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Aims: Although intensive statin therapy reduced cardiovascular risks, cardiovascular events have not been completely prevented. Probucol is a potent antioxidant and reduces tendon xanthomas in familial hypercholesterolemia patients despite reduction of high-density lipoprotein (HDL)-cholesterol (HDL-C). We investigated whether probucol can reduce cardiovascular events on top of conventional lipid-lowering therapy in patients with coronary heart disease (CHD). Methods: PROSPECTIVE is a multicenter, randomized, prospective study that recruited 876 Japanese patients with CHD and dyslipidemia with a low-density lipoprotein (LDL)-cholesterol (LDL-C) level of ≥ 140 mg/dL without medication or those treated with lipid-lowering drugs. Lipid-lowering agents were administered during the study period in the control group (n = 438), and probucol 500 mg/day was added to lipid-lowering therapy in the probucol group (n = 438). Patients were randomly assigned to two treatment groups by adjusting the LDL-C level and presence of diabetes and hypertension and followed up for more than 3 years. The primary end point was a composite of cerebrovascular and cardiovascular events (cardiovascular disease death including sudden death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, hospitalization for heart failure, or coronary revascularization). The secondary end point was carotid intima-media thickness in a subset of patients. Results: The incidence of the primary end point showed a trend to be lower in the probucol group compared with that in the control group despite reduced HDL-C without serious adverse events. Anti-atherogenic effects of probucol may be attributed to its potent antioxidative function and enhancement of reverse cholesterol transport. Conclusion: Since there was no statistical significance between the probucol and control groups despite a marked reduction of HDL-C, further studies on the clinical outcomes of probucol on top of conventional therapy may be necessary in the future (UMIN000003307).

BACKGROUND AND OBJECTIVES: Large, randomized, controlled trials targeting higher hemoglobin level with erythropoiesis-stimulating agents for Western patients with CKD showed harm. However, the effect of anemia correction using erythropoiesis-stimulating agents may differ between CKD subpopulations. The Prevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease study, a multicenter, randomized, open-label, parallel-group study, aimed to examine the effect of targeting hemoglobin levels of 11–13 g/dl using darbepoetin alfa with reference to a low-hemoglobin target of 9–11 g/dl on kidney outcome in patients with advanced CKD without diabetes in Japan. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We enrolled 491 patients with CKD without diabetes, and an eGFR of 8–20 ml/min per 1.73 m(2). Of these 491 patients, 239 and 240 were ultimately assigned to the high- and low-hemoglobin groups, respectively (12 patients were excluded). The primary outcome was a kidney composite end point (starting maintenance dialysis, kidney transplantation, eGFR≤6 ml/min per 1.73 m(2), and 50% reduction in eGFR). RESULTS: Mean hemoglobin levels were 11.2±1.1 and 10.0±0.9 g/dl in the high- and low-hemoglobin groups, respectively, during the mean study period of 73.5±29.7 weeks. The kidney composite end point occurred in 105 (44%) and 116 (48%) patients in the high- and low-hemoglobin groups, respectively (log-rank test; P=0.32). The adjusted Cox proportional hazards model showed that the hazard ratio for the high- versus low-hemoglobin group was 0.78 (95% confidence interval, 0.60 to 1.03; P=0.08). Cardiovascular events occurred in 19 (8%) and 16 (7%) patients in each group, respectively, with no significant between-group difference (log-rank test; P=0.66). CONCLUSIONS: Targeting a higher hemoglobin level (11–13 g/dl) with darbepoetin alfa did not improve kidney outcome compared with targeting a lower hemoglobin level (9–11 g/dl) in patients with advanced CKD without diabetes. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Prevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease (PREDICT), NCT01581073.

Background Most patients with human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) develop neurogenic bladder dysfunction. However, longitudinal changes and treatment effects remain poorly understood. This study aimed to characterize the clinical course of urinary dysfunction in this population. Methods This prospective observational study included 547 patients enrolled in HAM-net, a nationwide registry for HAM/TSP in Japan. Urinary dysfunction severity was evaluated using the HAM/TSP-bladder dysfunction symptom score (HAM-BDSS) and the HAM/TSP-bladder dysfunction severity grade (HAM-BDSG). These specific measures were recently developed for assessing urinary dysfunction in HAM/TSP. We analyzed longitudinal changes over a 6-year follow-up period, associations between urinary and gait dysfunction, and treatment efficacy of urinary catheterization and mirabegron (a β3-adrenergic agonist for overactive bladder symptoms). Results The mean (standard deviation [SD]) age and disease duration at enrollment were 61.9 (10.7) years and 16.6 (11.6) years, respectively, and 74.6% of patients were women. Only 8.0% were free from urinary symptoms (HAM-BDSG 0), 65.4% had urinary symptoms or were on medication (HAM-BDSG I), and 23.2% and 3.3% used intermittent and indwelling catheters (HAM-BDSG II and III), respectively. HAM-BDSG and BDSS were worse in patients with greater gait dysfunction (p p p = 0.001). Conclusions Urinary dysfunction affected 92% of patients and progressed over the 6-year follow-up. Urinary symptoms were more severe in patients with poorer gait function. Urinary catheterization and mirabegron were effective in relieving symptoms. Effective utilization of real-world data is key to establishing evidence for rare diseases, such as HAM/TSP.

Both natural viral infections and therapeutic interventions using viral vectors pose significant risks of malignant transformation. Monitoring for clonal expansion of infected cells is important for detecting cancer. Here we developed a novel method of tracking transgene integration sites. RAISING (Rapid Amplification of Integration Sites without Interference by Genomic DNA contamination) is a sensitive, inexpensive alternative to established methods. Its compatibility with Sanger sequencing combined with our CLOVA (Clonality Value) software is critical for those without access to expensive next-generation sequencing. To model our method, we analyzed samples from 698 patients infected with the retrovirus HTLV-1, which causes adult T-cell leukemia/lymphoma (ATL). We defined a clonality value identifying ATL patients with 100% sensitivity and 95.3% specificity, and our preliminary longitudinal analysis suggests this may also be useful for ATL risk assessment. We anticipate future studies will confirm the broad applicability of our technology, especially in the emerging gene therapy sector.

Both natural viral infections and therapeutic interventions using viral vectors pose significant risks of malignant transformation. Monitoring for clonal expansion of infected cells is important for detecting cancer. Here we developed a novel method of tracking clonality via the detection of transgene integration sites. RAISING (Rapid Amplification of Integration Sites without Interference by Genomic DNA contamination) is a sensitive, inexpensive alternative to established methods. Its compatibility with Sanger sequencing combined with our CLOVA (Clonality Value) software is critical for those without access to expensive high throughput sequencing. We analyzed samples from 688 individuals infected with the retrovirus HTLV-1, which causes adult T-cell leukemia/lymphoma (ATL) to model our method. We defined a clonality value identifying ATL patients with 100% sensitivity and 94.8% specificity, and our longitudinal analysis also demonstrates the usefulness of ATL risk assessment. Future studies will confirm the broad applicability of our technology, especially in the emerging gene therapy sector.

Aims In this study, we integrated two randomized control trials, PROSPECTIVE and IMPACT, to address the effect of probucol on cerebrocardiovascular events and carotid intima-media thickness (IMT) in Japanese, Korean, and Chinese patients with coronary artery disease (CAD). Methods A total of 1,025 patients from the PROSPECTIVE and IMPACT studies were enrolled. The time to the first major adverse cerebrocardiovascular event, in addition to carotid IMT and lipid levels, was compared between the control and probucol groups. Results In the integrated analysis, the adjusted hazard ratio (HR) and 95% confidence interval (CI) were 0.67 and 0.44-1.03, respectively, indicating a tendency to show the effect of probucol on cerebrocardiovascular events in secondary prevention. We also found no significant differences between the control and probucol groups in the mean IMT of the carotid arteries and its changes. However, we found a significant decrease in cerebrocardiovascular events in patients with reduced levels of HDL cholesterol (HDL-C) (≥ 6.25 mg/dL) compared with those with levels ＜6.25 mg/dL (p=0.024), without any increase in adverse events such as severe ventricular arrhythmias. Conclusion We demonstrated a marginal effect of probucol on cerebrocardiovascular events in Asian patients with CAD, with reasonable safety profiles. A larger study may be needed to support the effect of probucol for cardiovascular prevention.

Let $V_{L}$ be the vertex algebra associated to a non-degenerate even lattice $L$, $\theta$ the automorphism of $V_{L}$ induced from the $-1$-isometry of $L$, and $V_{L}^{+}$ the fixed point subalgebra of $V_{L}$ under the action of $\theta$. In this series of papers, we classify the irreducible weak $V_{L}^{+}$-modules and show that any irreducible weak $V_{L}^{+}$-module is isomorphic to a weak submodule of some irreducible weak $V_{L}$-module or to a submodule of some irreducible $\theta$-twisted $V_{L}$-module. In this paper (Part 1), we show that when the rank of $L$ is $1$, every non-zero weak $V_{L}^{+}$-module contains a non-zero $M(1)^{+}$-module, where $M(1)^{+}$ is the fixed point subalgebra of the Heisenberg vertex operator algebra $M(1)$ under the action of $\theta$., Comment: 29 pages. To appear in Journal of Algebra. We divide the article arXiv:1910.07126 into 3 parts for publication. This is the first part

Background Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with cardiovascular events and poor renal outcome in patients with chronic kidney disease (CKD). This study aimed to investigate the initial responsiveness to darbepoetin alfa (DA) and its contributing factors using the data from the BRIGHTEN. Methods Of 1980 patients enrolled at 168 facilities, 1695 were included in this analysis [285 patients were excluded mainly due to lack of hemoglobin (Hb) values]. The initial ESA response index (iEResI) was defined as a ratio of Hb changes over 12 weeks after DA administration per weight-adjusted total DA dose and contributing factors to iEResI were analyzed. Results The mean age was 70 ± 12 years (male 58.8%; diabetic nephropathy 27.6%). The median creatinine and mean Hb levels at DA initiation were 2.62 mg/dL and 9.8 g/dL, respectively. The most frequent number of DA administration during 12 weeks was 3 times (41.1%), followed by 4 (15.6%) times with a wide distribution of the total DA dose (15–900 μg). Remarkably, 225 patients (13.3%) did not respond to DA. Multivariate analysis showed that male gender, hypoglycemic agent use, iron supplementation, high eGFR, low Hb, low CRP, low NT-proBNP, and low urinary protein–creatinine ratio were independently associated with better initial response to DA (P = Conclusions Non-responder to DA accounted for 13.3% of patients with non-dialysis CKD. Iron supplementation, low CRP, low NT-proBNP, and less proteinuria were predictive and modifiable factors associated with better initial response to DA.

Let ${\mathscr M}(p)$ $(p=2,3,\ldots)$ be the singlet vertex operator algebra and $\omega$ its conformal vector. We classify the simple weak ${\mathscr M}(p)$-modules with a non-zero element $u$ such that for some integer $s\geq 2$, $\omega_i u\in{\mathbb C} u$ ($i=\lfloor s/2\rfloor+1,\lfloor s/2\rfloor+2,\ldots,s-1$), $\omega_{s} u\in{\mathbb C}^{\times} u$, and $\omega_i u=0$ for all $i>s$., Comment: 21 pages. arXiv admin note: text overlap with arXiv:1608.07890

Aim. To identify the factors protecting Abeta-positive subjects with normal cognition (NC) or mild cognitive impairment (MCI) from conversion to Alzheimer’s disease (AD). Methods. Subjects with MCI in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, with baseline data for neuropsychological tests, brain beta amyloid (Abeta), magnetic resonance imaging (MRI), APOE genotyping, and 18F-FDG-PET (FDG), were included for analysis. Results. Elevated brain amyloid was associated with a higher risk of conversion from MCI to AD (41.5%) relative to Abeta levels of FDG > 5.946 had a lower risk of AD. ApoE4 carrier status did not influence the protective effect. Conclusion. Higher average CGM based on FDG modified the progression to AD, indicating a protective function. The results suggest that the inclusion of this CGM measured by FDG would enrich clinical trial design and that increasing CGM along with the use of anti-Abeta agents might be a potential prevention strategy for AD.

The effect of HydroSoft coils on the prevention of recanalization and thrombosis after embolization is unclear. We herein report the results of the single-armed prospective Japanese HydroSoft Registry.Aneurysms with a diameter of10 mm that were treated with a ≥50% length of HydroSoft coils were registered. We evaluated the safety and recanalization rate and analyzed the factors related to their recanalization and thrombosis 1 year later.In total, 122 aneurysms were registered. Their mean maximum diameter and neck length were 6.4 and 3.9 mm, respectively. The mean length of the HydroSoft coils was 84.3%. No intracranial hemorrhage occurred, but 2 patients developed minor ischemic strokes. Angiographic examination immediately after the procedure showed complete obliteration, neck remnant (NR), and body filling (BF) in 20 (16.4%), 32 (26.2%), and 67 (54.9%) cases, respectively. One-year follow-up angiography showed complete obliteration, NR, and BF in 68 (55.7%), 15 (12.3%), and 15 (12.3%) cases, respectively, and 5 aneurysms (4.1%) were recanalized (4 and 1 with BF and NR as their initial angiographic result, respectively). Another 11 aneurysms still showed BF, although their thrombosis was promoted. No significant factors related to recanalization were identified. A high volume embolization ratio and small neck were significantly associated with thrombosis 1 year after embolization with HydroSoft coils.The safety and prevention of recanalization 1 year after the treatment appeared acceptable. The high volume embolization ratio associated with HydroSoft coils could induce progression of thrombosis for aneurysms characterized by NR and BF during the follow-up period.

Let $M(1)$ be the vertex operator algebra with the Virasoro element $\omega$ associated to the Heisenberg algebra of rank $1$ and let $M(1)^{+}$ be the subalgebra of $M(1)$ consisting of the fixed points of an automorphism of $M(1)$ of order $2$. We classify the simple weak $M(1)^{+}$-modules with a non-zero element $w$ such that for some integer $s\geq 2$, $\omega_i w\in{\mathbb C}w$ ($i=\lfloor s/2\rfloor+1,\lfloor s/2\rfloor+2,\ldots,s-1$), $\omega_{s}w\in{\mathbb C}^{\times}w$, and $\omega_i w=0$ for all $i>s$. The result says that any such simple weak $M(1)^{+}$-module is isomorphic to some simple weak $M(1)$-module or to some $\theta$-twisted simple weak $M(1)$-module., Comment: 20 pages; typos corrected

We generalize the notion of an intertwining operator to N-graded weak modules over a vertex operator algebra and study their properties. We show a formula for the dimensions of these intertwining operators in terms of modules over the Zhu algebras under some conditions on N-graded weak modules., Comment: 33 pages, typos corrected

Let $K$ be a differential field over $\C$ with derivation $D$, $G$ a finite linear automorphism group over $K$ which preserves $D$, and $K^G$ the fixed point subfield of $K$ under the action of $G$. We show that every finite-dimensional vertex algebra $K^G$-module is contained in some twisted vertex algebra $K$-module., 26 pages, some mistakes are corrected

Let $A$ be a connected commutative $\C$-algebra with derivation $D$, $G$ a finite linear automorphism group of $A$ which preserves $D$, and $R=A^G$ the fixed point subalgebra of $A$ under the action of $G$. We show that if $A$ is generated by a single element as an $R$-algebra and is a Galois extension over $R$ in the sense of M. Auslander and O. Goldman, then every finite-dimensional vertex algebra $R$-module has a structure of twisted vertex algebra $A$-module., 20 pages

In this paper, we investigate the covering radius of ternary extremal self-dual codes. The covering radii of all ternary extremal self-dual codes of lengths up to 20 were previously known. The complete coset weight distributions of the two inequivalent extremal self-dual codes of length 24 are determined. As a consequence, it is shown that every extremal ternary self-dual code of length up to 24 has covering radius which meets the Delsarte bound. The first example of a ternary extremal self-dual code with covering radius which does not meet the Delsarte bound is also found. It is worth mentioning that the found code is of length 32.

The W 3 algebra of central charge 6/5 is realized as a sub-algebra of the vertex operator algebra V√ 2A2 associated with a lattice of type √2A 2 by using both coset construction and orbifold theory. It is proved that W 3 is rational. Its irreducible modules are classified and constructed explicitly. The characters of those irreducible modules are also computed.

Let V be a vertex operator algebra and G a finite automorphism group of V. For each g∈G and nonnegative rational number n∈ Z /|g| , an associative algebra Ag,n(V) plays an important role in the theory of vertex operator algebras, but the given product in Ag,n(V) depends on the eigenspaces of g. We show that if V has no negative weights then there is a uniform definition of products on V and we introduce a G-twisted Zhu algebra AG,n(V) which covers all Ag,n(V). Let V be a simple vertex operator algebra with no negative weights and let S be a finite set of inequivalent irreducible twisted V-modules which is closed under the action of G. There is a finite dimensional semisimple associative algebra A α (G, S ) for a suitable 2-cocycle naturally determined by the G-action on S . We show that a duality theorem of Schur–Weyl type holds for the actions of A α (G, S ) and VG on the direct sum of twisted V-modules in S as an application of the theory of AG,n(V). It follows as a natural consequence of the result that for any g∈G every irreducible g-twisted V-module is a completely reducible VG-module.

We construct new extremal self-dual [40,20,8] codes with covering radius 7. It is also shown that the vectors of a fixed weight in a coset of weight 4n+2 in an extremal doubly even self-dual code of length 24n+16 such that the coset has no vector of weight 4n+4 form a 1-design.

The Assmus–Mattson theorem is known as a method to find designs in linear codes over a finite field. It is an interesting problem to find an analog of the theorem for Z4-codes. In a previous paper, the author gave a candidate of the theorem. The purpose of this paper is to give an improvement of the theorem. It is known that the lifted Golay code over Z4 contains 5-designs on Lee compositions. The improved method can find some of those without computational difficulty and without the help of a computer.

C. Bachoc gave a new proof of the Assmus–Mattson theorem for linear binary codes using harmonic weight enumerators which she defined B. We give a new proof of the Assmus–Mattson theorem for linear codes over any finite field using similar methods.

The imprimitive unitary reflection group G(m, p, n) acts on the vector space V =Cn naturally. The symmetric group Sk acts on ⊗kV by permuting the tensor product factors. We show that the algebra of all matrices on ⊗kV commuting with G(m, p, n) is generated by Sk and three other elements. This is a generalization of Jones’s results for the symmetric group case [J].

Let Y be any commutative association scheme and we fix any vertex x of Y. Terwilleger introduced a non-commutative, associative, and semi-simple {\bf C}-algebraT\,{=}\,T(x) for Y and x in [4]. We call T the Terwilliger (or subconstituent) algebra ofY with respect to x. Let W (\subset {\bf C}^{|X|}) be an irreducible T(x)-module. W is said to be thin if W satisfies a certain simple condition.Y is said to be thin with respect to x if each irreducible T(x) -module is thin. Y is said to be thin if Y is thin with respect to each vertex in X.The Doob schemes are direct product of a number of Shrikhande graphs and some complete graphsK_4 . Terwilliger proved in [4] that Doob scheme is not thin if the diameter is greater than two. I give the irreducible T(x)-modules of Doob schemes.

We introduce a notion of a (V,T)-module over a vertex algebra V for an arbitrary positive integer T, which is a generalization of a twisted V-module. Under some conditions on V, we construct an associative algebra A^{T}_{m}(V) for m\in(1/T)\N and an A^{T}_{m}(V)-A^{T}_{n}(V)-bimodule A^{T}_{n,m}(V) for n,m\in(1/T)\N and we establish a one-to-one correspondence between the set of isomorphism classes of simple left A^{T}_{0}(V)-modules and that of simple (1/T)\N-graded (V,T)-modules., Comment: 44 pages, List of Notations added

We study the subalgebra of the lattice vertex operator algebra $V_{\sqrt{2}A_2}$ consisting of the fixed points of an automorphism which is induced from an order 3 isometry of the root lattice $A_2$. We classify the simple modules for the subalgebra. The rationality and the $C_2$-cofiniteness are also established., 40 pages

Let V be a simple vertex operator algebra and G a finite automorphism group. We give a construction of intertwining operators for irreducible V^G-modules which occur as submodules of irreducible V-modules by using intertwining operators for V. We also determine some fusion rules for a vertex operator algebra as an application., Comment: 26 pages

Owing to its peculiar configuration of the ground, land utilization of a peneplain is markedly different from the one common to other areas in our country. So, here in this thesis, I am to take Yuki, Toyomatsu and neibourhood in Bingo District (Hiroshima Pref.) as an example of a region where characteristics of a peneplain are most remarkably observed, and study the form of the peneplain.Being of 460-580 metres height, the peneplain is marked by entangled masses of small valleys and low hills. The valleys are utilized as a paddyfield and a glass plot, and the hills as a farm, a pasture-ground and a forest. The land utilization of a valley which extends north and south is generally as follows. Namely, the bottom of the valley is used for a paddy-field, the south side slope (slope in the shade) for a glass plot, the north side slope (slope in the sun) for a farm and a pasture-ground, and the top and the inclined plane in the shade are used for forests. However, these are all on a small scale, and being divided into numerous blocks, they are intricated. The area of the blocks is, on an average, two cho of farm, there cho of pasture-ground and fifty cho of forest.Therefore, the pasture-ground being inadequate for grazing horses, it has been used for depasturing cattles. This area is a chief producing district of wagyu (indigenous cattle), and is a typical region where a glass plot is attached to a paddy-field.Farm houses are located within the farm blocks. These farm blocks are of various, and a farm house or two are attached to each of the blocks. The land they cultivate is limited within their respective blocks, and farmer in each block are mostly independent. So, from a viewpoint of form of villages and farm system, this is a representative area of scattered groups of farms. A pasture-ground is also attached to the block, and divided into many sections. The following tells how the farm land is situated in general. There is a farm around the farmhouse, a paddy-field and a glass plot in front of the house, a pasture-ground at the back, and forest at the circumference of the house. In short, with a farm house as the kernel, working land of farmers is grouped around it, and each house is almost cut off from the rest of the world.As in the case of the form of farm houses, the roads are also divided into a great many narrow paths, and no trunk line is seen. As well as the above-mentioned form of villages, this kind of traffic routes seem to have given a great influence upon the socety of the villages.

This is a summary of our recent work. We study a fixed-point subalgebra of a certain class of lattice vertex operator algebras by an automorphism of order 3, which is a lift of a fixed-point-free isometry of the underlying lattice. The classification of the irreducible modules, together with the rationality and the C2-cofiniteness of the subalgebra are established. Our result contains the case of the vertex operator algebra associated with the Leech lattice.