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Aim: To clarify the prevalence and degree of maternal microchimerism in Japanese children with type 1 diabetes, as well as its effect on phenotypic variation. Methods: We studied 153 Japanese children with type 1 diabetes, including 124 children positive for β‐cell autoantibodies, and their 71 unaffected siblings. The number of circulating microchimeric cells per 105 host cells was estimated by the use of quantitative‐polymerase chain reaction targeting non‐transmitted maternal human leukocyte antigen alleles. The results were compared to previous data from white European people. Phenotypic comparison was performed between maternal microchimerism carriers and non‐carriers with diabetes. Results: Maternal microchimerism was detected in 15% of children with autoantibody‐positive type 1 diabetes, 28% of children with autoantibody‐negative type 1 diabetes, and 16% of unaffected siblings. There were no differences in the prevalence or levels of maternal microchimerism among the three groups or between the children with type 1 diabetes and their unaffected siblings. Furthermore, maternal microchimerism carriers and non‐carriers exhibited similar phenotypes. Conclusions: Maternal microchimerism appears to be less common in Japanese children with type 1 diabetes than in white European people. Our data indicate that maternal microchimerism is unlikely to be a major trigger or a phenotypic determinant of type 1 diabetes in Japanese children and that the biological significance of maternal microchimerism in type 1 diabetes may differ among ethnic groups. What's new?: Maternal microchimerism appears to be less common in Japanese children with type 1 diabetes than in white European people with this condition.Circulating microchimeric cells are unlikely to be a major trigger or a phenotypic determinant of type 1 diabetes in Japanese children.The biological significance of maternal microchimerism in type 1 diabetes may differ among ethnic groups. [ABSTRACT FROM AUTHOR]

Aim To examine the contribution of PTPN2 coding variants to the risk of childhood-onset Type 1A diabetes. Methods PTPN2 mutation analysis was carried out for 169 unrelated Japanese people with childhood-onset Type 1A diabetes. We searched for coding variants that were absent or extremely rare in the general population and were scored as damaging by multiple in silico programs. We performed mRNA analysis and three-dimensional structural prediction of the detected variants, when possible. We also examined possible physical links between these variants and previously reported risk SNPs as well as clinical information from variant-positive children. Results One frameshift variant (p.Q286Yfs*24) and two probably damaging missense substitutions (p.C232W and p.R350Q) were identified in one child each. Of these, p.Q286Yfs*24 and p.C232W were hitherto unreported, while p.R350Q accounted for 2/121,122 alleles of the exome datasets. The p.Q286Yfs*24 variant did not encode stable mRNA, and p.C232W appeared to affect the structure of the tyrosine-protein phosphatase domain. The three variants were physically unrelated to known risk SNPs. The variant-positive children manifested Type 1A diabetes without additional clinical features and invariably carried risk human leukocyte antigen alleles. Conclusions The results provide the first indication that PTPN2 variants contribute to the risk of Type 1A diabetes, independently of known risk SNPs. PTPN2 coding variants possibly induce non-specific Type 1A diabetes phenotypes in individuals with human leukocyte antigen-mediated disease susceptibility. Our findings warrant further validation. [ABSTRACT FROM AUTHOR]

Aims A majority of children with Type 1 diabetes in Japan are registered with the government-subsidized Specified Pediatric Chronic Disease Treatment Research Projects ( SPCDTRP). In this study, the incidence and prevalence of childhood-onset (< 15 years) Type 1 diabetes in Japan were estimated by drawing on SPCDTRP data. Methods Data available for 2005-2012 from the SPCDTRP and Statistics Bureau, Ministry of Internal Affairs and Communications were used to estimate the incidence of Type 1 diabetes for 2005-2010, adjusted to cover those registered within 3 years of disease onset and stratified by sex, age at onset and period of onset. Results The incidence of Type 1 diabetes for 2005-2010 was 2.25/100,000 persons [95% confidence intervals (95% CI), 2.14-2.36] (boys: 1.91, 95% CI, 1.83-1.98; girls: 2.52, 95% CI, 2.34-2.69), with that for the age brackets 0-4, 5-9 and 10-14 years being 1.48 (95% CI, 1.29-1.66), 2.27 (95% CI, 2.08-2.47) and 3.00 (95% CI, 2.74-3.25), respectively. The onset of disease was shown to peak at age 13 among boys (3.28, 95% CI, 3.02-3.55) and at age 10 among girls (3.28, 95% CI, 3.02-3.55). The peak periods of disease onset were April/May and December. The number of children aged < 15 years with Type 1 diabetes for 2005-2012 was estimated to be 2326 (95% CI, 2202-2450) with the prevalence estimated as 13.53/100,000 persons (95% CI, 12.63-14.43). Conclusions Study findings demonstrated no increase in the incidence of Type 1 diabetes, although suggesting, in agreement with earlier reports, that the onset of disease peaks in adolescence with a female predominance. In addition, the incidence of childhood-onset diabetes exhibited an annual bimodal pattern in this study. [ABSTRACT FROM AUTHOR]

Aim To examine the contribution of the FUT2 gene and ABO blood type to the development of Type 1 diabetes in Japanese children. Methods We analysed FUT2 variants and ABO genotypes in a total of 531 Japanese children diagnosed with Type 1 diabetes and 448 control subjects. The possible association of FUT2 variants and ABO genotypes with the onset of Type 1 diabetes was statistically examined. Results The se2 genotype (c.385A>T) of the FUT2 gene was found to confer susceptibility to Type 1A diabetes in a recessive effects model [odds ratio for se2/se2, 1.68 (95% CI 1.20-2.35); corrected P value = 0.0075]. Conclusions The FUT2 gene contributed to the development of Type 1 diabetes in the present cohort of Japanese children. [ABSTRACT FROM AUTHOR]

Study design:Cross-sectional study.Objectives:To determine the effect of injury duration on plantar-flexor elastic properties in individuals with chronic spinal cord injury (SCI) and spasticity.Setting:National Rehabilitation Center for Persons with Disabilities, Japan.Methods:A total of 16 chronic SCI patients (age, 33±9.3 years; injury localization, C6-T12; injury duration, 11-371 months) participated. Spasticity of the ankle plantar-flexors was assessed using the Modified Ashworth Scale (MAS). The calf circumference and muscle thickness of the medial gastrocnemius (MG), lateral gastrocnemius and soleus were assessed using tape measure and ultrasonography. In addition, the ankle was rotated from 10° plantar-flexion to 20° dorsiflexion at 5 deg s−1 with a dynamometer, and the ankle angle and torque were recorded. After normalizing the data (the initial points of angle and torque were set to zero), we calculated the peak torque and energy. Furthermore, angle-torque data (before and after normalization) were fitted with a second- and fourth-order polynomial, and exponential (Sten-Knudsen) models, and stiffness indices (SISOP, SIFOP, SISK) and AngleSLACK (the angle at which plantar-flexor passive torque equals zero) were calculated. The stretch reflex gain and offset were determined from 0-10° dorsiflexion at 50, 90, 120 and 150 deg s−1. After logarithmic transformation, Pearson's correlation coefficients were calculated.Results:MAS, calf circumference, MG thickness, peak torque and SIFOP significantly decreased with injury duration (r log-log=−0.63, −0.69, −0.63, −0.53 and −0.55, respectively, P<0.05). The peak torque and SIFOP maintained significant relationships even after excluding impacts from muscle morphology.Conclusion:Plantar-flexor elasticity in chronic SCI patients decreased with increased injury duration. [ABSTRACT FROM AUTHOR]

Study design:A pilot cross-sectional study of patients with acute cervical spinal cord injury (SCI).Objectives:The precise evaluation of the severity of SCI is important for developing novel therapies. Although several biomarkers in cerebrospinal fluid have been tested, few analyses of blood samples have been reported. A novel biomarker for axonal injury, phosphorylated form of the high-molecular-weight neurofilament subunit NF-H (pNF-H), has been reported to be elevated in blood from rodent SCI model. The aim of this study is to investigate whether pNF-H values in blood can serve as a biomarker to evaluate the severity of patients with SCI.Setting:Tokyo Metropolitan Bokutoh Hospital and National Rehabilitation Center, Japan.Methods:This study enrolled 14 patients with acute cervical SCI. Sequential plasma samples were obtained from 6 h to 21 days after injury. Patients were classified according to American Spinal Injury Association impairment scale (AIS) at the end of the follow-up (average, 229.1 days). Plasma pNF-H values were compared between different AIS grades.Results:In patients with complete SCI, pNF-H became detectable at 12 h after injury and remained elevated at 21 days after injury. There was a statistically significant difference between AIS A (complete paralysis) patients and AIS C (incomplete paralysis) patients.Conclusions:Plasma pNF-H was elevated in accordance with the severity of SCI and reflected a greater magnitude of axonal damage. Therefore, pNF-H is a potential biomarker to independently distinguish AIS A patients (complete SCI) from AIS C-E patients (incomplete SCI). However, further studies are required to evaluate its utility in predicting prognosis of patients in the incomplete category. [ABSTRACT FROM AUTHOR]

Study design:An in vivo study in a rat model of acute spinal cord contusion.Objectives:To assess the efficacy of novel therapies for acute spinal cord injury (SCI), methods to evaluate accurately the effects of these therapies should be developed. Although neurological examination is commonly used for this purpose, unstable clinical conditions and the spontaneous recovery of neurological function in the acute and subacute phases after injury make this measurement unreliable. Recent studies have reported that the phosphorylated form of the high-molecular-weight neurofilament subunit NF-H (pNF-H), a new biomarker for axonal degeneration, can be measured in serum samples in experimental SCI animals. Therefore, we aimed to investigate the use of plasma pNF-H as an indicator of the efficacy of minocycline, a neuroprotective drug, for treating SCI.Setting:This study was carried out at Saitama, Japan.Methods:Spinal cord injured rats received either minocycline or saline intraperitoneally. The plasma pNF-H levels and functional hind limb score were determined after the injury.Results:Minocycline treatment reduced plasma pNF-H levels at 3 and 4 days post-injury (dpi). Rats with lower plasma pNF-H levels at 3 dpi had higher hind limb motor score at 28 dpi.Conclusions:pNF-H levels may serve as a biomarker for evaluating the efficacy of therapies for SCI. [ABSTRACT FROM AUTHOR]

To determine the anatomical basis for differences in fruit size in Japanese persimmon (Diospyros kaki Thunb.), the number and sizes of parenchymal cells were measured in four astringent cultivars and in wild D. lotus over a single season in Japan. Fruit weight at harvest correlated with the final number of parenchymal cells (r = 0.95*) and their size (r = 0.92*). There was also a correlation between fruit diameter and the number of cell layers at full bloom (r = 0.93*), which increased 1.7- 1.9-fold during fruit development. The duration of cell division and the sizes of the cells at full bloom were similar among the cultivars, whereas mean parenchymal cell lengths increased by 7.7-, 6.7-, 5.4-, 5.0- and 3.8-fold from full bloom to harvest in 'Otanenashi' (average fruit diameter = 96 mm), 'Hiratanenashi' (77 mm), 'Saijo' (54 mm), 'Tsurunoko' (44 mm), and D. lotus (20 mm), respectively. The final size of tannin cells was larger in 'Otanenashi' and 'Hiratanenashi' than in the other cultivars, including the wild species. These results indicate that the size of fruit at harvest was determined by the number of cells at full bloom, and their expansion during fruit development. [ABSTRACT FROM AUTHOR]

Unlabelled: Previous studies have indicated that Japanese children grow and mature significantly faster than Caucasian children, thus calling for a separate reference standard for each skeletal and sexual maturity index. To establish normal reference values for testicular volume in Japanese boys, we studied from 1985 to 1995, 900 healthy male children of 0 to 15 years of age for medical history, physical examination, height, weight, sitting height, and head circumference measurements, Tanner sex maturity stage, and testicular size. The testicular volume was determined using a Prader orchidometer by the same observer (N.M.). Based on these data, we established the cross-sectional percentile growth curves (90th, 50th, 10th percentiles) for testicular volume of Japanese boys. The testicular volume of 3 ml was attained at 9.3 years of age (90th percentile), 11.0 years of age (50th percentile), and 12.1 years of age (10th percentile), respectively.Conclusion: Swelling of the testis in Japanese children begins approximately 1 year earlier than in Swiss children in accordance with the earlier skeletal maturation in Japanese children. [ABSTRACT FROM AUTHOR]

Purpose: We investigated potential risk factors for visual prognosis in Japanese patients with exogenous endophthalmitis., Methods: In this retrospective observational multicenter cohort study, risk factors for legal blindness at 12 weeks after treatment initiation were evaluated based on patient characteristics, initial BCVA, causative events, pathogens, ocular symptoms, duration from symptom onset to initial treatment, and selected treatments., Results: Overall, 23.1% of eyes developed legal blindness. The six risk factors for legal blindness were presence of eye pain, pathogen identification, poor BCVA at the initial visit, longer duration from symptom onset to initial treatment, type of causative event, and type of causative pathogen. Regarding the type of causative pathogen, coagulase-negative staphylococci was associated with a better visual impairment outcome., Conclusion: Exogenous endophthalmitis remains a severe ocular infection; however, it can be managed with rapid treatment, as well as other advances in medical knowledge and technology.

We calculated attack rates for household contacts of COVID-19 patients during the SARS-CoV-2 Omicron BA.2-dominant period in Japan. Attack rates among household contacts without recent (<3 months) vaccination was lower for contacts of index patients with complete vaccination than for contacts of index patients without complete vaccination, demonstrating indirect vaccine effectiveness.

Background: First-line pembrolizumab plus chemotherapy (pembrolizumab-chemotherapy) demonstrated improved efficacy and a manageable safety profile versus placebo plus chemotherapy (placebo-chemotherapy) in the subgroup analysis of Japanese patients with advanced/metastatic esophageal cancer in KEYNOTE-590 at a median follow-up of 24.4 months. Longer-term data from the Japanese subgroup analysis of KEYNOTE-590 are reported., Methods: Patients were randomly assigned 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for ≤ 35 cycles plus chemotherapy (cisplatin 80 mg/m 2 and 5-fluorouracil 800 mg/m 2 /day). Endpoints included overall survival (OS) and progression-free survival (PFS; investigator-assessed per RECIST v1.1; dual primary) and safety (secondary). Early tumor shrinkage (ETS) and depth of response (DpR) were assessed post hoc., Results: Overall, 141 patients were enrolled in Japan. As of July 9, 2021, median follow-up was 36.6 months (range, 29.8-45.7). Pembrolizumab-chemotherapy showed a trend toward favorable OS (hazard ratio [HR], 0.70; 95% confidence interval [CI] 0.47-1.03) and PFS (0.57; 0.39-0.83) versus placebo-chemotherapy. In the pembrolizumab-chemotherapy group, patients with ETS ≥ 20% (55/74; 74.3%) versus < 20% (19/74; 25.7%) had favorable OS (HR, 0.23; 95% CI 0.12-0.42) and PFS (0.24; 0.13-0.43). Patients with DpR ≥ 60% (31/74; 41.9%) versus < 60% (43/74; 58.1%) had favorable OS (HR, 0.37; 95% CI 0.20-0.68) and PFS (0.24; 0.13-0.43). Grade 3-5 treatment-related adverse events occurred in 55/74 patients (74.3%) with pembrolizumab-chemotherapy and 41/67 patients (61.2%) with placebo-chemotherapy., Conclusions: With longer-term follow-up of Japanese patients with advanced/metastatic esophageal cancer, efficacy continued to favor pembrolizumab-chemotherapy compared with placebo-chemotherapy, with no new safety signals observed., Clinical Trial Registration: ClinicalTrials.gov, NCT03189719., (© 2024. The Author(s).)

Silver-Russell syndrome (SRS) is a representative imprinting disorder characterized by pre- and postnatal growth failure. We encountered two Japanese SRS cases with a de novo pathogenic frameshift variant of HMGA2 (NM&#95;003483.6:c.138&#95;141delinsCT, p.(Lys46Asnfs*16)) and a de novo ~ 3.4 Mb microdeletion at 12q14.2-q15 involving HMGA2, respectively. Furthermore, we compared clinical features in previously reported patients with various genetic conditions leading to compromised IGF2 expression, i.e., HMGA2 aberrations, PLAG1 aberrations, IGF2 aberrations, and H19/IGF2:IG-DMR epimutations (hypomethylations). The results provide further support for HMGA2 being involved in the development of SRS and imply some characteristic features in patients with HMGA2 aberrations., (© 2024. The Author(s).)

We report three Japanese patients with Sotos syndrome accompanied by marked overgrowth, i.e., a 2 8/12-year-old boy with a height of 105.2 cm (+4.4 SD) (patient 1), the mother of patient 1 with a height of 180.8 cm (+4.1 SD) (patient 2), and a 12 10/12-year-old girl with a height of 189.4 cm (+6.3 SD) (patient 3). In addition to the marked overgrowth (tall stature), patients 1-3 exhibited Sotos syndrome-compatible macrocephaly and characteristic features, whereas intellectual and developmental disabilities remained at a borderline level in patient 1 and were apparently absent from patients 2 and 3. Thus, whole exome sequencing was performed to confirm the diagnosis, revealing a likely pathogenic c.6356A>G:p.(Asp2119Gly) variant in NSD1 of patients 1 and 2, and a likely pathogenic c.6599dupT:p.(Ser2201Valfs*4) variant in NSD1 of patient 3 (NM&#95;022455.5). The results, in conjunction with the previously reported data in nine patients with marked overgrowth (≥4.0 SD), imply that several patients with Sotos syndrome have extreme tall stature even in adulthood. Thus, it is recommended to examine NSD1 in patients with marked overgrowth as the salient feature.

Prader-Willi syndrome (PWS) is a multisystem disorder with increased mortality predominantly due to obesity-associated complications; therefore, the management of obesity has been centric to therapeutic strategies for PWS. Although a multidisciplinary team approach has been successful for this purpose during childhood, it is generally difficult to implement during adulthood because of the lack of a structured transitional care program. A more detailed understanding of the current medical conditions of adults with PWS is needed to establish this program; however, limited information is currently available on this issue in Japan. Accordingly, we performed a questionnaire-based survey on 425 patients with PWS. There were 162 adult patients aged 18 years or older with median body mass indexes (kg/m 2 ) of 29.4 and 30.4 in males and females, respectively. The frequencies of type 2 diabetes mellitus (T2DM) and hypertension in adults with PWS were 40.4 and 19.4%, respectively. Growth hormone (GH) therapy during childhood correlated with lower rates of T2DM and hypertension during adulthood. Among adult patients, 54% were treated by pediatricians, whereas 44% were seen by internists with an endocrinologist/diabetologist being the most prevalent. Adult patients treated with GH during childhood showed a higher rate of being seen by pediatricians than those without, demonstrating that the multidisciplinary team approach, typically applied with GH therapy, may be continuously provided even after they reach adulthood. These results emphasize the importance of the seamless provision of the multidisciplinary team approach, which is of clinical importance for establishing an optimal transitional care program for PWS.

Background: A regional cancer hospital has been identified to be crucial in the management of malignancies of undefined primary origin (MUO) and cancer of unknown primary (CUP). This hospital primarily consists of oncologists with expertise in CUP, pathologists, and interventional radiologists. Early consultation or referral of MUO and CUP to a cancer hospital is deemed important., Methods: This study retrospectively collected and analyzed the clinical, pathological, and outcome data of all patients (n = 407) referred to the Aichi Cancer Center Hospital (ACCH) in Japan over an 8-year period., Results: In total, 30% of patients were referred for a second opinion. Among 285 patients, 13% had non-neoplastic disease or confirmed primary site and 76% had confirmed CUP (cCUP), with 29% of cCUP being identified as favorable risk. In 155 patients with unfavorable-risk CUP, 73% had primary sites predicted by immunohistochemistry (IHC) and distribution of metastatic sites, whereas 66% of them received site-specific therapies based on the predicted primary sites. The median overall survival (OS) was found to be poor in patients with MUO (1 month) and provisional CUP (6 months). In addition, the median OS of 206 patients with cCUP treated at the ACCH was 16 months (favorable risk, 27 months; unfavorable risk, 12 months). No significant difference was noted in OS between patients with non-predictable and predictable primary-sites (13 vs 12 months, p = 0.411)., Conclusion: The outcome of patients with unfavorable-risk CUP remains to be poor. Site-specific therapy based on IHC is not recommended for all patients with unfavorable-risk CUP., (© 2023. The Author(s).)

There is currently great interest in the salt-tolerant yeast strains used to produce miso and soy sauce. Since the isolation of Zygosaccharomyces sp. strain from Japanese miso more than 60 years, several hybrid strains have been identified in fermented foods. Studies have shown that the active mating-type locus of the original Zygosaccharomyces sp. yeast strain is located between the T-subgenome sequence and the P-subgenome sequence. In this study, 32 salt-tolerant Zygosaccharomyces sp. yeast strains were isolated from five miso factories in Hiroshima Prefecture, Japan. Analysis by flow cytometry revealed that 27 strains were diploid and five strains were haploid. PCR analysis indicated that the 27 diploid strains had the same chromosomal structure of the active mating-type (MAT) locus as the original yeast strain isolated from miso 60 years ago. In addition, the 27 diploid strains were allodiploid, namely, natural hybrids of Z. rouxii and a related species, while the five haploid strains were all Z. rouxii. We found that cells of yeast strains isolated from miso changed morphologically when co-cultured with a yeast strain of opposite mating-type under nitrogen starvation conditions. The DNA sequence of the active mating-type locus and the results of cell morphology changes by co-culture were consistent with the mating type of each strain shown in the mating experiments. These findings will be useful for the future production of miso and soy sauce.

The mean virus incubation period during the SARS-CoV-2 Omicron BA.5-dominant period in Japan was 2.6 (95% CI 2.5-2.8) days, which was less than during the Delta-dominant period. Incubation period correlated with shared meals and adult infectors. A shorter incubation suggests a shorter quarantine period for BA.5 than for other variants.

We report clinical and molecular findings in three Japanese patients with N-acetylneuraminic acid synthetase-congenital disorder of glycosylation (NANS-CDG). Patient 1 exhibited a unique constellation of clinical features including marked hydrocephalus, spondyloepimetaphyseal dysplasia (SEMD), and thrombocytopenia which is comparable to that of an infant reported by Faye-Peterson et al., whereas patients 2 and 3 showed Camera-Genevieve type SMED with intellectual/developmental disability which is currently known as the sole disease name for NANS-CDG. Molecular studies revealed a maternally inherited likely pathogenic c.207del:p.(Arg69Serfs*57) variant and a paternally derived likely pathogenic c.979&#95;981dup:p.(Ile327dup) variant in patient 1, a homozygous likely pathogenic c.979&#95;981dup:p.(Ile327dup) variant caused by maternal segmental isodisomy involving NANS in patient 2, and a paternally inherited pathogenic c.133-12T>A variant leading to aberrant splicing and a maternally inherited likely pathogenic c.607T>C:p.(Tyr203His) variant in patient 3 (reference mRNA: NM&#95;018946.4). The results, together with previously reported data, imply that (1) NANS plays an important role in postnatal growth and fetal brain development; (2) SMED is recognizable at birth and shows remarkable postnatal evolution; (3) NANS-CDG is associated with low-normal serum sialic acid, obviously elevated urine N-acetylmannosamine, and normal N- and O-glycosylation of serum proteins; and (4) NANS-CDG is divided into Camera-Genevieve type and more severe Faye-Peterson type., (© 2022. The Author(s).)

Background: The phase 3 KEYNOTE-590 (NCT03189719) study showed first-line pembrolizumab plus chemotherapy significantly prolonged overall survival and progression-free survival versus placebo plus chemotherapy in patients with advanced unresectable or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type I adenocarcinoma of the esophagogastric junction. We describe a subgroup analysis of Japanese patients from KEYNOTE-590., Methods: Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg intravenously every 3 weeks or placebo plus chemotherapy (cisplatin 80 mg/m 2 and 5-fluorouracil 800 mg/m 2 /day). Efficacy was evaluated in all Japanese patients and those with esophageal squamous cell carcinoma and programmed death ligand 1 combined positive score ≥ 10. Dual primary endpoints were overall survival and progression-free survival per RECIST v1.1 by investigator. Secondary endpoints included objective response rate per RECIST v1.1 by investigator and safety and tolerability., Results: At data cutoff (July 2, 2020), 141 Japanese patients were randomly assigned (pembrolizumab plus chemotherapy, 74; placebo plus chemotherapy, 67). In all Japanese patients, median overall survival was 17.6 months with pembrolizumab plus chemotherapy versus 11.7 months with chemotherapy (hazard ratio, 0.71; 95% confidence interval, 0.47-1.09), median progression-free survival was 6.3 versus 6.0 months (hazard ratio, 0.58; 95% confidence interval, 0.40-0.84), and objective response rate was 56.8% versus 38.8%. Grade 3-5 treatment-related adverse events were 74.3% and 61.2%., Conclusion: First-line pembrolizumab plus chemotherapy demonstrated improvement in overall survival and progression-free survival compared with placebo plus chemotherapy in Japanese patients with advanced/metastatic esophageal cancer; safety was comparable between treatment groups., Clinical Trial Registry: ClinicalTrials.gov, NCT03189719., (© 2022. Merck & Co., Inc., Rahway, NJ, USA and its affiliates and Takashi Kojima, Hiroki Hara, Akihito Tsuji, Hisateru Yasui, Kei Muro, Taroh Satoh, Takashi Ogata, Ryu Ishihara, Masahiro Goto, Hideo Baba, Tomohiro Nishina, Toshihiko Doi, Ken Kato.)

Objective: Equol is an active metabolite of soy isoflavone. As a phytoestrogen, equol has the potential to prevent metabolic disorders such as hyperglycemia, hyperlipidemia, and obesity. This study aimed to determine the association between equol production and metabolic syndrome (METS) in postmenopausal women., Methods: This cross-sectional study included 1,345 women aged 50 to 69 years who underwent health checkups from February 2018 to November 2021 at four health centers in Fukushima, Japan. Equol producers were defined as those with a urinary equol concentration of 1.0 μM or more. METS was defined based on Japanese diagnostic criteria including abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, and glucose intolerance. The association between equol production and METS was estimated by logistic regression analysis, with adjustments for age, exercise, physical activity, and fast walking., Results: Of the 1,345 women, 378 (28.1%) were equol producers. The proportion of women who had METS (6.6% vs 10.9%) was significantly lower in the equol-producing group than in the nonproducing group. Multivariable logistic regression analysis revealed that equol production was significantly associated with METS (odds ratio, 0.60; 95% CI, 0.38-0.95)., Conclusions: Equol production was associated with a lower prevalence of METS among women aged 50 to 69 years., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2022 by The North American Menopause Society.)

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge 1-5 . Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target., (© 2022. The Author(s).)

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection., (© 2022. The Author(s).)

This study investigated the household secondary attack rate (HSAR) of patients with coronavirus disease (COVID-19) during the omicron variant-dominant period. The HSAR of COVID-19 cases during the omicron variant-dominant period (4-20 January 2022) was calculated and compared with the delta variant-dominant period (20 August to 7 November 2021) in Itako, Japan. In Itako, all 47 and 119 samples tested during the omicron and delta variant-dominant periods were negative and positive, respectively, for the L452R mutation. We used a generalized estimating equation regression model. The HSAR was 31.8% (95% confidence interval (CI) 27.7-36.2) for 456 household contacts during the omicron variant-dominant period; it was higher than that during the delta variant-dominant period (25.2%) (adjusted risk ratio [aRR] 1.61, CI 1.13-2.28). During the omicron variant-dominant period, HSAR was lower for the household contacts of completely vaccinated index patients (27.3%) than for contacts of other index patients (41.2%) (vaccine effectiveness for infectee 0.43, 95% CI 0.16-0.62) and was significantly higher for female contacts than for male contacts (36.2% vs. 26.1%; aRR 1.29, 95% CI 1.01-1.65). The HSAR was significantly higher during the omicron variant-dominant period than the delta variant-dominant period. The vaccination of index patients might protect household contacts.

We aimed to elucidate the range of the incubation period in patients infected with the SARS-CoV-2 Omicron variant in comparison with the Alpha variant. Contact tracing data from three Japanese public health centers (total residents, 1.06 million) collected following the guidelines of the Infectious Diseases Control Law were reviewed for 1589 PCR-confirmed COVID-19 cases diagnosed in January 2022. We identified 77 eligible symptomatic patients for whom the date and setting of transmission were known, in the absence of any other probable routes of transmission. The observed incubation period was 3.03 ± 1.35 days (mean ± SDM). In the log-normal distribution, 5th, 50th and 95th percentile values were 1.3 days (95% CI: 1.0−1.6), 2.8 days (2.5−3.1) and 5.8 days (4.8−7.5), significantly shorter than among the 51 patients with the Alpha variant diagnosed in April and May in 2021 (4.94 days ± 2.19, 2.1 days (1.5−2.7), 4.5 days (4.0−5.1) and 9.6 days (7.4−13.0), p < 0.001). As this incubation period, mainly of sublineage BA.1, is even shorter than that in the Delta variant, it is thought to partially explain the variant replacement occurring in late 2021 to early 2022 in many countries.

This study aimed to elucidate the household secondary attack rate (HSAR) of the Delta variant in comparison to the Alpha variant, and evaluate the risk factors among unvaccinated household contacts of patients with coronavirus disease 2019 (COVID-19). We studied household contacts of index cases of COVID-19 infected with Delta (L452R mutation), Alpha (N501Y mutation), and wild strain from December 2020 through November 2021 in Itako, Japan. The HSARs of the entire household contact, and the contact of index case with Delta variant were calculated and compared across the risk factors. We used a generalized estimating equation regression model for the multivariate analysis. We enrolled 1257 unvaccinated contacts from 580 households. The HSAR was higher in household contacts of index patients with Delta (48.5%) than with Alpha variant (21.7%) (aOR = 3.34, p = 0.000). In Delta variants, the HSAR was higher in household contacts with spousal relationships to index patients (63.4%) than contacts with other relationships (45.5%) (aOR 1.94, p = 0.026), and was lower in household contacts of index patients aged ≤19 (33.1%) than for contacts of index cases aged 20-59 years (52.6%) (aOR = 0.50, p = 0.027). The result of our study can be used to devise informed strategy to prevent transmission within households.

Few studies have assessed incubation periods of the severe acute respiratory syndrome coronavirus 2 Delta variant. This study aimed to elucidate the transmission dynamics, especially the incubation period, for the Delta variant compared with non-Delta strains. We studied unvaccinated coronavirus disease 2019 patients with definite single exposure date from August 2020 to September 2021 in Japan. The incubation periods were calculated and compared by Mann-Whitney U test for Delta (with L452R mutation) and non-Delta cases. We estimated mean and percentiles of incubation period by fitting parametric distribution to data in the Bayesian statistical framework. We enrolled 214 patients (121 Delta and 103 non-Delta cases) with one specific date of exposure to the virus. The mean incubation period was 3.7 days and 4.9 days for Delta and non-Delta cases, respectively ( p -value = 0.000). When lognormal distributions were fitted, the estimated mean incubation periods were 3.7 (95% credible interval (CI) 3.4-4.0) and 5.0 (95% CI 4.5-5.6) days for Delta and non-Delta cases, respectively. The estimated 97.5th percentile of incubation period was 6.9 (95% CI 5.9-8.0) days and 10.4 (95% CI 8.6-12.7) days for Delta and non-Delta cases, respectively. Unvaccinated Delta variant cases had shorter incubation periods than non-Delta variant cases.

Background: Safe and effective treatments for advanced esophageal cancer are an unmet need in Japan. We report results of a subgroup analysis of Japanese patients enrolled in KEYNOTE-181, a randomized, open-label, phase 3 study of pembrolizumab versus chemotherapy as second-line therapy for patients with advanced or metastatic esophageal cancer whose disease progressed after standard first-line therapy., Methods: Patients were randomly assigned 1:1 to receive pembrolizumab 200 mg every 3 weeks or investigator's choice of paclitaxel, docetaxel, or irinotecan. Efficacy was evaluated in all Japanese patients and in those with programmed death ligand 1 combined positive score ≥ 10., Results: Of the 152 Japanese patients enrolled (pembrolizumab, n = 77; chemotherapy, n = 75), 150 (98.7%) had squamous cell carcinoma and 79 (52.0%) had combined positive score ≥ 10. At the final analysis, median overall survival was improved among all patients (12.4 vs 8.2 months with pembrolizumab and chemotherapy, respectively; hazard ratio, 0.68; 95% CI 0.48-0.97) and patients with combined positive score ≥ 10 (12.6 vs 8.4 months; hazard ratio, 0.68; 95% CI 0.42-1.10). Fewer patients had any-grade (74.0% vs 95.9%) or grade 3-5 (16.9 vs 50.0%) treatment-related adverse events with pembrolizumab than with chemotherapy., Conclusion: Consistent with the global trial results, second-line pembrolizumab therapy showed a survival benefit and a favorable safety profile compared with chemotherapy in Japanese patients with advanced esophageal cancer., (© 2021. The Author(s).)

Background: The latest clinical guidelines are mandatory for physicians to follow when practicing evidence-based medicine in the treatment of low back pain. Those guidelines should target not only Japanese board-certified orthopaedic surgeons, but also primary physicians, and they should be prepared based entirely on evidence-based medicine. The Japanese Orthopaedic Association Low Back Pain guideline committee decided to update the guideline and launched the formulation committee. The purpose of this study was to describe the formulation we implemented for the revision of the guideline with the latest data of evidence-based medicine., Methods: The Japanese Orthopaedic Association Low Back Pain guideline formulation committee revised the previous guideline based on a method for preparing clinical guidelines in Japan proposed by Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014. Two key phrases, "body of evidence" and "benefit and harm balance" were focused on in the revised version. Background and clinical questions were determined, followed by literature search related to each question. Appropriate articles were selected from all the searched literature. Structured abstracts were prepared, and then meta-analyses were performed. The strength of both the body of evidence and the recommendation was decided by the committee members., Results: Nine background and nine clinical qvuestions were determined. For each clinical question, outcomes from the literature were collected and meta-analysis was performed. Answers and explanations were described for each clinical question, and the strength of the recommendation was decided. For background questions, the recommendations were described based on previous literature., Conclusions: The 2019 clinical practice guideline for the management of low back pain was completed according to the latest evidence-based medicine. We strongly hope that this guideline serves as a benchmark for all physicians, as well as patients, in the management of low back pain., Competing Interests: Conflict of interest All guideline formulation committee members confirmed the COI through self-reporting. No companies or any other organizations were directly involved in any text pertaining to the guideline, including the recommendations for all CQs and BQs., (Copyright © 2021. Published by Elsevier B.V.)

Five years of datasets from 2015 to 2019 of whole genome shotgun sequencing for cells trapped on 0.2-µm filters of seawater collected monthly from Ofunato Bay, an enclosed bay in Japan, were analysed, which included the 2015 data that we had reported previously. Nucleotide sequences were determined for extracted DNA from three locations for both the upper (1 m) and deeper (8 or 10 m) depths. The biotic communities analysed at the domain level comprised bacteria, eukaryotes, archaea and viruses. The relative abundance of bacteria was over 60% in most months for the five years. The relative abundance of the SAR86 cluster was highest in the bacterial group, followed by Candidatus Pelagibacter and Planktomarina. The relative abundance of Ca. Pelagibacter showed no relationship with environmental factors, and those of SAR86 and Planktomarina showed positive correlations with salinity and dissolved oxygen, respectively. The bacterial community diversity showed seasonal changes, with high diversity around September and low diversity around January for all five years. Nonmetric multidimensional scaling analysis also revealed that the bacterial communities in the bay were grouped in a season-dependent manner and linked with environmental variables such as seawater temperature, salinity and dissolved oxygen., (© 2021. The Author(s).)

Household secondary attack rate (HSAR) by risk factor might have a higher transmission rate between spouses. We investigated risk factors for the HSAR among non-spousal household contacts of patients with coronavirus disease 2019 (COVID-19). We studied household contacts of index cases of COVID-19 in Tsuchiura, Japan, from August 2020 through February 2021. The HSARs of the whole household contacts and non-spousal household contacts were calculated and compared across risk factors. We used a generalized linear mixed regression model for multivariate analysis. We enrolled 496 household contacts of 236 index COVID-19 cases. The HSAR was higher for spousal household contacts (37.8%) than for other contacts (21.2%). The HSAR was lower for non-spousal household contacts with a household size (number of household members) of two (18.2%), compared to the HSAR for contacts with a household size ≥4. The HSAR was higher for non-spousal household contacts of index patients with ≥3 days of diagnostic delay (period between onset and diagnosis) (26.0%) compared to those with ≤2 days' delay (12.5%) ( p = 0.033). Among non-spousal household contacts, the HSAR was low for those with a household size of two and was high for contacts of index patients with a long diagnostic delay.

Objectives　There is little evidence supporting the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from presymptomatic or asymptomatic SARS-CoV-2-infected individuals in Japan, where the incidence of SARS-CoV-2 infection is lower than that in other developed countries. This study aimed to determine whether SARS-CoV-2 transmission can occur from presymptomatic or asymptomatic SARS-CoV-2-infected individuals.Methods　We surveyed all directors of Japanese public health centers for index cases and secondary patients who possibly contracted SARS-CoV-2 infection from a presymptomatic or asymptomatic SARS-CoV-2-infected individual who came under their care before June 20, 2020. The professional staff at the centers routinely perform contact tracing of infected persons based on the guidelines of the Infection Control Act. Four authors independently reviewed reports of 9 index cases of SARS-CoV-2-infected individuals with 17 secondary patients from 8 prefectures and examined the cases to determine whether transmission from a SARS-CoV-2-infected individual in the presymptomatic or asymptomatic state occurred.Results　We reported 7 index cases with 13 secondary patients. 1) An elderly woman acquired SARS-CoV-2 infection from her sustained asymptomatic granddaughter at home, 2) 4 guests and 1 accompanying child waiting at a hair salon acquired infection from the presymptomatic female hair stylist, 3) 2 inpatients acquired infection from a presymptomatic nurse while providing nursing care in close contact, 4) an elderly couple acquired SARS-CoV-2 infection from their presymptomatic relative who was in the 50s during household care at their home, 5) a man acquired SARS-CoV-2 infection from a presymptomatic adult neighbor in an enclosed space with poor ventilation, 6) a presymptomatic man had transmitted infection to another man at a coffee shop while having a discussion on business, and 7) a man in his 50s acquired SARS-CoV-2 infection from a presymptomatic man during 50 minutes of close contact at their office and in a car. These secondary patients had no other likely routes of infection. The interval between the date of symptom onset in the presymptomatic index case and the secondary patient ranged from 2 to 6 days. The incidence rates at the time these infections occurred in the corresponding prefectures ranged from 0.00 to 6.56 cases/1 million person-days.Conclusion　We report the first case of SARS-CoV-2 transmission from a sustained asymptomatic index case in Japan. All secondary patients came into close contact with presymptomatic index cases in areas with poor ventilation.

To assess the relative transmissibility of the SARS-CoV-2 Alpha variant compared to the pre-existing SARS-CoV-2 in Japan, we performed a cross-sectional study to determine the secondary attack rate of COVID-19 in household contacts before and after the Alpha variant became dominant in Osaka. We accessed 290 household contacts whose index cases were diagnosed between 1 and 20 December 2020 (the third epidemic group), at a time when Osaka was free of the Alpha variant. We also accessed 398 household contacts whose index cases were diagnosed between 20 April and 3 May 2021 (the fourth epidemic group), by which time the Alpha variant had become dominant. We identified 124 household contacts whose index case was determined positive for the Alpha variant (Alpha group) in this fourth group. The secondary attack rates in the fourth group (34.7%) and the Alpha group (38.7%) were significantly higher than that in the third group (19.3%, p < 0.001). Multivariable Poisson regression analysis with a robust error variance showed a significant excess risk in the fourth group (1.90, 95% CI = 1.47-2.48) and the Alpha group (2.34, 95% CI = 1.71-3.21). This finding indicates that the SARS-CoV-2 Alpha variant has an approximately 1.9-2.3-fold higher transmissibility than the pre-existing virus in the Japanese population.

Background: Congenital limb deficiency is a rare anomaly that impairs limb function. Transverse deficiency accounts for approximately half of congenital limb deficiency cases. In Japan, there have been no detailed data of clinical features, especially treatment approaches, of this disorder. The present study aimed to investigate the status of treatment approaches of congenital transverse limb deficiency in Japan., Methods: From the national epidemiological survey of congenital limb deficiency undertaken in Japan in 2016, all the data of 200 patients with congenital transverse limb deficiencies were extracted. These data were analysed to reveal the treatment approaches of congenital transverse limb deficiency and its basic clinical features., Results: Surgical treatments and prosthetic or orthotic intervention had been implemented or planned for about one-quarter of patients, respectively. In the upper limb deficiencies, prosthetic or orthotic intervention was likely chosen in cases of deficiency at the metacarpal or proximal to metacarpal level. Surgical treatment was chosen only in cases of deficiency at the carpal or distal to carpal level. Although the number of patients with transverse lower limb deficiencies was small, prosthetic or orthotic intervention was likely chosen in proximal deficiencies, and surgical treatment was likely chosen in distal deficiencies., Conclusions: Herein, we revealed the status of treatment approaches for congenital transverse limb deficiency in Japan. Approximately half of the patients had no history of-and no plans for-surgical, prosthetic, or orthotic interventions. Further treatment advances may enable patients with congenital limb deficiencies to increase their participation in daily activities., Study Design: Cross-sectional survey., (Copyright © 2020. Published by Elsevier B.V.)

Reports on irradiation dose distribution in breast cancer radiotherapy with sufficient sample size are limited in Asian patients. Elucidating dose distribution in Asian patients is particularly important as their breast volume differs compared to patients in Europe and North America. Here, we examined dose distribution in the irradiation field relative to breast volume for three irradiation methods historically used in our facility. We investigated the influence of breast volume on each irradiation method for Asian women. A total of 573 women with early-stage breast cancer were treated with breast-conserving surgery and adjuvant radiotherapy. Three methods were compared: wedge (W), field-in-field (FIF), and wedge-field-in-field (W-FIF). In patients with small breast volume, FIF decreased low- and high-dose areas within the planning target volume, and increased optimal dose area more than W. In patients with medium and large breast volumes, FIF decreased high-dose area more than W. The absolute values of correlation coefficients of breast volume to low-, optimal-, and high-dose areas and mean dose were significantly lower in FIF than in W. The correlation coefficients of V107% were 0.00 and 0.28 for FIF and W, respectively. FIF is an excellent irradiation method that is less affected by breast volume than W in Asian breast cancer patients., Competing Interests: No potential conflict of interest relevant to this article was reported.

Context: Aromatase excess syndrome (AEXS) is a very rare disorder characterized by prepubertal gynecomastia, bone age acceleration, and early growth arrest. Heterozygote submicroscopic rearrangements within the promotor of CYP19A1 result in overexpression of aromatase and enhanced aromatization of androgens., Objective: The objective was to study long-term treatment effects of an aromatase inhibitor., Methods: Data from 7 boys with AEXS were retrospectively collected. Genetic analysis revealed upstream of CYP19A1 a 165 901 bp deletion in 4 German cousins, a 198 662 bp deletion in 2 Japanese brothers, and a 387 622 bp tandem duplication in a Japanese boy., Results: All boys developed prepubertal gynecomastia, at median 9.0 years of age (range: 7.0-11.0). Height was +1.20 standard deviation score (SDS) (-0.24 to +1.98); predicted adult height was -1.29 SDS (-3.29 to +1.09). Four boys were treated with 1.0 mg of anastrozole daily, while 3 reached adult height untreated. Treatment with anastrozole was stopped after 5.6 years (4.0-6.8). Three treated boys exceeded their prognosis by 2.4, 6.9, and 8.1 cm, while 1 untreated boy fell below the prognosis by 8.6 cm. One treated with a low dose and 2 untreated reached their prognosis. Adult heights were -0.91 SDS with anastrozole (-2.86 to -0.29) and -0.15 SDS without (-2.31 to -0.03). Distance to target height was -0.22 SDS with anastrozole (-1.72 to +0.52) and +0.54 SDS without (+0.23 to +1.30)., Conclusion: Spontaneous growth in AEXS varied, even in the same family. Our data suggest that early started, long-term inhibition by anastrozole promotes adult height in boys with AEXS., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: To report on our primary experience with the placement of a hydrogel spacer following stereotactic body radiation therapy (SBRT) in low- and intermediate-risk prostate cancer patients and assess its impact on dosimetry as well as acute toxicity., Methods: A total of 70 patients treated with SBRT (total dose of 36.25 Gy) in 5 fractions were included. Hydrogel spacers were inserted in 53 patients along with gold fiducial markers. For dosimetry, we trisected the rectum on the sagittal image of magnetic resonance imaging and defined it as the upper rectum (UR), middle rectum (MR), and lower rectum (LR). We compared the dose to each part of the rectum with and without hydrogel spacer using dose volume histograms. Genitourinary (GU) and gastrointestinal (GI) toxicity assessments were conducted until 6 months of follow-up visits., Results: The median volume of the hydrogel spacer was 12.3 mL. Overall, the hydrogel spacer could significantly reduce the rectal dose in the middle-to-high-dose region (V20-V35). The rectum doses at the UR and MR were significantly lower in the spacer group in the middle to high dose region (V20-V35); the dose at the LR was significantly lower in the spacer group in the high-dose region (V30-V35). There was no grade ≥ 3 toxicity observed, but grade 2 toxicity of GU and GI occurred in 17.1% and 1.4% of the patients, respectively., Conclusion: Hydrogel spacers could contribute to rectal dose reduction, especially in high dose regions, by creating a prostate-rectum distance.

Long diagnostic delays (LDDs) may decrease the effectiveness of patient isolation in reducing subsequent transmission of coronavirus disease 2019 (COVID-19). This study aims to investigate the correlation between the proportion of LDD of COVID-19 patients with unknown transmission routes and the subsequent doubling time. LDD was defined as the duration between COVID-19 symptom onset and confirmation ≥6 days. We investigated the geographic correlation between the LDD proportion among 369 confirmed COVID-19 patients with symptom onset between the 9th and 11th week and the subsequent doubling time for 717 patients in the 12th-13th week among the six prefectures. The doubling time on March 29 (the end of the 13th week) ranged from 4.67 days in Chiba to 22.2 days in Aichi. Using a Pearson's product-moment correlation ( p -value = 0.00182) and multiple regression analyses that were adjusted for sex and age (correlation coefficient -0.729, 95% confidence interval: -0.923--0.535, p -value = 0.0179), the proportion of LDD for unknown exposure patients was correlated inversely with the base 10 logarithm of the subsequent doubling time. The LDD for unknown exposure patients was correlated significantly and inversely with the subsequent doubling time.

Background: (Epi)genetic disorders associated with small-for-gestational-age with short stature (SGA-SS) include imprinting disorders (IDs). Silver-Russell syndrome (SRS) is a representative ID in SGA-SS and has heterogenous (epi)genetic causes., Subjects and Methods: To clarify the contribution of IDs to SGA-SS and the molecular and phenotypic spectrum of SRS, we recruited 269 patients with SGA-SS, consisting of 103 and 166 patients referred to us for genetic testing for SGA-SS and SRS, respectively. After excluding 20 patients with structural abnormalities detected by comparative genomic hybridization analysis using catalog array, 249 patients were classified into 3 subgroups based on the Netchine-Harbison clinical scoring system (NH-CSS), SRS diagnostic criteria. We screened various IDs by methylation analysis for differentially methylated regions (DMRs) related to known IDs. We also performed clinical analysis., Results: These 249 patients with SGA-SS were classified into the "SRS-compatible group" (n = 148), the "non-SRS with normocephaly or relative macrocephaly at birth group" (non-SRS group) (n = 94), or the "non-SRS with relative microcephaly at birth group" (non-SRS with microcephaly group) (n = 7). The 44.6% of patients in the "SRS-compatible group," 21.3% of patients in the "non-SRS group," and 14.3% in the "non-SRS with microcephaly group" had various IDs. Loss of methylation of the H19/IGF2:intergenic-DMR and uniparental disomy chromosome 7, being major genetic causes of SRS, was detected in 30.4% of patients in the "SRS-compatible group" and in 13.8% of patients in the "non-SRS group.", Conclusion: We clarified the contribution of IDs as (epi)genetic causes of SGA-SS and the molecular and phenotypic spectrum of SRS. Various IDs constitute underlying factors for SGA-SS, including SRS., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: The efficacy and safety of nivolumab versus chemotherapy was evaluated in the Japanese subpopulation from the overall intent-to-treat (ITT) population of the ATTRACTION-3 trial conducted in patients with advanced esophageal squamous cell carcinoma (ESCC) as second-line treatment., Methods: Data from Japanese patients enrolled in the multicenter, randomized, open-label, phase 3 ATTRACTION-3 trial were analyzed. The primary endpoint was overall survival (OS). Secondary endpoints included duration of response (DOR), objective response rate (ORR), disease control rate (DCR), and safety. Exploratory subgroup analyses evaluated the association between OS and stratification factors/baseline variables., Results: Overall, 274 (nivolumab, 136; chemotherapy, 138) of the 419 patients in ATTRACTION-3 were enrolled from Japan: response-evaluable population (107; 108) and safety population (135; 138). OS tended to be longer in the nivolumab group versus the chemotherapy group (median: 13.4 months vs. 9.4 months; HR, 0.77; 95% CI 0.59-1.01). Median DOR was longer in the nivolumab group (7.6 months) versus the chemotherapy group (3.6 months). ORRs were similar between the nivolumab [22.4% of patients (24/107)] and chemotherapy groups [22.2% (24/108); odds ratio, 0.98; 95% CI 0.52-1.87]. DCR was lower in the nivolumab group [41.1% (44/107)] versus the chemotherapy group [66.7% (72/108)]. OS in the exploratory analysis consistently favored the nivolumab group versus the chemotherapy group. Overall, nivolumab demonstrated favorable efficacy and safety versus chemotherapy in the Japanese subpopulation, and the trend was similar to that observed in the overall ATTRACTION-3 ITT population., Conclusion: Nivolumab represents a new standard second-line treatment option for Japanese patients with advanced ESCC.

Long diagnostic delays (LDDs) in patients with coronavirus disease 2019 (COVID-19) might decrease the effectiveness of patient isolation in reducing subsequent transmission. We assumed that direction of government considerably increased probability of LDD among COVID-19 cases with unknown exposure in Japan. This study aimed to investigate association of route of case detection and proportion of LDD of COVID-19 in Japan. We included confirmed COVID-19 patients with symptom onset between the ninth and eleventh week in 2020, in 6 prefectures of Japan. LDD was defined as the duration between COVID-19 symptom onset and confirmation ≥6 days. We used multivariable logistic regression analyses to elucidate factors associated with LDD. The mean diagnostic delay for 364 cases was 6.3 days. Proportion of LDD was 38% for cases with known exposure, and 65% for cases with unknown exposure. The probability of LDD in cases with unknown exposure was significantly higher than that for known exposure cases (adjusted odds ratio: 2.38, 95% confidence interval: 1.354-4.21). Early PCR test after symptom onset, strengthening of PCR test capacity, and investigations to study impact of high proportion of LDD in cases without known exposure might be necessary.

This 4-year randomized, double-blind, multicenter trial (NCT01927861) investigated the long-term efficacy and safety of Norditropin ® (NN-220; somatropin) in Japanese children with short stature due to Noonan syndrome. Pre-pubertal children with Noonan syndrome were randomized 1:1 to receive 0.033 mg/kg/day (n = 25, mean age 6.57 years) or 0.066 mg/kg/day (n = 26, mean age 6.06 years) GH. Height standard deviation score (SDS) change after 208 weeks from baseline was evaluated using an analysis of covariance model. Height SDS improved from -3.24 at baseline with a significantly greater increase (estimated mean [95% confidence interval]) with 0.066 vs. 0.033 mg/kg/day GH (1.84 [1.58; 2.10] vs. 0.85 [0.59; 1.12]; estimated mean difference 0.99 [0.62; 1.36]; p < 0.0001). The majority of treatment-emergent adverse events (TEAEs) were non-serious, mild and assessed as unlikely treatment-related. TEAE rates and frequencies of serious TEAEs were similar between groups. Three patients receiving 0.066 mg/kg/day were withdrawn; two due to TEAEs at days 1,041 and 1,289. Mean insulin-like growth factor-I SDS increased from -1.71 to -0.75 (0.033 mg/kg/day) and 0.57 (0.066 mg/kg/day) (statistically significant difference). In both groups, there were only minor glycosylated hemoglobin changes, similar oral glucose tolerance test insulin response increases and no clinically relevant changes in oral glucose tolerance test blood glucose, vital signs, electrocardiogram or transthoracic echocardiography. In conclusion, treatment with 0.033 and 0.066 mg/kg/day GH for 208 weeks improved height SDS in Japanese children with short stature due to Noonan syndrome with a significantly greater increase with 0.066 vs. 0.033 mg/kg/day GH and was well tolerated, with no new safety concerns.

Backgrounds: The proportion of assisted reproductive technology (ART)-conceived livebirths of patients with imprinting disorders (IDs) is higher than that of the general population. Whether this is due to ART or confounding effects of advanced parental age was not investigated. We examined the association of ART and parental ages at childbirth for the development of eight epimutation-mediated imprinting disorders (epi-IDs)., Results: We enrolled 136 patients with epi-IDs and obtained general population ART data from the Japanese robust nationwide registry. We compared the proportion of ART-conceived livebirths and maternal childbearing ages between patients with epi-IDs and the general population. The proportion of ART-conceived livebirths in patients with epi-IDs was higher than that in mothers aged ≥ 30 years, the age group in which more than 90% of ART procedures performed. The maternal childbearing ages of patients with epi-IDs were widely distributed from 19 to 45 (median: 32) within the approximate 2.5th to 97.5th percentiles of maternal childbearing ages of the general population. In addition, we compared the proportion of ART-conceived livebirths and parental ages at childbirth across patients with eight epi-IDs. We demonstrated that more than 90% of ART-conceived patients with epi-IDs were found in Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) patients, and parental ages were almost consistent in patients with eight epi-IDs, except Prader-Willi syndrome., Conclusions: According to the prerequisite that most of the ART procedures in Japan are performed on mothers aged ≥ 30 years, ART can be a risk factor for the development of epi-IDs, particularly SRS and BWS, for mothers aged ≥ 30 years.

Background: Congenital central hypoventilation syndrome (CCHS) is a rare disease characterized by sleep apnea. Anoxia often occurs soon after birth, and it is important to prevent anoxia-mediated central nervous system complications; however, data on the relationship between respiratory management and the prognosis for intellectual development of patients with CCHS is not well yet investigate., Methods: We performed a retrospective chart review cohort study of patients with CCHS in Japan. We investigated the risk and prognostic factors for developmental outcomes and examined the disease in terms of its symptoms, diagnosis, complications, and treatment., Results: Of the 123 patients with CCHS included in the survey, 88 patients were 6 years old and older. They were divided into two group based on their intelligence quotient. Those treated using positive-pressure ventilation via tracheostomy in the first three months of life had a better developmental prognosis than those managed via tracheostomy after three months of age and those treated by ventilation using mask (OR = 3.80; 95% CI: 1.00-14.37, OR = 4.65; 95% CI: 1.11-19.37). There was no significant difference in physical development (P = 0.64)., Conclusions: The best respiratory treatment for patients with CCHS is ventilation via tracheostomy, initiated ideally before the age of three months.

Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) showed survival benefits in metastatic colorectal cancer patients previously treated with standard chemotherapies; therefore, we compared the efficacy and safety of these two treatments. Patients with metastatic colorectal cancer treated with REG or FTD/TPI as a salvage-line therapy from May 2014 to December 2017 were included. We retrospectively analyzed long-term survival, safety, and clinical outcomes. Among 134 patients, 57 and 77 received REG and FTD/TPI, respectively. The REG group received more prior systemic chemotherapies and significantly more frequent additional chemotherapies than the FTD/TPI group did. The median follow-up was 6.2 months, whereas the median overall survival was 9.9 and 11.4 months in the REG and FTD/TPI groups, respectively (hazard ratio = 0.954, p = 0.837). The median progression-free survival was 2.0 and 3.3 months in the REG and FTD/TPI groups, respectively (hazard ratio = 0.52, p = 0.00047), indicating significant differences, whereas the objective response and disease control rates did not differ. The median overall survival of patients with additional subsequent chemotherapies after disease progression was longer than that of patients without additional chemotherapy. The most frequent grade ≥3 adverse events were hypertension and neutropenia in the REG and FTD/TPI groups, respectively. Our study suggested that sequential use of both drugs may prolong survival., Competing Interests: The authors have declared that no competing interests exist.

Background: Cancer cells are often found postoperatively at surgical resection margins (RM) in patients with gastric cancer because of submucosal infiltration or hesitation to secure adequate RM. This study was designed to evaluate risk factors for microscopic positive RM and to clarify which patients should undergo intraoperative frozen section diagnosis (IFSD)., Methods: Patients who underwent R0/1 gastrectomy for gastric adenocarcinoma between 2000 and 2018 in a single cancer center in Japan were studied. We divided the patients into a positive RM group and negative RM group according to the results of definitive histopathological examinations. We performed multivariate analysis to analyze risk factors for positive RM by and used the identified risk factors to risk stratify the patients., Results: A total of 2757 patients were studied, including 49 (1.8%) in the positive RM group. The risk factors significantly associated with positive RM were remnant gastric cancer (odds ratio [OR] 4.7), esophageal invasion (OR 6.3), tumor size ≥80 mm (OR 3.9), and a histopathological diagnosis of undifferentiated type (OR 3.6), macroscopic type 4 (OR 3.7), or pT4 disease (OR 4.6). On risk stratification analysis, the incidence of positive RM was 0.1% without any risk factors, increasing to 0.4% with one risk factor, 3.1% with two risk factors, 5.3% with three risk factors, 21.3% with four risk factors, and 85.7% with five risk factors., Conclusions: The risk of macroscopically positive RM increased in patients who have risk factors. IFSD should be performed in patients who have four or more risk factors.

Objectives: To investigate whether body mass index (BMI) trajectory, lifestyle and reproductive factors are associated with knee pain risk among middle-aged women., Design: Prospective study of the Japan Nurses' Health Study (JNHS)., Setting: The JNHS investigates the health of female nurses in Japan. Biennial follow-up questionnaires are mailed to the participants., Participants: The 7434 women aged over 40 years who responded to the 10-year self-administered follow-up questionnaire., Primary Outcome Measure: Self-reported knee pain at the 10-year follow-up was the primary outcome. We analysed BMI (normal or overweight) trajectory data from a baseline survey to the 10-year follow-up survey using group-based trajectory modelling. Exposure measurements were BMI trajectory, BMI at age 18 years, lifestyle variables and reproductive history., Results: BMI trajectories from baseline to the 10-year follow-up were divided into four groups: remained normal, remained overweight, gained weight or lost weight. At the 10-year follow-up, 1281 women (17.2%) reported knee pain. Multivariable logistic regression analysis revealed that compared with the remained normal group, multivariable-adjusted ORs (95% CI) of knee pain were 1.93 (1.60 to 2.33) for the remained overweight group, 1.60 (1.23 to 2.08) for the gained weight group and 1.40 (0.88 to 2.21) for the lost weight group. The attributable risk percent (95% CI) of the remained overweight group was 48.1% (37.3% to 57.0%) compared with the reference group of remained normal. Alcohol intake at baseline was significantly associated with knee pain., Conclusions: The lost weight group had a lower risk than the remained overweight group and the gained weight group and did not carry statistically significant risks for knee pain. Weight reduction and maintaining a normal BMI in middle age was important for preventing knee pain in women., 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.)

Background: Laparoscopic gastrectomy is becoming more commonly performed, but acquisition of its technique remains challenging. We investigated whether laparoscopy-assisted distal gastrectomy (LDG) performed by trainees (TR) supervised by a technically qualified experienced surgeon (QS) is feasible and safe., Methods: The short-term outcomes of LDG were assessed in patients with gastric cancer between 2008 and 2018. We compared patients who underwent LDG performed by qualified experienced surgeons (QS group) with patients who underwent LDG performed by the trainees (TR group)., Results: The operation time was longer in the TR group than in the QS group (median time: 270 min vs. 239 min, p < 0.001). The median duration of the postoperative hospital stay was 9 days in the QS group and 8 days in the TR group (p = 0.003). The incidence of postoperative complications did not differ significantly between the two groups. Grade 2 or higher postoperative complications occurred in 18 patients (12.9%) in the QS group and 47 patients (11.7%) in the TR group (p = 0.763). Grade 3 or higher postoperative complications occurred in 9 patients (6.4%) in the QS group and 17 patients (4.2%) in the TR group (p = 0.357). Multivariate analysis showed that the American Society of Anesthesiologist Physical Status was an independent predictor of grade 2 or higher postoperative complications and that gender was an independent predictor of grade 3 or higher postoperative complications. The main operator (TR/QS) was not an independent predictor of complications., Conclusions: Laparoscopy-assisted distal gastrectomy performed by trainees supervised by an experienced surgeon is a feasible and safe procedure similar to that performed by experienced surgeons.