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Blood pressure measurement has been commonly performed in many fitness clubs or sports clubs in Japan, with the spread of the availability of oscillometric automated devices. In blood pressure measurements, sometimes clothing (T shirt, sweat shirt, and a combination of sweat shirt and fleece jacket) or wearing sleeves was an issue while measurements were being taken. In this study, we investigated the difference of results that were measured with clothing or wearing sleeves by using the mercury auscultatory method and oscillometric automated device in twenty young college students. When a blood pressure measurement was performed by the oscillometric automated device, the blood pressure was significantly higher in the phase of diastole if subjects were wearing a combination of sweat shirt and fleece than compared to the other two conditions of clothing such as wearing only a T shirt or sweat shirt. Accurate results are reported in the blood pressure measurements in young normotensive students, if they are wearing clothing that is thinner than a sweat shirt on the arms being measured. [ABSTRACT FROM AUTHOR]

Aims: To investigate the occurrence and distribution of thermo-acidophilic bacteria (TAB) associated with various commercial fruit crop soils in Japan and to assess their ability to produce the odorous phenolic compound, guaiacol. Methods and Results: Phylogenetic analysis based on the 5′ end of the 16S rRNA gene (approximately 500 bp), was performed on 62 TAB isolated from the soil of several Japanese fruit orchards. The results suggested that 60 of the bacterial strains analysed belonged to the genus Alicyclobacillus, while the remaining two belonged to the genus Bacillus. The majority of strains (58%) were identified as Alicyclobacillus acidoterrestris. This group partitioned into three phylogenetically distinct subgroups (A–C). Isolates identified as A. acidiphilus (two strains), A. acidoterrestris (36 strains), and A. hesperidum subsp. aigle (one strain), produced guaiacol from vanillic acid. Levels of guaiacol production varied significantly among strains. The guaiacol producing phenotype was conserved among certain species, however no correlation was observed between levels of guaiacol production and 16S rRNA gene-based phylogenetic relatedness. Conclusions: Alicyclobacillus acidoterrestris and Alicyclobacillus contaminans were widely distributed among various fruit orchards in Japan. Guaiacol production was common at the species/subspecies level; however the amount of guaiacol produced by each strain varied significantly. Significance and Impact of the Study: This study provides a comprehensive phylogenetic survey of Alicyclobacillus species in Japanese fruit orchards. Quality control standards for guaiacol producing Alicyclobacillus have also been described. [ABSTRACT FROM AUTHOR]

There are size-related differences in the use of feeding habitats (planktonic or benthic; oceanic or neritic) by adult female loggerhead sea turtles (Caretta caretta) within Japanese populations. We thus hypothesized that the differences may be reflected in their remigration and growth patterns, and investigated the relationships between body size and remigration intervals, growth rates, and remigration percentages, for female loggerheads nesting on a Japanese beach between 1991 and 2001. Although remigration intervals, growth rates, and remigration percentages were not significantly different among females, there were trends for longer remigration intervals and lower remigration percentages in smaller females. All females grew little. Considering these results along with previous findings, we speculated on the life-history strategy of female Japanese loggerheads. [ABSTRACT FROM AUTHOR]

Nucleotide sequences from the control region of the mitochondrial (mr) DNA were analyzed for Japanese loggerhead turtles (Caretta caretta) to elucidate population genetic structure and phylogeography. Three haplotypes were detected among 259 females sampled from four nesting sites in 1994-1999. Within nesting colonies, haplotype frequencies were not significantly different between sampling years, whereas among nesting colonies, they were significantly different and fixation indices (F[sub st]) were significantly >0 in most comparisons. These findings indicate that nesting colonies of Japanese loggerheads are genetically distinct and that Japanese females show precise natal homing on an ecological time scale. There were no obvious latitudinal variations in the mtDNA diversity among Japanese nesting populations in contrast with those of the USA, where a series of colonization bottlenecks on northern nesting populations accompanied by postglacial expansion are supposed to be the cause of the trend. Since (1) the mtDNA diversity of Pacific loggerheads consists of a small number of divergent haplotypes and (2) their population size is smaller than those of loggerheads inhabiting other regions, the Pacific loggerheads might have experienced more critical bottlenecks than the others. The discovery of a female with the haplotype that had previously been detected in the nesting colonies of the South Pacific but not the North Pacific made us reconsider the stock composition of loggerheads observed in the North Pacific; that is, all loggerheads inhabiting the North Pacific are derived from Japanese beaches. [ABSTRACT FROM AUTHOR]

A CPITN survey was conducted involving 12832 Japanese subjects from 7 to 64 years of age. Subjects under 18 were schoolchildren, and 18-year-old and older subjects represented various social backgrounds, having been randomly selected from both urban and rural Japan. Fifty percent of the 7-yr-old children had signs of periodontal disease, and this percentage increased with increasing age. In those under 14, this increase in periodontal disease was mainly due to an increase in the proportion of children developing dental calculus. Subjects with 6 mm or deeper pockets were observed starting from the 20-29-yr-old age group. In subjects over this age, the prevalence of periodontal disease was higher in men than in women. The percentages of subjects having pathologic pockets had increased remarkably in the 30-44-yr-olds. In the 45-64-yr-old group, almost all subjects had some sign of periodontal disease, and the percentage of those with 4 or 5 mm pockets and 6 mm or deeper pockets were 37% and 21%, respectively. [ABSTRACT FROM AUTHOR]

The article presents the registration of Nanryo Tall Fescue that was developed by the Kyushu Okinawa National Agricultural Research Station in Kumamoto, Japan.

The article focuses on warm-water coral species' poleward range expansions to temperate areas due to sea-surface temperature warning. It features the poleward range expansion of Acropora solitaryensis in Japan to Tateyama. It mentions that expansions suggest rapid establishment by crab symbionts after the settlement of warm-water corals, which can contribute to the changes in temperate areas biodiversity during global warming.

We use temperature-dependent viscous remanent magnetization to estimate the emplacement age of tsunamigenic coral boulders along the shorelines of Ishigaki Island, Japan. The boulders consist of the hermatypic coral Porites, and the time of their deposition by tsunamis has been established using radiocarbon dating. Recently deceased corals at reef edges around Ishigaki Island record the Earth's current magnetic field (present Earth field, PEF) as a remanence parallel to the field in the skeleton. Since the time when the coral skeletons were emplaced on the shorelines as boulders by destructive tsunami waves, a new viscous magnetization was partially overprinted in the boulder parallel to the PEF. The results of thermal demagnetization indicated that the boulders were rotated at least once, and their emplacement ages determined from L. Néel's relaxation theory for single-domain magnetite agree well with the radiocarbon ages, although there are traces of multidomain magnetites. New application of Néel's theory to tsunamigenic coral boulders gives us an opportunity to ascertain the age and transportation mode of individual tsunamigenic coral boulders in this area. [ABSTRACT FROM AUTHOR]

Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the efficacy of anti-programmed cell death 1 (anti-PD-1) antibodies in advanced AM. We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, RECIST), survival estimated using Kaplan–Meier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies. In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within the normal concentration in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH concentrations showed a significantly stronger association with better OS than abnormal concentrations (median OS 24.9 versus 10.7 months; P < 0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group [6/70 patients (8.6%) versus 26/123 patients (21.1%); P = 0.026]. Moreover, the median OS in this group was significantly poorer (12.8 versus 22.3 months; P = 0.03). Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors. • Acral melanoma is a distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. • We retrospectively examined advanced-stage acral melanoma patients treated with an anti-PD-1 antibody. • Anti-PD-1 antibodies have limited efficacy in Japanese acral melanoma patients. • Patients with nail apparatus melanoma had poorer response and survival than patients with palm and sole melanoma. [ABSTRACT FROM AUTHOR]

Generics and biosimilars play an important role in sustaining the universal healthcare insurance systems in Japan. The Pharmaceuticals and Medical Devices Agency (PMDA) reviews the quality, efficacy, and safety of generics and biosimilars for marketing authorization in Japan. Trend analyses of generics and biosimilars in terms of regulatory science have rarely been published. The PMDA and National Institute of Health Sciences websites were verified for generics and biosimilars, and information related to guidelines and notifications and the number of newly approved generics and biosimilars for fiscal year (FY) 2009-2023 were compiled. Approximately 1,900 and 200 generic drug products were approved in Japan in FY 2010 and 2023, respectively. The number of approved generic drug products has gradually decreased to one-tenth in the past 15 years. Overall, 35 biosimilars were approved in FY 2009-2023. The number of approved biosimilars has increased since FY 2017. This article reported a trend analysis of generics and biosimilars in terms of guidelines, notifications, and the number of applied and approved drug products in FY 2009-2023. Our primary goal is to increase patient access to affordable generics and biosimilars with assurance in appropriate quality., Competing Interests: Declarations Disclaimer The views expressed in this article are those of the authors and do not necessarily reflect the official views of the Pharmaceuticals and Medical Devices Agency. Ethics Approval and Consent to Participate Not Applicable. Consent for Publication All authors consent for publication. Conflict of Interest Ryosuke Kuribayash, Kanoko Goto, and Takumi Ogawa declare that they have no conflict of interest that might be relevant to the contents of this article., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The phenotypes of RP1-related inherited retinal dystrophies (RP1-IRD), causing autosomal dominant (AD) and autosomal recessive (AR) diseases, vary depending on specific RP1 variants. A common nonsense mutation near the C-terminus, c.5797 C > T (p.Arg1933*), is associated with RP1-IRD, but the exact role of this mutation in genotype-phenotype correlation remains unclear. In this study, we retrospectively analyzed patients with RP1-IRD (N = 42) from a single center in Japan. AR RP1-IRD patients with the c.5797 C > T mutation (N = 14) mostly displayed macular dystrophy but rarely retinitis pigmentosa or cone-rod dystrophy. Conversely, AR RP1-IRD patients without the c.5797 C > T mutation, including those with other pathogenic RP1 variants, were mostly diagnosed with severe retinitis pigmentosa. Full-field electroretinograms were significantly better in patients homozygous or compound heterozygous for the c.5797 C > T mutation than in those without this mutation, corresponding to their milder phenotypes. Clinical tests also revealed a slower onset of age and a better mean deviation value with the static visual field in AR RP1-IRD patients with the c.5797 C > T mutation compared to those without. Therefore, the presence of c.5797 C > T may partly account for the phenotypic variety of RP1-IRD and may yield milder phenotypes. These findings may be useful for predicting the prognosis of RP1-IRD patients., (© 2024. The Author(s).)

Purpose: To ascertain the characteristics of achromatopsia (ACHM) in Japan by analyzing the genetic and phenotypic features of patients with ACHM., Methods: The medical records of 52 patients from 47 Japanese families who were clinically diagnosed with ACHM were reviewed in this retrospective observational study., Results: Thirty-six causative variants of ACHM were identified in 26 families via whole-exome sequencing: PDE6C (12 families), CNGA3 (10 families), CNGB3 (two families), and GNAT2 (two families). However, none of the 6 causative variants that are known to cause ACHM, or the 275 other genes listed in RetNet, were observed in 19 families. A significant trend toward older age and worsening of ellipsoid zone disruption on optical coherence tomography images was observed (P < 0.01). Progressive ellipsoid zone disruptions were observed in 13 eyes of seven patients during the follow-up visits. These patients harbored one or more variants in PDE6C., Conclusion: The ACHM phenotype observed in this study was similar to those observed in previous reports; however, the causative gene variants differed from those in Europe. The low identification ratio of causative genes in whole-exome sequencing suggests the presence of unique hotspots in Japanese patients with ACHM that were not detectable via ordinal whole-exome sequencing.

Background: IL10RA (IL10 receptor subunit alpha) deficiency is an autosomal recessive disease that causes inflammatory bowel disease during early infancy. Its clinical course is often fatal and the only curative treatment is allogeneic hematopoietic cell transplantation (HCT). In Japan, only case reports are available, and there are no comprehensive reports of treatment outcomes., Methods: We retrospectively analyzed patients with IL10RA deficiency in Japan., Results: Two newly identified and five previously reported patients were included in this study. Five patients underwent HCT; one untransplanted patient survived to age 14, and one died of influenza encephalopathy before transplantation. All five HCT recipients underwent HCT at the age before 2 years. They all were conditioned with fludarabine/busulfan- or fludarabine /melphalan-based regimens. The donor source was human leukocyte antigen haploidentical donor bone marrow (BM) for two patients and unrelated umbilical cord blood (CB) for two patients. One patient experienced graft failure with unrelated CB and required a second transplant with unrelated BM. All patients who underwent HCT survived and demonstrated an improved performance status., Conclusion: In cases of IL10RA deficiency, the need for transplantation should be promptly assessed, and early transplantation should be considered. (190/250)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: MET exon 14 skipping mutations occur in 3-4% and MET high amplifications occur in < 1% of patients with non-small-cell lung cancer (NSCLC). Crizotinib, a selective ATP-competitive small-molecule inhibitor of c-Met, ALK, and ROS1 tyrosine kinases, has shown activity in cancer models with various types of MET activation., Methods: The Co-MET study is a single-arm phase 2 trial to assess the safety and efficacy of crizotinib in MET inhibitor-naïve patients with advanced NSCLC harboring MET exon 14 skipping mutation (cohort 1) or high MET gene copy number of ≥ 7 (cohort 2). The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by independent radiology review in cohort 1. The key secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety., Results: A total of 28 patients (23 in cohort 1 and 5 in cohort 2) were enrolled between March 2018 and February 2020. The primary endpoint was met as the ORR (90% confidence interval: CI) in cohort 1 was 38.1% (20.6-58.3). Median DoR, PFS, and OS (95% CI) were 7.6 (1.9-NE), 5.7 (2.1-11.3), 9.1 (4.0-19.9) months, respectively, in cohort 1. ORR in cohort 2 was 40.0% (18.9-92.4). The safety signals were generally consistent with the known safety profile of crizotinib., Conclusions: Crizotinib showed a clinical activity similar to that of tepotinib and capmatinib in patients with NSCLC harboring MET exon 14 skipping mutations., Clinical Trial Information: UMIN000031623., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

This study explored the impact of varying energy availability (EA) on the 24-h interstitial fluid glucose concentration (IGC) in five elite male Japanese triathletes at a training camp. Measurements of IGC, energy and macronutrient intake, and exercise energy expenditure (EEE) through metabolic equivalents (METs) from training logs were conducted. Three subjects were evaluated over two 4-day periods, and two subjects over one 4-day period. Findings revealed significant correlations of daily mean nocturnal IGC with daily EA (r = 0.553, p = 0.001) and energy intake (EI) (r = 0.595, p < 0.001). However, no significant correlation was found between mean daily nocturnal IGC and EEE (r = -0.278, p = 0.124). Daytime IGC was ≥110 mg/dL for >50% of the time in all subjects, except on 1 day in one subject, and never fell <70 mg/dL. Therefore, daily EA may influence nocturnal IGC in elite male triathletes, although high daytime IGC levels were maintained without hypoglycemia.

Background: As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases., Methods: We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines., Results: A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases., Conclusion: A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies., Competing Interests: Competing interests: KMN reports grants from JCR Pharmaceuticals Co, Sysmex and Novartis Pharma Co; consulting fees from Sysmex and Novartis Pharma Co; and lecture fees from Sysmex, Novartis Pharma Co and Janssen Co. KMN has patents related to gene therapy for retinitis pigmentosa. In addition, KMN is an advisory board member of Sysmex and Novartis Pharma Co., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The incidence of developmental dysplasia of the hip (DDH) in Japanese newborns has reduced drastically following a primary prevention campaign initiated around 1972 to 1973; this perinatal education campaign promoted maintaining the hips of newborns in the naturally flexed-leg position. The purpose of the present study was to describe the life course epidemiology of hip osteoarthritis (OA) in adolescent and adult patients and to assess its association with exposure to the primary prevention campaign for DDH., Methods: We included new patients with hip OA diagnosed from January 1, 2022, to December 31, 2022, at 12 core hospitals (8 special-function hospitals and 4 regional medical care support hospitals). The trend in the percentage of hips with a history of DDH treatment in childhood was estimated with use of a centered moving average using the birth year of the patient. We compared the prevalence of severe subluxation (Crowe type II, III, or IV) between patients with secondary hip OA due to hip dysplasia who were born in or before 1972 and those who were born in or after 1973., Results: Overall, 1,095 patients (1,381 hips) were included. The mean age at the time of the survey was 63.5 years (range, 15 to 95 years). A total of 795 patients (1,019 hips; 73.8% of hips) were diagnosed with secondary OA due to hip dysplasia. Approximately 13% to 15% of hips among patients born from 1963 to 1972 had a history of DDH treatment in childhood; however, the percentage decreased among patients born in or after 1973. The prevalence of severe subluxation (Crowe type II, III, or IV) among patients born in or after 1973 was 2.4%, which was significantly less than that among patients born in or before 1972 (11.1%; odds ratio, 0.20; p < 0.001)., Conclusions: As of 2022, secondary hip OA due to hip dysplasia is still responsible for most new cases of adolescent and adult hip OA seen in core hospitals in Japan. However, the perinatal education campaign initiated 50 years ago, which utilized a population approach and advocated for maintaining the hips of newborns in the naturally flexed-leg position, may have improved the environmental factors of DDH, as indicated by the apparently reduced need for treatment of DDH in childhood and the associated severe subluxation. This may result in a reduced need for challenging hip surgery later in life., Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: This work was supported by the Japan Society for the Promotion of Science (KAKENHI) (grant JP23K08654). The Article Processing Charge for open access publication was funded by the Japan Society for the Promotion of Science (KAKENHI) (grant JP23K08654). The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H969 )., (Copyright © 2024 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

Sleep-related breathing disorder (SRBD) causes hypertension, and obesity has been highly associated with SRBD, which has become a serious health problem in young and middle-aged Japanese males. However, the relation between SRBD and hypertension considering the effects of obesity remains unknown. In this cross-sectional study, we examined the relationship between SRBD and hypertension, with consideration for the effects of obesity, in Japanese occupational population. Using 3% oxygen desaturation index (3%ODI) obtained by simplified polysomnography (PSG), participants were classified into low (0 ≤ 3%ODI < 5), medium (5 ≤ 3%ODI < 15), and high (15 ≤ 3%ODI) 3%ODI groups. We excluded employees who had not undergone medical examination with simplified PSG in the same year from 2012 to 2018. Logistic regression analysis was performed to calculate odds ratios for having hypertension according to 3%ODI levels. In total, 2532 employees were included. Among them, 25% and 4% were categorized into the medium and high 3%ODI groups, respectively. The odds ratio for hypertension increased significantly with higher 3%ODI levels after adjustment for age, sex, alcohol drinking status and smoking status (p for trend < 0.0001). However, further adjustment for obesity status (body mass index ≥ 25 kg/m 2 ) attenuated the associations. When we performed the stratified analysis by obesity status, the odds ratio for hypertension increased significantly with higher 3%ODI only for non-obese individuals, with significant interaction (p for interaction = 0.014). Higher 3%ODI was significantly associated with higher prevalence of hypertension especially in non-obese participants, suggesting the importance of vigilance for the presence of SRBD even in non-obese individuals. We investigated the association between SRBD and hypertension considering the effects of obesity, which would suggest the need to keep in mind the presence of SRBD even in non-obese individuals., (© 2024. The Author(s).)

A new species of Caloptilia, C. rhynchosiae n. sp. is described, based on 16 specimens from Japan and Korea. The species is characterized by the presence of the saccular process in the male genitalia. A fabaceous vine, Rhynchosia tomentosa (L.) Hook. & Arn. is reported as the larval host of C. rhynchosiae n. sp. Larval feeding preference, biology and pupation process are described for the species. The species turned out to be host-specific. Two sets of COI barcodes were generated for C. rhynchosiae n. sp. The genetic distances of COI barcodes between the new species and other congeners in the public databases are compared. The conclusion was made that C. rhynchosiae n. sp. was misidentified as C. soyella in the BOLD and GenBank DNA barcode depositories.

Objective: This study aimed to evaluate the timing of elective cesarean sections at 37 to 41 weeks from a tertiary hospital in Japan. The primary outcome was the rate of adverse neonatal outcomes, especially focusing on neonates delivered at 38 weeks of gestation., Study Design: The study population was drawn from singleton pregnancies delivered following planned cesarean birth at the Fukuda Hospital from 2012 to 2019. Information on deliveries was obtained from the hospital database, which contains clinical, administrative, laboratory, and operating room databases., Results: After excluding women with chronic conditions, maternal complications, indications for multiple births, or a neonate with an anomaly, 2,208 neonates remained in the analysis. Among adverse neonatal outcomes, the rate was significantly higher in neonates delivered at 37 weeks of gestation (unadjusted odds ratio [OR] = 13.22 [95% confidence interval [CI]: 6.28, 27.86], p  < 0.001) or 38 weeks of gestation (unadjusted OR = 1.82 [95% CI: 1.04, 3.19], p  = 0.036) compared with neonates delivered at 39 to 41 weeks. The adjusted risk of any adverse outcome was significantly higher at 38 0-1/7 weeks (adjusted OR = 2.40 [95% CI: 1.35, 4.30], p  = 0.003) and 38 2-3/7 weeks (adjusted OR = 1.89 [95% CI: 1.04, 3.44], p  = 0.038) compared with neonates delivered at 39 to 41 weeks, respectively., Conclusion: Our findings suggest that elective cesarean sections might be best scheduled at 39 weeks or later. When considering a cesarean at 38 weeks, it appears that 38 4/7 weeks of gestation or later could be a preferable timing in the context of reducing neonatal risks. However, as the composite outcome includes mostly minor conditions, the clinical significance of this finding needs to be carefully interpreted., Key Points: · Timing of elective cesarean sections from 37 to 41 weeks was evaluated in a Japanese tertiary hospital.. · Neonates delivered at 37 and 38 weeks had higher adverse outcome rates compared with 39 to 41 weeks.. · Scheduling elective cesarean sections at least 384/7 weeks or later may reduce neonatal risk.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background and Aims: Conversion to laparotomy is among the serious intraoperative complications and carries an increased risk of postoperative complications. In this cohort study, we investigated whether or not the Endoscopic Surgical Skill Qualification System (ESSQS) affects the conversion rate among patients undergoing laparoscopic surgery for rectal cancer., Methods: We performed a retrospective secondary analysis of data collected from patients undergoing laparoscopic surgery for cStage II and III rectal cancer from 2014 to 2016 across 56 institutions affiliated with the Japan Society of Laparoscopic Colorectal Surgery. Data from the original EnSSURE study were analyzed to investigate risk factors for conversion to laparotomy by performing univariate and multivariate analyses based on the reason for conversion., Results: Data were collected for 3,168 cases, including 65 (2.1%) involving conversion to laparotomy. Indicated conversion accounted for 27 cases (0.9%), while technical conversion accounted for 35 cases (1.1%). The multivariate analysis identified the following independent risk factors for indicated conversion to laparotomy: tumor diameter [mm] (odds ratio [OR] 1.01, 95% confidence interval [CI] 1.01-1.05, p = 0.0002), combined resection of adjacent organs [+/-] (OR 7.92, 95% CI 3.14-19.97, p < 0.0001), and surgical participation of an ESSQS-certified physician [-/+] (OR 4.46, 95% CI 2.01-9.90, p = 0.0002). The multivariate analysis identified the following risk factors for technical conversion to laparotomy: registered case number of institution (OR 0.99, 95% CI 0.99-1.00, p = 0.0029), institution type [non-university/university hospital] (OR 3.52, 95% CI 1.54-8.04, p = 0.0028), combined resection of adjacent organs [+/-] (OR 5.96, 95% CI 2.15-16.53, p = 0.0006), and surgical participation of an ESSQS-certified physician [-/+] (OR 6.26, 95% CI 3.01-13.05, p < 0.0001)., Conclusions: Participation of ESSQS-certified physicians may reduce the risk of both indicated and technical conversion. Referral to specialized institutions, such as high-volume centers and university hospitals, especially for patients exhibiting relevant background risk factors, may reduce the risk of conversion to laparotomy and lead to better outcomes for patients., Trial Registration: This study was registered with the Japanese Clinical Trials Registry as UMIN000040645., (© 2024. The Author(s).)

Hypertension is the leading cardiovascular risk factor worldwide. However, in Japan, only 30% of patients have their blood pressure controlled under 140/90 mmHg, and nonadherence to antihypertensives is thought to be a reason for the poor control of hypertension. We therefore sought to assess the adherence to hypertension treatment and to evaluate factors influencing patients' adherence in a large, representative sample of the Japanese population. To this end, we analyzed claims data from the LIFE Study database, which includes 112 506 Japanese adults with newly diagnosed hypertension. Medication adherence was measured for a year postdiagnosis using the proportion of days covered (PDC) method. Factors associated with adherence to antihypertensives were also assessed. Among the total 112 506 hypertensive patients, the nonadherence rate (PDC ≤ 80%) for antihypertensives during the first year after initiation of the treatment was 26.2%. Younger age [31-35 years: odds ratio (OR), 0.15; 95% confidence interval (95% CI), 0.12-0.19 compared with 71-74-year-old patients], male gender, monotherapy, and diuretics use [OR, 0.87; 95% CI, 0.82-0.91 compared with angiotensin II receptor blockers (ARBs)] were associated with poor adherence in the present study. Cancer comorbidity (OR, 0.84; 95% CI, 0.79-0.91 compared with no comorbidity), prescription at a hospital, and living in a medium-sized to regional city were also associated with poor adherence. Our present findings showing the current status of adherence to antihypertensive medications and its associated factors using claims data in Japan should help to improve adherence to antihypertensives and blood pressure control., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Thromboembolic events have occurred in clinical trials of roxadustat. This post hoc analysis explored potential factors related to thromboembolic events in dialysis-dependent patients treated with roxadustat in four phase 3 clinical trials in Japan., Methods: Thromboembolic events with onset before and after week 12 were evaluated. Baseline risk factors for thromboembolic events were investigated by Cox regression analyses. Nested case-control analyses using conditional logistic models with matched pairs of case-control data explored relationships between thromboembolic events and laboratory parameters., Results: Of the 444 patients, 56 thromboembolic events were observed in 44 patients during ≤ 52 weeks of treatment. The proportion of venous and arterial thromboembolic events gradually increased after week 12. Baseline risk factors included hemodialysis (vs peritoneal dialysis), advanced age (≥ 65 years), shorter dialysis vintage (< 4 months), and history of thromboembolism. The absence of concomitant intravenous or oral iron therapy (including ferric citrate) was associated with thromboembolic events before week 12 (hazard ratio 11.25; 95% confidence interval [CI] 3.36-37.71; vs presence). Case-control analysis revealed that low average transferrin saturation (< 10%; unadjusted odds ratio [OR] 6.25; 95% CI 1.52-25.62; vs ≥ 20%), high average transferrin level (≥ 2.5 g/L; unadjusted OR 4.36; 95% CI 1.23-15.39; vs < 2.0 g/L), and high average roxadustat dose (≥ 150 mg; unadjusted OR 5.95; 95% CI 1.07-33.16; vs < 50 mg) over the previous 8 weeks before the event onset were associated with thromboembolic events after week 12. However, adjustment for iron status extinguished the significant relationship between roxadustat dose and events. Multivariate case-control analysis showed that increased transferrin from baseline (≥ 1.0 g/L; adjusted OR 7.85; 95% CI 1.82-33.90; vs < 0.5 g/dL) and decreased mean corpuscular volume (< - 2 fL; adjusted OR 5.55; 95% CI 1.73-17.83; vs ≥ 0 fL) were associated with increased risk of thromboembolic events., Conclusion: In addition to established risk factors, iron deficiency may be related to thromboembolic events. Graphical Abstract available for this article., Trial Registration: NCT02780726, NCT02952092, NCT02780141, NCT02779764., (© 2024. The Author(s).)

Objective: Comprehensive genomic profiling testing using a hybrid-capture next-generation sequencing is commonly used in clinical practice to employ precision medicine in cancer treatment worldwide. In this study, we aimed to analyze the profiles obtained using comprehensive genomic profiling testing that was performed in Japanese castration-resistant prostate cancer patients and to discuss the genetic findings in a real-world setting., Methods: A total of 60 cases and 57 castration-resistant prostate cancer patients underwent comprehensive genomic profiling testing between 1 January 2021 and 31 December 2022. Four types of comprehensive genomic profiling testing were selected, and clinically significant cancer-specific gene alterations were identified., Results: The median age of patients was 74 years, and the median prostate-specific antigen value at the time of submission was 18.6 ng/ml. Fifty-seven (95%) of 60 cases were metastatic castration-resistant prostate cancers, and 3 cases (5%) were non-metastatic. Among all genetic alterations, androgen-receptor alteration was the most frequently detected in 17 cases (28.3%), followed by 15 cases of TP53 (25.0%), 14 cases of CDK12 (23.3%), 10 cases of phosphatase and tensin homolog (16.7%) and 9 cases of ATM (15.0%) mutations. A total of 13 patients (21.7%) received systemic therapy according to the comprehensive genomic profiling testing results. Overall, the survival rate was significantly greater in the group treated through systemic therapy based on comprehensive genomic profiling testing compared with the group without new therapeutic treatment (P = 0.041)., Conclusions: Comprehensive genomic profiling testing is recommended in castration-resistant prostate cancer patients identified as resistant to standard therapy as this can provide a new therapeutic option., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Purpose: Restricted kinematic alignment (rKA) is a modified technique of kinematically aligned total knee arthroplasty (TKA) within a safe alignment range for long-term implant survivorship. The purpose of this study was to clarify (1) the distribution of functional knee phenotypes in patients who underwent TKA in Japan and (2) whether the application of this classification results in anatomically neutral alignment after rKA TKA., Methods: Overall, 114 TKA surgeries (mechanical alignment [MA]: 49; rKA: 65) were performed. The joint line orientation angle (JLOA), hip-knee-ankle angle (HKA), femoral mechanical angle (FMA) and tibial mechanical angle (TMA) were obtained. The knees were categorized using a functional knee phenotype classification. Clinical evaluations, including the Knee Injury and Osteoarthritis Outcome, 12-question Forgotten Joint and Oxford Knee Scores, were performed 3 years postoperatively. Between-group comparisons were made., Results: The most common preoperative functional knee phenotype was VAR HKA 3° + NEU FMA 0° + VAR TMA 3° (11.4%). In the preoperative population, 51 knees (44.7%) had VAR FMA  ≥ 3°. Postoperatively, the most common functional knee phenotype was NEU HKA 0° + VAR FMA 3° + VAL TMA 3° (14 knees, 28.6%) in the MA and NEU HKA 0° + NEU FMA 0° + NEU TMA 0° in the rKA group. The percentage of postoperative JLOA within ±3° from the floor was 27% and 72% in the MA and rKA groups, respectively (p < 0.001). The functional knee phenotype after rKA TKA was neutrally reproduced, and the joint line was more parallel to the ground in the standing position than that of MA. Between-group differences in clinical outcomes were not significant., Conclusion: The application of functional knee phenotyping to knee osteoarthritis in Japan suggested the presence of racial morphological characteristics. This classification could help better visualize potential femoral varus, contributing to protocol deviation in applying restricted KA TKA., Level of Evidence: Level IV., (© 2024 European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background: The Japan Renal Biopsy Registry (J-RBR), a nationwide, web-based, registry system, started in 2007. This study aimed to summarise the epidemiology of biopsy-diagnosed kidney disease in Japan over 10 years., Methods: We analysed the J-RBR database, from 2007 to 2017. Patients' clinical data collected at the time of biopsy and histopathological diagnoses were used for epidemiological and clinicopathologic analyses., Results: The predominant renal biopsy diagnoses were immunoglobulin A nephropathy (39.2%), lupus nephritis (6.5%) and minimal change disease (6.0%) in younger adults (19-64 years), and membranous nephropathy (17.4%), antineutrophil cytoplasmic antibody-associated vasculitis or anti-glomerular basement membrane glomerulonephritis (13.0%), and immunoglobulin A nephropathy (12.5%) in older adults (≥ 65 years). The percentages of patients diagnosed with membranoproliferative glomerulonephritis and immunoglobulin A nephropathy decreased, whereas those with immunoglobulin A vasculitis and diabetic nephropathy increased over the decade. In paediatric patients (< 19 years), immunoglobulin A nephropathy (36.1%), minimal change disease (17.6%), and immunoglobulin A vasculitis (8.6%) were the predominant diagnoses. The percentage of patients diagnosed with immunoglobulin A vasculitis increased over the decade. Based on the sex distribution, minimal change disease and membranous nephropathy were predominant in men aged < 20 and > 40 years, respectively, whereas immunoglobulin A vasculitis and antineutrophil cytoplasmic antibody-associated vasculitis or anti-glomerular basement membrane glomerulonephritis were predominant in women in their 20s and 30s and aged < 50 years, respectively. Immunoglobulin A nephropathy was predominant in men at most ages and in women in their 20s to 40s., Conclusions: This study describes the distribution and changes in kidney biopsy diagnoses over 10 years in Japan and paves the way for future research on kidney diseases in adults and children., (© 2023. The Author(s).)

We launched SCRUM-Japan platform for the cancer genome profiling (CGP) test screening followed by the enrollment to genomically-matched clinical trials in 2015. More than 30,000 tissue-based and 10,000 liquid-based CGP tests have already been performed for enrolling to a total of 127 industry-/investigator-initiated registration trials, which resulted in regulatory approvals of 12 new agents with 14 indications in Japan. Using the clinical-genomic database, a new driver gene was recently discovered with dramatic response by genomically-matched agent. Our comparative study with tissue-based CGPs revealed more usefulness of liquid biopsy in terms of less invasive manner, shorter turn-round time, and higher enrollment rate for matched treatments than tissue-based in gastrointestinal cancers. For detecting minimal/molecular residual disease (MRD) after surgery, post-surgical monitoring with tumor-informed liquid biopsy assay in association with two randomized control trials have also started in 2020 (CIRCULATE-Japan). The observational cohort study showed obvious efficacy of the MRD monitoring for predicting recurrence, leading to change clinical practice in patient selection who should receive adjuvant therapy in the near future.

Background: Among early stage prostate cancer patients, intraductal carcinoma of the prostate (IDC-P) and invasive cribriform are key prognostic factors; however, their presence and clinical significance following active surveillance (AS) are unknown. In men who opted for AS, we aimed to examine the presence and impact of IDC-P or cribriform, utilizing radical prostatectomy (RP) specimens., Methods: We re-reviewed 137 RP specimens available in the PRIAS-JAPAN prospective cohort between January 2010 and September 2020. We assessed the presence of IDC-P or cribriform, and compared the patients' characteristics and prostate-specific antigen (PSA) recurrence-free survival after RP between groups with and without IDC-P or cribriform. In addition, we examined the predictive factors associated with IDC-P or cribriform., Results: The percentage of patients with IDC-P or cribriform presence was 34.3% (47 patients). IDC-P or cribriform pattern was more abundant in the higher Gleason grade group in RP specimens (P < 0.001). The rates of PSA recurrence-free survival were significantly lower in the IDC-P or cribriform groups than in those without them (log rank P = 0.0211). There was no association between IDC-P or cribriform on RP with the Prostate Imaging-Reporting and Data System (PI-RADS) 4,5 score on magnetic resonance imaging (MRI) before RP even with adjustments for other covariates (OR, 1.43; 95% confidence interval [CI] 0.511-3.980, P = 0.497)., Conclusions: IDC-P or cribriform comprised approximately one-third of all RP specimens in men who underwent RP following AS, confirming their prognostic significance., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: We evaluated the safety and efficacy of the anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) brigatinib in Japanese patients with TKI-naive ALK-positive non-small cell lung cancer (NSCLC) from the phase 2, open-label, single-arm, multicenter J-ALTA study., Methods: In the TKI-naive cohort of J-ALTA, the primary end point was independent review committee (IRC)-assessed 12-month progression-free survival (PFS). Secondary end points included objective response rate (ORR), intracranial response, overall survival (OS), and safety., Results: The data were cut approximately 12 months after last patient enrollment. Thirty-two patients with ALK TKI-naive ALK-positive NSCLC were enrolled (median age [range], 60.5 [29-85] years; median duration of follow-up, 14.2 [3.2-19.3] months; median treatment duration, 13.8 [0.4-19.3] months). IRC-assessed 12-month PFS was 93.0% (90% confidence interval (CI) 79.2-97.8%); ORR, 96.9% (95% CI 83.8-99.9%), 12-month OS, 96.9% (95% CI 79.8-99.6%), and median OS was not reached. Of five patients with measurable baseline CNS metastases, two had partial intracranial response. The most common treatment-emergent adverse events were increased blood creatine phosphokinase (81%), hypertension (59%), and diarrhea (47%). Grade ≥ 3 adverse events occurred in 91% of patients; pneumonitis was reported in 3 (9%) patients., Conclusions: In the J-ALTA TKI-naive cohort, brigatinib demonstrated clinically meaningful efficacy consistent with the international phase 3 study. The safety profile in Japanese patients was consistent with previous studies. Brigatinib is an important first-line option for Japanese patients with ALK-positive NSCLC., Clinical Registration: NCT03410108., (© 2022. The Author(s).)

Autosomal recessive spinocerebellar ataxia of type 10 (SCAR10) is a very rare neurodegenerative disease caused by mutations in the TMEM16K (ANO10) gene. This disorder is characterized by slowly progressive cerebellar ataxia and pyramidal signs inconstantly associated with cognitive decline, polyneuropathy, epilepsy, and vesicorectal dysfunction. To date, more than 40 cases have been reported in Europe. In contrast, only three cases have been identified in Asian countries. We herein report the third Japanese case of SCAR10 harboring a novel homozygous deletion mutation (c.616delG, p.Glu206Lysfs*17). This case presented with adult-onset slowly progressive spastic ataxia with cerebellar atrophy and mild cognitive decline.

Purpose: Selpercatinib is a highly selective, potent, rearranged during transfection(RET)inhibitor. A global, multicenter, open-label, phase 1/2 study of selpercatinib(LIBRETTO-001, NCT03157128)has been ongoing since 2017. We evaluated the data of Japanese patients with RET fusion-positive non-small cell lung cancer(NSCLC)using 30 March 2020 cut-off data., Methods: Phase 2 of LIBRETTO-001 started after confirming the safety of the recommended phase 2 dose(160 mg bid, orally, 28-day cycles)in Japanese. The primary endpoint was the independently assessed objective response rate(RECIST v1.1)., Results: Japanese NSCLC patients, including 44 patients in cohort 1 who had previously received platinum-based(or other)chemotherapy, programmed cell death-1/programmed death-ligand 1 immunotherapy, or both, and four previously untreated patients in cohort 2, were analyzed. The objective response rate was 55.3%(95% confidence interval: 38.3, 71.4; one confirmed complete response, 20 confirmed partial responses)in 38 evaluable patients in cohort 1 who could be followed for ≥2 post-baseline scans. The only evaluable patient in cohort 2 had no response. The most frequent treatment- emergent adverse events were increased alanine aminotransferase, increased aspartate aminotransferase, and diarrhea., Conclusions: Selpercatinib appeared to be effective in Japanese patients with RET fusion-positive NSCLC, and the safety profile was not substantially different from published results.

Afidopyropen, a novel insecticide, is a derivative of pyripyropene A, which is produced by the filamentous fungus Penicillium coprobium. Afidopyropen has strong insecticidal activity against aphids and is currently used as a control agent of sucking pests worldwide. In this study, we summarized the biological properties and field efficacies of its derivatives against agricultural pests using official field trials conducted in Japan. Afidopyropen showed good residual efficacies against a variety of aphids, whiteflies and other sucking pests under field conditions. Furthermore, toxicological studies revealed its safety profiles against nontarget organisms, such as the honeybee, natural enemies and other beneficial insects, as well as mammals. Thus, afidopyropen is a next-generation agrochemical for crop protection that has a low environmental impact., (© 2022. The Author(s).)

Peripheral pulmonary arterial stenosis (PPAS) is known to cause pulmonary hypertension (PH). Although adult patients at advanced stage have been increasingly reported, there are few reports on clinical characteristics and pulmonary angiography (PAG) findings of early stage PPAS. We present two Japanese siblings with PPAS with homozygosity of RNF213 p.Arg4810Lys-one with advanced stage and the other with early stage. The latter case was an asymptomatic 37-year-old woman with mild PH. Notably, her PAG demonstrated nonthrombotic stenosis in the subsegmental branches of the pulmonary arteries with varying degrees of stenosis among lung segments. Taken together with a family history, genetic analysis, and cerebral angiography, the obtained images were considered as showing PPAS with early stage. This result is clinically informative to diagnose PPAS at an early stage and is also important to understand the pathogenesis of PPAS., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to determine the proportion of near-miss dispensing errors in hospital pharmacies in Japan. A prospective multi-center observational study was conducted between December 2018 and March 2019. The primary objective was to determine the proportion of near-miss dispensing errors in hospital pharmacy departments. The secondary objective was to determine the predictive factors for near-miss dispensing errors using multiple logistic regression analysis. The study was approved by the ethical committee at The Institute of Medical Sciences, University of Tokyo, Japan. A multi-center prospective observational study was conducted in 20 hospitals comprising 8862 beds. Across the 20 hospitals, we assessed data from 553 pharmacists and 53039 prescriptions. A near-miss dispensing error proportion of 0.87% (n = 461) was observed in the study. We found predictive factors for dispensing errors in day-time shifts: a higher number of drugs in a prescription, higher number of quantified drugs, such as liquid or powder formula, in a prescription, and higher number of topical agents in a prescription; but we did not observe for career experience level for clinical pharmacists. For night-time and weekend shifts, we observed a negative correlation of near-miss dispensing errors with clinical pharmacist experience level. We found an overall incidence of near-miss dispensing errors of 0.87%. Predictive factors for errors in night-time and weekend shifts was inexperienced pharmacists. We recommended that pharmacy managers should consider education or improved work flow to avoid near-miss dispensing errors by younger pharmacists, especially those working night or weekend shifts.

Background: Spinal disorders and low back pain (LBP) have been associated with worse clinical outcomes of total hip arthroplasty (THA). It is essential to identify spinal factors associated with post-THA LBP improvement. Therefore, we aimed to determine the proportion of patients with improved LBP after THA and to identify the preoperative spinal factors associated with LBP improvement., Methods: We included 151 patients who underwent primary THA between December 2015 and December 2019 and had a preoperative visual analog scale score for LBP of ≥2. The patients were classified into the LBP improved or LBP continued group based on a visual analog scale score for LBP at 1 year after THA. Preoperative spinal parameters were compared between the 2 groups., Results: Ninety-five patients (62.9%) were classified into the LBP improved group. Among the coronal spinal parameters, the Cobb angle was significantly lower in the LBP improved group. Among the sagittal spinal parameters, the LBP continued group showed a significantly more posteriorly titled pelvis, lower lumbar lordosis, greater sagittal vertical axis, and greater pelvic incidence minus lumbar lordosis mismatch, indicating a sagittal spinal imbalance. Logistic regression analysis found that preoperative factors associated with LBP improvement after THA had a low Cobb angle and high anterior pelvic plane angle (anteriorly tilted pelvis)., Conclusion: Among patients with LBP before THA, 62.9% had improved LBP. Sagittal spinal imbalance and high Cobb angle were the key spinal factors associated with persistent LBP. Our findings suggest that hip surgeons should evaluate spinal alignment before THA in patients with LBP., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Percutaneous left atrial appendage occlusion (LAAO) using a WATCHMAN device could be a treatment option for patients with non-valvular atrial fibrillation (AF) with thromboembolic and bleeding risk. We sought to determine the prevalence and characteristics of patients with AF ablation who are potential candidates for WATCHMAN implantation in a Japanese population., Methods: We enrolled 2443 consecutive patients who had previously undergone AF ablation and transesophageal echocardiography (TEE). We assessed their clinical characteristics and measured their LAA orifice diameter and depth retrospectively using the obtained TEE images. We defined patients who met both anatomical criteria (LAA orifice max diameter: 17-31 mm and LAA max depth > LAA orifice max diameter) and clinical criteria (CHA 2 DS 2 -VASc score ≥ 2 and HAS-BLED score ≥ 3) as LAAO candidates., Results: Among the 2443 enrolled patients, 361 (15%) met the clinical criteria, and 1928 (79%) met the anatomical criteria. Thus 12% (293/2443) of the total patient group met the criteria of LAAO candidates. LAAO candidates showed larger left atrial (LA) volume (77.6 ± 30.1 vs. 67.7 ± 29.1 mL, P < 0.001), larger LAA orifice diameter (22.5 ± 3.2 vs. 22.0 ± 4.3 mm, P = 0.026), and larger LAA depth (28.9 ± 4.6 vs. 27.0 ± 4.8 mm, P < 0.001). LAAO candidates made up only 23% of patients with CHA 2 DS 2 -VASc score ≥ 2 (N = 1295), whereas 78% of patients with a HAS-BLED score ≥ 3 (N = 378) were LAAO candidates., Conclusion: Twelve percent of patients who underwent AF ablation were potential candidates for LAAO using a WATCHMAN device in this Japanese population. It is imperative to evaluate bleeding risk when considering the indications for LAAO., (© 2021. Japanese Society of Echocardiography.)

Three COVID-19 waves in Japan have been characterized by the presence of distinct PANGO lineages (B.1.1. 162, B.1.1.284, and B.1.1.214). Recently, in addition to the B.1.1.7 lineage, which shows 25% abundance, an R.1 lineage carrying the E484K mutation in the spike protein was found to show up to 40% predominance. E484K could be a pivotal amino acid substitution with the potential to mediate immune escape; thus, more attention should be paid to such potential variants of concern to avoid the emergence of mutants of concern. Such comprehensive real-time genome surveillance has become essential for the containment of COVID-19 clusters., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: During the 2014 to 2018 seasons, we conducted a longitudinal study involving enteric virus surveillance in bivalves, including natural oysters and clams harvested in Ibaraki Prefecture, Japan. Some norovirus (NoV) contaminations were detected in natural oysters, whereas no enteric virus was found in clams. NoVs detected in oysters were of the genotypes GII.4 and GII.6, both of which are closely related genetically to the NoV strains prevalent in humans. We found low level of enteric virus contamination in bivalves collected along the coast of Ibaraki Prefecture. The possibility of food poisoning caused by these viruses appears low, and few cases of infectious disease have been observed in the surrounding area. The harvest timing was more related to contamination quantity than the harvest area in many enteric viruses. Our results highlight that contamination of bivalves by enteric viruses may depend upon the prevalence of human diarrhea and illness., (Copyright ©, International Association for Food Protection.)

For patients with non-traumatic osteonecrosis of the femoral head (ONFH), core decompression (CD) and bone grafts (BG) are mainly performed in the West, while osteotomy is found to be predominant in Japan. It is not well recognized how the surgical procedures for joint preservation in patients with ONFH are completely different between the United States and Japan. This paper identifies the contexts and the differences in treatment strategies for ONFH between the two countries. We compared the surgical trends of the two countries over three periods, 1997-2001, 2002-2006, and 2007-2011 (the US data for the third period was 2007-2008), based on a 2014 US paper and a 2013 national publication in Japan. We compared the details of surgery for non-traumatic ONFH under the same conditions in the two reports. For the period 1997-2001, the rates of surgeries for ONFH in the US were as follows: total hip arthroplasty (THA), 86%; CD, 10%; and osteotomy, 0.4%. In Japan, THA was 61%, osteotomy 38%, and CD 0%. For the recent period, 2007-2011 (US 2007-2008), the rate of THA was 91%, CD 6%, and osteotomy 0.1%, in the US, compared to a THA rate of 73%, CD 0%, and osteotomy 26% in Japan. The results for the interim period (2002-2006) were between the old and new data. The use of joint-preserving surgery for ONFH differs greatly between the US and Japan. The first-line joint-preserving surgery was CD in the US and osteotomy in Japan. Each procedure was rarely done in the other country. From about 2000 to 2010, the percentage of THA increased in both countries. The proportion of joint-preserving surgery (CD in the US and osteotomy in Japan) declined. The decrease in joint-preserving procedures may be largely attributed to improved long-term outcomes of THA due to technological advances. There is also a reluctance for young ONFH patients to undergo joint-preserving procedures, such as osteotomy, that require long-term hospitalization., (© 2021 The Authors. Orthopaedic Surgery published by Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Objective: The purpose of the present study was to investigate the effects of serum triglyceride levels on the risk of new-onset hypertension in Japanese., Methods: Five thousand nine hundred and thirty-three Japanese workers without hypertension at baseline, who participated in medical check-ups from 2006 to 2018, were followed retrospectively. The participants were divided into quartiles of casual serum triglyceride levels and were followed from the first to last visit of the study period. The outcome was development of hypertension. Risk estimates were computed using Cox's proportional hazards model., Results: During the follow-up period (average: 6.7 years), 946 individuals developed hypertension. The crude incidence rates of hypertension (per 1000 person-years) increased with rising serum triglyceride levels: 10.1 for quartile 1 (<0.76 mmol/l), 19.6 for quartile 2 (0.76-1.17 mmol/l), 26.0 for quartile 3 (1.18-1.84 mmol/l), and 36.5 for quartile 4 (>1.84 mmol/l) (P < 0.0001 for trend). These associations remained significant even after adjustment for other risk factors: the multivariable-adjusted hazard ratio was 1.29 (1.01-1.66) for the second quartile, 1.27 (0.99-1.63) for the third quartile, and 1.39 (1.09-1.77) for the highest quartile compared with the lowest. There were comparable effects of serum triglyceride levels for incidence of hypertension between subgroups defined by sex, obesity, and diabetes (all P > 0.1 for interaction), whereas stronger associations were observed for participants under 40 years of age than for those aged 40 or above (P = 0.002 for interaction)., Conclusion: Serum triglyceride levels were significantly associated with development of hypertension in a Japanese worksite population., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Small cell lung cancer(SCLC)is one of the histological types of lung cancer showing the worst prognosis, and is often diagnosed as an inoperable advanced stage disease. Recently, several comprehensive genomic analyses for SCLC have shown that inactivating mutations of tumor suppressor genes such as TP53 and RB1 and MYC family gene amplifications are involved in the development and progression of SCLC. However, actionable gene alterations for targeted therapies have not yet been identified, and there has been no significant advance in the development of targeted therapies for SCLC. In a nationwide lung cancer genome screening project in Japan, LC‒SCRUM‒Japan, a large‒scale genomic analysis was prospectively performed for Japanese SCLC patients, and based on this genomic analysis, a clinical study to evaluate the efficacy of a targeted therapy for PI3K/AKT/mTOR pathway gene‒altered SCLC(EAGLE‒PAT trial)was conducted. In this article, we describe the results of the genomic analysis in LC‒SCRUM‒Japan and the EAGLE‒PAT trial, and also provide the overview of genetic alterations reported in SCLC and the current and future development of targeted therapies for SCLC.

IMpower132 explored the safety and efficacy of atezolizumab plus pemetrexed and platinum-based chemotherapy as first-line treatment for advanced non-small-cell lung cancer (NSCLC). Key eligibility criteria for the phase 3, open-label, IMpower132 study included age ≥18 y, histologically or cytologically confirmed advanced non-squamous NSCLC per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status of 0/1, and no prior systemic treatment for stage IV NSCLC. Patients received atezolizumab (1200 mg) plus pemetrexed (500 mg/m 2 ) and cisplatin (75 mg/m 2 ) or carboplatin (area under the concentration curve, 6 mg/mL/min) (APP arm) or chemotherapy alone (PP arm). The co-primary study endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS) per RECIST 1.1 in the intention-to-treat population. A subgroup analysis was conducted in Japanese patients. In the Japanese subgroup (n = 101), median OS was 30.8 (95% CI, 24.3 to not estimable) mo in the APP arm (n = 48) and 22.2 (95% CI, 15.7-30.8) mo in the PP arm (n = 53; hazard ratio [HR], 0.63 [95% CI, 0.36-1.14]). PFS was 12.8 (95% CI, 8.6-16.6) mo in the APP arm vs 4.5 (95% CI, 4.1-6.7) mo in the PP arm (HR, 0.33 [95% CI, 0.21-0.58]). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 68.8% of APP arm patients and 44.2% of PP arm patients. Consistent with global study results, atezolizumab plus pemetrexed and platinum-based chemotherapy improved efficacy and was well tolerated in Japanese patients with advanced NSCLC despite a higher incidence of grade 3/4 TRAEs., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Abstract: Adenoid cystic carcinoma (ACC) is an infiltrating carcinoma composed of 2 cell types, myoepithelial and ductoglandular epithelial cells. Although approximately 70% of ACC exhibit translocations of the MYB proto-oncogene or MYB proto-oncogene like 1 (MYBL1), expression of MYB is known to be limited in myoepithelial cells. We investigated the histopathologic and genetic characteristics of ACC in 6 primary cutaneous cases. Histopathologically, 3 cases (50%) exhibited well-demarcated nodules composed of large nests, easily misdiagnosed as polymorphous sweat gland carcinoma. Two cases (33%) harbored large cystic structures resembling spiradenoma, hidradenoma, and digital papillary adenocarcinoma. A papillary pattern was focally observed in 2 cases (33%). A melting phenomenon within the myxoid stroma was seen in one case (17%). Fluorescence in situ hybridization (FISH) revealed MYB break-apart in 3 cases (50%). A combined FISH and immunohistochemical method revealed MYB break-apart signals in both p63-positive myoepithelial and p63-negative ductoglandular epithelial cells, suggesting that both cell types constitute elements of the tumor in ACC. Moreover, we established a well-circumscribed variant of ACC and proposed 3 new patterns of cystic, papillary, and melting in addition to the 3 patterns of cribriform, tubular, and solid growth., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: This phase 2 trial evaluated the efficacy and safety of brigatinib in patients with advanced ALK-positive NSCLC refractory to alectinib or other ALK tyrosine kinase inhibitors (TKIs)., Methods: This single-arm, multicenter, open-label study in Japanese patients consisted of a safety lead-in followed by an expansion stage in patients refractory to ALK TKI or those naive for ALK TKI. Patients received brigatinib 180 mg once daily with 7-day lead-in at 90 mg once daily. Primary end point was independent review committee (IRC)-assessed confirmed objective response rate per the Response Evaluation Criteria in Solid Tumors version 1.1., Results: We report the results of the lead-in and expansion in the patients refractory to ALK TKI. Of 72 patients enrolled, 47 had alectinib as most recent ALK TKI (with or without previous crizotinib). At analysis cutoff, 14 of the 47 remained on brigatinib (median follow-up: 12.4 mo). In the alectinib-refractory population, IRC-assessed confirmed objective response rate was 34% (95% confidence interval [CI]: 21%-49%) with median duration of response of 11.8 months (95% CI: 5.5-16.4). Disease control rate was 79% (95% CI: 64%-89%). Median IRC-assessed progression-free survival was 7.3 months (95% CI: 3.7-9.3). Two of eight patients with measurable brain lesions at baseline had confirmed intracranial partial response. Brigatinib has been found to have antitumor activity in patients with G1202R, I1171N, V1180L, and L1196M secondary mutations. The safety profile in Japanese patients was consistent with that in previous reports in broader populations., Conclusions: Brigatinib has been found to have clinically meaningful efficacy in Japanese patients with ALK+ NSCLC refractory to alectinib (with or without previous crizotinib)., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Hyperactive delirium is known to increase family distress and the burden on health care providers. We compared the prevalence and associated factors of agitated delirium in advanced cancer patients between inpatient palliative care and palliative home care on admission and at 3 days before death., Methods: This was a post hoc exploratory analysis of two multicenter, prospective cohort studies of advanced cancer patients, which were performed at 23 palliative care units (PCUs) between Jan and Dec 2017, and on 45 palliative home care services between July and Dec 2017., Results: In total, 2998 patients were enrolled and 2829 were analyzed in this study: 1883 patients in PCUs and 947 patients in palliative home care. The prevalence of agitated delirium between PCUs and palliative home care was 5.2% (95% CI: 4.2% - 6.3%) vs. 1.4% (0.7% - 2.3%) on admission (p < 0.001) and 7.6% (6.4% - 8.9%) vs. 5.4% (4.0% - 7.0%) 3 days before death (p < 0.001). However, multivariate logistic regression analysis revealed that the place of care was not significantly associated with the prevalence of agitated delirium at 3 days before death after adjusting for prognostic factors, physical risk factors, and symptoms., Conclusions: There was no significant difference in the prevalence of agitated delirium at 3 days before death between inpatient palliative care and palliative home care after adjusting for the patient background, prognostic factors, symptoms, and treatment., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The purpose of this study was to determine the efficacy and safety of tolvaptan in Japanese patients with hyponatremia secondary to syndrome of inappropriate secretion of antidiuretic hormone (SIADH). This multicenter, open-label, dose-escalation, phase III study enrolled Japanese patients (20-85 years old) with hyponatremia secondary to SIADH who were unresponsive to fluid restriction. Oral tolvaptan was administered for up to 30 days, initially at 7.5 mg/day, but escalated daily as necessary, based on the serum sodium concentration and safety, over the first 10 days until the optimal maintenance dose was determined for each patient (maximum 60 mg/day). The primary endpoint was the proportion of patients with normalized serum sodium concentration on the day after the final tolvaptan dose. Secondary endpoints included the mean change in serum sodium concentration from baseline on the day after the final dose. Sixteen patients (male, 81.3%; mean ± standard deviation age 71.9 ± 6.1 years) received tolvaptan treatment and 11 patients completed the study with one patient re-administered tolvaptan in the treatment period. Serum sodium concentrations normalized in 13 of 16 (81.3%) patients on the day after the final tolvaptan dose. The mean change in serum sodium concentration from baseline on the day after the final dose was 11.0 ± 4.3 mEq/L. Adverse events considered related to tolvaptan (10 [62.5%] patients) were generally of mild to moderate severity. Oral tolvaptan corrects hyponatremia in Japanese patients with SIADH with a similar efficacy and safety profile as that noted in non-Japanese patients.

Background: The Columbia classification is widely used for diagnosis of focal segmental glomerulosclerosis (FSGS). In practice, we occasionally encounter segmental glomerular lesions unclassified as Columbia classification. We analyzed the clinical implication of unclassified segmental lesions comparing with Columbia-classified FSGS., Methods: A retrospective cohort study from 13 local hospitals in Japan. From 172 biopsy cases diagnosed with FSGS or minimal change disease (MCD)/FSGS spectrum with unclassified segmental lesions, adult patients with nephrotic syndrome who received immunosuppressive therapies were included. The cases are classified by pathology, i.e., typical FSGS lesions sufficiently classified into subgroups of Columbia classification: collapsing (COL), tip (TIP), cellular (CEL), perihilar (PH), and not otherwise specified (NOS), and unclassified by the Columbia classification into three subgroups: "endothelial damage,"; "simple attachment,"; and "minor cellular lesion,". The response to immunosuppressive treatment and 30% decline of eGFR were compared., Results: Among 48 eligible cases, all were Japanese, 34 were typical FSGS; 13 TIP, 15 CEL, 6 NOS, and no COL or PH cases. Fourteen were unclassified cases: endothelial damage (n = 6), simple attachment (n = 5), and minor cellular lesion (n = 3). The median age of overall patients was 60 years old and the median of eGFR and urinary protein creatinine ratio was 51.5 mL/min/1.73m2 and 7.35, respectively. They received similar therapeutic regimen. Kaplan-Meier analysis revealed no significant difference in treatment response between typical FSGS and unclassified cases. Evaluating among the subgroups, endothelial damage, simple attachment and minor cellular lesion showed similar treatment response to TIP or CEL. No significant difference was also observed in the 30% decline of eGFR., Conclusions: Japanese adult patients with nephrotic syndrome showing unclassified segmental lesions as Columbia classification may be equivalent clinical impact as Columbia classification of FSGS., Competing Interests: Shoichi Maruyama has received funding and honoraria from Chugai Pharmaceutical Co. All other authors have declared no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

We aimed to construct a novel population pharmacokinetics (PPK) model of doripenem (DRPM) for Japanese patients in intensive care unit, incorporating the clearance of DRPM by continuous renal replacement therapy (CRRT). Twenty-one patients treated with DRPM (0.25 or 0.5 g) by intravenous infusion over 1 h were included in the study. Nine of the 21 patients were receiving CRRT. Plasma samples were obtained before and 1, 2, 4, 6 and 8 h after the first DRPM administration. PPK analysis was conducted by nonlinear mixed effects modeling using a two-compartment model. Total clearance (CL total ) in the model was divided into CRRT clearance (CL CRRT ) and body clearance (CL body ). The final model was: CL total (L h -1 ) = CL body(non-CRRT)  = 3.65 × (Ccr/62.25) 0.64 in the absence of CRRT, or = CL body(CRRT)  + CL CRRT  = 2.49 × (Ccr/52.75) 0.42  + CL CRRT in the presence of CRRT; CL CRRT  = Q E  × 0.919 (0.919 represents non-protein binding rate of DRPM); V 1 (L) = 10.04; V 2 (L) = 8.13; and Q (L h -1 ) = 3.53. Using this model, CL total was lower and the distribution volumes (V 1 and V 2 ) tended to be higher compared to previous reports. Also, Ccr was selected as a significant covariate for CL body . Furthermore, the contribution rate of CL CRRT to CL total was 30-40%, suggesting the importance of drug removal by CRRT. The population analysis model used in this study is a useful tool for planning DRPM regimen and administration. Our novel model may contribute greatly to proper use of DRPM in patients requiring intensive care.

Introduction: It has been suggested that palliative care integrated into standard cancer treatment from the early phase of the disease can improve the quality of life of patients with cancer. In this paper, we present the protocol for a multicentre randomised controlled trial to examine the effectiveness of a nurse-led, screening-triggered, early specialised palliative care intervention programme for patients with advanced lung cancer., Methods and Analysis: A total of 206 patients will be randomised (1:1) to the intervention group or the control group (usual care). The intervention, triggered with a brief self-administered screening tool, comprises comprehensive need assessments, counselling and service coordination by advanced-level nurses. The primary outcome is the Trial Outcome Index of the Functional Assessment of Cancer Therapy (FACT) at 12 weeks. The secondary outcomes include participants' quality of life (FACT-Lung), depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder-7), illness perception (Prognosis and Treatment Perceptions Questionnaire), medical service use and survival. A mixed-method approach is expected to provide an insight about how this intervention works., Ethics and Dissemination: This study has been approved by the Institutional Review Board of the National Cancer Center Japan (approval number: 2016-235). The findings will be disseminated through peer-reviewed publications and conference presentations and will be reflected on to the national healthcare policy., Trial Registration Number: UMIN000025491., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)