who underwent secondary alveolar bone grafting were obtained before and 1 year after surgery. Six anatomical landmarks were used to superimpose the preoperative and mirrored preoperative volume and postoperative volume data. The cleft region was segmented by subtracting the preoperative from mirrored preoperative volume data, and the failed osteogenesis region was segmented by subtracting the postoperative volume data from the cleft region; subsequently, the bone formation ratio was calculated. Two observers performed this method using a free software 3D slicer and the average evaluation times were 12.7 and 13.2 min for observers 1 and 2, respectively. Method reliability was determined by evaluating intraclass correlation coefficients. The intra-observer intraclass correlation coefficients were 0.97 and 0.96 for observers 1 and 2, respectively. The inter-observer intraclass correlation coefficient was 0.97. Our method is practical for assessing bone formation after treatment, which does not require specific knowledge or software and can be used by ordinary physicians., (© 2023 The Authors. Congenital Anomalies published by John Wiley & Sons Australia, Ltd on behalf of Japanese Teratology Society.)

Skin substitutes have emerged as an alternative to autografts for the treatment of skin defects. Among them, scaffold-based dermal substitutes have been extensively studied; however, they have certain limitations, such as delayed vascularization, limited elasticity, and the inability to achieve permanent engraftment. Self-assembled, cell-based dermal substitutes are a promising alternative that may overcome these shortcomings but have not yet been developed. In this study, we successfully developed a cell-based dermal substitute (cultured dermis) through the long-term culture of human dermal fibroblasts using the net-mold method, which enables three-dimensional cell culture without the use of a scaffold. Spheroids prepared from human dermal fibroblasts were poured into a net-shaped mold and cultured for 2, 4, or 6 months. The dry weight, tensile strength, collagen and glycosaminoglycan levels, and cell proliferation capacity were assessed and compared among the 2-, 4-, and 6-month culture periods. We found that collagen and glycosaminoglycan levels decreased over time, while the dry weight remained unchanged. Tensile strength increased at 4 months, suggesting that remodeling had progressed. In addition, the cell proliferation capacity was maintained, even after a 6-month culture period. Unexpectedly, the internal part of the cultured dermis became fragile, resulting in the division of the cultured dermis into two collagen-rich tissues, each of which had a thickness of 400 μm and sufficient strength to be sutured during in vivo analysis. The divided 4-month cultured dermis was transplanted to skin defects of immunocompromised mice and its wound healing effects were compared to those of a clinically available collagen-based artificial dermis. The cultured dermis promoted epithelialization and angiogenesis more effectively than the collagen-based artificial dermis. Although further improvements are needed, such as the shortening of the culture period and increasing the size of the cultured dermis, we believe that the cultured dermis presented in this study has the potential to be an innovative material for permanent skin coverage.