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Objectives: This study aimed to describe the treatment selection for systemic lupus erythematosus (SLE) using data from the Kyushu Collagen Disease Network for SLE (KCDN-SLE) registry, a multicenter prospective registry in Japan., Methods: This study used data from patients registered between August 2022 and November 2023. Clinical characteristics, purpose of agent initiation, other candidate agents, and short-term efficacy and safety were evaluated., Results: We analyzed 69 previously treated patients with SLE (mean age 43.7 years; 62 females, 7 males). Hydroxychloroquine, biological agents, and immunosuppressive agents were initiated during the maintenance phase in 12, 41, and 16 patients, respectively. In patients with active organ involvement, hydroxychloroquine and biological agents were widely used for initiation. In those who already achieved treatment goals, biological agents alone were predominantly selected. The SLE Disease Activity Index 2000 score and prednisolone dose declined significantly over a 6-month follow-up period. Among 48 patients with active disease, 22 achieved a lupus low disease activity state, but this had no evident association with the initiation of a biological agent. In total, 14 adverse events, predominantly infections, were observed., Conclusions: Biological agents were used preferentially, and the therapeutic agents were appropriately effective and mostly achieved the purpose of agent initiation., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Evidence-based medicine (EBM) is helpful for laypersons' decision-making. This study aimed to evaluate the effectiveness of e-learning materials on the essential components of EBM for laypersons. We conducted a web-based, open-label, randomized controlled trial with laypersons in Japan aged ≥20 years who used the internet. Participants were randomly assigned to the intervention group with the e-learning material and the control group with only the 'Introduction' section of the same material. The primary and secondary outcomes were the self-created acquirement test scores (responding correctly with confidence) immediately after using the material and after 4 weeks. A multiple linear regression analysis was conducted. Of the 122 participants, 62 were randomly assigned to the intervention group and 59 to the control group; finally, 59 and 58, respectively, were included in the full analysis set. The mean (standard deviation) of the acquirement test score immediately after learning was 14.11 and (3.11) and 11.07 (3.88) in the intervention and control groups, respectively, indicating statistical significance (multivariable P < 0.001). The secondary long-term outcome was also statistically significant. The results showed that the e-learning material was effective for laypersons in acquiring the essential components of EBM. The material may increase laypersons' confidence in appraising health information, which can be used in decision-making., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Context: Women with polycystic ovary syndrome (PCOS), which is the most common endocrine disorder in women of reproductive age, have a potentially increased risk of gestational diabetes mellitus (GDM)., Objective: To examine the impact of PCOS on GDM based on maternal body mass index (BMI) using data from a large birth cohort study in Japan., Design: Prospective observational study using data from the Japan Environment and Children's Study (JECS)., Participants: Singleton pregnancies in the JECS during 2011-2014 were included. Mothers with HbA1c levels of ≥6.5% in the first trimester and history of DM or steroid use during pregnancy were excluded., Main Outcome Measures: Participants were categorized according to their pre-pregnancy BMIs: G1 (<18.5 kg/m2), G2 (18.5-19.99 kg/m2), G3 (20.0-22.99 kg/m2), G4 (23.0-24.99 kg/m2), and G5 (≥25.0 kg/m2). The impact of PCOS on early (Ed) and late-onset (Ld) GDM for each group was estimated using a multiple logistic regression model., Results: We included 92774 participants, comprising 2012 PCOS(+) cases. GDM occurrence was higher in women with PCOS (p<0.001). PCOS had no effect on GDM in G1, G2, and G3. In G4, PCOS increased the risk of Ed GDM (adjusted odds ratio [aOR]: 3.27, 95% confidence interval [CI]: 1.29-8.29). In G5, PCOS increased the risk of both Ed (aOR: 2.48, 95% CI: 1.53-4.02) and Ld GDM (aOR: 1.94, 95% CI: 1.23-3.07)., Conclusions: The impact of PCOS on GDM occurrence depended on the pre-pregnancy BMIs, which may facilitate personalized preconception counseling among women with PCOS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Based on the efficacy of intravenous immunoglobulin (IVIg) for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), we developed a recombinant single-chain-fragment variable clone, VasSF, therapeutic against AAV in a mouse model (SCG/Kj mice). VasSF is thought to bind to vasculitis-associated apolipoprotein A-II (APOA2) as a target molecule. VasSF is a promising new drug against AAV, but difficulties in the yield and purification of VasSF remain unresolved. We produced monomers of new VasSF molecules by modifying the plasmid structure for VasSF expression and simplifying the purification method using high-performance liquid chromatography. We compared the therapeutic effects between 5-day continuous administration of the monomers, as in IVIg treatment, and single shots of 5-day-equivalent doses. We also evaluated the life-prolonging effect of the single-shot treatment. Two-dimensional western blots were used to examine the binding of VasSF to APOA2. Our improved manufacturing method resulted in a 100-fold higher yield of VasSF than in our previous study. Monomerization of VasSF stabilized its efficacy. Single shots of a small amount (1/80 000 of IVIg) produced sufficient therapeutic effects, including decreased glomerular crescent formation, a decreasing trend of serum ANCA against myeloperoxidase (MPO-ANCA), decreases in multiple proinflammatory cytokines, and a trend toward prolonged survival. Two-dimensional western blots confirmed the binding of VasSF to APOA2. The newly produced pure VasSF monomers are stable and therapeutic for AAV with a single low-dose injection, possibly by removing vasculitis-associated APOA2. Thus, the new VasSF described herein is a promising drug against AAV., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Immune thrombocytopenia (ITP) is a common complication of systemic lupus erythematosus (SLE). Glucocorticoids (GCs) and hydroxychloroquine are first-line therapy for SLE-associated ITP (SLE-ITP). SLE-ITP in most of patients is less severe and well controlled with GCs, but some of the patients are GC resistant and require additional immunosuppressants including calcineurin inhibitors, azathioprine, and rituximab. We present two cases of SLE-ITP patients treated with belimumab who were resistant to GCs and achieved remission. For severe SLE-ITP, belimumab has emerged as a novel induction therapeutic option., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The extended tubular shape of root hairs is established by tip growth and concomitant hardening. Here, we demonstrate that a syntaxin of plants (SYP)123-vesicle-associated membrane protein (VAMP)727-dependent secretion system delivers secondary cell wall components for hardening the subapical zone and shank of Arabidopsis (Arabidopsis thaliana) root hairs. We found increased SYP123 localization at the plasma membrane (PM) of the subapical and shank zones compared with the tip region in elongating root hairs. Inhibition of phosphatidylinositol (PtdIns)(3,5)P2 production impaired SYP123 localization at the PM and SYP123-mediated root hair shank hardening. Moreover, root hair elongation in the syp123 mutant was insensitive to a PtdIns(3,5)P2 synthesis inhibitor. SYP123 interacts with both VAMP721 and VAMP727. syp123 and vamp727 mutants exhibited reduced shank cell wall stiffness due to impaired secondary cell wall component deposition. Based on these results, we conclude that SYP123 is involved in VAMP721-mediated conventional secretion for root hair elongation as well as in VAMP727-mediated secretory functions for the delivery of secondary cell wall components to maintain root hair tubular morphology., Competing Interests: Conflict of interest statement. The authors declare that they have no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

The sesaminol triglucoside (STG)-hydrolyzing β-glucosidase from Paenibacillus sp. (PSTG1), which belongs to glycoside hydrolase family 3 (GH3), is a promising catalyst for the industrial production of sesaminol. We determined the X-ray crystal structure of PSTG1 with bound glycerol molecule in the putative active site. PSTG1 monomer contained typical three domains of GH3 with the active site in domain 1 (TIM barrel). In addition, PSTG1 contained an additional domain (domain 4) at the C-terminus that interacts with the active site of the other protomer as a lid in the dimer unit. Interestingly, the interface of domain 4 and the active site forms a hydrophobic cavity probably for recognizing the hydrophobic aglycone moiety of substrate. The short flexible loop region of TIM barrel was found to be approaching the interface of domain 4 and the active site. We found that n-heptyl-β-D-thioglucopyranoside detergent acts as an inhibitor for PSTG1. Thus, we propose that the recognition of hydrophobic aglycone moiety is important for PSTG1-catalyzed reactions. Domain 4 might be a potential target for elucidating the aglycone recognition mechanism of PSTG1 as well as for engineering PSTG1 to create a further excellent enzyme to degrade STG more efficiently to produce sesaminol., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Although current long-read sequencing technologies have a long-read length that facilitates assembly for genome reconstruction, they have high sequence errors. While various assemblers with different perspectives have been developed, no systematic evaluation of assemblers with long reads for diploid genomes with varying heterozygosity has been performed. Here, we evaluated a series of processes, including the estimation of genome characteristics such as genome size and heterozygosity, de novo assembly, polishing, and removal of allelic contigs, using six genomes with various heterozygosity levels. We evaluated five long-read-only assemblers (Canu, Flye, miniasm, NextDenovo and Redbean) and five hybrid assemblers that combine short and long reads (HASLR, MaSuRCA, Platanus-allee, SPAdes and WENGAN) and proposed a concrete guideline for the construction of haplotype representation according to the degree of heterozygosity, followed by polishing and purging haplotigs, using stable and high-performance assemblers: Redbean, Flye and MaSuRCA., (© The Author(s) 2023. Published by Oxford University Press.)

The detection sensitivity of immunostick colorimetric assay has been increased by using a bio-nanocapsule as a scaffold for oriented immobilization of immunoglobulin Gs. This immunostick produced ∼82-folds stronger coloration in the detection of food allergens and reduced detection time by a factor of 5., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Hereditary angio-oedema (HAE) is a rare genetic disease characterised by repeated episodes of temporary organ swelling. Three types of HAE are known, of which HAE with normal C1 inactivator is difficult to be diagnosed due to its lack of laboratory abnormalities. Here, we describe a case of HAE with normal C1 inactivator and recurrent acute abdomen following low-dose oestrogen-progestin therapy. Notably, genetic analysis by Sanger sequencing led to the identification of a recurrent heterozygous missense mutation c.988A > G (p.K330E) in the plasminogen (PLG) gene of the patient. Prophylactic tranexamic acid and on-demand selective bradykinin B2 receptor blockers are used to treat her symptoms., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aurones constitute one of the major classes of flavonoids, with a characteristic furanone structure that acts as the C-ring of flavonoids. Members of various enzyme families are involved in aurone biosynthesis in different higher plants, suggesting that during evolution plants acquired the ability to biosynthesize aurones independently and convergently. Bryophytes also produce aurones, but the biosynthetic pathways and enzymes involved have not been determined. The present study describes the identification and characterization of a polyphenol oxidase (PPO) that acts as an aureusidin synthase (MpAS1) in the model liverwort, Marchantia polymorpha. Crude enzyme assays using an M. polymorpha line overexpressing MpMYB14 with high accumulation of aureusidin showed that aureusidin was biosynthesized from naringenin chalcone and converted to riccionidin A. This activity was inhibited by N-phenylthiourea, an inhibitor specific to enzymes of the PPO family. Of the six PPOs highly induced in the line overexpressing MpMyb14, one, MpAS1, was found to biosynthesize aureusidin from naringenin chalcone when expressed in Saccharomyces cerevisiae. MpAS1 also recognized eriodictyol chalcone, isoliquiritigenin and butein, showing the highest activity for eriodictyol chalcone. Members of the PPO family in M. polymorpha evolved independently from PPOs in higher plants, indicating that aureusidin synthases evolved in parallel in land plants., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: the role of benzodiazepines in relieving dyspnea in patients with cancer has not yet been established. This systematic review and meta-analysis aimed to determine the efficacy and safety of benzodiazepines alone or in combination with opioids for dyspnea in patients with cancer., Methods: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and Ichushi-Web were searched for articles published from database inception to 23 September 2019. Studies of benzodiazepines alone or in combination with opioids for dyspnea were included. The primary outcome measure was the relief of dyspnea. The secondary outcome measures were anxiety, somnolence and severe adverse events., Results: of 505 publications initially identified, two trials and one trial were included in the meta-analysis of midazolam alone and in combination with morphine, respectively. With regard to the relief of dyspnea, midazolam alone showed no significant difference compared with morphine alone, with a relative risk of 0.95 (95% confidence interval: 0.47-1.89). Meanwhile, midazolam plus morphine was significantly more effective than morphine alone, with a relative risk of 1.33 (95% confidence interval: 1.02-1.75). For anxiety relief, a meta-analysis could not be performed because of insufficient data. The incidence of somnolence and severe adverse events was not significantly different between the experimental and control groups for either midazolam alone or in combination with morphine., Conclusions: benzodiazepines alone do not significantly improve dyspnea compared with opioids alone, but a combination of benzodiazepines and opioids may be more effective. Evidence from randomized controlled trials focusing on patients with cancer has not been generated in recent years. Further appropriately designed randomized controlled trials are required., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Blue light causes retinal damage that can lead to ocular diseases such as age-related macular degeneration. In this study, we determined the protective effect of blueberry stem extract (BStEx) and active components on blue light-emitting diode (LED) light-induced retinal photoreceptor cell damage in vitro. Photoreceptor cells cultured in the presence of BStEx or components were exposed to blue light to induce cell damage. BStEx, fractions of BStEx containing proanthocyanidins, chlorogenic acid, catechin, and epicatechin prevented the cell damage and/or inhibited the generation of reactive oxygen species (ROS). Furthermore, BStEx reduced apoptosis and cell death, and inhibited the phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase leading to cellular apoptosis induced by blue light exposure. These findings suggest that BStEx and components exert a protective effect against blue light-induced photoreceptor cell damage through the inhibition of MAPK phosphorylation and ROS production., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background: Only old evidence exists to back up the use of medroxyprogesterone acetate. Therefore, this study aimed to explore the factors that influence the time to treatment failure of medroxyprogesterone acetate in real-world settings as late-line treatment., Methods: This was a cohort study that used the database of the Safari study on oestrogen receptor-positive post-menopausal advanced breast cancer (UMIN000015168). We created Kaplan-Meier curves for time to treatment failure with medroxyprogesterone acetate. Further, univariate and multivariate analyses were performed using a Cox hazard model of the clinicopathological factors involved in the time to treatment failure of medroxyprogesterone acetate., Results: From the 1031 patients in the Safari study, 279 patients were selected as the population for the analysis of effectiveness of medroxyprogesterone acetate monotherapy. In the analysis of medroxyprogesterone acetate by treatment line, the median time to treatment failure was 3.0 months for third-line treatment and 4.1 months for fourth and subsequent treatment lines. In cases where medroxyprogesterone acetate was used as a third-line or later endocrine treatment, multivariate analysis showed that the length of the disease-free interval was correlated with the length of time to treatment failure of medroxyprogesterone acetate (P = 0.004). With medroxyprogesterone acetate monotherapy as the fourth-line or later treatment, 20% of the patients achieved a time to treatment failure of 12 months or longer., Conclusion: In actual clinical practice, patients treated with medroxyprogesterone acetate alone as the fourth or subsequent treatment lines showed a time to treatment failure of 4 months, suggesting that there is merit in using medroxyprogesterone acetate even in late treatment lines, especially in patients with long disease-free interval and those who are difficult to treat using other antineoplastic agents., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The aim of this study was to update the Japan College of Rheumatology (JCR) clinical practice guidelines (CPG) for the management of rheumatoid arthritis (RA; JCR CPG for RA) according to recent changes in the medical environment in Japan. This article is a digest version of the guidance., Methods: We used the Grading of Recommendations, Assessment, Development, and Evaluation method to update the 2014 JCR CPG for RA. A consensus was formed by CPG panel members., Results: We identified 36 important clinical questions regarding drug treatment and developed corresponding recommendations for RA. The recommendations included the following RA medications: non-steroidal anti-inflammatory drugs, corticosteroids, conventional synthetic disease-modifying antirheumatic drugs, biological disease-modifying antirheumatic drugs, anti-receptor activator for nuclear factor-κB ligand antibodies, and Janus kinase inhibitors, as well as the tapering and discontinuation of these medications. Recommendations regarding the efficacy and safety of treatments in the elderly and patients with comorbidities were also developed. Finally, we used these recommendations to create an original algorithm for drug treatment for RA based on the Treat-to-Target approach., Conclusion: The 2020 JCR CPG for RA provides a useful tool for rheumatologists, health care professionals, and patients with RA, enabling shared decision-making in a variety of clinical situations., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Objectives: The aim of this study was to update the Japan College of Rheumatology (JCR) clinical practice guidelines (CPGs) for the management of rheumatoid arthritis (RA) and prepare an algorithm for non-drug and surgical treatments. This article is a digest version of the guidelines., Methods: The Japanese Ministry of Health, Labour and Welfare's research group, in collaboration with the JCR, used the Grading of Recommendations, Assessment, Development, and Evaluation method to update the 2014 JCR CPG for RA. The consensus was formed by CPG panel members., Results: We raised 19 clinical questions regarding non-drug and surgical treatments for RA and developed recommendations. The treatments included exercise therapy; occupational therapy; joint injection of corticosteroids; and orthopaedic surgeries including cervical spine surgery, wrist and foot arthroplasty, ankle arthrodesis, and replacement arthroplasty of the shoulder, elbow, finger, hip, knee, and ankle. Recommendations regarding the risks of surgery and perioperative discontinuation of medications have also been developed. Based on these recommendations, we created an original algorithm for the non-drug and surgical treatment of RA., Conclusions: These recommendations are expected to serve rheumatologists, health care professionals, and patients with RA as tools for shared decision-making to treat residual limb joint symptoms and functional impairment., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

The tarsal plate is an eyelid tissue that maintains lid structure from inside the upper/lower eyelids, and it surrounds the meibomian glands and supports their unique secretion mechanism. Sebaceous carcinoma, a malignant eyelid tumour, can sometimes develop from the meibomian glands and is usually excised together with the tarsal plate during surgery, so the tarsal plate serves as a control research tissue. However, since the plate is thick, hard and heterogeneous with few cells, obtaining enough genomic DNA and/or total RNA is often difficult. Therefore, we attempted to establish an efficient protocol to obtain DNA and RNA simultaneously by comparing the combinations of homogenization (mortar/pestle, pellet pestle or SK mill) and purification (organic solvent or spin column) methods using rabbit tarsal plates. Based on the yield, quality and hands-on time, the SK mill and spin column was found to be the most efficient combination. We then applied the established protocol to extract DNA/RNA from six human tarsal-plate samples and succeeded in generating high-quality exome and transcriptome datasets via a next-generation sequencer with sufficient coverage and meibomian gland-specific expression of representative genes, respectively. Our new findings will provide ideal reference data for future genetic and gene-expression studies of sebaceous carcinoma., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Black tea extracts (BTEs) from four different production areas showed a higher aggregation strength for phosphatidylcholine-based liposomes containing cholesterol used as a viral membrane model. Furthermore, the anti-influenza A virus (IAV) activity of each BTE in vitro demonstrated that although Sri Lanka, Kenya, and Assam had higher anti-IAV activities, Darjeeling had a lower anti-IAV activity, showing a correlation between each BTE and the liposome aggregation strength. Moreover, the antiviral activity strength of BTEs was consistent with the antioxidant activity strength of BTEs, suggesting that the component(s) in black tea that exhibits antioxidant activity would also be the component(s) that accounts for its antiviral activity. Thus, our results propose that BTEs exert their antiviral effects by binding not only hemagglutinin and neuraminidase but also viral membranes directly, especially "cholesterol-rich lipid rafts" and affect the membrane structure, causing the virus to aggregate, thereby inhibiting infection of the host cells., (© The Author(s) 2022. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Objective: To develop and validate deep convolutional neural network (DCNN) models for the diagnosis of adrenal adenoma (AA) using CT., Methods: This retrospective study enrolled 112 patients who underwent abdominal CT (non-contrast, early, and delayed phases) with 107 adrenal lesions (83 AAs and 24 non-AAs) confirmed pathologically and with 8 lesions confirmed by follow-up as metastatic carcinomas. Three patients had adrenal lesions on both sides. We constructed six DCNN models from six types of input images for comparison: non-contrast images only (Model A), delayed phase images only (Model B), three phasic images merged into a 3-channel (Model C), relative washout rate (RWR) image maps only (Model D), non-contrast and RWR maps merged into a 2-channel (Model E), and delayed phase and RWR maps merged into a 2-channel (Model F). These input images were prepared manually with cropping and registration of CT images. Each DCNN model with six convolutional layers was trained with data augmentation and hyperparameter tuning. The optimal threshold values for binary classification were determined from the receiver-operating characteristic curve analyses. We adopted the nested cross-validation method, in which the outer fivefold cross-validation was used to assess the diagnostic performance of the models and the inner fivefold cross-validation was used to tune hyperparameters of the models., Results: The areas under the curve with 95% confidence intervals of Models A-F were 0.94 [0.90, 0.98], 0.80 [0.69, 0.89], 0.97 [0.94, 1.00], 0.92 [0.85, 0.97], 0.99 [0.97, 1.00] and 0.94 [0.86, 0.99], respectively. Model E showed high area under the curve greater than 0.95., Conclusion: DCNN models may be a useful tool for the diagnosis of AA using CT., Advances in Knowledge: The current study demonstrates a deep learning-based approach could differentiate adrenal adenoma from non-adenoma using multiphasic CT.

The assembly of misfolded proteins into amyloid fibrils is associated with amyloidosis, including neurodegenerative diseases such as Alzheimer's, Parkinson's and prion diseases. The self-propagation of amyloid fibrils is widely observed in the aggregation pathways of numerous amyloidogenic proteins. This propensity with plasticity in primary nucleation allows amyloid fibril polymorphism, which is correlated with the pathology/phenotypes of patients. Because the interference with the nucleation and replication processes of amyloid fibrils can alter the amyloid structure and the outcome of the disease, these processes can be a target for developing clinical drugs. Single-molecule observations of amyloid fibril replication can be an experimental system to provide the kinetic parameters for simulation studies and confirm the effect of clinical drugs. Here, we review the single-molecule observation of the amyloid fibril replication process using fluorescence microscopy and time-lapse atomic force microscopy, including high-speed atomic force microscopy. We discussed the amyloid fibril replication process and combined single-molecule observation results with molecular dynamics simulations., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The Safari study (UMIN000015168) was a retrospective, multicenter study in which 1072 consecutive cases of estrogen receptor-positive advanced breast cancer treated using 500 mg fulvestrant were registered. We previously reported the relationship between the patient factors and overall survival after the diagnosis using the same cases and the same factors for the analysis of time to treatment failure in patients with estrogen receptor-positive advanced breast cancer. The current study is an ad hoc analysis that focused on the relationship between the patient factors and overall survival after recurrence by adding factors generally associated with overall survival after recurrence., Methods: The overall survival after recurrence in patients with estrogen receptor-positive human epidermal growth factor receptor 2 negative recurrent breast cancer was analyzed via univariate and multivariate analyses with a Cox proportional hazards model., Results: A total of 598 cases were used for the analysis of overall survival after recurrence. Multivariate analysis revealed that favorable overall survival (median, 6.4 years) was significantly correlated with long time from recurrence to fulvestrant use (≥3 years), low nuclear or histological grade (G3 vs. G1), long time to treatment failure of initial palliative endocrine therapy (≥12 months) and long time to initial palliative chemotherapy (≥2 years)., Conclusion: The results of this study indicate that sequential endocrine monotherapy may be a useful treatment option for patients with estrogen receptor-positive/human epidermal growth factor receptor 2 negative recurrent breast cancer who have been successfully treated with initial long-term palliative endocrine therapy., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Aurones are a group of flavonoids that confer a bright yellow coloration to certain ornamental flowers and are a promising structural target for the development of new therapeutic drugs. Since the first identification of the snapdragon aurone synthase as a polyphenol oxidase (PPO) in 2000, several important advances in the biochemistry and regulation of aurone biosynthesis have been achieved. For example, several other aurone synthases have been identified in distantly related plants, which not only include PPOs but also peroxidases. Elucidation of the subcellular localization of aurone biosynthesis in snapdragon led to the establishment of a method to genetically engineer novel yellow flowers. The crystal structure of an aurone-producing PPO was clarified and provided important insights into the structure-function relationship of aurone-producing PPOs. A locus (SULFUREA) that negatively regulates aurone biosynthesis in snapdragon was identified, illustrating the evolution of flower color pattern through selection on regulatory small RNAs., (© The Author(s) 2022. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background: Screening is one of the effective interventions for the reduction of colorectal cancer mortality. Though the Japanese government recommends faecal occult blood test and colonoscopy as a follow-up examination following a diagnosis, both participation rates have not been so high and the national mortality rate has not shown a clear decreasing trend., Methods: Microsimulation models simulate the life histories of a large population of individuals under various scenarios. In this study, we applied a microsimulation model to estimate the reduction of colorectal cancer mortality based on screening scenarios., Results: The effect of reducing the age-standardized mortality rate for colorectal cancer was estimated at 9.4% for men and 6.0% for women under the scenario which calls for 50% participation in faecal occult blood test and 90% participation of follow-up examination. This scenario corresponds to the goal setting for screening in the third-term of the Basic Plan to Promote Cancer Control Programs in Japan., Conclusions: Our microsimulation model was found to be useful in estimating the mortality reduction effect of cancer control policy. Such modelling techniques can be utilized to develop effective and optimal cancer control programs., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To provide an evidence base for clinical practice guidelines (CPG) for the management of rheumatoid arthritis (RA) in older adults., Methods: PubMed, Cochrane library, and Japan Centra Revuo Medicina databases were searched for articles published between 1990 and 2019. Quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation system, with some modifications., Results: Among 702 identified articles, there were 5 post-hoc analyses of randomized controlled trials and 10 observational studies. Meta-analysis of the former yielded a mean difference of the van der Heijde-modified total Sharp score of -2.79 (95% confidence interval [CI] - 3.74 to -1.84) for treatment with tumor necrosis factor inhibitors. The risk ratio (RR) for the American College of Rheumatology 50% response rate, and for serious adverse events was 2.83 (95%CI 1.90-4.21) and 1.32 (95%CI 0.53-3.31), respectively, for Janus kinase inhibitors. Meta-analysis of the observational studies yielded an RR for disease activity score-28 remission and serious infections of 0.76 (95%CI 0.64-0.91) and 1.92 (95%CI 1.31-2.81) for older-versus-younger patients receiving biological disease-modifying antirheumatic drugs, respectively., Conclusion: This systematic review provides the necessary evidence for developing CPG for the management of RA in older adults., (© 2021 Japan College of Rheumatology.)

Objectives: To examine the risk factors of surgical site infection (SSI), delayed wound healing, and death after orthopedic surgery in patients with rheumatoid arthritis (RA)., Methods: We identified articles indexed in the Cochrane Library, PubMed, and Japan Centra Revuo Medicina Web published from 2013 to 2019 and other articles. Articles fulfilling the predefined inclusion criteria were reviewed systematically and their quality was appraised according to the Grading of Recommendations Assessment, Development, and Evaluation system with some modifications., Results: After inclusion and exclusion by full-text review, 29 articles were analyzed. Use of biological disease modifying antirheumatic drugs was a risk factor of SSI (risk ratio 1.66, 95% confidence interval 1.25-2.19), but not of delayed wound healing. RA itself was a risk factor of SSI, and oral glucocorticoid use was a risk factor of SSI in three of the four studies analyzed and of postoperative death. Age, male sex, comorbidities such as diabetes mellitus and chronic obstructive pulmonary disease, surgical factors such as foot/ankle and spine surgery and longer operative time were risk factors of those postoperative complications., Conclusion: Patients with those factors should be dealt with appropriate cautions to strike a risk-benefit balance of orthopedic surgeries., (© 2021 Japan College of Rheumatology.)

Objectives: This study aimed to evaluate patients' opinions regarding their rheumatoid arthritis (RA) therapy and to reflect the patients' perspectives in the 2020 update of the Japan College of Rheumatology clinical practice guidelines., Methods: A self-administered questionnaire was mailed to 1600 members of the Japan Rheumatology Friendship Association, who were randomly selected by age and prefecture., Results: A total of 1156 patients returned the questionnaire (response rate, 72.3%; mean age, 63.0 ± 11.9 years). Those who reported having discussed their treatment goals with their doctors (450 respondents, 38.9%) were more likely to be satisfied with their current medical care (odds ratio, 7.13; 95% CI 4.72-10.8) compared with those who had not discussed their goals nor had them explained (287 respondents, 24.8%). The benefits exceeded the adverse effects for all pharmacotherapy (methotrexate, corticosteroids, conventional synthetic antirheumatic drugs, biological agents, Janus kinase inhibitor, and anti-RANKL antibodies). However, while 74.2% of the respondents using biological agents perceived that 'the favorable aspects outweighed the unfavorable aspects,' most of those taking anti-RANKL antibodies (69.2%) felt uncertain., Conclusions: The questionnaire successfully collected information regarding patients' perceptions regarding their therapy. Further implementation of treat-to-target is necessary in Japan to improve patient satisfaction., (© 2021 Japan College of Rheumatology.)

Objectives: To evaluate the efficacy and safety of biosimilars compared with reference biological disease modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) as a part of the process of developing the 2020 update of the Japan College of Rheumatology guidelines for the management of RA., Methods: PubMed, Cochrane Library, and Japan Centra Revuo Medicina were searched for articles to conduct a systematic review (SR). The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system., Results: Twenty randomized controlled trials were included (biosimilars of infliximab, etanercept, and adalimumab). A meta-analysis revealed that the risk ratios (RRs) and 95% confidence intervals (CIs) of achieving the American College of Rheumatology 50% response (ACR50) at week 24 and serious adverse events (SAEs) for biosimilars compared with the reference bDMARDs were 1.04 (0.98-1.10) and 0.84 (0.61-1.18), respectively. The RRs of achieving ACR50 and SAEs at week 24 were respectively 0.93 (0.69-1.26) and 2.15 (0.55-8.35) in the patients who switched to biosimilars from the reference bDMARDs and 0.92 (0.76-1.12) and 1.41 (0.32-6.15) in those who continued the reference bDMARDs., Conclusion: Biosimilars and reference bDMARDs were equally useful for the management of RA., (© 2021 Japan College of Rheumatology.)

Objectives: This study aimed to evaluate the impact of exercise therapy on patient-reported outcomes (PROs) in rheumatoid arthritis (RA) as part of the process of updating the 2020 Japanese guidelines for the management of RA according to the Grading of Recommendations, Assessment, Development, and Evaluation system., Methods: We searched PubMed, Japana Centra Revuo Medicina Web, and the Cochrane Library (from 2009 to 2018) to identify articles that evaluated PROs of exercise therapy and RA disease activity., Results: A total of 662 articles were identified, including nine RCTs, and meta-analyses were performed on six RCTs on systemic exercise therapy and three RCTs on upper extremity exercise therapy. Analyzed exercise therapies were diverse, differing in target population, intervention method, and duration. Significant improvements were observed in the Health Assessment Questionnaire Disability Index (mean difference -0.35, 95% confidence interval (CI): -0.60 to -0.10), pain (standardized mean difference -2.04, 95% CI: -3.77 to -0.32), and SF-36. For upper extremity exercise therapy, significant improvements in PROs (Disabilities of the Arm, Shoulder, and Hand Questionnaire, Michigan Hand Outcome Questionnaire) were observed., Conclusion: Exercise therapy in RA treatment improves patient subjective assessment of pain, physical function, and quality of life., (© 2021 Japan College of Rheumatology.)

Objective: This study aimed to evaluate satisfaction with total joint replacement (TJR) surgery among patients with rheumatoid arthritis (RA)., Methods: We mailed questionnaires to randomly selected members of the Japan Rheumatism Friendship Association, stratified by age and prefecture, throughout Japan. The questionnaire collected demographic and clinical characteristics as well as patients' satisfaction with TJR and their current therapy., Results: Of the 1156 patients who returned the questionnaire, 339 (29.3%) responded that they had had TJR of any type. The mean age was 66.6 years, and 94.4% were women. The mean time period from the hip and knee TJR was 14-15 years. Over half of the patients who had had TJR were satisfied with the results, especially those who had had hip (89.6%) and knee TJR (87.3%), who reported a high level of satisfaction. Multivariable linear regression analysis revealed that, in patients with knee TJR, satisfaction with current therapy was significantly related to whether they were satisfied with the results of the surgery., Conclusion: Most patients with RA who had undergone TJR were satisfied with the results even after a long period of time, and their level of satisfaction was associated with their satisfaction with current therapy., (© 2021 Japan College of Rheumatology.)

Context: Maternal cholesterol is important for fetal development. Whether maternal serum total cholesterol (maternal TC) levels in midpregnancy are associated with small (SGA) or large (LGA) for gestational age independent of prepregnancy body mass index (BMI) and weight gain during pregnancy is inconclusive., Objective: This work aimed to prospectively investigate the association between maternal TC in midpregnancy and SGA or LGA., Methods: The Japan Environment and Children's Study is a nationwide prospective birth cohort study in Japan. Participants in this study included 37 449 nondiabetic, nonhypertensive mothers with singleton birth at term without congenital abnormalities. Birth weight for gestational age less than the 10th percentile and greater than or equal to the 90th percentile were respectively defined as SGA and LGA by the Japanese neonatal anthropometric charts., Results: The mean gestational age at blood sampling was 22.7 ± 4.0 weeks. After adjustment for maternal age, sex of child, parity, weight gain during pregnancy, prepregnancy BMI, smoking, alcohol drinking, blood glucose levels, household income, and study areas, 1-SD decrement of maternal TC was linearly associated with SGA (odds ratio [OR]: 1.20; 95% CI, 1.15-1.25). In contrast, 1-SD increment of maternal TC was linearly associated with LGA (OR: 1.13; 95% CI, 1.09-1.16). Associations did not differ according to prepregnancy BMI and gestational weight gain (P for interaction > .20)., Conclusion: Maternal TC levels in midpregnancy were associated with SGA or LGA in a Japanese cohort. It may help to predict SGA and LGA. Favorable maternal lipid profiles for fetal development must be explored., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Carthamin, a dimeric quinochalcone that is sparingly soluble in water, is obtained from the yellow-orange corolla of fully blooming safflower (Carthamus tinctorius L.) florets. Carthamin is a natural red colorant, which has been used worldwide for more than 4500 years and is the major component of Japanese 'beni' used for dyeing textiles, in cosmetics and as a food colorant. The biosynthetic pathway of carthamin has long remained uncertain. Previously, carthamin was proposed to be derived from precarthamin (PC), a water-soluble quinochalcone, via a single enzymatic process. In this study, we identified the genes coding for the enzyme responsible for the formation of carthamin from PC, termed 'carthamin synthase' (CarS), using enzyme purification and transcriptome analysis. The CarS proteins were purified from the cream-colored corolla of safflower and identified as peroxidase homologs (CtPOD1, CtPOD2 and CtPOD3). The purified enzyme catalyzed the oxidative decarboxylation of PC to produce carthamin using O2, instead of H2O2, as an electron acceptor. In addition, CarS catalyzed the decomposition of carthamin. However, this enzymatic decomposition of carthamin could be circumvented by adsorption of the pigment to cellulose. These CtPOD isozymes were not only expressed in the corolla of the carthamin-producing orange safflower cultivars but were also abundantly expressed in tissues and organs that did not produce carthamin and PC. One CtPOD isozyme, CtPOD2, was localized in the extracellular space. Based on the results obtained, a model for the stable red pigmentation of safflower florets during flower senescence and the traditional 'beni' manufacturing process is proposed., (© The Author(s) 2021. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Chernobyl accident on 26 April 1986 led to a sharp increase in thyroid cancer (TC) incidence in the individuals exposed to radiation in childhood. The major risk factor for TC was exposure to Iodine-131 (131I). Here, we estimated the thyroid doses due to 131I intake for 2041 participants of the genome-wide association study of TC in Belarusian people exposed to radioactive fallout from the Chernobyl accident. The following parameter-values specially developed in this study were used to estimate individual thyroid doses: (i) scaling factors for adjustment of the model-based doses, (ii) age and gender diet to characterize 131I intake, and (iii) area-, age- and gender-specific S-values for the thyroid gland per 131I decay in the thyroid. The most reliable doses were calculated for 103 people with measured 131I thyroid activity (the arithmetic mean of 1.2 Gy, median 0.52 Gy), and 275 individuals with detailed residential history and dietary data (the arithmetic mean of 0.41 Gy, median 0.24 Gy). The arithmetic mean of thyroid doses among all study participants was 0.23 Gy (median 0.082 Gy); the highest individual dose was 9.0 Gy. Special attention was paid to the reliability and validity of the obtained estimates, in particular for the individuals without 131I thyroid activity measurements and individual data on residential history and diet, by comparing those with the doses from other post-Chernobyl epidemiological studies. Overall, the doses estimated in the current study were in reasonable agreement with previously reported thyroid doses. These doses will be used in the genome-wide association study of TC in people exposed in Belarus to 131I after the Chernobyl accident., (Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology 2021.)

In order to survive subzero temperatures, some plants undergo cold acclimation (CA) where low, nonfreezing temperatures, and/or shortened day lengths allow cold-hardening and survival during subsequent freeze events. Central to this response is the plasma membrane (PM), where low temperature is perceived and cellular homeostasis must be preserved by maintaining membrane integrity. Here, we present the first PM proteome of cold-acclimated Brachypodium distachyon, a model species for the study of monocot crops. A time-course experiment investigated CA-induced changes in the proteome following two-phase partitioning PM enrichment and label-free quantification by nano-liquid chromatography-mass spectrophotometry. Two days of CA were sufficient for membrane protection as well as an initial increase in sugar levels and coincided with a significant change in the abundance of 154 proteins. Prolonged CA resulted in further increases in soluble sugars and abundance changes in more than 680 proteins, suggesting both a necessary early response to low-temperature treatment, as well as a sustained CA response elicited over several days. A meta-analysis revealed that the identified PM proteins have known roles in low-temperature tolerance, metabolism, transport, and pathogen defense as well as drought, osmotic stress, and salt resistance suggesting crosstalk between stress responses, such that CA may prime plants for other abiotic and biotic stresses. The PM proteins identified here present keys to an understanding of cold tolerance in monocot crops and the hope of addressing economic losses associated with modern climate-mediated increases in frost events., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

Objectives: In patients with atherosclerotic disease, minimally invasive cardiac surgery using retrograde perfusion for cardiopulmonary bypass via femoral cannulation (FC) carries a higher risk of brain embolization compared with antegrade perfusion. However, guidelines for selecting antegrade versus retrograde perfusion do not exist. We developed a computed tomography (CT)-based perfusion strategy and assessed outcomes., Methods: We studied 270 minimally invasive cardiac surgery patients, aged 68 ± 13, 124 female, body surface area 1.6 ± 0.2 m2. Antegrade perfusion using axillary cannulation (AC) was selected if any of the following preoperative enhanced CT scan criteria were satisfied anywhere in the aorta or iliac arteries: thrombosis thickness >3 mm, thrombosis >one-third of the total circumference and calcification present in the total circumference. FC was selected otherwise. Asymptomatic brain injury was assessed by diffusion-weighted magnetic resonance imaging., Results: AC and FC were selected in 95 (35%) and 175 patients, respectively. AC patients were 10 years older (P < 0.001) and had higher EuroSCORE II (2.7 ± 3.4 vs 1.7 ± 1.9, P = 0.002). The median cardiopulmonary time and cross-clamp times were not significantly different. No patients died in hospital. There was no immediate stroke in either group during 48 h after surgery. Asymptomatic brain injury was detected in 25 (26%) and 27 (15%) AC and FC patients, respectively, P = 0.03., Conclusions: We believe our CT-based perfusion strategy using AC or FC minimized brain embolic rates. AC can be a good alternative to prevent brain embolization for minimally invasive cardiac surgery patients with advanced atherosclerotic disease., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: RCTs are considered the standard in surgical research, whereas case-matched studies and propensity score matching studies are conducted as an alternative option. Both study designs have been used to investigate the potential superiority of robotic surgery over laparoscopic surgery for rectal cancer. However, no conclusion has been reached regarding whether there are differences in findings according to study design. This study aimed to examine similarities and differences in findings relating to robotic surgery for rectal cancer by study design., Methods: A comprehensive literature search was conducted using PubMed, Scopus, and Cochrane CENTRAL to identify RCTs, case-matched studies, and cohort studies that compared robotic versus laparoscopic surgery for rectal cancer. Primary outcomes were incidence of postoperative overall complications, incidence of anastomotic leakage, and postoperative mortality. Meta-analyses were performed for each study design using a random-effects model., Results: Fifty-nine articles were identified and reviewed. No differences were observed in incidence of anastomotic leakage, mortality, rate of positive circumferential resection margins, conversion rate, and duration of operation by study design. With respect to the incidence of postoperative overall complications and duration of hospital stay, the superiority of robotic surgery was most evident in cohort studies (risk ratio (RR) 0.83, 95 per cent c.i. 0.74 to 0.92, P < 0.001; mean difference (MD) -1.11 (95 per cent c.i. -1.86 to -0.36) days, P = 0.004; respectively), and least evident in RCTs (RR 1.12, 0.91 to 1.38, P = 0.27; MD -0.28 (-1.44 to 0.88) days, P = 0.64; respectively)., Conclusion: Results of case-matched studies were often similar to those of RCTs in terms of outcomes of robotic surgery for rectal cancer. However, case-matched studies occasionally overestimated the effects of interventions compared with RCTs., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: Despite dramatic declines in prenatal maternal blood lead levels (BLLs) in most developed countries, little is known about the effects of extremely low-level (<1.0 µg/dL) lead exposure on fetal growth., Methods: We measured maternal BLL during the second or third trimester of pregnancy and assessed birth outcomes, including birthweight, preterm birth (<37 gestational weeks) risk, small for gestational age births (SGA; birthweight <10th percentile) and low birthweight (LBW; <2500 g). The association between birthweight and maternal BLL was estimated using linear and quadratic spline models. Multivariable logistic models were used to examine the risk of binary responses., Results: From 103 099 pregnant women, 20 000 blood samples were randomly selected for analysis. The maternal BLL range was 0.16-7.4 µg/dL, and the median was 0.63 µg/dL. After adjusting for covariates, the linear model showed that each 0.1 μg/dL increase in maternal BLL was associated with a 5.4 g decrease in mean birthweight [95% confidence interval (CI), 3.4 to 7.5 g]. The risk of SGA [adjusted odds ratio (aOR), 1.03; 95% CI, 1.02 to 1.05) and LBW (aOR, 1.03; 95% CI, 1.02 to 1.05) increased, whereas the risk of preterm delivery did not (aOR, 0.99; 95% CI, 0.97 to 1.02)., Conclusions: Even at a maternal BLL below 1.0 µg/dL, prenatal lead exposure was associated with decreased birthweight and increased risk of SGA and LBW, but not preterm delivery. The adverse effect estimates of prenatal lead exposure on birth outcomes were quantitatively small and clinically limited at this low level., (© The Author(s) 2020; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Study Question: Is oocyte cryopreservation an applicable option for fertility preservation in unmarried patients with haematological malignancies?, Summary Answer: Oocyte cryopreservation via the vitrification method is accessible and may be considered an option for fertility preservation in unmarried patients with haematological malignancies., What Is Known Already: Haematological malignancies are most commonly observed amongst adolescent and young adult women. Although the survival rate and life expectancy of those with haematological malignancies have improved, chemotherapy and radiotherapy may impair their reproductive potential. Oocyte cryopreservation is thus an ideal option to preserve their fertility., Study Design Size Duration: This study retrospectively evaluated 193 unmarried patients (age: 26.2 ± 0.4 years) with haematological malignancies, who consulted for oocyte cryopreservation across 20 different fertility centres in Japan between February 2007 and January 2015. The primary outcome measures were the oocyte retrievals and oocyte cryopreservation outcomes. The secondary outcome measures were the outcomes following oocyte warming for IVF., Participants/materials Setting Methods: The patients had commenced ovarian stimulation cycles via antagonist, agonist, natural and minimal methods for oocyte retrievals, defined according to the treatment strategy of each respective fertility centre. A vitrification method using the Cryotop safety kit was used for oocyte cryopreservation. ICSIs were used for insemination of warmed oocytes. The endometrial preparation method for embryo transfer was hormonal replacement therapy, except in the case of a patient who underwent a spontaneous ovulatory cycle., Main Results and the Role of Chance: Among 193 patients, acute myeloid leukaemia (n = 45, 23.3%) was most common, followed by acute lymphoid leukaemia (n = 38, 19.7%) and Hodgkin's lymphoma (n = 30, 15.5%). In total, 162 patients (83.9%) underwent oocyte retrieval, and oocytes were successfully cryopreserved for 155 patients (80.3%). The mean number of oocyte retrieval cycles and cryopreserved oocytes were 1.7 ± 0.2 and 6.3 ± 0.4, respectively. As of December 2019, 14 patients (9.2%) had requested oocyte warming for IVF. The survival rate of oocytes after vitrification-warming was 85.2% (75/88). The rates of fertilisation and embryo development were 80.0% (60/75) and 46.7% (28/60), respectively. Ten patients (71.4%) had successful embryo transfers, and seven live births (50.0%) were achieved., Limitations Reasons for Caution: This study was limited by its retrospective nature. Additionally, there remains an insufficient number of cases regarding the warming of vitrified oocytes to reliably conclude whether oocyte cryopreservation is effective for patients with haematological malignancies. Further long-term follow-up study is required., Wider Implications of the Findings: Oocyte retrieval and oocyte cryopreservation were accessible for patients with haematological malignancies; however, the number of oocyte retrievals may have been limited due to the initiation of cancer treatments. Acceptable embryonic and pregnancy outcomes could be achieved following oocyte warming; therefore, our results suggest that oocyte cryopreservation can be considered an option for fertility preservation in patients with haematological malignancies., Study Funding/competing Interests: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. The authors declare no conflict of interest., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Objectives: To evaluate the efficacy and safety of tacrolimus in adult patients with rheumatoid arthritis (RA) by using the GRADE approach., Methods: We searched PubMed, Japana Centra Revuo Medicina Web (Ichu-shi web), and the Cochrane Database of Systematic Reviews. Articles fulfilling the predefined inclusion criteria were appraised and used for meta-analysis. The primary outcomes were American College of Rheumatology 20 (ACR20) and serum creatinine elevation. Other outcomes included ACR50, ACR70, changes in C-reactive protein, modified Health Assessment Questionnaire Disability Index, gastrointestinal disorders, metabolic and nutritional disorders, and infections and infestations., Results: We identified five randomized controlled studies, four of which compared tacrolimus to placebo and were included in the meta-analysis. The risk ratio of ACR20 achievement was 1.71 (95% confidence interval [CI] 1.20-2.42) for 1-2 mg/day and 2.30 (95% CI 1.79-2.96) for 3 mg/day. The risk ratio of creatinine elevation was 1.95 (95% CI 1.18-3.23) for 1-2 mg/day and 3.81 (95% CI 2.43-5.99) for 3 mg/day., Conclusion: Tacrolimus is effective with acceptable safety in the management of RA.

Objectives: Prevention of and early treatment for noncommunicable diseases such as hypertension, hyperglycemia, and dyslipidemia are important, as these diseases are asymptomatic in early stages but can lead to critical conditions such as macro- and microvascular disorders later on. While screening is conducted worldwide, low rates of hospital visits after screening is a common issue. We aimed to investigate the effect of reminder letters on the consultation behavior of screened participants., Methods: We used administrative claims data from a database managed by JMDC Inc for participants of health checkups in 2014, 2015, 2016, and 2017, who belonged to a health insurance society. Reminder letters were sent regularly 6 months after checkups to improve participant consultation behavior. Participants who screened positive for hypertension, hyperglycemia, and dyslipidemia, and who were not taking medication for any of these diseases at the time of health checkups, were included in the analyses., Results: A total of 1739 participants in 2014, 1693 in 2015, 2002 in 2016, and 2144 in 2017 were included in the analysis for hypertension. The cumulative proportion of hospital visits gradually increased over the course of 12 months after checkups in all years. After 2015, spikes, albeit very small ones, were observed at 6 months after checkups in accordance with the timing of reminder letters. Similar trends were observed for hyperglycemia and dyslipidemia., Conclusions: Sending reminder letters is a potentially effective approach to increase hospital visits, but further improvements (ie, multiple reminders) may be necessary to affect enhancements in participant consultation behavior., (© 2021 The Authors. Journal of Occupational Health published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society for Occupational Health.)

Objectives: To elucidate the epidemiological characteristics of patients with rheumatoid arthritis (RA) in Japan using data from the Comprehensive Survey of Living Conditions, a nationwide questionnaire survey conducted in 2016. Methods: In total, 222,365 men and 245,251 women aged ≥16 years were included in the study. RA patients were defined as those who reported 'currently receiving treatment for RA at hospitals, clinics, or a facility for Japanese traditional massage, acupuncture, moxibustion, or judo-orthopedics.' The number of RA patients was estimated from the age-specific prevalence and total Japanese population in 2016. Further, the prevalence of individuals experiencing difficulties in activities of daily living due to health problems and those with mental distress as evaluated by K6 Scale was examined. Results: The estimated number and prevalence of RA in Japan with 95% confidence interval was 822 (768-880) thousand and 0.75% (0.70-0.80%). The population peaked in the late 60s, and the prevalence continued increasing until the early 80s, regardless of sex. Compared with non-RA participants, RA patients were more likely to experience difficulties in activities and to be distressed. Conclusion: High prevalence of RA in older age and mental and physical burden among RA patients were confirmed.

We report a novel scaffold for clustering and oriented immobilization of human IgG1 Fc-fused lectins on biosensors without chemical modifications. This approach uses a bio-nanocapsule (BNC) displaying a tandem form of IgG Fc-binding Z domains derived from Staphylococcus aureus protein A (ZZ-BNC). Incorporating ZZ-BNC effectively increased both the sensitivity and sugar chain-binding capacity compared with the condition without ZZ-BNC.

This study investigated the existence of sulfonamides and colistin resistance genes among extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli recovered from fish gut in Vietnam and evaluated the susceptibility patterns of the ESBL-producing E. coli to relevant antimicrobials. A total of 88 ESBL-producing E. coli isolates were analysed for the presence of the ESBLs, sul (1, 2, 3) and mcr (1-3) genes by PCR. Antimicrobial resistance phenotypes of isolates were determined by disc diffusion. Results showed that: (i) A high prevalence of 94·3% of sulfonamide resistance was observed in 88 isolates. Moreover, the existence of 2·3% of ESBL-producing E. coli harbouring mcr-1 gene were detected; (ii) The phylogenetic types A and B1 were most frequent, and the bla CTX-M group1 and bla TEM genes encoding ESBL were detected in 47·7% of the isolates; (iii) ESBL-producing E. coli harbouring mcr-1 gene exhibited resistance to 11 antibiotics. The existence of mcr-1 and sul1,2,3 genes and the extremely high level of multiple drug resistance in all ESBL-producing E. coli isolates obtained from sampled fish in Vietnam is a major concern. Therefore, it is imperative to monitor ESBL-producing E. coli in the river waters of Vietnam., (© 2019 The Society for Applied Microbiology.)

The risk of cancer due to exposure to ionizing radiation is higher in infants than in adults. In a previous study, the effect of adult-onset calorie restriction (CR) on carcinogenesis in mice after early-life exposure to X-rays was examined (Shang, Y, Kakinuma, S, Yamauchi, K, et al. Cancer prevention by adult-onset calorie restriction after infant exposure to ionizing radiation in B6C3F1 male mice. Int J Cancer. 2014; 135: 1038-47). The results showed that the tumor frequency was reduced in the CR group. However, the mechanism of tumor suppression by CR is not yet clear. In this study, we examined the effects of CR on radiation-induced mutations using gpt delta mice, which are useful to analyze mutations in various tissues throughout the whole body. Infant male mice (1-week old) were exposed to 3.8 Gy X-rays and fed a control (95 kcal/week/mouse) or CR (65 kcal/week/mouse) diet from adult stage (7-weeks old). Mice were sacrificed at the age of 7 weeks, 8 weeks and 100 days, and organs (spleen, liver, lung, thymus) were harvested. Mutations at the gpt gene in the DNA from the spleen were analyzed by using a gpt assay protocol that detects primarily point mutations in the gpt gene. The results showed that mutation frequencies were decreased in CR groups compared with non-CR groups. Sequence analysis of the gpt gene in mutants revealed a reduction in the G:C to T:A transversion in CR groups. Since it is known that 8-oxoguanine could result in this base substitution and that CR has an effect of reducing oxidative stress, these results indicate that the suppression of oxidative stress by CR is the cause of the reduction of this transversion., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Purpose: To examine the update status of clinical practice guidelines (CPGs) for 24 main diseases in Japan, and to clarify the quality of and issues pertaining to the most recent versions of CPGs for each disease., Data Sources: CPGs were searched in two Japanese guideline databases., Study Selection: All relevant Japanese CPGs published between January 1999 and July 2016 were selected., Data Extraction: The developer and issue date were extracted for all target CPGs. The most recent CPGs were assessed using the Appraisal of Guidelines for Research and Evaluation-II (AGREE II) instrument., Results of Data Synthesis: Among 106 target CPGs, 24 most recent CPGs were subjected to assessment using the AGREE II instrument. CPGs for 11 diseases (46%) had a mean time interval for update of ≥5 years. Among the 24 CPGs subjected to AGREE II assessment, median domain scores were 74% for "Domain 1: Scope and Purpose," 43% for "Domain 2: Stakeholder Involvement," 46% for "Domain 3: Rigor of Development," 69% for "Domain 4: Clarity of Presentation," 24% for "Domain 5: Applicability" and 27% for "Domain 6: Editorial Independence.", Conclusions: The systematic assessment of CPGs for 24 major diseases in Japan revealed a trend for a delay in timing of update for many CPGs. Moreover, the 24 most recent CPGs had low domain scores for domains 2, 3, 5 and 6. In the future, concrete measures will need to be considered in order to improve the quality of CPGs., (© The Author(s) 2019. Published by Oxford University Press in association with the International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To demonstrate how the confidence, attitude and job satisfaction of pharmacists who provide interventions and lifestyle support services to patients with hypertension are altered., Methods: This study was a before-and-after study that used data from 50 pharmacists who participated in the Community Pharmacists Assist for Blood Pressure (COMPASS-BP) study, which was an interventional study that was conducted in Japan to evaluate the effects of lifestyle support services provided to hypertension patients. The pharmacists received 4 h of training before the study was initiated to learn how to quickly provide patients with guidance about diet and exercise and tobacco and alcohol consumption. During the interventional period, each pharmacist provided concise lifestyle guidance to 1-3 hypertension patients. The pharmacists met with the patients a total of 5 times. The parameters that were assessed were the pharmacists' attitudes towards and confidence in their lifestyle support services, as well as their level of job satisfaction. We verified the scores of each parameter assessed before and after the study, as well as changes in the relationships among the different parameters., Key Findings: Significant increases from baseline to the end of the study were observed for Confidence (P < 0.01), Job satisfaction, including 'Knowledge' (P < 0.01), 'Patient counselling management' (P = 0.04) and 'Sense of personal growth' (P < 0.01). Additionally, path analysis results revealed that after the study, the causal relationship between 'Knowledge' and 'Attitude' disappeared, and a new causal relationship appeared between 'Patient counselling and management' and 'Attitude'., Conclusions: Providing lifestyle guidance improved pharmacists' confidence and attitude. Also, 'Attitude' tended to improve as the 'Patient counselling and management' score increased., (© 2019 Royal Pharmaceutical Society.)

Hypomineralized matrix is a factor determining bone mineral density. Increased perilacunar hypomineralized bone area is caused by reduced mineralization by osteocytes. The importance of vitamin D in the mineralization by osteocytes was investigated in hemodialysis patients who underwent total parathyroidectomy (PTX) with immediate autotransplantation of diffuse hyperplastic parathyroid tissue. No previous reports on this subject exist. The study was conducted in 19 patients with renal hyperparathyroidism treated with PTX. In 15 patients, the serum calcium levels were maintained by subsequent administration of alfacalcidol (2.0 μg/day), i.v. calcium gluconate, and oral calcium carbonate for 4 weeks after PTX (group I). This was followed in a subset of 4 patients in group I by a reduced dose of 0.5 μg/day until 1 year following PTX; this was defined as group II. In the remaining 4 patients, who were not in group I, the serum calcium (Ca) levels were maintained without subsequent administration of alfacalcidol (group III). Transiliac bone biopsy specimens were obtained in all groups before and 3 or 4 weeks after PTX to evaluate the change of the hypomineralized bone area. In addition, patients from group II underwent a third bone biopsy 1 year following PTX. A significant decrease of perilacunar hypomineralized bone area was observed 3 or 4 weeks after PTX in all group I and II patients. The area was increased again in the group II patients 1 year following PTX. In group III patients, an increase of the hypomineralized bone area was observed 4 weeks after PTX. The maintenance of a proper dose of vitamin D is necessary for mineralization by osteocytes, which is important to increase bone mineral density after PTX for renal hyperparathyroidism. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research., (© 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.)

Context: Intake of stable iodine helps prevent childhood thyroid cancer in nuclear emergencies, but there is limited case information., Objective: We identified the intake rate and the factors associated with no intake among children who did not take stable iodine after the Fukushima disaster., Design: Retrospective observational study., Setting: Data were obtained from thyroid cancer screenings performed from August through November 2017., Participants: Children in Miharu Town, Fukushima, Japan., Intervention: No intervention., Main Outcome Measures: We performed multilevel logistic regression analysis at the regional and individual levels. We qualitatively examined the reasons for no intake of stable iodine based on closed- and open-ended questions., Results: The rate of distribution was 94.9%, but the intake rate was only 63.5%. Intake was lower in those aged 0 to 2 years compared with those aged ≥3 years (OR, 0.21; 95% CI, 0.11 to 0.36). Parents' intake was positively associated with their children's intake (OR, 61.0; 95% CI, 37.9 to 102.9). The variance partition coefficient for regions was 0.021, suggesting that the intake of stable iodine was more likely affected by individual than by regional factors. Closed-ended questions showed that the main reason for avoiding intake was concern about safety. Open-ended questions for other reasons revealed issues related to the distribution method, information about the effects and adverse effects of iodine, and instructions for iodine intake. There were no symptomatic adverse effects claimed to the town., Conclusions: The distribution and consumption of stable iodine occurred in Miharu Town after the Fukushima disaster. To prepare for future nuclear emergencies, it is important to explain to both children and parents the need for intake of stable iodine, particularly among young children., (Copyright © 2019 Endocrine Society.)