Risk of hospitalized infections in older elderly patients with rheumatoid arthritis treated with tocilizumab or other biological/targeted synthetic disease-modifying antirheumatic drugs: Evaluation of data from a Japanese claims database.

OBJECTIVE: We compared the incidence rates of hospitalized infections (HIs) between tocilizumab (TCZ) and other biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in adults aged ≥75 years with rheumatoid arthritis (RA). METHODS: We used a Japanese claims database from Medical Data Vision Co., Ltd (Tokyo, Japan) to perform a retrospective longitudinal population-based study in patients with RA who were prescribed b/tsDMARDs between 2014 and 2019. We calculated adjusted risk ratios (aRRs) for HIs in three age groups (<65, ≥65 and <75, and ≥75 years). RESULTS: Of 5506 patients, 2265 (41.1%) were <65 years, 1709 (31.0%) were 65-74 years, and 1532 (27.8%) were ≥75 years. Crude incidence rates (/100 person-years) of HIs were 3.99, 7.27, and 10.77, respectively. In the oldest group, aRRs (95% confidence interval) for HIs (b/tsDMARDs versus TCZ) were as follows: etanercept, 2.40 (1.24-4.61); adalimumab, 1.90 (0.75-4.83); golimumab, 1.21 (0.66-2.23); and abatacept, 0.89 (0.49-1.62). In the other age groups, the noticeable difference was a lower aRR of etanercept versus TCZ in the youngest group (0.30, 0.11-0.85). CONCLUSION: In patients with RA aged ≥75 years, b/tsDMARDs have a similar risk of HIs to tocilizumab except for etanercept.

Coronary artery established through amniote evolution.

Coronary arteries are a critical part of the vascular system and provide nourishment to the heart. In humans, even minor defects in coronary arteries can be lethal, emphasizing their importance for survival. However, some teleosts survive without coronary arteries, suggesting that there may have been some evolutionary changes in the morphology and function of coronary arteries in the tetrapod lineage. Here, we propose that the true ventricular coronary arteries were newly established during amniote evolution through remodeling of the ancestral coronary vasculature. In mouse (Mus musculus) and Japanese quail (Coturnix japonica) embryos, the coronary arteries unique to amniotes are established by the reconstitution of transient vascular plexuses: aortic subepicardial vessels (ASVs) in the outflow tract and the primitive coronary plexus on the ventricle. In contrast, amphibians (Hyla japonica, Lithobates catesbeianus, Xenopus laevis, and Cynops pyrrhogaster) retain the ASV-like vasculature as truncal coronary arteries throughout their lives and have no primitive coronary plexus. The anatomy and development of zebrafish (Danio rerio) and chondrichthyans suggest that their hypobranchial arteries are ASV-like structures serving as the root of the coronary vasculature throughout their lives. Thus, the ventricular coronary artery of adult amniotes is a novel structure that has acquired a new remodeling process, while the ASVs, which occur transiently during embryonic development, are remnants of the ancestral coronary vessels. This evolutionary change may be related to the modification of branchial arteries, indicating considerable morphological changes underlying the physiological transition during amniote evolution.

Coronary arteries are tasked with supplying the heart with oxygenated blood and nutrients. Any blockage or developmental problem in these blood vessels can have severe and sometimes lethal consequences. Due to their importance for health, researchers have extensively studied how coronary arteries form in humans and mice; a more limited range of studies have also looked at their equivalent in zebrafish. However, little is known about these structures develop in animals such as birds, amphibians, or other groups of fish. This makes it difficult to retrace the evolutionary processes that have given rise to the coronary arteries we are familiar with in mammals. To address this knowledge gap, Mizukami et al. set out to compare blood vessel development around the heart of mammals, birds, amphibians, and fish. To do this, they performed detailed anatomical studies of blood vessel structure at different stages of development in mice as well as quail, frogs and newts, zebrafish and sharks. In both mice and quail, small arterial subepicardial vessels (or ASVs) emerged early in development around the heart; these subsequently reorganised and remodelled themselves to give rise to the 'true' coronary arteries characteristic of the mature heart. Frogs and newts also developed similar ASV-like structures; however, unlike their mammalian and bird equivalents, these vessels did not reorganise, instead being retained into adulthood. In fish, blood vessel development resembled that of amphibians, suggesting that the coronary artery-like structures seen in some fish are an 'ancestral' form of ASVs, rather than the equivalent of the mature coronary arteries in mammals and birds. This work sheds light on the evolutionary processes shaping essential structures in the heart. In the future, Mizukami et al. hope that this knowledge will help develop a greater range of experimental animal models for studying heart disease and potential treatments.

ORIHIME study: real-world treatment patterns and clinical outcomes of 338 patients with acquired hemophilia A from a Japanese administrative database.

BACKGROUND: Acquired hemophilia A (AHA) is a rare disorder, and clinical practices for treating AHA have not been fully clarified in Japan. OBJECTIVES: This study aims to investigate the epidemiology of AHA and real-world treatment practices in Japan. PATIENTS/METHODS: This observational study was based on a health administrative database of hospitalized patients diagnosed with AHA who were treated with immunosuppressants. RESULTS: The study included 214 males and 124 females (mean age 75.7 years). The most frequently used bypassing agent was recombinant activated factor VII. The predominant choice of immunosuppressant for first-line treatment was steroid monotherapy. Median days from the index date to the start of rehabilitation was 65.0 for cardiovascular, 35.5 for respiratory and 23.0 for locomotor. The proportion of patients with an activities of daily living (ADL) score < 70 points was high at both first admission and final discharge (47.4% and 38.8%). The percentage of deaths during hospitalization was 18.6%. CONCLUSIONS: This study clarified the treatment patterns and clinical outcomes of AHA in a large population in Japan. This was the first study showing ADL score distribution and time to rehabilitation. Further investigation is needed to develop better clinical practices for treatment of AHA.

Burden of congenital hemophilia A requiring treatment in Japan: The HIKOBOSHI study.

Background: Treatment of congenital hemophilia A (HA) in Japan has greatly improved with the widespread adoption of prophylactic factor (F)VIII concentrates. However, it is unknown if this has translated into a real-world reduction in disease and treatment burden. Objectives: To describe HA disease burden in Japan based on information from two medical information databases, JMDC and Real World Data Co., Ltd. (RWD). Methods: Eligible individuals were diagnosed with congenital HA and prescribed FVIII concentrates, bypassing agents, or emicizumab. Treatment patterns and disease burden data were derived from health insurance claims and electronic medical records. Results: Data on 459 people with HA were retrospectively collected from 2005 to 2020 in the JMDC database (median [min, max] of 37 [2, 186] months of available records), and 229 people with HA from 1985 to 2020 in the RWD database (median [min, max] of 154 [0, 409] months of available records). Mean (standard deviation) ages at the time of the first record were 25.0 (16.8) years (JMDC) and 19.2 (20.3) years (RWD). In the JMDC database, mean monthly FVIII dose increased from 2201 IU in 2005 to 8239 IU in 2013 to 11,377 IU in 2019; HA-related drug costs increased accordingly. Mean (95% confidence interval) annual outpatient and out-of-hours visits decreased slightly between 2013 and 2019 (outpatient visits: from 22.9 [16.8-29.0] to 14.3 [12.6-16.1] per person; out-of-hours visits: from 1.3 [0.2-2.5] to 0.6 [0-1.4]). There was no change in mean number of hospitalizations. Conclusions: Challenges remain in HA, including treatment burden, outpatient visits, and hospitalizations.

SINEs as Credible Signs to Prove Common Ancestry in the Tree of Life: A Brief Review of Pioneering Case Studies in Retroposon Systematics.

Currently, the insertions of SINEs (and other retrotransposed elements) are regarded as one of the most reliable synapomorphies in molecular systematics. The methodological mainstream of molecular systematics is the calculation of nucleotide (or amino acid) sequence divergences under a suitable substitution model. In contrast, SINE insertion analysis does not require any complex model because SINE insertions are unidirectional and irreversible. This straightforward methodology was named the "SINE method," which resolved various taxonomic issues that could not be settled by sequence comparison alone. The SINE method has challenged several traditional hypotheses proposed based on the fossil record and anatomy, prompting constructive discussions in the Evo/Devo era. Here, we review our pioneering SINE studies on salmon, cichlids, cetaceans, Afrotherian mammals, and birds. We emphasize the power of the SINE method in detecting incomplete lineage sorting by tracing the genealogy of specific genomic loci with minimal noise. Finally, in the context of the whole-genome era, we discuss how the SINE method can be applied to further our understanding of the tree of life.

Alternative splicing plays key roles in response to stress across different stages of fighting in the fish Betta splendens.

BACKGROUND: Aggression is an evolutionarily conserved behavior critical for animal survival. In the fish Betta splendens, across different stages of fighting interactions, fighting opponents suffer from various stressors, especially from the great demand for oxygen. Using RNA sequencing, we profiled differential alternative splicing (DAS) events in the brains of fish collected before fighting, during fighting, and after fighting to study the involvement of alternative splicing (AS) in the response to stress during the fight. RESULTS: We found that fighting interactions induced the greatest increase in AS in the 'during-fighting' fish, followed by that of the 'after-fighting' fish. Intron retention (IR) was the most enriched type among all the basic AS events. DAS genes were mainly associated with synapse assembly, ion transport, and regulation of protein secretion. We further observed that IR events significantly differentiated between winners and losers for 19 genes, which were associated with messenger RNA biogenesis, DNA repair, and transcription machinery. These genes share many common features, including shorter intron length and higher GC content. CONCLUSIONS: This study is the first comprehensive view of AS induced by fighting interactions in a fish species across different stages of those interactions, especially with respect to IR events in winners and losers. Together, these findings facilitate future investigations into transcriptome complexity and AS regulation in response to stress under the context of aggression in vertebrates.

Data of RNA-seq transcriptomes of liver, bone, heart, kidney and blood in klotho mice at a pre-symptomatic state and the effect of a traditional Japanese multi-herbal medicine, juzentaihoto.

We performed RNA-seq analyses of mRNA isolated from five organs, liver, bone, heart, kidney and blood at the pre-symptomatic state of klotho mice with/without administration of a Japanese traditional herbal medicine, juzentaihoto (JTT). Data of differentially expressed genes (DEG) with/without JTT was included. Intron retention (IR) is an important regulatory mechanism that affects gene expression and protein functions. We collected data in which retained-introns were accumulated in a particular set of genes of these organs, and showed that among these retained introns in the liver and bone a subset was recovered to the normal state by the medicine. All of the data present changes of molecular events on the levels of metabolites, proteins and gene expressions observed at the pre- symptomatic state of aging in klotho mice with/without JTT. The research article related to this Data in Brief is published in GENE entitled as "Intron retention as a new pre-symptomatic marker of aging and its recovery to the normal state by a traditional Japanese herbal medicine".

Intron retention is a stress response in sensor genes and is restored by Japanese herbal medicines: A basis for future clinical applications.

Intron retention (IR) is a regulatory mechanism that can retard protein production by acting at the level of mRNA processing. We recently demonstrated that IR occurs at the pre-symptomatic state during the aging process of a mouse model of aging, providing a promising biomarker for that state, and can be restored to the normal state by juzentaihoto (JTT), a Japanese herbal medicine (Kampo) (Okada et al. 2021). Here we characterized the genes that accumulate retained introns, examined the biological significance of increased IR in these genes for the host, and determined whether drugs other than JTT can have this effect. By analyzing RNA-sequencing data generated from the hippocampus of the 19-week-old SAMP8 mouse, a model for studying age-related depression and Alzheimer's disease, we showed that genes with increased IR are generally involved in multiple metabolic pathways and have pivotal roles in sensing homeostasis. We thus propose that IR is a stress response and works to fine-tune the expression of many downstream target genes, leading to lower levels of their translation under stress conditions. Interestingly, Kampo medicines, as well as other organic compounds, restored splicing of a specific set of retained introns in these sensor genes in accordance with the physiological recovery conditions of the host, which corresponds with the recovery of transcripts represented by differentially expressed genes. Thus, analysis of IR genes may have broad applicability in evaluating the pre-symptomatic state based on the extent of IR of selective sensor genes, opening a promising early diagnosis of any diseases and a strategy for evaluating efficacies of several drugs based on the extent of IR restoration of these sensor genes.

Reduction of bleeding complications on puncture site after percutaneous coronary intervention using a 6.5-French sheathless guiding catheter.

BACKGROUND: Reducing complications at the puncture site after percutaneous coronary intervention (PCI) is important. The diameter of a 6.5-French (Fr) sheathless guiding catheter (GC) is smaller by approximately 2-Fr compared to a 6-Fr conventional sheath. In the present study, we investigated the post-PCI puncture site complications of a transradial approach in each gender while using a 6.5-Fr sheathless GC. METHODS AND RESULTS: Our study consisted of 332 patients who underwent transradial coronary intervention (TRI) between August 2017 and July 2019. We classified the patients into either the 6.5-Fr sheathless GC (Asahi, Intecc, Aichi, Japan) Group (Sheathless group: n = 182 males, 58 females) or the 6-Fr sheathed GC Group (Sheathed group: n = 150 males, 36 females). We determined the complications at the puncture site: oozing, subcutaneous hemorrhage, formation of hematoma, pseudoaneurysms, and peripheral neuropathy. The body mass index of the patients was greater in the sheathless GC group compared to the sheathed GC group (24.5 ± 3.5 kg/m2 vs. 23.6 ± 3.7 kg/m2, p = 0.02). In males, there was no significant difference in the complication rate at the puncture site between the sheathless GC and sheathed GC groups (19.3% vs. 18.6%, p = 0.88). However, the complication rate at the puncture site in females was higher in the sheathed GC group than in the sheathless GC group (36% vs. 15.5%, p = 0.02). A multiple logistic regression analysis revealed that the use of a 6.5-Fr sheathless GC independently reduced the complications in female patients (p = 0.006). CONCLUSION: The use of the 6.5-Fr sheathless GC system in a transradial approach reduced the complications at the puncture site in female patients. The 6.5-Fr sheathless GC system may be a safe option for them compared to the conventional sheath system.

Kampo formulas alleviate aging-related emotional disturbances and neuroinflammation in male senescence-accelerated mouse prone 8 mice.

Aging-induced neuroinflammation, also known as neuroinflammaging, plays a pivotal role in emotional disturbances, including depression and anxiety, in older individuals, thereby leading to cognitive dysfunction. Although numerous studies have focused on therapeutic strategies for cognitive impairment in older individuals, little research has been performed on treating its preceding emotional disturbances. Here, we examined whether Kampo formulas (kososan [KS], nobiletin-rich kososan [NKS], and hachimijiogan [HJG]) can ameliorate aging-induced emotional disturbances and neuroinflammation in mice. The depression-like behaviors observed in SAMP8 mice, relative to normally aging SAMR1 mice, were significantly prevented by treatment with Kampo formulas for 13 weeks. Western blot analysis revealed that hippocampal neuroinflammation was significantly abrogated by Kampo formulas. KS and NKS also significantly attenuated the hippocampal neuroinflammatory priming induced by lipopolysaccharide (LPS, 0.33 mg/kg, i.p.) challenge in SAMP8 mice. Hippocampal IL-1ß, IL-6, and MCP-1 levels were significantly decreased in NKS-treated SAMP8 mice. KS and NKS showed significantly reduced tau accumulation in the brains of SAMP8 mice. RNA-sequencing revealed that each Kampo formula led to unique dynamics of hippocampal gene expression and appeared to abrogate hippocampal inflammatory responses. HJG significantly blocked the LPS-induced increase in serum IL-6 and MCP-1. These results suggest that Kampo formulas would be useful for treating aging-induced depression, in part by regulating neuroinflammatory pathways. This finding may pave the way for the development of therapeutic strategies for aging-related emotional disturbances, which may contribute to the prevention of cognitive dysfunction in older individuals.

Vascular imaging of patients with refractory Takayasu arteritis treated with tocilizumab: post hoc analysis of a randomized controlled trial.

OBJECTIVES: Tocilizumab, an anti-IL-6 receptor antibody, was investigated in patients with refractory Takayasu arteritis (TAK) in a phase 3 randomized controlled trial. In this post hoc analysis, we investigated whether tocilizumab treatment inhibited the progression of vascular lesions caused by TAK in these patients. METHODS: Included patients received at least one dose of tocilizumab and underwent CT at baseline and at week 48 after tocilizumab initiation. Three radiologists not involved in the original trial independently evaluated the CT images. Twenty-two arteries from each patient were assessed for change from baseline in wall thickness (primary endpoint), dilatation/aneurysm, stenosis/occlusion or wall enhancement for at least 96 weeks after tocilizumab initiation. Patient-level assessments were also conducted. RESULTS: In 28 patients, 86.7% of 22 arteries had improved or stable wall thickness at week 96. Proportions of patients with improved or stable, partially progressed or newly progressed lesions were 57.1%, 10.7% and 28.6%, respectively, for wall thickness; proportions with improved or stable lesions were 92.9% for dilatation/aneurysm, and 85.7% for stenosis/occlusion. Patients with newly progressed lesions, reflecting more refractory disease, were prescribed glucocorticoids at dosages that could not be reduced below 0.1 mg/kg/day at week 96. CONCLUSIONS: Approximately 60% of patients with TAK did not experience progression in wall thickness within 96 weeks after initiation of tocilizumab treatment. Few patients experienced progressed dilatation/aneurysm, or stenosis/occlusion. Wall thickness progression likely resulted from refractory TAK. Patients who experience this should be monitored regularly by imaging, and additional glucocorticoid or immunosuppressive treatment should be considered to avoid vascular progression. TRIAL REGISTRATION: Japan Pharmaceutical Information Centre number, JapicCTI-142616.

Data of RNA-seq transcriptomes in the brain associated with aggression in males of the fish Betta splendens.

Siamese fighting fish Betta splendens are notorious for their aggressiveness and males of this fish have been widely used to study aggression. However, an understanding of brain transcriptome signature associated with aggression in the context of male-male interaction in this fish remains to be understood. Herein, RNA-Seq transcriptome data from 37 brains samples collected at different fighting stages are described. These brain samples were collected before fighting (B), during fighting (D20 and D60), and after fighting (A0 and A30). The raw data were analyzed for differential gene expression using edgeR package in R. A criterion of FDR cut-off ≤ 0.05 and an absolute fold change (FC) of 0 or greater were used to identify top upregulated and downregulated genes in fighting groups (D20, D60, A0, and A30) relative to non-fighting group (B). The data presented hereafter enable fundamental studies on genes and molecular events mediating aggressive behavior in this fish and will lay a valuable foundation for future research on the aggression of vertebrates.

Intron retention as a new pre-symptomatic marker of aging and its recovery to the normal state by a traditional Japanese multi-herbal medicine.

Intron retention (IR) is an important regulatory mechanism that affects gene expression and protein functions. Using klotho mice at the pre-symptomatic state, we discovered that retained-introns accumulated in several organs including the liver and that among these retained introns in the liver a subset was recovered to the normal state by a Japanese traditional herbal medicine. This is the first report of IR recovery by a medicine. IR-recovered genes fell into two categories: those involved in liver-specific metabolism and in splicing. Metabolome analysis of the liver showed that the klotho mice were under starvation stress. In addition, our differentially expressed gene analysis showed that liver metabolism was actually recovered by the herbal medicine at the transcriptional level. By analogy with the widespread accumulation of intron-retained pre-mRNAs induced by heat shock stress, we propose a model in which retained-introns in klotho mice were induced by an aging stress and in which this medicine-related IR recovery is indicative of the actual recovery of liver-specific metabolic function to the healthy state. Accumulation of retained-introns was also observed at the pre-symptomatic state of aging in wild-type mice and may be an excellent marker for this state in general.

A unique neurogenomic state emerges after aggressive confrontations in males of the fish Betta splendens.

Territorial defense involves frequent aggressive confrontations with competitors, but little is known about how brain-transcriptomic profiles change between individuals competing for territory establishment. Our previous study elucidated that when two fish Betta splendens males interact, transcriptomes across their brains synchronize in a way that reflects a mutual assessment process between them at the gene expression level. Here we aim to evaluate how the brain-transcriptomic profiles of opponents change immediately after shifting their social status (i.e., the winner/loser has emerged) and 30 min after this shift. We showed that changes in the expression of certain genes are unique to different fighting stages and the expression patterns of certain genes are transiently or persistently changed across all fighting stages. These brain transcriptomic responses are in accordance with behavioral changes across the fight. Strikingly, the specificity of the brain-transcriptomic synchronization of a pair during fighting was gradually lost after fighting ceased, leading to the emergence of a basal neurogenomic state in which the changes in gene expression were reduced to minimum and consistent across all individuals. This state shares common characteristics with the hibernation state that animals adopt to minimize their metabolic rates to save energy. Interestingly, expression changes for genes related to metabolism, autism spectrum disorder, and long-term memory still differentiated losers from winners. Together, the fighting system using male B. splendens provides a promising platform for investigating neurogenomic states of aggression in vertebrates.

Distinctively different predictors for long-term outcomes between responders and nonresponders who underwent cardiac resynchronization therapy.

BACKGROUND: It is common to develop heart failure (HF) events even in respondents to cardiac resynchronization therapy (CRT) during a long-term observation period. We investigated the predictors for long-term outcome in responders in comparison with nonresponders in patients diagnosed with HF along with implanted CRT. METHODS: We enrolled 133 consecutive patients (mean age, 70 ± 10 years; 72 males) implanted with CRT from April 2010 to July 2019. Accurate follow-up information (mean follow-up period, 983 ± 801 days) was obtained from 66 responders and 53 nonresponders. RESULTS: Kaplan-Meier event-free curves showed that major adverse cerebral and cardiovascular event (MACCE)-free ratio was significantly lower as the stage of renal function progresses (log rank, 19.5; P < .0001). The baseline estimated glomerular filtration rate (e-GFR) before CRT was not significantly different between nonresponders and responders. The e-GFR after judgment of CRT response was lower in patients with MACCEs than those without. Cox proportional hazards regression analysis revealed that low baseline e-GFR before CRT and after judgment of CRT response was closely related with MACCEs in responders, but not in nonresponders. The survival rate in responders without MACCEs assessed using Kaplan-Meier analysis was significantly larger in the preserved e-GFR (baseline value before CRT, >44 mL/min/1.73 m2) group than in the depressed group (log rank, 20.29; P < .0001). CONCLUSION: We demonstrate that the factors for MACCEs during long follow-up periods were distinctively different between responders and nonresponders. Patients with depressed e-GFRs are suggested to have poor prognosis even if they are responders to CRT.

Genomic Signatures for Species-Specific Adaptation in Lake Victoria Cichlids Derived from Large-Scale Standing Genetic Variation.

The cichlids of Lake Victoria are a textbook example of adaptive radiation, as >500 endemic species arose in just 14,600 years. The degree of genetic differentiation among species is very low due to the short period of time after the radiation, which allows us to ascertain highly differentiated genes that are strong candidates for driving speciation and adaptation. Previous studies have revealed the critical contribution of vision to speciation by showing the existence of highly differentiated alleles in the visual opsin gene among species with different habitat depths. In contrast, the processes of species-specific adaptation to different ecological backgrounds remain to be investigated. Here, we used genome-wide comparative analyses of three species of Lake Victoria cichlids that inhabit different environments-Haplochromis chilotes, H. sauvagei, and Lithochromis rufus-to elucidate the processes of adaptation by estimating population history and by searching for candidate genes that contribute to adaptation. The patterns of changes in population size were quite distinct among the species according to their habitats. We identified many novel adaptive candidate genes, some of which had surprisingly long divergent haplotypes between species, thus showing the footprint of selective sweep events. Molecular phylogenetic analyses revealed that a large fraction of the allelic diversity among Lake Victoria cichlids was derived from standing genetic variation that originated before the adaptive radiation. Our analyses uncovered the processes of species-specific adaptation of Lake Victoria cichlids and the complexity of the genomic substrate that facilitated this adaptation.

Long-term safety and efficacy of emicizumab for up to 5.8 years and patients' perceptions of symptoms and daily life: A phase 1/2 study in patients with severe haemophilia A.

INTRODUCTION: Safety and efficacy results of the phase 1 study and phase 1/2 extension study of the bispecific antibody emicizumab in patients with severe haemophilia A with or without factor VIII inhibitors for up to 2.8 years were reported previously. AIM: To evaluate further longer-term data including patients' perceptions at study completion. METHODS: Emicizumab was administered subcutaneously once weekly at maintenance doses of 0.3, 1 or 3 mg/kg with potential up-titration. All patients were later switched to the approved maintenance dose of 1.5 mg/kg. RESULTS: Eighteen patients received emicizumab for up to 5.8 years. Most adverse events were mild and unrelated to emicizumab. Annualized bleeding rates (ABRs) for bleeds treated with coagulation factors decreased from pre-emicizumab rates or remained zero in all patients. The median ABRs were low at 1.25, 0.83 and 0.22 during the 0.3, 1 and 3 mg/kg dosing periods, respectively. Of 8 patients who decreased their doses from 3 to 1.5 mg/kg, ABRs decreased in 4, remained at zero in 2, and increased in 2. Total time spent with symptoms associated with treated bleeds decreased in all patients except 2. All patients answered 'improved' for bleeding severity and time until bleeding stops, except 1 answering 'slightly improved'. Most patients answered 'improved' or 'slightly improved'' for daily life and feelings; in particular, all patients except 1 answered 'improved' or 'slightly improved' for anxiety. CONCLUSIONS: Long-term emicizumab prophylaxis for up to 5.8 years was safe and efficacious, and may improve patients' daily lives and feelings, regardless of inhibitor status.

Implication of a new function of human tDNAs in chromatin organization.

Transfer RNA genes (tDNAs) are essential genes that encode tRNAs in all species. To understand new functions of tDNAs, other than that of encoding tRNAs, we used ENCODE data to examine binding characteristics of transcription factors (TFs) for all tDNA regions (489 loci) in the human genome. We divided the tDNAs into three groups based on the number of TFs that bound to them. At the two extremes were tDNAs to which many TFs bound (Group 1) and those to which no TFs bound (Group 3). Several TFs involved in chromatin remodeling such as ATF3, EP300 and TBL1XR1 bound to almost all Group 1 tDNAs. Furthermore, almost all Group 1 tDNAs included DNase I hypersensitivity sites and may thus interact with other chromatin regions through their bound TFs, and they showed highly conserved synteny across tetrapods. In contrast, Group 3 tDNAs did not possess these characteristics. These data suggest the presence of a previously uncharacterized function of these tDNAs. We also examined binding of CTCF to tDNAs and their involvement in topologically associating domains (TADs) and lamina-associated domains (LADs), which suggest a new perspective on the evolution and function of tDNAs.

Potential Risk of Hypoglycemia in Patients with Heart Failure.

The properties of glucose changes in patients with chronic heart failure remain elusive. In the present study, we investigated the sequential changes of interstitial glucose concentrations in patients with chronic heart failure and heart disease who were not undergoing antidiabetic therapy.A glucose monitoring device (FreeStyle Libre Pro) was attached to the backside of an upper arm and the interstitial glucose concentration was monitored every 15 minutes for 1 week. Eleven patients with chronic heart failure (Heart failure (+) ) and 7 patients with chronic heart diseases but not with heart failure (Heart failure (-) ) were enrolled. The average level and peak value of interstitial glucose concentrations, and the duration of hyperglycemia (≥ 140 mg/dL) were not significantly different between Heart failure (+) and Heart failure (-). The duration of hypoglycemia (< 80 mg/dL) was significantly longer and the trough value was significantly lower in Heart failure (+) compared with Heart failure (-). Most of the patients in Heart failure (+) were exposed to a long duration of hypoglycemia from midnight to morning. Importantly, none of the patients who showed hypoglycemia complained of any subjective symptoms during hypoglycemia. Malabsorption may be one of the mechanisms of hypoglycemia.In summary, patients with chronic heart failure are at risk of developing hypoglycemia even if they do not undergo any antidiabetic therapy.