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Purpose: This trial was conducted to confirm the non-inferiority of remimazolam versus propofol in the induction and maintenance of general anesthesia in surgical patients., Methods: Surgical patients (n = 375) were randomized to remimazolam started at 6 or 12 mg/kg/h by continuous intravenous (IV) infusion until the loss of consciousness (LoC), followed by 1 mg/kg/h to be adjusted as appropriate until the end of surgery or IV propofol administered as a slow bolus of 2.0-2.5 mg/kg until LoC followed by 4-10 mg/kg/h until the end of surgery. Efficacy was measured via the combined primary endpoint of no intraoperative awakening/recall, no need for rescue sedatives, and no body movements. Adverse events and adverse drug reactions (ADRs) were monitored for safety., Results: Efficacy rates were 100% in all treatment groups, and the non-inferiority of remimazolam was demonstrated [95% confidence interval (- 0.0487; 0.0250)]. The time to LoC was longer in the remimazolam 6 (p < 0.0001) and 12 mg/kg/h (p = 0.0149) groups versus propofol. The time to extubation was longer in both remimazolam groups versus the propofol group (p ≤ 0.0001). The incidence of ADRs was similar in the remimazolam groups (39.3% and 42.7%, respectively) compared with the propofol group (61.3%). Decreased blood pressure occurred in 20.0% and 24.0% of patients treated with 6 and 12 mg/kg/h remimazolam, respectively, compared with 49.3% of patients receiving propofol. Injection site pain was reported in 18.7% of propofol patients but not in those receiving remimazolam., Conclusions: This trial demonstrated that remimazolam was well tolerated and non-inferior to propofol with regard to efficacy as a sedative hypnotics for general anesthesia., Clinical Trial Registration: This trial is registered with the Japan Pharmaceutical Information Center - Clinical Trials Information (JapicCTI). JapicCTI number: 121973.

We demonstrate spatially resolved supercontinuum spectral phase interferometry with an isolated attosecond pulse (IAP). The measured spatial-spectral interferogram over the broadband region indicates a high degree of IAP coherence in both spatial and spectral domains. In addition, the spectral-delay interferogram shows periodic temporal oscillations over the full IAP continuous spectrum, which indicates high temporal coherence. The supercontinuum spectral phase interferometry with broadband IAP will contribute to exploring spatiotemporal dispersive electronic dynamics through phase-based spectroscopy in the future.

Objectives: We previously reported that fetal heart rate (FHR) accelerations could be obtained after fetal sound stimulation. We examined FHR accelerations during 20-37 weeks gestational age (GA) in order to assess the optimal time for the test., Methods: The fetus was stimulated from the maternal abdomen with pure tone 2000 Hz, 90 dB, 5 s. Changes in the FHR before and after the sound stimulation were measured by a cardiotocometer., Results: Compared with the positive rate of FHR accelerations at 20-21 weeks GA, significant increases were recognized in 26-27, 28 to 29, 30 to 31, and 34-35 weeks GA. Comparing the positive rate of FHR accelerations between the minimal and moderate variability of FHR baseline, no significant differences were observed at 20-27 weeks GA. On the other hand, at 28-37 weeks GA, the positive rate to detect FHR accelerations due to sound stimulation was 100% in moderate FHR baseline variability., Conclusion: Considering development of human fetal hearing, the method should be performed between 28 and 37 weeks GA and during moderate FHR variability corresponding to active sleep conditions. The method developed in the present study may provide a promising tool for evaluating the fetal hearing., Competing Interests: Declaration of competing interest The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: To clarify the usefulness of glucose challenge test (GCT), the rate of gestational diabetes mellitus (GDM) detection and perinatal outcomes were compared between the groups of random blood glucose level (RBG) and 50 g GCT in this study., Methods: The first survey was conducted at 255 institutions registered by the Kanto Society of Obstetrics and Gynecology and clinical training institutions in the Kanto Area, followed by a second survey. The included women were broadly classified into the RBG and GCT groups, according to the mid-trimester blood glucose screening method, and the perinatal outcomes of the two groups were retrospectively compared. The primary outcomes were the proportion of infants weighing 3,500 g or more and birth weight ≥90 th -percentile infants., Results: The rate of GDM diagnosis was significantly higher in the GCT group (7.6%) than that in the RBG group (4.8%). However, no significant differences were observed in perinatal outcomes, i.e., the proportion of infants weighing 3,500 g or more or birth weight ≥90 th percentile., Conclusions: GCT is not superior for predicting infants weighing 3,500 g or more and birth weight ≥90 th percentile, as compared with RBG., Competing Interests: None, (Copyright © Japan Medical Association.)

Ionic motion significantly contributes to conductivity in devices such as memory, switches, and rechargeable batteries. In our work, we experimentally demonstrate that intense terahertz electric-field transients can be used to manipulate ions in a superionic conductor, namely Na^{+} β-alumina. The cations trapped in the local potential minima are accelerated using single-cycle terahertz pulses, thereby inducing a macroscopic current flow on a subpicosecond timescale. Our results clearly show that single-cycle terahertz pulses can be used to significantly modulate the nature of superionic conductors and could possibly serve as a basic tool for application in future electronic devices.

Objective: Contrast-enhanced ultrasonography (CEU) has been used in critical trauma situations to visualize extravasation; however, its use is limited in the field of obstetrics. Cases of ruptured uterine artery pseudoaneurysm (UAP) were analyzed to clarify the efficacy to CEU during uterine balloon tamponade., Methods: Cases of ruptured UAP diagnosed at a teaching university hospital from January 2015 to December 2017 were retrospectively analyzed. UAP was diagnosed using color Doppler ultrasonography. Extravasation was identified using computed tomography and double checked using CEU with an intravenously administered contrast agent (Sonazoid; Daiichi Sankyo Company, Ltd., Tokyo, Japan) and an ultrasound instrument (HI VISION Preirus; Hitachi Aloka Medical, Ltd., Tokyo, Japan). A balloon was then inserted into the uterine cavity and inflated at the point of bleeding until extravasation ceased., Results: Three patients exhibited ruptured UAP during the study period. Bleeding points were successfully identified using CEU in all cases, and hemostasis was achieved using uterine balloon tamponade. Obliteration of UAP was confirmed using magnetic resonance imaging, and no patients developed recurrent UAP or any complications., Conclusion: CEU can be used at the bedside to promptly diagnose ruptured UAP. Moreover, it precisely facilitates balloon compression at the point of bleeding.

Aims: A questionnaire survey of the prevalence of diabetic retinopathy was recently conducted in Japan. A subgroup analysis to examine the association of periodontal disease with diabetic retinopathy in subjects with diabetes and prediabetes was conducted., Methods: The association of the presence of periodontal disease with the occurrence of diabetic retinopathy was examined using multivariate logistic regression analysis., Results: Of 27 016 subjects who completed a survey at 217 community pharmacies, 5 572 had diabetes or prediabetes, among whom 522 and 1 421 had retinopathy or periodontal disease, respectively. Therapy duration≥10 years (OR: 2.73, 95% CI: 2.17-3.43, P<0.001), periodontal disease (OR: 2.10, 95% CI: 1.68-2.62, P<0.001) and glycated hemoglobin (HbA1c) ≥ 7.0% (OR: 1.64, 95% CI: 1.32-2.04, P<0.001) were significantly associated with the occurrence of retinopathy, while retinopathy (OR: 2.11, 95% CI: 1.: 69-2.63, P<0.001) and therapy duration ≥10 years (OR: 1.24, 95% CI: 1.06-1.46, P=0.007) were significantly associated with the occurrence of periodontal disease. The prevalence of retinopathy was much higher in diabetic subjects with periodontal disease than in those without it (15.1% vs. 7.8%, P<0.001). Notably, the difference of prevalence of retinopathy between subjects with and without periodontal disease was statistically significant even at HbA1c 6.0-6.9% (15.2% vs. 7.3%, P<0.01)., Conclusions: These findings indicate that the target HbA1c level for diabetes patients with periodontal disease may be set lower than for those without it, and that regular dental visits should be prescribed for the management of periodontal disease and the prevention of diabetic retinopathy., Competing Interests: No conflict of interest has been declared by the authors., (© Georg Thieme Verlag KG Stuttgart · New York.)

Cesarean section in breech or transverse presentation involves more complicated procedures than cesarean section in cephalic presentation because the former requires additional manipulations for guiding the presenting part of the fetus, liberation of the arms, and the after-coming head delivery; therefore, those cesarean sections are likely to be more invasive. Making a rather wide uterine incision to prevent uterine injury during delivery of the fetus facilitates smooth delivery of the fetus. Furthermore, in cases of breech or transverse presentation, it is important to initially identify the presenting part of the fetus and guide it to the incision opening in the lower uterine segment, because delivering the presenting part of the fetus first is a basic rule of delivery of the fetus. Smooth delivery of the fetus by means of breech extraction can prevent excessive stress or injury to the fetus. Therefore, it is important to acquire the knowledge and skills necessary to perform these techniques, including the internal version. Smooth delivery of the fetus is also less invasive for the mother because an extension of the uterine excision or injury to arteries and veins in the uterus and parametrium can be avoided. Incarcerated uterus occurring in cases of pregnancy with intrapelvic adhesion, endometriosis, cervical myoma, or extended cervix may result in excessive uterine and cervical injury when a transverse incision of the lower uterine segment is performed without caution. These conditions may result in difficulty in fetal delivery. Therefore, it is important to identify risks in advance and to choose the incision line with great care. Countermeasures for difficult delivery of the fetus need to be mastered by all practitioners of obstetrics. If the transverse incision fails to reach the uterine cavity, an inverted T-shaped or J-shaped incision should be made. Risks of complications such as injury to the cervical canal, the vagina, the bladder or ureter, and massive hemorrhage must be kept in mind., Competing Interests: Conflict of Interest None.

According to the increase in the rate of cesarean section and the increase of high-aged pregnancy, we seem to more often encounter cases with placenta previa and placenta previa accrete spectrum. There are concerns about these cases, such as difficulty in controlling bleeding from the separation surface of placenta previa, the need for hysterectomy as a life-saving procedure, systemic management and hemostasis during massive hemorrhage, and treatment of disseminated intravascular coagulation (DIC). These cases are most frequently associated with cesarean hysterectomy.

Germline DDX41 mutations were recently reported to cause MDS/AML and donor-derived leukemia after transplantation. While previously described in Western countries, DDX41 variants have not been reported in a Southeast Asian population. We performed targeted sequencing of blood or bone marrow samples from 109 Thai patients with myeloid malignancies. Among the 109 patients (75 MDS, 8 MPN, 11 MDS/MPN and 15 AML), the most frequent mutations were in ASXL1 (17.4%), TET2 (16.5%) and SRSF2 (12.8%), respectively. DDX41 variants were detectable in six (5.5%) cases. Four patients exhibited three presumable germline DDX41 mutations: p.S21fs (n = 2), p.F235fs (n = 1), and p.R339H (n = 1). While p.S21fs was previously reported in myeloid neoplasm, the latter two variants have not been described. Two of these cases harbored concomitant probable germline/somatic DDX41 mutations (p.S21fs/p.R525H and p.R339H/p.K494T), while the other two patients carried only somatic mutations (p.R525H and p.F438L). The p.K494T and p.F438L variants have not been previously reported. In patients with DDX41 alterations, the diagnoses were MDS with excess blasts (4), secondary AML (1) and low-risk MDS (1). In conclusion, we identified DDX41 variants in Thai patients with myeloid malignancies in which these variants could be used to assess predisposition to MDS in Southeast Asia.

Aim: This study aimed to investigate the rate of labor-onset hypertension (LOH) under neuraxial labor analgesia and the effect of neuraxial labor analgesia on LOH., Methods: A retrospective study was conducted in a tertiary university hospital from 2015 to 2016. Patients who were admitted to the hospital for vaginal delivery under combined spinal and epidural anesthesia were selected. LOH was defined as the elevation of systolic blood pressure (BP) to ≥140 mmHg or diastolic BP to ≥90 mmHg for the first time after the onset of labor. Cases of LOH that persisted after neuraxial labor analgesia (prolonged LOH) were further analyzed to determine the hypertension severity and therapeutic intervention rate., Results: Among 775 patients, 213 (28.4%) developed LOH. Prolonged LOH was observed in 30 patients (3.9%). LOH severity and the likelihood of prolonged LOH were positively correlated. Therapeutic intervention was administered only to the patients with prolonged LOH, that is, to 100% of those with emergent hypertension, to 21.1% of those with severe hypertension during labor, and to 36.8% of those with severe hypertension, to 55.6% of those with mild hypertension in the post-partum period., Conclusion: The rate of LOH was reduced significantly after neuraxial labor analgesia. Patients with prolonged LOH should be carefully followed up during labor and in the post-partum period because such patients often require antihypertensive therapy., (© 2019 Japan Society of Obstetrics and Gynecology.)

In type 2 diabetes mellitus, metformin suppresses excessive insulin secretion in relation to the intake of glucose. We herein report the case of a 45-year-old man with glucose-responsive insulinoma whose responsive hypoglycemia was alleviated by metformin. The patient had a history of a postprandial loss of consciousness, resulting in hospital admission. He refused surgery and diazoxide administration. A 75-g oral glucose tolerance test after metformin administration revealed the suppression of glucose-responsive insulin hypersecretion and responsive hypoglycemia. Pancreatic head duodenectomy was performed, which alleviated the symptoms. Metformin administration in patients with glucose-responsive insulinoma may therefore be effective for preventing responsive hypoglycemia and hyperinsulinemia.

Although single-component Class 2 CRISPR systems, such as type II Cas9 or type V Cas12a (Cpf1), are widely used for genome editing in eukaryotic cells, the application of multi-component Class 1 CRISPR has been less developed. Here we demonstrate that type I-E CRISPR mediates distinct DNA cleavage activity in human cells. Notably, Cas3, which possesses helicase and nuclease activity, predominantly triggered several thousand base pair deletions upstream of the 5'-ARG protospacer adjacent motif (PAM), without prominent off-target activity. This Cas3-mediated directional and broad DNA degradation can be used to introduce functional gene knockouts and knock-ins. As an example of potential therapeutic applications, we show Cas3-mediated exon-skipping of the Duchenne muscular dystrophy (DMD) gene in patient-induced pluripotent stem cells (iPSCs). These findings broaden our understanding of the Class 1 CRISPR system, which may serve as a unique genome editing tool in eukaryotic cells distinct from the Class 2 CRISPR system.

When loss of heterozygosity (LOH) is correlated with loss or gain of a disease phenotype, it is often necessary to identify which gene or genes are involved. Here, we developed a region-specific LOH-inducing system based on mitotic crossover in human induced pluripotent stem cells (hiPSCs). We first tested our system on chromosome 19. To detect homozygous clones generated by LOH, a positive selection cassette was inserted at the AASV1 locus of chromosome 19. LOHs were generated by the combination of allele-specific double-stranded DNA breaks introduced by CRISPR/Cas9 and suppression of Bloom syndrome (BLM) gene expression by the Tet-Off system. The BLM protein inhibitor ML216 exhibited a similar crossover efficiency and distribution of crossover sites. We next applied this system to the short arm of chromosome 6, where human leukocyte antigen (HLA) loci are located. Genotyping and flow cytometric analysis demonstrated that LOHs associated with chromosomal crossover occurred at the expected positions. Although careful examination of HLA-homozygous hiPSCs generated from parental cells is needed for cancer predisposition and effectiveness of differentiation, they may help to mitigate the current shortcoming of hiPSC-based transplantation related to the immunological differences between the donor and host., Competing Interests: The authors have declared that no competing interests exist.

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C, SETD1B, YTHDF2, and PDCD1. We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2. Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.

We produce subcycle mid-infrared (MIR) pulses at a 4 MHz repetition rate via the optical rectification (OR) of sub-10 fs near-infrared pulses delivered by an optical parametric chirped pulse amplifier. The coherent MIR pulses generated in a GaSe crystal under an ultrabroadband phase-matching condition contain only 0.58-0.85 oscillation cycles within the full width at half-maximum of the intensity envelope. The use of OR enables excellent phase stability of 56 mrad over 5.6 h, which is confirmed by field-resolved detection using electro-optic sampling. An electromagnetic simulation using a finite integration technique reveals that the peak field strength can easily exceed 10 V/nm owing to the field enhancement resulting from focusing MIR pulses onto a tunnel junction.

Lysin motif (LysM) receptor-like kinase CERK1 is a co-receptor essential for plant immune responses against carbohydrate microbe-associated molecular patterns (MAMPs). Concerning the immediate downstream signaling components of CERK1, receptor-like cytoplasmic kinases such as PBL27 and other RLCK VII members have been reported to regulate immune responses positively. In this study, we report that a novel CERK1-interacting E3 ubiquitin ligase, PUB4, is also involved in the regulation of MAMP-triggered immune responses. Knockout of PUB4 resulted in the alteration of chitin-induced defense responses, indicating that PUB4 positively regulates reactive oxygen species generation and callose deposition but negatively regulates MAPK activation and defense gene expression. On the other hand, detailed analyses of a double knockout mutant of pub4 and sid2, a mutant of salicylic acid (SA) synthesis pathway, showed that the contradictory phenotype of the pub4 mutant was actually caused by abnormal accumulation of SA in this mutant and that PUB4 is a positive regulator of immune responses. The present and recent findings on the role of PUB4 indicate that PUB4 is a unique E3 ubiquitin ligase involved in the regulation of both plant immunity and growth/development., (� The Author(s) 2019. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A two-dimensional nanocarbon, graphene, has attracted substantial interest due to its excellent properties. The reduction of graphene oxide (GO) has been investigated for the mass production of graphene used in practical applications. Different reduction processes produce different properties in graphene, affecting the performance of the final materials or devices. Therefore, an understanding of the mechanisms of GO reduction is important for controlling the properties of functional two-dimensional systems. Here, we determined the average structure of reduced GO prepared via heating and photoexcitation and clearly distinguished their reduction mechanisms using ultrafast time-resolved electron diffraction, time-resolved infrared vibrational spectroscopy, and time-dependent density functional theory calculations. The oxygen atoms of epoxy groups are selectively removed from the basal plane of GO by photoexcitation (photon mode), in stark contrast to the behavior observed for the thermal reduction of hydroxyl and epoxy groups (thermal mode). The difference originates from the selective excitation of epoxy bonds via an electronic transition due to their antibonding character. This work will enable the preparation of the optimum GO for the intended applications and expands the application scope of two-dimensional systems.

Higher-order genomic architecture varies according to cell type and changes dramatically during differentiation. One of the remarkable examples of spatial genomic reorganization is the rod photoreceptor cell differentiation in nocturnal mammals. The inverted nuclear architecture found in adult mouse rod cells is formed through the reorganization of the conventional architecture during terminal differentiation. However, the mechanisms underlying these changes remain largely unknown. Here, we found that the dynamic deformation of nuclei via actomyosin-mediated contractility contributes to chromocenter clustering and promotes genomic architecture reorganization during differentiation by conducting an in cellulo experiment coupled with phase-field modeling. Similar patterns of dynamic deformation of the nucleus and a concomitant migration of the nuclear content were also observed in rod cells derived from the developing mouse retina. These results indicate that the common phenomenon of dynamic nuclear deformation, which accompanies dynamic cell behavior, can be a universal mechanism for spatiotemporal genomic reorganization., Competing Interests: The authors have declared that no competing interests exist.

Placental abruption is a condition that should be carefully considered in perinatal management because it is associated with serious events in both the mother and neonate, such as intrauterine fetal death, cerebral palsy, obstetric critical bleeding, and uncontrollable bleeding. The concomitant presence of disseminated intravascular coagulation (DIC) more easily causes critical bleeding that may necessitate hysterectomy or multi-organ failure resulting in maternal death. Therefore, early management should be provided to prevent progression to serious conditions by performing both hemostatic procedures and DIC treatment. To take measures to improve the outcomes in both the mother and neonate, health guidance for pregnant women, early diagnosis, early treatment, development of the emergency care system, and provision of a system for transport to higher-level medical institutions should be implemented., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported.

Chromosome abnormalities induces profound alterations in gene expression, leading to various disease phenotypes. Recent studies on yeast and mammalian cells have demonstrated that aneuploidy exerts detrimental effects on organismal growth and development, regardless of the karyotype, suggesting that aneuploidy-associated stress plays an important role in disease pathogenesis. However, whether and how this effect alters cellular homeostasis and long-term features of human disease are not fully understood. Here, we aimed to investigate cellular stress responses in human trisomy syndromes, using fibroblasts and induced pluripotent stem cells (iPSCs). Dermal fibroblasts derived from patients with trisomy 21, 18 and 13 showed a severe impairment of cell proliferation and enhanced premature senescence. These phenomena were accompanied by perturbation of protein homeostasis, leading to the accumulation of protein aggregates. We found that treatment with sodium 4-phenylbutyrate (4-PBA), a chemical chaperone, decreased the protein aggregates in trisomy fibroblasts. Notably, 4-PBA treatment successfully prevented the progression of premature senescence in secondary fibroblasts derived from trisomy 21 iPSCs. Our study reveals aneuploidy-associated stress as a potential therapeutic target for human trisomies, including Down syndrome., Competing Interests: The authors have read the journal's policy and have the following competing interests: This study received funding from Mitsui Life Social Welfare Foundation, and Shionogi & Co., Ltd. Dr. Mahito Nakanishi is the founder and chief technology officer (CTO) of Tokiwa-Bio, Inc. Method to generate iPS cells with SeVdp vector installing reprogramming genes is protected by following patents: JP 4936482; JP 5633075; JP 5963309; US 9145564; US 8496941 B2; US 9365866 B2; EP 2434012; EP 2639297. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

POEMS syndrome is a rare paraneoplastic disease associated with monoclonal plasma cells; however, the pathogenic importance of plasma cells remains unclear. We performed comprehensive genetic analyses of plasma cells in 20 patients with POEMS syndrome. Whole exome sequencing was performed in 11 cases and found a total of 308 somatic mutations in 285 genes. Targeted sequencing was performed in all 20 cases and identified 20 mutations in 7 recurrently mutated genes, namely KLHL6, LTB, EHD1, EML4, HEPHL1, HIPK1, and PCDH10. None of the driver gene mutations frequently found in multiple myeloma (MM) such as NRAS, KRAS, BRAF, and TP53 was detected. Copy number analysis showed chromosomal abnormalities shared with monoclonal gammopathy of undetermined significance (MGUS), suggesting a partial overlap in the early development of MGUS and POEMS syndrome. RNA sequencing revealed a transcription profile specific to POEMS syndrome when compared with normal plasma cells, MGUS and MM. Unexpectedly, disease-specific VEGFA expression was not increased in POEMS syndrome. Our study illustrates that the genetic and transcriptional profiles of plasma cells in POEMS syndrome are distinct from MM and MGUS, indicating unique function of clonal plasma cells in its pathogenesis.

The present study evaluated the specific intermolecular interactions between carbamazepine (CBZ) and substituents of hypromellose acetate succinate (HPMC-AS), as well as the mechanism of inhibition of recrystallization of solid dispersions (SDs) using Fourier-transform infrared (FTIR) and solid-state nuclear magnetic resonance (NMR) spectroscopy. CBZ and HPMC derivatives, including HPMC, hypromellose acetate (HPMC-A), and hypromellose succinate (HPMC-S), were spray-dried to prepare CBZ/polymer spray-dried samples (SPDs). CBZ/HPMC SPD and CBZ/HPMC-A SPD recrystallized within 10 days at 60 °C and 0% relative humidity, whereas CBZ/HPMC-S SPD maintained its amorphous state for a longer period. FTIR and solid-state NMR measurements using 13 C cross polarization (CP), 1 H single-pulse, and 1 H- 15 N CP-based heteronuclear single quantum correlation filter experiment with very fast magic angle spinning (MAS) at 70 kHz identified molecular interactions in CBZ/polymer SPDs. Although the HPMC backbone and substituents did not interact notably with CBZ and disrupt CBZ-CBZ intermolecular interactions (formed in the amorphous CBZ), acetate and succinate substituents on HPMC-A and HPMC-S disrupted CBZ-CBZ intermolecular interactions through formation of CBZ/polymer interactions. The acetate substituent formed a hydrogen bond with the NH 2 group of CBZ, whereas the succinate substituent formed molecular interactions with both the C═O and NH 2 groups of CBZ. Formation of relatively strong molecular interactions between CBZ and the succinate substituent followed by disruption of CBZ-CBZ intermolecular interactions effectively stabilized the amorphous state of CBZ in CBZ/HPMC-S SPD. The correlation between CBZ-polymer interactions and ability of polymers to effectively inhibit CBZ recrystallization is reflected in various commercial HPMC-AS. For example, HPMC-AS LF grade, containing higher amounts of the succinate group, was found to effectively inhibit the recrystallization of CBZ through strong molecular interactions as compared with the HPMC-AS HF grade. The present study demonstrated that a detailed investigation of molecular interactions between the drug and the polymer using FTIR and solid-state NMR spectroscopy could contribute to a suitable selection of the SD carrier.

Objective: To assess general knowledge of diabetes and its determinants among adult men and women in a Japanese community., Setting: A cross-sectional study with the residential registry in Gifu City. Blood tests were conducted to measure fasting blood glucose levels and the levels after 2 hours of a 75-gram oral glucose load. Participants' previous diagnosis of diabetes and demographic status were identified from a questionnaire. A validated food frequency questionnaire was also administered. To assess the association between good knowledge of diabetes and the level of each factor, a logistic regression was utilised with adjustments for age, education and parental history of diabetes., Participants: A total of 1019 men and women aged 40-78 years., Primary Outcome Measure: The Diabetes Knowledge Questionnaire was administered. Participants with ≥75% of answers correct were defined as having a good knowledge of diabetes., Results: Previous diagnosis of diabetes was significantly associated with good knowledge of diabetes (OR=2.36; 95% CI 1.19 to 4.68). Among individuals with no previous diagnosis of diabetes, age ≥60 years (OR=0.55; 95% CI 0.36 to 0.86, p value for trend=0.02) and education <12 years (OR=0.54; 95% CI 0.30 to 0.97) were significantly associated with low knowledge of diabetes. The highest tertile intakes of green-yellow vegetables (OR=1.77; 95% CI 1.07 to 2.91, p value for trend=0.03) and seafood (OR=1.76; 95% CI 1.04 to 2.95, p value for trend=0.03) were associated with high knowledge of diabetes., Conclusions: Some diabetes risk factors were implied to determine the general knowledge of diabetes. Conducting further studies of knowledge in various populations is warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We report on the design and performance of an echelon-based single shot visible/near-infrared spectrometer with adequate sensitivity to measure the nonlinear optical and terahertz Kerr effects in neat molecular liquids at room temperature. Useful molecular information spanning tens of picoseconds can be measured in just a few milliseconds, and the signal-to-noise performance scales favorably with respect to the standard stage scan technique. These results demonstrate the viability of stage-free nonlinear Kerr effect measurements and provide a route for improvements to the speed of future multidimensional Kerr effect studies.

Aim: To clarify the frequency of occurrence of uterine rupture and its prognosis, a nationwide survey was performed., Methods: Cases of uterine rupture recorded for a period of 5 years were included., Results: There were 152 cases of uterine rupture with an incidence rate of 0.015%. The scarred uterine rupture cases were found to have a significantly earlier occurrence of uterine ruptures in comparison to the unscarred cases: unscarred 39.0 weeks, cesarean section 37.0 weeks, myomectomy 32 weeks and adenomyomectomy 30-32 weeks. And it became apparent that the frequency of hysterectomy, cerebral palsy and neonatal death were higher in the cases of uterine rupture during labor than before delivery. Among the cases of scarred uterine rupture, neonatal prognosis was poorer in cases of pregnancy after myomectomy or adenomyomectomy in comparison with postcesarean section cases., Conclusion: This survey revealed the current incidence of uterine rupture in Japan., (© 2019 Japan Society of Obstetrics and Gynecology.)

Leukemic relapse is frequently accompanied by progressively aggressive clinical course. To understand the molecular mechanism of leukemic relapse, MLL/AF9-transformed mouse leukemia cells were serially transplanted in C57BL/6 mice (N = 96) by mimicking repeated recurrences, where mutations were monitored by exome sequencing (N = 42). The onset of leukemia was progressively promoted with advanced transplants, during which increasing numbers of somatic mutations were acquired (P < 0.005). Among these, mutations in Ptpn11 (p.G60R) and Braf (p.V637E) corresponded to those identified in human MLL-AML, while recurrent mutations affecting Msn (p.R295C) were observed only in mouse but not in human MLL-AML. Another mutated gene of interest was Gnb2 which was reported to be recurrently mutated in various hematological neoplasms. Gnb2 mutations (p.G77R) were significantly increased in clone size (P = 0.007) and associated with earlier leukemia onset (P = 0.011). GNB2 transcripts were significantly upregulated in human MLL-AML compared to MLL-negative AML (P < 0.05), which was supported by significantly increased Gnb2 transcript induced by MLL/AF9 overexpression (P < 0.001). In in vivo model, both mutation and overexpression of GNB2 caused leukemogenesis, and downregulation of GNB2 expression reduced proliferative potential and survival benefit, suggesting a driver role of GNB2. In conclusion, alterations of driver genes over time may play an important role in the progression of MLL-AML.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of peripheral T-cell lymphoma affecting younger patients and associated with hemophagocytic lymphohistiocytosis. To clarify the molecular pathogenesis of SPTCL, we analyzed paired tumor and germline DNAs from 13 patients by whole-exome sequencing. All cases were Asians and were phenotypically sporadic with no family history of SPTCL. Consistent with a recent report, germline mutations in HAVCR2 , encoding T-cell immunoglobulin mucin 3 (TIM3), were identified in 11 of 13 (85%) cases. All mutated cases were primary SPTCL, whereas the 2 cases without mutation were secondary SPTCL associated with underlying diseases, including viral infection and autoimmune disease. Ten patients harbored homozygous p.Y82C mutations, and 1 showed compound heterozygous mutations (p.Y82C and p.T101I). Both missense mutations altered highly conserved residues located in the extracellular immunoglobulin variable-like domain. According to the Genome Aggregation Database of >138 500 general individuals, both mutations were documented with minor allele frequencies < 0.007, indicating remarkable enrichment of these HAVCR2 alleles in SPTCL. SPTCL cells also harbored somatic mutations (6.2 per patient) that are frequently identified in genes associated with epigenetic regulation and signal transduction. In conclusion, individuals harboring biallelic HAVCR2 (TIM3) germline mutations were highly susceptible to sporadic SPTCL, which was also associated with clonal somatic mutations., (© 2019 by The American Society of Hematology.)

Introduction: Glycated hemoglobin (A1c) and glycated albumin (GA) are often used as indicators of glycemic control. In this study, we determined whether prednisolone (PSL) administration lowers plasma GA., Methods: We investigated the factors affecting GA using multivariate analysis in 48 subjects with connective tissue diseases (CTDs)., Results: Multiple regression analysis of GA showed that the dose of PSL [β = - 1.36; 95% confidence interval (CI) - 2.59 to - 0.14; p = 0.03], age (β = 0.06; 95% CI 0.03-0.09; p < 0.001), body mass index (BMI) (β = - 0.14; 95% CI - 0.28 to - 0.01; p = 0.042), and A1c (β = 1.4; 95% CI 0.38-2.42; p = 0.008) significantly correlated with GA (adjusted R 2  = 0.518). Moreover, GA levels adjusted for age, sex, BMI, plasma albumin (Alb) and creatinine (Cre), and A1c in the subjects taking ≥ 5 mg PSL was significantly lower than those in those taking < 5 mg PSL. Finally, the dose of PSL (as a continuous variable) was negatively correlated with GA adjusted for age, sex, BMI, Alb, Cre, and A1c., Conclusion: High dose (≥ 5 mg) PSL reduces GA concentration more than glycemia.

A 60-year-old male patient with type 1 diabetes mellitus (T1DM) was admitted for glycemic control. The patient exhibited abdominal adiposity, osteoporosis, and high insulin requirement (>100 U), and we suspected hypogonadism. A physical examination revealed small testes and thin pubic hair, laboratory examination found high luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels and low testosterone levels, and a chromosome analysis (47, XXY) indicated hypogonadism due to Klinefelter syndrome (KS). KS is associated with autoimmune diseases and patients positive for diabetes related auto-antibodies. In male patients with T1DM and abdominal adiposity, the concurrence of KS should be taken into consideration.

Background: A delicate balance between cell death and keratinocyte proliferation is crucial for normal skin development. Previous studies have reported that cellular FLICE (FADD-like ICE)-inhibitory protein plays a crucial role in prevention of keratinocytes from TNF-α-dependent apoptosis and blocking of dermatitis. However, a role for cellular FLICE-inhibitory protein in TNF-α-independent cell death remains unclear., Objective: We investigated contribution of TNF-α-dependent and TNF-α-independent signals to the development of dermatitis in epidermis-specific Cflar-deficient (Cflar E-KO ) mice., Methods: We examined the histology and expression of epidermal differentiation markers and inflammatory cytokines in the skin of Cflar E-KO ;Tnfrsf1a +/- and Cflar E-KO ;Tnfrsf1a -/- mice. Mice were treated with neutralizing antibodies against Fas ligand and TNF-related apoptosis-inducing ligand to block TNF-α-independent cell death of Cflar E-KO ;Tnfrsf1a -/- mice., Results: Cflar E-KO ;Tnfrsf1a -/- mice were born but experienced severe dermatitis and succumbed soon after birth. Cflar E-KO ;Tnfrsf1a +/- mice exhibited embryonic lethality caused by massive keratinocyte apoptosis. Although keratinocytes from Cflar E-KO ;Tnfrsf1a -/- mice still died of apoptosis, neutralizing antibodies against Fas ligand and TNF-related apoptosis-inducing ligand substantially prolonged survival of Cflar E-KO ;Tnfrsf1a -/- mice. Expression of inflammatory cytokines, such as Il6 and Il17a was increased; conversely, expression of epidermal differentiation markers was severely downregulated in the skin of Cflar E-KO ;Tnfrsf1a -/- mice. Treatment of primary keratinocytes with IL-6 and, to a lesser extent, IL-17A suppressed expression of epidermal differentiation markers., Conclusion: TNF receptor superfamily 1 (TNFR1)-dependent or TNFR1-independent apoptosis of keratinocytes promotes inflammatory cytokine production, which subsequently blocks epidermal differentiation. Thus blockade of both TNFR1-dependent and TNFR1-independent cell death might be an alternative strategy to treat skin diseases when treatment with anti-TNF-α antibody alone is not sufficient., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia (ET), and primary myelofibrosis, mainly occur in older patients, but have also been reported in younger patients. A "second peak" occurs in female patients in their thirties, particularly in ET; thus, the management of pregnancy is often discussed. We herein present the case of a 33-year-old woman with a high platelet count and multiple placental infarcts during delivery who was subsequently diagnosed with ET. Although there are no worldwide guidelines for the management of MPNs in pregnancy, the risk of thrombosis is markedly increased in these patients, and antithrombotic therapy should be considered.

In acute myeloid leukemia (AML), MLL ( KMT2A ) rearrangements are among the most frequent chromosomal abnormalities; however, knowledge of the genetic landscape of MLL -rearranged AML is limited. In this study, we performed whole-exome sequencing (n = 9) and targeted sequencing (n = 56) of samples from pediatric MLL -rearranged AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. Additionally, we analyzed 105 pediatric t(8;21) AML samples and 30 adult MLL -rearranged AML samples. RNA-sequencing data from 31 patients published in a previous study were also reanalyzed. As a result, we identified 115 mutations in pediatric MLL -rearranged AML patients (2.1 mutations/patient), with mutations in signaling pathway genes being the most frequently detected (60.7%). Mutations in genes associated with epigenetic regulation (21.4%), transcription factors (16.1%), and the cohesin complex (8.9%) were also commonly detected. Novel CCND3 mutations were identified in 5 pediatric MLL -rearranged AML patients (8.9%) and 2 adult MLL -rearranged AML patients (3.3%). Recurrent mutations of CCND1 (n = 3, 2.9%) and CCND2 (n = 8, 7.6%) were found in pediatric t(8;21) AML patients, whereas no CCND3 mutations were found, suggesting that D-type cyclins exhibit a subtype-specific mutation pattern in AML. Treatment of MLL -rearranged AML cell lines with CDK4/6 inhibitors (abemaciclib and palbociclib) blocked G1 to S phase cell-cycle progression and impaired proliferation. Pediatric MLL-MLLT3 -rearranged AML patients with coexisting mutations (n = 16) had significantly reduced relapse-free survival and overall survival compared with those without coexisting mutations (n = 9) ( P = .048 and .046, respectively). These data provide insights into the genetics of MLL -rearranged AML and suggest therapeutic strategies., (© 2018 by The American Society of Hematology.)

Calpain-10 (CAPN10) is the calpain family protease identified as the first candidate susceptibility gene for type 2 diabetes mellitus (T2DM). However, the detailed molecular mechanism has not yet been elucidated. Here we report that CAPN10 processes microtubule associated protein 1 (MAP1) family proteins into heavy and light chains and regulates their binding activities to microtubules and actin filaments. Immunofluorescent analysis of Capn10 -/- mouse embryonic fibroblasts shows that MAP1B, a member of the MAP1 family of proteins, is localized at actin filaments rather than at microtubules. Furthermore, fluorescence recovery after photo-bleaching analysis shows that calpain-10 regulates actin dynamics via MAP1B cleavage. Moreover, in pancreatic islets from CAPN10 knockout mice, insulin secretion was significantly increased both at the high and low glucose levels. These findings indicate that deficiency of calpain-10 expression may affect insulin secretion by abnormal actin reorganization, coordination and dynamics through MAP1 family processing.

Here we demonstrate simultaneous measurements of the complex transmittance and birefringence using left- and right-handed circularly polarized terahertz (THz) pulses. We change the polarization of the THz pulses periodically by modulating the polarization of the pump pulses directed onto a ZnTe (111) crystal, and we convert linear to circular polarization using a broadband THz quarter-wave retarder. By integrating the alternating-emission system with the polarization-sensitive terahertz time-domain spectrometer, we are able to obtain the electric-field vector of the transmitted terahertz pulses for both the left- and right-handed circular polarizations. Utilizing this technique, we are able to measure simultaneously the frequency-dependent complex refractive indices (real and imaginary parts) and the orientations of the slow and fast axes of birefringent materials, a quartz disc and a barium borate crystal, in a single temporal sweep.

Carbohydrate response element-binding protein (ChREBP) has an important role in the carbohydrate-mediated regulation of hepatic de novo lipogenesis, but the mechanism for how it regulates plasma triacylglycerol (TAG) levels has not been established. This study aimed to clarify the role of ChREBP in regulation of plasma TAG levels. We analyzed the metabolic changes in mice infected with an adenovirus expressing ChREBP Δ196 (Ad-ChREBP). Compared with adenovirus harboring green fluorescent protein infected mice, Ad-ChREBP-infected mice had higher plasma free fatty acid levels and paradoxically lower plasma 3-hydroxybutyrate levels through decreased fatty acid oxidation, rather than ketogenesis. Consistent with their hepatomegaly and increased lipogenic gene expression, the liver TAG contents were much higher. Regarding lipid composition, C16:0 was much lower and C18:1n-9 was much higher, compatible with increased stearoyl CoA desaturase-1 and ELOVL fatty acid elongase 6 expression. Furthermore, Ad-ChREBP-infected mice had decreased plasma TAG and very low density lipoprotein (VLDL)-TAG levels, consistent with decreased Angiopoietin-like protein 3 (Angptl3) and increased fibroblast growth factor (Fgf21) mRNA and protein levels. Finally, Ad-ChREBP infection increased white adipose tissue Ucp1 mRNA levels with increased plasma Fgf21 levels. Because Fgf21 and Angptl3 are known to activate and suppress lipolysis in adipose tissues and oxidative tissues, ChREBP appears to regulate plasma TAG levels by modulating Fgf21 and Angptl3 levels. Thus, ChREBP overexpression led to dissociation of hepatic steatosis from hyperlipidemia.

Aims: A number of epidemiologic surveys have demonstrated that improving lifestyle habits, providing patient education, and regular screening of patients for early diabetic symptoms and complications through multidisciplinary collaboration are crucial for the management of diabetes., Methods: To evaluate the Diabetes Coordination Notebook and the Diabetes Regional Coordination Path in management of diabetes, 217 community pharmacies conducted a survey by questionnaire in Gifu Prefecture, Japan., Results: A reply to the questionnaire was obtained from 27,016 individuals, of whom 5,572 claimed to have diabetes or prediabetes. The rate of usage of the Diabetes Coordination Notebook and the Diabetes Regional Coordination Path was 40% and 7%, respectively. Interestingly, patients using the Diabetes Regional Coordination Path more frequently visited an ophthalmic clinic ( p  < 0.001) and a dental clinic ( p  < 0.05) than those not using it. Furthermore, multivariate logistic regression analysis revealed that use of the Diabetes Regional Coordination Path was the only factor associated with control of HbA1c < 7.0% (OR: 0.613, 95% CI: 0.395-0.951, p  = 0.029)., Conclusions: The usage of the Diabetes Regional Coordination Path together with the Diabetes Coordination Notebook is associated not only with regular visits to both an ophthalmic clinic and a dental clinic but also with the maintenance of appropriate HbA1c., Competing Interests: Conflict of interestAll authors report no conflicts of interest relevant to this article.

Light-field-driven processes occurring under conditions far beyond the diffraction limit of the light can be manipulated by harnessing spatiotemporally tunable near fields. A tailor-made carrier envelope phase in a tunnel junction formed between nanogap electrodes allows precisely controlled manipulation of these processes. In particular, the characterization and active control of near fields in a tunnel junction are essential for advancing elaborate manipulation of light-field-driven processes at the atomic-scale. Here, we demonstrate that desirable phase-controlled near fields can be produced in a tunnel junction via terahertz scanning tunneling microscopy (THz-STM) with a phase shifter. Measurements of the phase-resolved subcycle electron tunneling dynamics revealed an unexpected large carrier-envelope phase shift between far-field and near-field single-cycle THz waveforms. The phase shift stems from the wavelength-scale feature of the tip-sample configuration. By using a dual-phase double-pulse scheme, the electron tunneling was coherently manipulated over the femtosecond time scale. Our new prescription-in situ tailoring of single-cycle THz near fields in a tunnel junction-will offer unprecedented control of electrons for ultrafast atomic-scale electronics and metrology.

MODY 5 and 6 have been shown to be low-penetrant MODYs. As the genetic background of unknown MODY is assumed to be similar, a new analytical strategy is applied here to elucidate genetic predispositions to unknown MODY. We examined to find whether there are major MODY gene loci remaining to be identified using SNP linkage analysis in Japanese. Whole-exome sequencing was performed with seven families with typical MODY. Candidates for novel MODY genes were examined combined with in silico network analysis. Some peaks were found only in either parametric or non-parametric analysis; however, none of these peaks showed a LOD score greater than 3.7, which is approved to be the significance threshold of evidence for linkage. Exome sequencing revealed that three mutated genes were common among 3 families and 42 mutated genes were common in two families. Only one of these genes, MYO5A, having rare amino acid mutations p.R849Q and p.V1601G, was involved in the biological network of known MODY genes through the intermediary of the INS. Although only one promising candidate gene, MYO5A, was identified, no novel, high penetrant MODY genes might remain to be found in Japanese MODY.

Hematopoietic stem cells (HSCs) comprise a heterogeneous population exhibiting self-renewal and differentiation capabilities; however, the mechanisms involved in maintaining this heterogeneity remain unclear. Here, we show that SATB1 is involved in regulating HSC heterogeneity. Results in conditional Satb1-knockout mice revealed that SATB1 was important for the self-renewal and lymphopoiesis of adult HSCs. Additionally, HSCs from Satb1/Tomato-knockin reporter mice were classified based on SATB1/Tomato intensity, with transplantation experiments revealing stronger differentiation toward the lymphocytic lineage along with high SATB1 levels, whereas SATB1 - HSCs followed the myeloid lineage in agreement with genome-wide transcription and cell culture studies. Importantly, SATB1 - and SATB1 + HSC populations were interconvertible upon transplantation, with SATB1 + HSCs showing higher reconstituting and lymphopoietic potentials in primary recipients relative to SATB1 - HSCs, whereas both HSCs exhibited equally efficient reconstituted lympho-hematopoiesis in secondary recipients. These results suggest that SATB1 levels regulate the maintenance of HSC multipotency, with variations contributing to HSC heterogeneity., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Rupture of uterine artery pseudoaneurysm (UAP) is a life-threatening event after childbirth. Hysterectomy or uterine arterial embolization was often needed for hemostasis. However, such procedures may cause severe morbidities for these women. To estimate the efficacy of uterine balloon tamponade (UBT) for controlling ruptured UAP bleeding, a retrospective analysis in a single teaching hospital was performed., Materials and Methods: We reviewed the medical record of Juntendo University Hospital in 2015. All the women diagnosed with UAP were recruited to this study and management for UAP was investigated., Results: Three women were treated with UBT for ruptured UAP. All cases achieved hemostasis. One case had recurrent UAP after 24 h of UBT, and was retreated with UBT for a longer duration. The UAP was obliterated after more than 2 days of UBT in all cases., Conclusion: UBT has potential as a therapeutic technique not only for treatment of a ruptured UAP but also for obliteration of a UAP., (Copyright © 2018. Published by Elsevier B.V.)