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2-Amino-4-arylazulene derivatives were prepared from 8-aryl-2 H -cyclohepta[ b ]furan-2-ones, which were converted into 6-aryl-7 H -naphth[3,2,1- cd ]azulen-7-ones through a several step process. The reaction of 8-aryl-2 H -cyclohepta[ b ]furan-2-ones bearing an ester group at the 3-position with malononitrile in the presence of triethylamine afforded 2-amino-4-arylazulenes. The prepared 2-amino-4-arylazulenes were converted to the corresponding 2-chloro derivatives by the Sandmeyer reaction, which were subsequently transformed into 2,4-diarylazulenes by Suzuki-Miyaura coupling with various aryl boronic acids. 2,4-Diarylazulenes underwent intramolecular cyclization between aryl and cyano groups by Brønsted acid to give 6-aryl-7 H -naphth[3,2,1- cd ]azulen-7-ones. UV/vis spectral analysis revealed that 6-aryl-7 H -naphth[3,2,1- cd ]azulen-7-one with a N , N -dimethylaminophenyl group at the 6-position exhibited a broad and strong absorption band in the visible region due to intramolecular charge transfer. Furthermore, 6-aryl-7 H -naphth[3,2,1- cd ]azulen-7-ones exhibited halochromism in 30% CF 3 CO 2 H/CH 2 Cl 2 . Although fluorescence was not observed in solution, 8-aryl-2 H -cyclohepta[ b ]furan-2-ones with an ester function were found to fluoresce in the solid state. 6-Aryl-7 H -naphth[3,2,1- cd ]azulen-7-ones also displayed spectral changes with good reversibility under the electrochemical redox conditions.

Aim: Genome-wide association studies (GWAS) of postpartum depression (PPD) based on accumulated cohorts with multiple ethnic backgrounds have failed to identify significantly associated loci. Herein, we conducted a GWAS of Japanese perinatal women along with detailed confounding information to uncover PPD-associated loci., Methods: The first and second cohorts (n = 9260 and n = 8582 perinatal women enrolled in the Tohoku Medical Megabank Project) and the third cohort (n = 997), recruited at Nagoya University, underwent genotyping. Of them, 1421, 1264, and 225 were classified as PPD based on the Edinburgh Postnatal Depression Scale 1 month after delivery. The most influential confounding factors of genetic liability to PPD were selected, and logistic regression analyses were performed to evaluate genetic associations with PPD after adjusting for confounders., Results: A meta-analysis of GWAS results from the three cohorts identified significant associations between PPD and the following loci (P < 5 × 10 -8 ) by integrating the number of deliveries and the number of family members living together as the most influential confounders: rs377546683 at DAB1, rs11940752 near UGT8, rs141172317, rs117928019, rs76631412, rs118131805 at DOCK2, rs188907279 near ZNF572, rs504378, rs690150, rs491868, rs689917, rs474978, rs690118, rs690253 near DIRAS2, rs1435984417 at ZNF618, rs57705782 near PTPRM, and rs185293917 near PDGFB. Pathway analyses indicated that SNPs suggestively associated with PPD were mostly over-represented in categories including long-term depression, GnRH signaling, glutamatergic synapse, oxytocin signaling, and Rap1 signaling., Conclusion: The current GWAS study identified eight loci significantly associated with PPD, which may clarify the genetic structure underlying its pathogenesis., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Poor medication compliance in children can affect treatment efficacy. We examined the impact of a picture book created by pharmacists to improve medication compliance in children. Our study aim was to assess the effects of the pharmacist-created picture book on medication compliance in children and their parents in collaboration with an outpatient pharmacy. This study included 74 children [recovery rate 28/74 (37.8%)] aged 3-6 years and their parents between March 2023 and March 2024. In the item "Have you experienced any difficulties in giving medication to your child?" the proportion of respondents answering, "Always" or "Sometimes" decreased from 78.3% (18/23) to 34.7% (8/23) after reading the picture book (p<0.01). When answering the question "What specific situations have you found challenging when giving medication?" the number of responses decreased from (an average/mean) of 1.5 situations before reading the picture book to 1 situation. Regarding whether guardians felt a greater appreciation for the importance of giving medication to their children after reading the book, 64.3% answered "Yes," the highest response. A positive correlation (correlation coefficient=0.77, p<0.01) was observed between "Is the child interested in taking the medication?" and "Is the child able to take the medicine? Pharmacists need to raise public awareness of the importance of medication adherence. Since picture books are likely to be repeatedly read aloud, they are considered effective. The results of this study suggest that pharmacist-created picture books may contribute to improving medication compliance in children.

Objective: To examine the efficacy and safety of minimally invasive surgery (MIS) and conventional abdominal surgery for epithelial ovarian cancer (EOC), stratified by treatment type., Methods: A systematic review and meta-analysis were conducted by an Expert Panel of the Japan Society of Gynecologic Oncology Ovarian Cancer Committee. Several academic databases, including PubMed/MEDLINE, Cochrane Database, and Ichushi were searched by the Japan Medical Library Association on November 11, 2023, using the keywords "epithelial ovarian cancer", "minimally invasive surgery", "laparoscopic", and "robot-assisted". Articles describing MIS treatment for EOC compared with conventional abdominal surgery were independently assessed by two authors. The primary outcomes were survival and perioperative adverse events., Results: After screening 1114 studies, 35 articles were identified, including primary staging surgery (PSS) for early-stage EOC EOC (n = 20) and neoadjuvant chemotherapy following interval debulking surgery (NACT-IDS; n = 10) and upfront primary debulking surgery (PDS; n = 5) for advanced-stage EOC. These studies included 29,888 patients (7661 undergoing MIS and 22,227 undergoing abdominal surgery). Patients receiving MIS and abdominal surgery had similar overall survival (PSS: odds ratio [OR] 1.02, 95% confidence interval [CI] 0.75-1.37; NACT-IDS: OR 0.93, 95%CI 0.25-3.44 and PDS: OR 0.66, 95%CI 0.36-1.22, all P > 0.05). MIS showed perioperative complication rates comparable to those of abdominal surgery (intraoperative and postoperative, all treatment types P ≥ 0.05). However, the rate of lymph node dissection in early-stage EOC (PSS: OR 0.49, 95%CI0.26-0.91) and multivisceral resections in advanced-stage EOC (NACT-IDS: OR 0.27 95%CI 0.16-0.44 and PDS: OR 0.27, 95%CI 0.16-0.44) was lower in MIS than in abdominal surgery (all P < 0.05)., Conclusion: MIS did not negatively impact the survival and perioperative complications of patients with EOC compared to abdominal surgery. While MIS is a viable option, varied case selection and surgical procedures suggest potential bias, requiring further validation studies., Competing Interests: Declaration of competing interest Tokai University Research Organization (H.M). All other authors report no conflicts of 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.)

Aims: Evidence for risk stratification using exercise stress echocardiography (ESE) in patients undergoing transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS) is currently lacking. Cardiac power output (CPO) has demonstrated prognostic value in patients undergoing TAVI for severe AS. This study investigated prognoses in patients undergoing TAVI for severe AS and to explore the additional information that ESE can provide for risk stratification., Methods: In this retrospective observational study, we included 96 consecutive patients who underwent TAVI for severe AS and patients with preserved left ventricular (LV) ejection fraction (≥ 50%) who underwent ESE at 3-6 months after TAVI. CPO was calculated as 0.222 × cardiac output × mean blood pressure/LV mass, where 0.222 was the conversion constant to W/100 g of the LV myocardium. All patients were followed up for all-cause mortality and hospitalization for heart failure., Results: Of the 96 patients, 3 were excluded and 93 patients (82.0 years; 45.2% male) were included in this study. During a median follow-up period of 1446 (1271-1825) days, the composite end point was reached in 17 patients. Multivariable Cox regression analysis revealed that CPO at rest and the change in CPO from rest to exercise (ΔCPO) were independently associated with the composite end point (hazard ratio = 0.278, p = 0.023). The addition of ΔCPO resulted in an incremental value of the model containing clinical and resting echocardiography variables (p = 0.030)., Conclusions: This study suggests that resting CPO and exercise-induced changes in CPO are useful for risk stratification of patients undergoing TAVI for severe AS., (© 2024. Japanese Society of Echocardiography.)

Competing Interests: Intérêts concurrents :: Aucun déclaré.

Objectives: To evaluate and characterise articular cartilage degeneration in patients with osteonecrosis of the femoral head (ONFH) using T2 mapping magnetic resonance imaging., Methods: We reviewed 35 patients with ONFH (20 males and 15 females, mean age: 45.7 ± 12.9 years) without obvious cartilage abnormalities on plain magnetic resonance imaging (ONFH group) and 25 healthy volunteers (9 males and 16 females, mean age: 42.9 ± 5.8 years) (control group). All patients underwent T2 mapping magnetic resonance imaging after ONFH onset. The region of interest was defined as the weight-bearing portion of the articular cartilage in the femoral head and acetabulum in the coronal view., Results: The T2 values of the articular cartilage of the acetabulum and femoral head, including necrotic and normal regions, were significantly higher in the ONFH group than those in the control group. These T2 values of the acetabulum and femoral head in Stages 3A and 2 were significantly higher in the ONFH group than those in the control group., Conclusions: The articular cartilage of the acetabulum and femoral head can deteriorate after the onset of ONFH, which may affect the natural history of ONFH and ONFH treatment. Our findings suggest the need for early intervention in joint preservation surgery., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Aim/introduction: Xanthine oxidoreductase (XOR) inhibitor treatment, which reduces reactive oxygen species (ROS) production and increases adenosine triphosphate (ATP) synthesis, has been reported to improve glycemic control. The possible protective effects of XOR inhibitor treatment on insulin secretory capacity were investigated in patients with type 2 diabetes., Materials and Methods: This retrospective cross-sectional study included 428 patients with type 2 diabetes. Insulin secretory capacity was assessed based on fasting serum C-peptide concentration (CPR) and C-peptide index (CPI) in all subjects, while insulin resistance in non-insulin users (n = 312) was determined using the homeostasis model assessment of insulin resistance (HOMA-IR) index., Results: Median values for CPR and CPI in all subjects were 2.4 ng/mL and 1.5, respectively, while that for HOMA-IR in non-insulin users was 3.2. The XOR inhibitor users (n = 72) had significantly (P < 0.001) higher CPR and CPI levels than non-users (n = 356). Multivariable regression analyses showed XOR inhibitor use was positively associated with CPR (β = 0.153, P = 0.001) and CPI (β = 0.144, P = 0.001). Similar results were observed in propensity score analyses. In subgroup analyses of patients with a preserved estimated glomerular filtration rate (≥60 mL/min/1.73 m 2 ) and non-insulin users, these associations remained significant. Furthermore, the associations were significant in patients with lower (≤6.0 mg/dL) but not with higher (>6.0 mg/dL) uric acid levels (P for interaction <0.05). On the other hand, XOR inhibitor use showed no significant association with HOMA-IR., Conclusions: The results of XOR inhibitor treatment, especially a sufficient reduction in serum uric acid level, may provide protective effects on insulin secretory capacity in patients with type 2 diabetes., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background/objectives: Zinc is an essential microelement, and its deficiency is common in patients undergoing hemodialysis. However, the association between serum zinc and mortality in these patients remains unclear. The aim of this study was to explore the possible association between serum zinc levels and all-cause mortality in prevalent patients with kidney failure on maintenance hemodialysis., Methods: This was a prospective cohort study of maintenance hemodialysis patients followed up for 5 years. The key exposure was serum zinc level measured at baseline, and the outcome was all-cause mortality. Their association was analyzed using Cox proportional hazard models., Results: Among 1662 eligible patients selected for this analysis, 468 (28%) died. Lower serum zinc levels were associated with a higher risk for mortality, independent of the major demographic factors and factors including mineral and bone disorder and renal anemia. However, this association was no longer significant when adjusted for serum albumin. Because there was a close correlation between serum zinc and albumin levels, we performed further analyses in which participants were categorized into four groups by median serum zinc (68 µg/dL) and albumin (3.7 g/dL) levels. In the lower serum albumin groups, risk of death was significantly higher in those with lower zinc than those with higher zinc levels, whereas such a difference was not significant in the high serum albumin groups., Conclusions: In patients undergoing maintenance hemodialysis with lower serum albumin levels, a lower serum zinc level was associated with a higher risk of mortality.

Purpose: To evaluate the effect of drug-coated balloon (DCB) with high-dose paclitaxel for the treatment of restenotic dysfunctional arteriovenous fistulae (AVFs)., Materials and Methods: In this single-arm, multicenter, prospective, observational study, 334 patients who underwent DCB angioplasty using IN.PACT AV (Medtronic, Plymouth, Minnesota) for the first time for restenotic lesions of dysfunctional AVFs between April 2021 and March 2022 were registered. Outcomes were compared with the outcomes of plain angioplasty performed previously, leading up to the restenosis., Results: Procedural success, defined as <30% residual stenosis, was achieved in 96.7% of cases. During a median follow-up of 7.4 months, 179 target lesion reinterventions (TLRs) were observed, and the 6-month freedom from TLR was 73.2% (68.2%-78.2%). When compared with the previous plain angioplasty, the median time to reintervention was significantly longer with DCB (9.1 [8.0-10.6] vs 3.2 [3.0-3.4] months; P < .001). Baseline characteristics that were independently associated with TLR were as follows: months from the last intervention (adjusted hazard ratio, 0.50 [95% confidence interval, 0.40-0.62] per doubling; P < .001), partial lesion coverage by DCB (2.13 [1.10-4.12]; P = .024), and residual stenosis after DCB (2.19 [1.53-3.12] per 15% increase; P < .001) with its time interaction (0.91 [0.86-0.97] per month; P = .003). Of the 179 TLRs, 84 used DCB once again. The median time to reintervention was significantly longer for TLR using DCB (7.1 [6.2-9.7] vs 3.3 [3.1-4.0] months; P < .001)., Conclusions: DCB with high-dose paclitaxel is effective at both the initial treatment of restenotic lesions of dysfunctional AVFs and during TLR after DCB use. Partial lesion coverage by DCB and residual stenosis may compromise patency., (Copyright © 2024 SIR. Published by Elsevier Inc. All rights reserved.)

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2, and various complications have been reported. Furthermore, there have been increasing reports of endocrinopathy related to COVID-19 following the pandemic. We report a 49-year-old healthy woman who developed rapid onset of polydipsia and polyuria three weeks after COVID-19. Laboratory tests indicated low urine osmolarity and increased serum osmolarity, and antidiuretic hormone (ADH) was undetectable. Urine osmolality remained low with water deprivation. Similarly, plasma ADH responses to hypertonic-saline infusion were blunted and urine osmolality increased in response to desmopressin. There was no clear evidence of anterior pituitary dysfunction. T1-weighted magnetic resonance imaging (MRI) showed pituitary stalk thickening and absence of posterior pituitary bright signal spots, suggesting the presence of hypophysitis. Based on these results, we made a probable diagnosis of lymphocytic infundibulo-neurohypophysitis (LINH) which have caused central diabetes insipidus. Positive findings for serum anti-rabphilin-3A antibodies, reported as a potential diagnostic marker for LINH, were also noted. Following oral desmopressin administration, polydipsia and polyuria were quickly improved, though treatment with desmopressin was still required over four months. This is the first report of a patient with a probable diagnosis of LINH after COVID-19 who tested positive for anti-rabphilin-3A antibodies. Positive findings for those antibodies suggest that pituitary dysfunction associated with COVID-19 is hypophysitis involving an abnormal immune mechanism. The presence of anti-rabphilin-3A antibodies may be useful as a non-invasive diagnostic marker of LINH and potentially serve as a valuable diagnostic aid in cases of LINH associated with COVID-19.

We investigated the single particle kinetics of the molecular release processes from two types of microcapsules used as drug delivery systems (DDS): biodegradable poly(lactic- co -glycolic) acid (PLGA) and a light-triggered-degradable liposome encapsulating gold nanospheres (liposome-GNP). To optimize the design of DDS capsules, it is highly desirable to develop a method for real-time monitoring of the release process. Using a combination of optical tweezers and confocal fluorescence microspectroscopy we successfully analyzed a single optically trapped PLGA particle and liposome-GNPs in solution. From temporal decay profiles of the fluorescence intensity, we determined the time constant τ of the release processes. We demonstrated that the release rate of spontaneously degradable microcapsules (PLGA) decreased with increasing size, while conversely, the release rate of external stimuli-degradable microcapsules (liposome-GNPs) increased in proportion to their size. This result is explained by the differences in the disruption mechanisms of the capsules, with PLGA undergoing hydrolysis and the GNPs in the liposome-GNP undergoing a photoacoustic effect under nanosecond pulsed laser irradiation. The present approach offers a way forward to an alternative microanalysis system for single drug delivery nanocarriers.

Competing Interests: Competing interests:: None declared.

Background: Transcription factors (TFs) of plant-specific SHORT INTERNODES (SHI) family play a significant role in regulating development and metabolism in plants. In Artemisia annua, various TFs from different families have been discovered to regulate the accumulation of artemisinin. However, specific members of the SHI family in A. annua (AaSHIs) have not been identified to regulate the biosynthesis of artemisinin., Results: We found five AaSHI genes (AaSHI1 to AaSHI5) in the A. annua genome. The expression levels of AaSHI1, AaSHI2, AaSHI3 and AaSHI4 genes were higher in trichomes and young leaves, also induced by light and decreased when the plants were subjected to dark treatment. The expression pattern of these four AaSHI genes was consistent with the expression pattern of four structural genes of artemisinin biosynthesis and their specific regulatory factors. Dual-luciferase reporter assays, yeast one-hybrid assays, and transient transformation in A. annua provided the evidence that AaSHI1 could directly bind to the promoters of structural genes AaADS and AaCYP71AV1, and positively regulate their expressions. This study has presented candidate genes, with AaSHI1 in particular, that can be considered for the metabolic engineering of artemisinin biosynthesis in A. annua., Conclusions: Overall, a genome-wide analysis of the AaSHI TF family of A. annua was conducted. Five AaSHIs were identified in A. annua genome. Among the identified AaSHIs, AaSHI1 was found to be localized to the nucleus and activate the expression of structural genes of artemisinin biosynthesis including AaADS and AaCYP71AV1. These results indicated that AaSHI1 had positive roles in modulating artemisinin biosynthesis, providing candidate genes for obtaining high-quality new A. annua germplasms., (© 2024. The Author(s).)

Purpose: To investigate the association between comorbidities associated with diabetes and higher-level functional status as well as the relationship between comorbidities associated with diabetes and higher-level functional status in older patients with type 2 diabetes mellitus who have better social networks., Methods: Participants were outpatients with type 2 diabetes aged ≥ 65 years, excluding individuals with severe cardiovascular or respiratory illness, hyperglycaemic crisis, type 1 diabetes, or diabetic foot. The Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) was used to evaluate the higher-level functional status. A TMIG-IC score of ≤ 9, instrumental activities of daily living (IADL) ≤ 4, intellectual activity or social role ≤ 3 were defined as decline in higher-level functional status. The comorbidities investigated included peripheral neuropathy, retinopathy, nephropathy, cognitive impairment, depression, frailty, sarcopenia, low muscle strength, stroke, heart disease, and arthritis., Results: The analysis included 198 patients (mean age 75.9 ± 5.7 years, male 60.1%). After adjusting for potential confounders, depression was associated with TMIG-IC (Prevalence ratio (PR) 2.34, 95% confidence interval (CI) 1.44-3.82), low muscle strength was associated with IADL (PR 2.85, 95% CI 1.30-6.27), and frailty was associated with intellectual activity (PR 1.38, 95% CI 1.10-1.74). In the model with social networks added as a confounder, the relationship between depression or low muscle strength and higher-level functional status was not statistically significant., Conclusion: Comorbidities of depression and low muscle strength for older patients with type 2 diabetes mellitus increase the risk of malfunctioning of higher-level functional status. Increased interactions with family, friends and neighbours may reduce this event., (© 2024. The Author(s).)

Purpose: To determine the physiological status of the retina of eyes with endophthalmitis by examining the electroretinograms (ERGs) recorded with a portable recording system and to determine whether the pretreatment ERG findings were correlated with the best-corrected visual acuity (BCVA) after the treatment., Methods: We examined the medical records of 118 eyes of 108 patients who were diagnosed and treated for infectious endophthalmitis at Saitama Medical University Hospital, Japan, between January 2015 to November 2022. Of these, we studied the 25 eyes of 21 patients who had been evaluated by electroretinography. In bilateral cases, one eye was analyzed. The eyes were classified into those with postoperative endophthalmitis (group S, n = 12) and those with endogenous endophthalmitis (group E, n = 9). Photopic and flicker ERGs were recorded with the RETeval system. The pretreatment clinical factors studied were the ERG components that might be correlated with the post-treatment BCVA., Results: Eyes in Group E with larger amplitude flicker ERGs (P = 0.0053, ρ = -0.8333) had better BCVA after treatment. In Group S, eyes with larger amplitude flicker ERGs (P = 0.0086, ρ = -0.7173), photopic a-waves (P = 0.0323, ρ = 0.6177), and photopic b-waves (P = 0.0055, ρ = -0.7443) had better BCVA after treatment., Conclusions: Simple and rapid ERG evaluations under light-adapted condition are helpful in evaluating the pretreatment retinal function and to determine the visual prognosis in eyes with endophthalmitis., Translational Relevance: Simple and non-time-consuming ERG evaluations are helpful in evaluating the retinal function in eyes with endophthalmitis and predicting the visual prognosis.

Background: Iliopsoas impingement after total hip arthroplasty can result not only from acetabular cup but also from cup fixation screw. However, research addressing this screw impingement is scarce, leaving the details undetermined. This study aimed to elucidate the incidence and threshold of symptomatic iliopsoas impingement attributable to protrusion of the cup fixation screw into the iliopsoas muscle and to evaluate its impact on postoperative radiographic imaging findings and patient-reported outcome measures., Methods: A total of 152 hips were included in this study. The symptomatic threshold of screw protrusion was determined using a receiver operating characteristic curve, and patients were divided into low-protrusion and high-protrusion groups using this threshold. The area and Hounsfield Unit values of the iliopsoas muscle on CT and the Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire postoperatively were investigated., Findings: 10 hips (6.5%) were exhibited symptoms of IPI in this series. The threshold for screw protrusion length was identified as 6.4 mm. Patients in the high protrusion group exhibited significantly larger area and lower Hounsfield Unit values of the iliopsoas muscle. In addition, the high protrusion group revealed significantly lower scores (total, pain, movement, mental). Furthermore, subscales scores (pain, movement) in the high protrusion group didn't improve from 3 months to 12 months postoperatively with significance., Interpretation: This study underscores the imperative for surgeons to consider the length of the cup fixation screw. This careful consideration is crucial for mitigating the incidence of postoperative iliopsoas impingement and enhancing total hip arthroplasty outcomes., Competing Interests: Declaration of competing interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2024. Published by Elsevier Ltd.)

Background: We investigate whether Intensive uric acid (UA)-lowering therapy (ULT) provides increased renal protection compared with standard therapy in chronic kidney disease (CKD) patients., Methods: This was a multicenter randomized controlled trial. Only CKD patients with hyperuricemia were included in this study. The participants were randomly assigned to either the Intensive therapy group (target serum UA level ≥ 4.0 mg/dL and < 5.0 mg/dL) or the standard therapy group (serum UA level ≥ 6.0 mg/dL and < 7.0 mg/dL). ULT was performed using topiroxostat, a non-purine-type selective xanthine oxidase inhibitor. The primary endpoint was change in the logarithmic value of urine albumin to the creatinine ratio (ACR) between baseline and week 52 of the treatment., Results: Three hundred fifty-two patients were included in the full analysis set. In the Standard therapy group, mean serum UA was 8.23 mg/dL at baseline and 6.13 mg/dL at 52 weeks. In the Intensive therapy group, mean serum UA was 8.15 mg/dL at baseline and 5.25 mg/dL at 52 weeks. There was no significant difference in changes in log ACR at 52 weeks between the Intensive therapy and the Standard therapy groups., Conclusion: This study did not reveal the benefit of Intensive ULT to improve albuminuria levels. (UMIN000026741 and jRCTs051180146)., (© 2024. The Author(s).)

Purpose: The extraaortic-valvular cardiac damage (EVCD) Stage has shown potential for risk stratification for patients with aortic stenosis (AS). This study aimed to examine the usefulness of the EVCD Stage in risk stratification of patients with moderate AS and reduced left ventricular ejection fraction (LVEF)., Methods: Clinical data from patients with moderate AS (aortic valve area, .60-.85 cm 2 /m 2 ; peak aortic valve velocity, 2.0-4.0 m/s) and reduced LVEF (LVEF 20%-50%) were analyzed during 2010-2019. Patients were categorized into three groups: EVCD Stages 1 (LV damage), 2 (left atrium and/or mitral valve damage), and 3/4 (pulmonary artery vasculature and/or tricuspid valve damage or right ventricular damage). The primary endpoint included a composite of cardiac death and heart failure hospitalization, with non-cardiac death as a competing risk., Results: The study included 130 patients (mean age 76.4 ± 6.8 years; 62.3% men). They were categorized into three groups: 26 (20.0%) in EVCD Stage 1, 66 (50.8%) in Stage 2, and 48 (29.2%) in Stage 3/4. The endpoint occurred in 54 (41.5%) patients during a median follow-up of 3.2 years (interquartile range, 1.4-5.1). Multivariate analysis indicated EVCD Stage 3/4 was significantly associated with the endpoint (hazard ratio 2.784; 95% confidence interval 1.197-6.476; P = .017) compared to Stage 1, while Stage 2 did not (hazard ratio 1.340; 95% confidence interval .577-3.115; P = .500)., Conclusion: The EVCD staging system may aid in the risk stratification of patients with moderate AS and reduced LVEF., (© 2024 Wiley Periodicals LLC.)

An efficient metal-free, triflic acid-promoted intramolecular Friedel-Crafts-type carbocyclization of alkenylated biphenyl derivatives is discussed. This method provides an elegant route for the construction of 9,10-dihydrophenanthrenes of biological significance in good to excellent yields. The carbocyclization reaction is likely to proceeds via activation of terminal C[bond, double bond]C bond of alkenylated biphenyl derivatives followed by subsequent aromatic electrophilic substitution to give desired carbocyclic products. Single crystal X-ray diffraction analysis of compound 10d revealed that the crystals are packed in AB-AB layer packing, where the molecules are aligned in anti-parallel fashion. Notably, all of the synthesized 9,10-dihydrophenanthrenes exhibited blue to greenish yellow fluorescence with λ max  = 418-481 nm range. The stokes shift, quantum yield and optical band gap of tricyclic products were computed using their absorption and emission spectra. A significant positive solvatochromic effect was observed for 9,10-dihydrophenanthrene derivative 10l , which is a characteristic of ICT interactions., 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 Authors. Published by Elsevier Ltd.)

β-(1,3/1,4)-glucan is a major component of cereal grains, such as oats and barley. In this study, we investigated the effects of cooked waxy barley, which contains β-(1,3/1,4)-glucan, on upper respiratory tract physical symptoms and mood status by performing a randomized, parallel-group, comparative trial. The primary outcome was assessed using the Wisconsin Upper Respiratory Symptom Survey-21 and Profile of Mood States second edition. Twenty-seven healthy Japanese adult participants were supplemented with 100 g of cooked waxy barley (containing 1.8 g of β-glucan) or 100 g of cooked white rice daily for 8 weeks. Participants receiving cooked waxy barley reported a reduction in cumulative days of sneezing ( p < 0.05) and feeling tired ( p < 0.0001) compared with the control group. After the intervention period, there were significantly less severe nasal symptoms, such as runny nose, plugged nose, and sneezing ( p < 0.05), and a significantly greater reduction of the Tension-Anguish score ( p < 0.05) in the barley group than in the control group. This study suggests that supplementation of cooked waxy barley containing β-(1,3/1,4)-glucan prevents or alleviates nasal upper respiratory tract symptoms and improves mood status. The findings of this study should be confirmed by double-blind trials with a larger number of participants.

Ovarian cancer (OC), accounting for approximately 200,000 deaths worldwide annually, is a heterogeneous disease showing major differences in terms of its incidence, tumor behavior, and outcomes across histological subtypes. In OC, primary chemotherapy, paclitaxel carboplatin, bevacizumab, and PARP inhibitors have shown prolonged progression-free survival and a favorable overall response rate compared to conventional treatments. However, treatment options for platinum-resistant recurrence cases are limited, with no effective therapies that significantly prolong the prognosis. Recently, mirvetuximab soravtansine, an alpha-folate receptor (FRα)-targeted antibody-drug conjugate (ADC), was approved by the US Food and Drug Administration for patients with FRα-positive recurrent epithelial OC (EOC). This approval was based on a Phase II study, which demonstrated its efficacy in such patients. ADCs comprise an antibody, a linker, and a payload, representing new concept agents without precedence. Advanced clinical studies are developing ADCs for patients with OC, targeting solid tumors such as gynecologic cancer. Ongoing clinical trials are evaluating ADCs targeting FRα and human epidermal growth factor receptor 2, trophoblast cell surface antigen-2, sodium-dependent phosphate transport protein 2B, and cadherin-6 in Phase II/III studies. In this review, we summarize the existing evidence supporting the use of ADCs in OC, discuss ongoing clinical trials and preclinical studies, and explore the potential of these innovative agents to address the challenges in OC treatment.

Macrophages are the primary cell type orchestrating bioresorbable vascular graft (BVG) remodeling and infiltrate from three sources: the adjacent native vessel, circulating blood, and transmural migration from outer surface of the graft. To elucidate the kinetics of macrophage infiltration into the BVG, we fabricated two different bilayer arterial BVGs consisting of a macroporous sponge layer and a microporous electrospun (ES) layer. The Outer ES graft was designed to reduce transmural cell infiltration from the outer surface and the Inner ES graft was designed to reduce cell infiltration from the circulation. These BVGs were implanted in mice as infrarenal abdominal aorta grafts and extracted at 1, 4, and 8 weeks (n = 5, 10, and 10 per group, respectively) for evaluation. Cell migration into BVGs was higher in the Inner ES graft than in the Outer ES graft. For Inner ES grafts, the majority of macrophage largely expressed a pro-inflammatory M1 phenotype but gradually changed to tissue-remodeling M2 macrophages. In contrast, in Outer ES grafts macrophages primarily maintained an M1 phenotype. The luminal surface endothelialized faster in the Inner ES graft; however, the smooth muscle cell layer was thicker in the Outer ES graft. Collagen fibers were more abundant and matured faster in the Inner ES graft than that in the Outer ES graft. In conclusion, compared to macrophages infiltrating from the circulating blood, transmural macrophages from outside promote the acute inflammatory-mediated response for vascular remodeling and subsequent collagen deposition within BVGs. STATEMENT OF SIGNIFICANCE: To elucidate the kinetics of macrophage infiltration into the bioresorbable vascular graft (BVG), two different bilayer arterial BVGs were implanted in mice as infrarenal abdominal aorta grafts. Cell migration into BVGs was higher in the inner electrospun graft which cells mainly infiltrate from outer surface than in the outer electrospun graft which cells mainly infiltrate from the circulating blood. In the inner electrospun grafts, the majority of macrophages changed from the M1 phenotype to the M2 phenotype, however, outer electrospun grafts maintained the M1 phenotype. Collagen fibers matured faster in the Inner electrospun graft. Compared to macrophages infiltrating from the circulating blood, transmural macrophages from outside promote the acute inflammatory-mediated response for vascular remodeling and subsequent collagen deposition within BVGs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Breuer is on the scientific advisory board for Cook Biomedical and is the founder of Lyst Therapeutics. Dr. Shinoka receives research support from Gunze Limited. The other authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We experimentally clarify the interaction of acoustic pressure and heat release rate fluctuations during a transition to high-frequency combustion instability in a model rocket engine combustor. The dynamical state of acoustic pressure fluctuations undergoes a transition from high-dimensional chaotic oscillations to strongly correlated limit cycle oscillations. The coherent structure in the heat release rate field emerges with the initiation of weakly correlated limit cycle oscillations. The effect of the heat release rate on acoustic pressure fluctuations predominates during high-dimensional chaotic oscillations. In contrast, the effect of acoustic pressure on the heat release rate fluctuations markedly increases during the correlated limit cycle oscillations. These are reasonably shown by an ordinal pattern-based analysis involving the concepts of information theory, synchronization, and complex networks.

Introduction: Syndecan (SDC)-1 is a transmembrane heparan sulfate proteoglycan and is a major component of endothelial glycocalyx (EG). This study aimed to investigate the association of serum SDC-1 concentration as a marker of EG degradation with albuminuria in type 2 diabetes., Methods: We included 370 patients with type 2 diabetes and 219 individuals with no diabetes. The individuals with estimate glomerular filtration rate <30 mL/min/1.73 m 2 were excluded., Results: Serum SDC-1 concentration was higher in type 2 diabetes than in no diabetes. The presence of diabetes was independently associated with log [SDC-1] in multivariate analysis. In type 2 diabetes, serum SDC-1 concentration was correlated with log [urinary albumin-to-creatinine ratio (ACR)]. Moreover, log [SDC-1] was an independent determinant of log [ACR] after adjustment for known risk factors of albuminuria., Conclusions: Serum SDC-1 concentration was higher in patients with type 2 diabetes compared to individuals with no diabetes and an independent determinant of ACR. This study implicates the role of the EG degradation in albuminuria in type 2 diabetes., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Previous research on the changes in resting-state functional connectivity (rsFC) in anorexia nervosa (AN) has been limited by an insufficient sample size, which reduced the reliability of the results and made it difficult to set the whole brain as regions of interest (ROIs)., Methods: We analyzed functional magnetic resonance imaging data from 114 female AN patients and 135 healthy controls (HC) and obtained self-reported psychological scales, including eating disorder examination questionnaire 6.0. One hundred sixty-four cortical, subcortical, cerebellar, and network parcellation regions were considered as ROIs. We calculated the ROI-to-ROI rsFCs and performed group comparisons., Results: Compared to HC, AN patients showed 12 stronger rsFCs mainly in regions containing dorsolateral prefrontal cortex (DLPFC), and 33 weaker rsFCs primarily in regions containing cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between anterior cingulate cortex (ACC) and thalamus ( p < 0.01, false discovery rate [FDR] correction). Comparisons between AN subtypes showed that there were stronger rsFCs between right lingual gyrus and right supracalcarine cortex and between left temporal occipital fusiform cortex and medial part of visual network in the restricting type compared to the binge/purging type ( p < 0.01, FDR correction)., Conclusion: Stronger rsFCs in regions containing mainly DLPFC, and weaker rsFCs in regions containing primarily cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between ACC and thalamus, may represent categorical diagnostic markers discriminating AN patients from HC.

Introduction: Antimicrobial resistance is a global issue, and implementation of antimicrobial stewardship programs in outpatient settings is crucial. Japan has also focused on outpatient oral antimicrobial stewardship programs and difficulties in standardizing prescriptions have led to overprescription in primary emergency medical centers. There is a lack of research investigating the antibiotic prescription status of pediatric primary emergency medical centers and the benchmark prescription rates in pediatric outpatient settings., Methods: We conducted a multi-center, cross-sectional study of seven pediatric primary emergency medical centers located in five prefectures of Japan. We retrospectively extracted data from health claims or directly obtained them from charts at each institution and evaluated trends in the antibiotic prescription rate based on the AWaRe classification between April 2016 and December 2019., Results: Our study included 383,525 encounters, with the most common infectious disease diagnosis being acute upper respiratory tract infection in 93,449 cases (24.4 %). The antibiotic prescription rate during the study period was 7.4 %, representing a decrease of 46 %, from 10.2 % in 2016 to 5.5 % in 2019. The percentage of prescriptions in the Access group increased at all institutions; however, it exceeded 60 % in only three facilities in 2019. The percentage of third-generation cephalosporins varied among facilities, ranging from 1.7 % to 59.4 %, as of 2019., Conclusions: For pediatric primary emergency medical centers where antimicrobial stewardship programs are implemented, we suggest 5 % as a reasonable benchmark level for the antibiotic prescription rate. Prescribing the antibiotics in the Access groups less frequently remains a domestic challenge in Japan., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest to disclose. Informed Consent and Ethical Approval. We obtained opt-out consent from the patients' parents. This study was approved by the institutional ethics committees of Kobe Children's Hospital (Approval Number 2021–61)., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Aim: Patients undergoing haemodialysis have reduced muscle strength and impaired activities of daily living (ADL). We examined possible relationship between difficult ADL and corresponding muscle weakness in elderly haemodialysis patients., Methods: This was a single-centre, cross-sectional study. Patient-reported ADL difficulty was examined using a questionnaire in six ADL using upper limbs (eating, grooming and dressing) and lower limbs (bathing, toileting and locomotion). We measured six muscle strengths by dynamometers of shoulder flexion, shoulder abduction, elbow flexion, handgrip, hip abduction and knee extension. The muscle strength with the lowest Z-score was considered as the weakest muscle strength for the patient., Results: The six scores of ADL difficulty were all inversely associated with the six muscle strengths in the 81 total participants of whom 71 individuals (87.7%) had any ADL difficulty. Among the six measurements of muscle strength, handgrip strength showed the highest associations with all ADL difficulties. In 25 patients who perceived that the most difficult ADL was an activity using upper limbs, the common weakest muscle strengths were the hip abduction, handgrip and elbow flexion. In 44 patients who perceived that the most difficult ADL was an activity using lower limbs, knee extension was the most prevalent weakest muscle strength., Conclusion: This study suggested preferential relationship between the most difficult ADL and corresponding muscle weakness in elderly haemodialysis patients. This finding may be useful in prevention and treatment., (© 2024 Asian Pacific Society of Nephrology.)

Aims: Cardiac power output (CPO) measures cardiac performance, and its prognostic significance in heart failure with preserved ejection fraction (EF) has been previously reported. However, the effectiveness of CPO in risk stratification of patients with valvular heart disease and post-operative valvular disease has not been reported. We aimed to determine the association between CPO and clinical outcomes in patients with preserved left ventricular (LV) EF after transcatheter aortic valve implantation (TAVI)., Methods and Results: This retrospective observational study included 1047 consecutive patients with severe aortic stenosis after TAVI. All patients were followed up for all-cause mortality and hospitalization for HF. CPO was calculated as 0.222 × cardiac output × mean blood pressure (BP)/LV mass, where 0.222 was the conversion constant to W/100 g of the LV myocardium. CPO was assessed using transthoracic echocardiography at discharge after TAVI. Of the 1047 patients, 253 were excluded following the exclusion criteria, including those with low LVEF, and 794 patients (84.0 [80.0-88.0] years; 35.8% male) were included in this study. During a median follow-up period of 684 (237-1114) days, the composite endpoint occurred in 196 patients. A dose-dependent association was observed between the CPO levels and all-cause mortality. Patients in the lowest CPO tertile had significantly lower event-free survival rates (log-rank test, P = 0.043). Multivariate Cox regression analysis showed that CPO was independently associated with adverse outcomes (hazard ratio = 0.561, P = 0.020). CPO provided an incremental prognostic effect in the model based on clinical and echocardiographic markers ( P = 0.034)., Conclusion: CPO is independently and incrementally associated with adverse outcomes in patients with preserved LVEF following TAVI., Competing Interests: Conflict of interest: M.I. is a consultant of Edwards Lifesciences and Abbott Medical Japan, and S.K. is a consultant of Abbott Medical Japan. All other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: The objective of this study was to present the outcomes of rotational acetabular osteotomy (RAO) over a 30-year period for osteoarthritis (OA) secondary to dysplasia of the hip in pre- or early-stage OA., Methods: Between September 1987 and December 1994, we provided treatment to 47 patients (55 hips) with RAO for the management of pre- or early-stage OA due to developmental hip dysplasia. Of those, eight patients (11 hips) with pre-OA (follow-up rate 79%) and 27 patients (32 hips) with early-stage OA (follow-up rate 78%), totalling 35 patients (43 hips) (follow-up rate 78%), were available at a minimum of 28 years after surgery., Results: In the pre-OA group, the mean Merle d'Aubigné score improved significantly from 14.5 points (SD 0.7) preoperatively to 17.4 points at final follow-up (SD 1.2; p = 0.004) and in the early-stage group, the mean score did not improve significantly from 14.0 (SD 0.3) to 14.6 (SD 2.4; p = 0.280). Radiologically, the centre-edge angle, acetabular roof angle, and head lateralization index were significantly improved postoperatively in both groups. Radiological progression of OA was observed in two patients (two hips) in the pre-OA group and 17 patients (18 hips) in the early-stage group. Kaplan-Meier survival analysis, with radiological progression of OA as the primary outcome, projected a 30-year survival rate of 81.8% (95% confidence interval (CI) 0.59 to 1.00) for the pre-OA group and 42.2% (95% CI 0.244 to 0.600) for the early-stage group. In all cases, the overall survival rate stood at 51.5% (95% CI 0.365 to 0.674) over a 30-year period, and when the endpoint was conversion to total hip arthroplasty, the survival rate was 74.0% (95% CI 0.608 to 0.873)., Conclusion: For younger patients with pre-OA, joint preservation of over 30 years can be expected after RAO., Competing Interests: S. Oshima reports consulting fees from Microport Orthopedics, unrelated to this study., (© 2024 The British Editorial Society of Bone & Joint Surgery.)

Background: To evaluate the relationships among hip instability, pain, and morphology of the iliofemoral ligament (ILFL) in patients with developmental dysplasia of the hip (DDH) using ultrasonography (US)., Methods: We reviewed 86 patients (109 hips) with DDH (Group D), 40 patients (46 hips) with borderline hip dysplasia (BDDH) (Group B) and 20 patients (23 hips) without hip pain and bony abnormality (control group). Group D was classified into three subgroups-the severe (group SP), moderate (group MP), and none/mild (group NMP) hip pain groups-using the visual analogue scale (VAS). For evaluating hip instability and ILFL morphology, the distance between the anterior edge of the anterior inferior iliac spine (AIIS) and the horizontal line to the femoral head, and ILFL thickness were measured using US. The difference between the distance in the neutral position and Patrick position was calculated and defined as the femoral head translation distance (FTD)., Results: FTD and ILFL thickness in group D were significantly larger than those in the control group and group B (P < 0.05). There was a significant positive correlation between FTD and ILFL thickness in three groups (r = 0.57, P < 0.05; r = 0.55, P < 0.05; r = 0.62, P < 0.05, respectively). FTD and ILFL thickness in group SP were significantly larger than those in group NMP (P < 0.05). FTD and ILFL thickness in group D had significantly negative correlations with the lateral center edge (r = -0.54, P < 0.05; r = -0.40, P < 0.05, respectively) and vertical-center-anterior angle (r = -0.51, P < 0.05; r = -0.43, P < 0.05, respectively)., Conclusions: Acetabular bony deficiency, especially in the anterior and lateral region can result in antero-posterior hip instability, leading to thickened ILFL and hip pain, even in patients with BDDH. These findings may facilitate our understanding and treatment of patients with DDH. When hip instability is suspected, hip US examination may help confirm the diagnosis and assist in providing objective clinical diagnostic evidence., Competing Interests: Conflicts of interest None., (Published by Elsevier B.V.)

Purpose: This study retrospectively evaluated long-term clinical outcomes and patient-reported outcome measures (PROMs) in patients with osteonecrosis of the femoral head (ONFH) who underwent transtrochanteric rotational osteotomy (TRO), curved varus osteotomy (CVO), and total hip arthroplasty (THA)., Methods: We retrospectively reviewed the 109 hips in 96 patients (46 men, 50 women) who underwent CVO, TRO, or THA for ONFH treatment. The mean follow-up period for the TRO, CVO, and THA groups was 14.8, 11.5, and 13.3 years, respectively., Results: The THA conversion rate of the TRO patients was significantly higher than that of the patients with CVO, and the final clinical scores in the patients with TRO did not improve compared with preoperative scores. Postoperative PROMs showed that the total and pain scores of the patients with THA were significantly higher than those of patients with TRO and CVO, while the PROM score did not change between patients with TRO and CVO. The analysis further showed that the preoperative type C2, stage 3A, or postoperative type C1 and C2 were significant predictors of decreased final PROM scores., Conclusion: This study found that CVO and THA are clinically effective treatments for ONFH, with significant improvements compared with preoperative scores. However, THA was associated with significantly higher PROMs and pain scores than those of CVO and TRO in long-term follow-up. Furthermore, our results suggest that postoperative PROMs depend mainly on the preoperative level of collapse and postoperative transposed intact ratio of the articular surface of the femoral head., (© 2024. The Author(s).)

Background: The Proactive Molecular Risk Classifier for Endometrial Cancer has identified four risk groups for the prognosis of endometrial cancer. Lenvatinib plus pembrolizumab was recently approved as a second-line treatment for unresectable endometrial cancer, but reports in clinical practice are lacking. The relationship between the efficacy of lenvatinib/pembrolizumab and Proactive Molecular Risk Classifier for Endometrial Cancer classification is unclear., Methods: This single-centre retrospective study included patients who underwent lenvatinib/pembrolizumab therapy at Iwate Medical University Hospital between January 2022 and March 2023. Formalin-fixed paraffin-embedded specimens obtained from patients before treatment were collected and classified into the mismatch repair-deficient, p53 abnormal and no specific molecular profile subtypes using immunohistochemistry. The response rate, progression-free survival and adverse events were evaluated using electronic medical records. The study was approved by the hospital's ethics committee (approval number: MH2022-093)., Results: This study enrolled 20 patients, who underwent a median follow-up of 17.8 months (95% confidence interval: 16.6-18.9). The best overall response rate was 60.0% (36.1-80.9), and the median progression-free survival was 11.6 months (2.9-20.3). The median progression-free survival in the p53 abnormal group (n = 9) was 3.4 months (3.0-3.8); however, progression-free survival did not reach the median (P < 0.001) in the mismatch repair-deficient/no specific molecular profile group (n = 11). Symptomatic immune-related adverse events (except hypothyroidism) occurred in 4/20 (25.0%) patients, and partial responses were observed in all cases. No treatment-related deaths occurred., Conclusion: The p53abn group in the Proactive Molecular Risk Classifier for Endometrial Cancer classification has a poor prognosis even after treatment with lenvatinib/pembrolizumab., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Although brain morphological abnormalities have been reported in anorexia nervosa (AN), the reliability and reproducibility of previous studies were limited due to insufficient sample sizes, which prevented exploratory analysis of the whole brain as opposed to regions of interest (ROIs). Objective was to identify brain morphological abnormalities in AN and the association with severity of AN by brain structural magnetic resonance imaging (MRI) in a multicenter study, and to conduct exploratory analysis of the whole brain. Here, we conducted a cross-sectional multicenter study using T1-weighted imaging (T1WI) data collected between May 2014 and February 2019 in Japan. We analyzed MRI data from 103 female AN patients (58 anorexia nervosa restricting type [ANR] and 45 anorexia nervosa binge-purging type [ANBP]) and 102 age-matched female healthy controls (HC). MRI data from five centers were preprocessed using the latest harmonization method to correct for intercenter differences. Gray matter volume (GMV) was calculated from T1WI data of all participants. Of the 205 participants, we obtained severity of eating disorder symptom scores from 179 participants, including 87 in the AN group (51 ANR, 36 ANBP) and 92 HC using the Eating Disorder Examination Questionnaire (EDE-Q) 6.0. GMV reduction were observed in the AN brain, including the bilateral cerebellum, middle and posterior cingulate gyrus, supplementary motor cortex, precentral gyrus medial segment, and thalamus. In addition, the orbitofrontal cortex (OFC), ventromedial prefrontal cortex (vmPFC), rostral anterior cingulate cortex (ACC), and posterior insula volumes showed positive correlations with severity of symptoms. This multicenter study was conducted with a large sample size to identify brain morphological abnormalities in AN. The findings provide a better understanding of the pathogenesis of AN and have potential for the development of brain imaging biomarkers of AN. Trial Registration: UMIN000017456. https://center6.umin.ac.jp/cgi-open-bin/icdr/ctr&#95;view.cgi?recptno=R000019303 ., (© 2023. The Author(s).)

Objectives: This study documents the time elapsed from the diagnosis of osteonecrosis of the femoral head (ONFH) to surgery, exploring the factors that influence ONFH severity., Design: Retrospective observational study of a nationwide database., Setting: The Kaplan-Meier method with log-rank tests was applied to examine the period from definitive diagnosis of ONFH to surgery using any surgery as the end point. For bilateral cases, the date of the first surgery was the endpoint., Participants: This study included 2074 ONFH cases registered in 34 university hospitals and highly specialised hospitals of the multicentre sentinel monitoring system of the Japanese Investigation Committee between 1997 and 2018., Main Outcome Measure: The primary outcome was the time from diagnosis to surgery. The secondary outcome was the proportion of subjects remaining without surgery at 3, 6 and 9 months, and at 1, 2 and 5 years after diagnosis., Results: The median time to surgery was 9 months (IQR 4-22 months) after diagnosis of ONFH. The time to surgery was significantly shorter in the alcohol alone group and the combined corticosteroid and alcohol group than in the corticosteroid alone group (p=0.018 and p<0.001, respectively), in early stage ONFH with no or mild joint destruction (stages II and III, p<0.001), and with joint preserving surgery (p<0.001). The proportion without surgery was 75.8% at 3 months, 59.6% at 6 months, 48.2% at 9 months, 40.5% at 1 year, 22.2% at 2 years and 8.3% at 5 years., Conclusion: ONFH has been considered to be an intractable disease that often requires surgical treatment, but the fact that surgery was performed in more than half of the patients within 9 months from diagnosis suggests severe disease with a significant clinical impact., Trial Registration Number: Chiba University ID1049., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aim: Anti-aminoacyl-tRNA synthetase (ARS) antibodies form a condition called Antisynthetase syndrome (ASSD). While interstitial lung disease (ILD) is a particularly frequent manifestation of ASSD and is closely associated with morbidity and mortality, few studies have been conducted on its characteristics on high-resolution computed tomography (HRCT). In this study, we clarified the HRCT findings in patients with anti-ARS antibody-positive ILD (ARS-ILD).  Methods: The HRCT findings at the time of the ILD diagnosis in 24 ARS-ILD patients were retrospectively evaluated by 2 pulmonologists and one radiologist. We also assessed the clinical symptoms, physical examination findings, and laboratory data including the type of anti-ARS antibodies. For a further analysis, the data of patients were divided into two groups: the polymyositis (PM)/dermatomyositis (DM) group and the non-PM/DM group., Results: The ratio of men to women was almost 1:1. The median age at the time of the diagnosis was 53 years old. Anti-glycyl (anti-EJ) and anti-histidyl (anti-Jo-1) antibodies were more common than others. An analysis of the HRCT patterns of 23 ARS-ILD patients showed that the most common pattern was the nonspecific interstitial pneumonia (NSIP) pattern. The second most common pattern was the usual interstitial pneumonia (UIP) pattern. Between the PM/DM and non-PM/DM groups, no clear trends were noted in the age, sex ratio, proportion of HRCT patterns, or type of anti-ARS antibodies., Conclusions: This retrospective study demonstrated that ARS-ILD patients, regardless of myositis symptoms, most often showed the NSIP pattern on HRCT, as previously reported. However, unlike previous reports, the UIP pattern on HRCT was not rare.

Procyanidins are one of the polyphenols consisting of multiple flavan-3-ols (eg epicatechin). They have a complex chemical structure, with the degree of polymerization and linked position of flavan-3-ols varying among various foods, such as apples and chocolate. Physiological functional studies of procyanidins have investigated their mechanisms in cells and animals based on their antioxidant effects. Recently, the intestinal environment, including the intestinal microflora, has played an important role in the energy metabolism and health status of the host. Regulation of the intestinal environment by dietary polyphenols is becoming a new concept in health functions, and we have begun to investigate the mechanism of apple procyanidins, focusing on the gut microbiota and metabolites in our functional research. In this minireview, we will discuss the effects of procyanidin ingestion on the gut microbiota and metabolites., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Tobacco (Nicotiana tabacum L.) is a widely cultivated crop of the genus Nicotiana. Due to the highly addictive nature of tobacco products, tobacco smoking remains the leading cause of preventable death and disease. There is therefore a critical need to develop tobacco varieties with reduced or non-addictive nicotine levels. Nicotine and related pyridine alkaloids biosynthesized in the roots of tobacco plants are transported to the leaves, where they are stored in vacuoles as a defense against predators. Jasmonate, a defense-related plant hormone, plays a crucial signaling role in activating transcriptional regulators that coordinate the expression of downstream metabolic and transport genes involved in nicotine production. In recent years, substantial progress has been made in molecular and genomics research, revealing many metabolic and regulatory genes involved in nicotine biosynthesis. These advances have enabled us to develop tobacco plants with low or ultra-low nicotine levels through various methodologies, such as mutational breeding, genetic engineering, and genome editing. We review the recent progress on genetic manipulation of nicotine production in tobacco, which serves as an excellent example of plant metabolic engineering with profound social implications., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Aims: Current evidence on the prognostic value of exercise stress echocardiography (ESE) in asymptomatic patients with low-gradient severe aortic stenosis (AS) is limited. Therefore, this study aimed to elucidate its prognostic implications for patients with low-gradient severe AS and determine the added value of ESE in risk stratification for this population., Methods and Results: This retrospective observational study included 122 consecutive asymptomatic patients with either moderate [mean pressure gradient (MPG) < 40 mmHg and aortic valve area (AVA) 1.0-1.5 cm 2 ] or low-gradient severe (MPG < 40 mmHg and AVA < 1.0 cm 2 ) AS and preserved left ventricular ejection fraction (≥50%) who underwent ESE. All patients were followed up for AS-related events. Of 143 patients, 21 who met any exclusion criteria, including early interventions, were excluded, and 122 conservatively managed patients [76.5 (71.0-80.3) years; 48.3% male] were included in this study. During a median follow-up period of 989 (578-1571) days, 64 patients experienced AS-related events. Patients with low-gradient severe AS had significantly lower event-free survival rates than those with moderate AS (log-rank test, P < 0.001). Multivariable Cox regression analysis showed that the mitral E / e ' ratio during exercise was independently associated with AS-related events (hazard ratio = 1.075, P < 0.001) in patients with low-gradient severe AS., Conclusion: This study suggests that asymptomatic patients with low-gradient severe AS have worse prognoses than those with moderate AS. Additionally, the mitral E / e ' ratio during exercise is a useful parameter for risk stratification in patients with low-gradient severe AS., Competing Interests: Conflict of interest: M.I. is a consultant of Edwards Lifesciences and Abbott Medical Japan, and S.K. is a consultant of Abbott Medical Japan. All other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Fetuin-A inhibits precipitation of calcium-phosphate crystals by forming calciprotein particles (CPP). A novel T50 test, which measures transformation time from primary to secondary CPP, is an index for calcification propensity. Both lower fetuin-A and shorter T50 levels were associated with cardiovascular disease (CVD) risk in patients with chronic kidney disease (CKD). Extremely high risk for CVD death in advanced CKD patients consists of high-incidental CVD event and high mortality after CVD event. To date, it is unclear whether fetuin-A and/or T50 can equally predict each CVD outcome., Methods: This prospective cohort study examined patients undergoing maintenance hemodialysis. The exposures were fetuin-A and T50. The outcomes of interests were new CVD events and subsequent deaths. The patients were categorized into tertiles of fetuin-A or T50 (T1 to T3)., Results: We identified 190 new CVD events during the 5-year follow-up of the 513 patients and 59 deaths subsequent to the CVD events during 2.5-year follow-up. A lower fetuin-A but not T50 was significantly associated with new CVD events [subdistribution hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.15-2.61, P  = .009 for T1 vs T3]. In contrast, a shorter T50 but not fetuin-A was a significant predictor of deaths after CVD events (HR 3.31, 95% CI 1.42-7.74, P  = .006 for T1 + T2 vs T3). A lower fetuin-A was predictive of new CVD events, whereas a shorter T50 was more preferentially associated with subsequent death., Conclusion: These results indicate that fetuin-A and T50 are involved in cardiovascular risk in different manners., Competing Interests: MK received research funds from JSPS KAKENHI (Grant Number 22H00473), AMED-CREST (Grant Number JP23gm1510012h0002), and Cabinet Office, Government of Japan, Moonshot R&D Program for Agriculture, Forestry and Fisheries. The other authors declared no competing interest relevant to this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Introduction: Immune checkpoint inhibitor (ICI)-based treatment has become standard treatment for patients with advanced NSCLC. We aimed to determine the survival benefit of upfront radiotherapy for brain metastases (BMs) in patients with NSCLC who received ICI alone (ICI-alone) or with chemotherapy (ICI-chemo)., Methods: This study included consecutive patients with NSCLC having BMs who received ICI alone or ICI-chemo at 50 institutes between February 2017 and September 2021. The presence of BMs was confirmed by imaging before treatment. Treatment outcomes were compared between patients who did and did not receive upfront radiotherapy for BMs. Potential confounding factors were adjusted between the groups through inverse probability treatment weighting (IPTW) analysis and overlap weighting (OW) analysis with propensity scores., Results: Patients were grouped as ICI-alone cohort, 224 patients (upfront-radiotherapy group, 135 patients; no-radiotherapy group, 89 patients) and ICI-chemo cohort, 367 patients (upfront-radiotherapy group, 212 patients; no-radiotherapy group, 155 patients). In the ICI-alone cohort, the overall survival of the upfront-radiotherapy group was significantly longer than that of the no-radiotherapy group (IPTW-adjusted hazards ratio [HR] = 0.45 [95% confidence interval [CI]: 0.29-0.72], OW-adjusted HR = 0.52 [95% CI: 0.35-0.77]). In contrast, in the ICI-chemo cohort, the OS of the upfront-radiotherapy group was not significantly different from that of the no-radiotherapy group (IPTW-adjusted HR = 1.02 [95% CI: 0.70-1.48], OW-adjusted HR = 0.93 [95% CI: 0.65-1.33])., Conclusions: Upfront radiotherapy for BMs was associated with longer overall survival in patients with NSCLC who received ICI alone; however, it did not exhibit survival benefits in the patients who received ICI-chemo., Competing Interests: Dr. Tozuka has received honoraria from Chugai Pharmaceutical and AstraZeneca. Dr. Minegishi has received honoraria from AstraZeneca, Boehringer Ingelheim Japan, Eli Lilly Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Eisai, Bristol-Myers Squibb, Daiichi-Sankyo, Nippon Kayaku, Takeda Pharmaceutical, and GlaxoSmithKline. Dr. Yamaguchi has received honoraria from Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., and Chugai Pharmaceutical Co. Ltd. Dr. Toi has received honoraria from Bristol-Myers Squibb Company, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme K.K., AstraZeneca Plc., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Pfizer Inc., and Kyowa Kirin Co., Ltd. Dr. Tamura has received honoraria from Merck Sharp & Dohme (Merck & Co., Inc.), Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., and Ono Pharmaceutical Co., Ltd. Dr. Sakai has received grants from Eli Lilly Japan K.K.; and has received honoraria from AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Chugai Pharmaceutical Co., Ltd., Pfizer Japan Inc., and ThermoFisher Scientific K.K. Dr. Watanabe has received funding from Bristol-Myers Squibb K.K. and 10.13039/501100013170Ono Pharmaceutical Co., Ltd.; has received grants from Boehringer Ingelheim and 10.13039/100018046Nippon Kayaku; and has received honoraria from Eli Lilly, Novartis Pharma, Chugai Pharma, Bristol-Myers, Ono Pharmaceutical, Daiichi-Sankyo, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Kirin, Merck, Takeda Pharmaceutical, Celltrion, and AstraZeneca. Dr. Morita has received honoraria from AstraZeneca K.K, Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Merck Sharp & Dohme K.K., Pfizer Japan Inc., and Taiho Pharmaceutical Co., Ltd. Dr. Kobayashi has received honoraria from AstraZeneca, Daiichi-Sankyo Pharmaceutical Co., and Takeda Pharmaceutical Co.; and is the Board Chairman in NPO North East Japan Study Group. Dr. Seike has received honoraria from AstraZeneca, Merck Sharp & Dohme K.K, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Pfizer, Novartis, Takeda Pharmaceutical, Kyowa Hakko Kirin, Nippon Kayaku, Daiichi-Sankyo Company, Merck Biopharma, and Amgen Inc.; and has received research funding from 10.13039/100009954Taiho Pharmaceutical, 10.13039/100010795Chugai Pharmaceutical, Eli Lilly, 10.13039/100017346Nippon Boehringer Ingelheim, Nippon Kayaku and 10.13039/501100004095Kyowa Hakko Kirin. The remaining authors declare no conflict of interest., (© 2024 by the International Association for the Study of Lung Cancer.)

Introduction: Kidney disease of unknown etiology accounts for 1 in 10 adult end-stage renal disease (ESRD) cases worldwide. The aim of this study is to clarify the genetic background of patients with chronic kidney disease (CKD) of unknown etiology who initiated renal replacement therapy (RRT) in adulthood., Methods: This is a multicenter cross-sectional cohort study. Of the 1164 patients who attended 4 dialysis clinics in Japan, we first selected patients who started RRT between the ages of 20 and 49 years. After excluding patients with apparent causes of CKD (e.g., diabetic nephropathy, polycystic kidney disease (PKD) with family history, patients who underwent renal biopsy), 90 patients with CKD of unknown cause were included. The 298 genes associated with CKD were analyzed using capture-based targeted next-generation sequencing., Results: Of the 90 patients, 10 (11.1%) had pathogenic variants in CKD-causing genes and 17 (18.9%) had variant of unknown significance (VUS). Three patients had PKD1 pathogenic variants, and 1 patient had PKD1 and COL4A4 pathogenic variants. In addition, 2 patients were diagnosed with atypical hemolytic uremic syndrome (aHUS) due to C3 or CFHR5 . One patient each was diagnosed with Alport syndrome due to COL4A4 and COL4A3 variants , nephronophthisis due to NPHP1 variants, Fabry disease due to GLA variants, and autosomal-dominant tubulointerstitial kidney disease due to UMOD variants. Genetic diagnoses were not concordant with clinical diagnoses, except for patients with PKD1 variant., Conclusion: This largest study on genetic analysis in hemodialysis-dependent adults revealed the presence of undiagnosed inherited kidney diseases., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Background: To compare the potential of various bone evaluations by considering photon-counting CT (PCCT) and multiple energy-integrating-detector CT (EIDCT), including three dual-energy CT (DECT) scanners with standardized various parameters in both standard resolution (STD) and ultra-high-resolution (UHR) modes., Methods: Four cadaveric forearms were scanned using PCCT and five EIDCTs, by applying STD and UHR modes. Visibility of bone architecture, image quality, and a non-displaced fracture were subjectively scored against a reference EIDCT image by using a five-point scale. Image noise, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were also compared. To assess metal artifacts, a forearm with radial plate fixation was scanned by with and without Tin filter (Sn+ and Sn-), and virtual monoenergetic image (VMI) at 120 keV was created. Regarding Sn+ and VMI, images were only obtained from the technically available scanners. Subjective scores and the areas of streak artifacts were compared., Results: PCCT demonstrated significantly lower noise ( p < 0.001) and higher bone SNR and CNR ( p < 0.001) than all EIDCTs in both resolution modes. However, there was no significant difference between PCCT and EIDCTs in almost all subjective scores, regardless of scan modes, except for image quality where a significant difference was observed, compared to several EIDCTs. Metal artifact analysis revealed PCCT had larger artifact in Sn- and Sn+ ( p < 0.001), but fewer in VMIs than three DECTs ( p < 0.001 or 0.001)., Conclusions: Under standardized conditions, while PCCT had almost no subjective superiority in visualizing bone structures and fracture line when compared to EIDCTs, it outperformed in quantitative analysis related to image quality, especially in lower noise and higher tissue contrast. When using PCCT to assess cases with metal implants, it may be recommended to use VMIs to minimize the possible tendency for artifact to be pronounced.

Background: Latent chronic inflammation has been proposed as a key mediator of multiple derangements in metabolic syndrome (MetS), which are increasingly becoming recognized as risk factors for age-related cognitive decline. However, the question remains whether latent chronic inflammation indeed induces brain inflammation and cognitive decline., Methods: A mouse model of latent chronic inflammation was constructed by a chronic subcutaneous infusion of low dose lipopolysaccharide (LPS) for four weeks. A receptor for advanced glycation end products (RAGE) knockout mouse, a chimeric myeloid cell specific RAGE-deficient mouse established by bone marrow transplantation and a human endogenous secretory RAGE (esRAGE) overexpressing adenovirus system were utilized to examine the role of RAGE in vivo. The cognitive function was examined by a Y-maze test, and the expression level of genes was determined by quantitative RT-PCR, western blot, immunohistochemical staining, or ELISA assays., Results: Latent chronic inflammation induced MetS features in C57BL/6J mice, which were associated with cognitive decline and brain inflammation characterized by microgliosis, monocyte infiltration and endothelial inflammation, without significant changes in circulating cytokines including TNF-α and IL-1β. These changes as well as cognitive impairment were rescued in RAGE knockout mice or chimeric mice lacking RAGE in bone marrow cells. P-selectin glycoprotein ligand-1 (PSGL-1), a critical adhesion molecule, was induced in circulating mononuclear cells in latent chronic inflammation in wild-type but not RAGE knockout mice. These inflammatory changes and cognitive decline induced in the wild-type mice were ameliorated by an adenoviral increase in circulating esRAGE. Meanwhile, chimeric RAGE knockout mice possessing RAGE in myeloid cells were still resistant to cognitive decline and brain inflammation., Conclusions: These findings indicate that RAGE in inflammatory cells is necessary to mediate stimuli of latent chronic inflammation that cause brain inflammation and cognitive decline, potentially by orchestrating monocyte activation via regulation of PSGL-1 expression. Our results also suggest esRAGE-mediated inflammatory regulation as a potential therapeutic option for cognitive dysfunction in MetS with latent chronic inflammation., 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.)

[Purpose] This study aimed to determine the relationship between acceleration parameters in the sit-to-stand (STS) movement and falls, and the strength of the association between acceleration in STS movements and falls in older adults. [Participants and Methods] In total, 330 older adults were included. Four acceleration parameters were measured in STS movement: maximum acceleration (MA), velocity (MV), power (MP), and stand-up time (ST). For the conventional STS tests, 5 times STS test (5xSTS) and ground reaction force (maximal rate of force development per body weight: RFD/w, peak reaction force per body weight: F/w, chair-rise time: T) were measured. Poisson regression analysis adjusted for confounding factors was used. [Results] In the model adjusted for confounders, significant associations were observed among MV (Prevalence ratio (PR): 0.75; 95% confidence interval (CI): 0.58-0.98), MP (PR: 0.67; 95% Cl: 0.68-0.93), RFD/w (PR: 0.70; 95% Cl: 0.56-0.87), and T (PR: 1.14; 95% Cl: 1.05-1.24). [Conclusion] Among the acceleration parameters, MP was most strongly associated with falls and was considered the most useful parameter for evaluation. In addition, comparisons with the conventional chair rise tests suggested that MP was stronger than the 5xSTS test and may be equally related to the RFD/w., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (2024©by the Society of Physical Therapy Science. Published by IPEC Inc.)

Serine metabolism is involved in various biological processes. Here we investigate primary functions of the phosphorylated pathway of serine biosynthesis in a non-vascular plant Marchantia polymorpha by analyzing knockout mutants of MpPGDH encoding 3-phosphoglycerate dehydrogenase in this pathway. Growth phenotypes indicate that serine from the phosphorylated pathway in the dark is crucial for thallus growth. Sperm development requires serine from the phosphorylated pathway, while egg formation does not. Functional MpPGDH in the maternal genome is necessary for embryo and sporophyte development. Under high CO 2 where the glycolate pathway of serine biosynthesis is inhibited, suppressed thallus growth of the mutants is not fully recovered by exogenously-supplemented serine, suggesting the importance of serine homeostasis involving the phosphorylated and glycolate pathways. Metabolomic phenotypes indicate that the phosphorylated pathway mainly influences the tricarboxylic acid cycle, the amino acid and nucleotide metabolism, and lipid metabolism. These results indicate the importance of the phosphorylated pathway of serine biosynthesis in the dark, in the development of sperm, embryo, and sporophyte, and metabolism in M. polymorpha., (© 2024. The Author(s).)

We developed a simultaneous determination method for the environmentally persistent organochlorine pesticides aldrin/dieldrin, γ-BHC, DDT, endrin, and heptachlor in beef products. In the method, we adopted incremental reduction for sample collection in order to improve the uniformity of the samples. In incremental reduction, a sample was ground and spread to an even thickness, divided into sections, and collected in an equal amount from each section. After extraction with an acetonitrile/ethanol mixture (1 : 1 v/v), sample clean-up was performed by refrigerated centrifu-gation and solid-phase extraction. This process was easy and did not require gel permeation chromatography. The sample was analyzed by GC-MS. A validation study of the development method showed that the tested pesticides met the target values indicated in the validity evaluation guideline.