Adherence to Daily, Weekly, and Monthly Dosing Regimens of Bisphosphonates for Osteoporosis Treatment in Postmenopausal Women in Japan: A Retrospective Study Using Claims Data.

Poor medication adherence of osteoporosis patients is a major global medical problem because of its negative impact on health outcomes and quality of life. The aim of this study was to evaluate how differences in dosing regimens influence adherence to oral bisphosphonates using data from a large health insurance provider in Japan. This was a retrospective observational study using claims data obtained between October 2012 and January 2018, from the community-based National Health Insurance program of a large city in Japan. The data included in the analysis were obtained from women 60 to 74 years old whose oral bisphosphonate prescription was detected between April 2013 and February 2017. Treatment adherence was monitored from the initial prescription for one year, i.e., up to January 2018. Primary comparisons among the daily-dosing, weekly-dosing, and monthly-dosing groups were based on the mean medication possession ratio (MPR). Data from a total of 3,958 patients were analyzed. The numbers of patients aged 60-64, 65-69, and 70-74 were 425, 1,400, and 2,133, respectively. The highest mean MPR was 69.4% for the monthly-dosing of bisphosphonates, followed by the weekly-dosing at 63.5%, and daily-dosing at 57.2%. Using the Kruskal-Wallis test with Dunn-Bonferroni correction, there were significant differences in mean MPR for daily versus weekly (p < 0.01), daily versus monthly (p < 0.001), and weekly versus monthly dosing regimens (p < 0.05). These results suggest significantly more patients adhere to a monthly or weekly regimen of bisphosphonates in the treatment of osteoporosis than to a daily regimen.

Multiple plastids collected by the dinoflagellate Dinophysis mitra through kleptoplastidy.

Kleptoplastidy is the retention of plastids obtained from ingested algal prey, which may remain temporarily functional and be used for photosynthesis by the predator. We showed that the marine dinoflagellate Dinophysis mitra has great kleptoplastid diversity. We obtained 308 plastid rbcL sequences by gene cloning from 14 D. mitra cells and 102 operational taxonomic units (OTUs). Most sequences were new in the genetic database and positioned within Haptophyceae (227 sequences [73.7%], 80 OTUs [78.4%]), particularly within the genus Chrysochromulina. Others were closely related to Prasinophyceae (16 sequences [5.2%], 5 OTUs [4.9%]), Dictyochophyceae (14 sequences [4.5%], 5 OTUs [4.9%]), Pelagophyceae (14 sequences [4.5%], 1 OTU [1.0%]), Bolidophyceae (3 sequences [1.0%], 1 OTU [1.0%]), and Bacillariophyceae (1 sequence [0.3%], 1 OTU [1.0%]); however, 33 sequences (10.8%) as 9 OTUs (8.8%) were not closely clustered with any particular group. Only six sequences were identical to those of Chrysochromulina simplex, Chrysochromulina hirta, Chrysochromulina sp. TKB8936, Micromonas pusilla NEPCC29, Micromonas pusilla CCMP491, and an unidentified diatom. Thus, we detected >100 different plastid sequences from 14 D. mitra cells, strongly suggesting kleptoplastidy and the need for mixotrophic prey such as Laboea, Tontonia, and Strombidium-like ciliates, which retain numerous symbiotic plastids from different origins, for propagation and plastid sequestration.

Simulation of optical radiation force distribution in interference patterns and necessary conditions for chiral structure formation on dielectrics.

A chiral structure is formed by the optical radiation force induced by a circularly polarized light that has spin angular momentum; chiral structures are expected to be used for light control devices and molecular chirality discrimination devices. In this paper, we clarify the relationship between the differences in the distributions of the optical radiation force and the possibility of formation of chiral structures. We first simulate the optical radiation force distribution in the case of a Gaussian beam that successfully forms a chiral structure. Given a vector [Formula: see text] with a centre of the light spot [Formula: see text] and polar coordinates [Formula: see text], and an optical radiation force vector [Formula: see text] at [Formula: see text], the angle [Formula: see text] and [Formula: see text] must be constant with respect to the declination angle [Formula: see text] for a chiral structure to form. These conditions are fulfilled in the case of a 6-beam interference pattern, but not in the case of a 4-beam interference pattern, which is consistent with the result that no chiral structure is formed in the latter case. The equations derived for simulation of optical radiation force distribution can be used for any optical intensity distribution, and will be of great help in the research of any dielectrics deformation.

Morphological variation and phylogeny of Karenia selliformis (Gymnodiniales, Dinophyceae) in an intensive cold-water algal bloom in eastern Hokkaido, Japan.

Harmful algal blooms responsible for mass mortalities of marine organisms have been rare in Hokkaido, northern Japan, although fish-killing blooms have been frequently reported from western Japanese coasts. In September-November 2021, a huge and prolonged cold-water bloom occurred along the Pacific coast of eastern Hokkaido, and was associated with intensive mortalities of sea urchin, fish, octopus, shellfish, etc. In this study, morphology and phylogeny of the dominant and co-occurring unarmored dinoflagellates of the Kareniaceae in the bloom were examined by using light microscopy, scanning electron microscopy and molecular phylogeny inferred from ITS and LSU rDNA (D1-D3) sequences. Morphological observation and molecular phylogeny showed that the dominant species was Karenia selliformis, with co-occurrences of other kareniacean dinoflagellates, Kr. longicanalis, Kr. mikimotoi, Karlodinium sp., Takayama cf. acrotrocha, Takayama tuberculata and Takayama sp. The typical cell forms of Kr. selliformis in the bloom were discoid, dorsoventrally flattened, and 35.3-43.6 (39.4  ±  2.1) µm in length, which was larger than the cell sizes in previous reports. Transparent cells of Kr. selliformis, lacking chloroplasts or having a few shrunken chloroplasts and oil droplets, were also found. Cells of Kr. selliformis showed morphological variation, but the species could be distinguished from other co-occurring Karenia species by the nucleus positioned in the hypocone and chloroplasts numerous (46-105) in number and small (2.9-4.6 µm) in diameter. Cell density of Kr. selliformis exceeding 100 cells mL-1 was recorded in the temperature range of 9.8-17.6 °C. The rDNA sequences determined from Kr. selliformis in the blooms of Hokkaido, Japan in 2021 were identical to those from the bloom in Kamchatka, Russia in 2020.

Identification of mild cognitive impairment subtypes predicting conversion to Alzheimer's disease using multimodal data.

Mild cognitive impairment (MCI) is a high-risk condition for conversion to Alzheimer's disease (AD) dementia. However, individuals with MCI show heterogeneous patterns of pathology and conversion to AD dementia. Thus, detailed subtyping of MCI subjects and accurate prediction of the patients in whom MCI will convert to AD dementia is critical for identifying at-risk populations and the underlying biological features. To this end, we developed a model that simultaneously subtypes MCI subjects and predicts conversion to AD and performed an analysis of the underlying biological characteristics of each subtype. In particular, a heterogeneous mixture learning (HML) method was used to build a decision tree-based model based on multimodal data, including cerebrospinal fluid (CSF) biomarker data, structural magnetic resonance imaging (MRI) data, APOE genotype data, and age at examination. The HML model showed an average F1 score of 0.721, which was comparable to the random forest method and had significantly more predictive accuracy than the CART method. The HML-generated decision tree was also used to classify-five subtypes of MCI. Each MCI subtype was characterized in terms of the degree of abnormality in CSF biomarkers, brain atrophy, and cognitive decline. The five subtypes of MCI were further categorized into three groups: one subtype with low conversion rates (similar to cognitively normal subjects); three subtypes with moderate conversion rates; and one subtype with high conversion rates (similar to AD dementia patients). The subtypes with moderate conversion rates were subsequently separated into a group with CSF biomarker abnormalities and a group with brain atrophy. The subtypes identified in this study exhibited varying MCI-to-AD conversion rates and differing biological profiles.

Enantioselective synthesis of trans-aryl- and -heteroaryl-substituted cyclopropylboronates by copper(I)-catalyzed reactions of allylic phosphates with a diboron derivative.

A new asymmetric route for the synthesis of trans-2-aryl- and -heteroaryl-substituted cyclopropylboronates has been developed. (Z)-3-arylallylic phosphates were converted to the optically active products with high yield and diastereo- and enantioselectivity through a copper(I)-catalyzed reaction with a diboron derivative. Under mild reaction conditions, the reaction affords the arylcyclopropane products with a functional group and a heteroaromatic group in a highly enantioselective manner. When (E)-allylic phosphates were used as substrates, a ligand-controlled product switch between the trans and cis configurations was observed.

High-level congruence of Myrionecta rubra prey and Dinophysis species plastid identities as revealed by genetic analyses of isolates from Japanese coastal waters.

We analyzed cryptophyte nucleomorph 18S rRNA gene sequences retained in natural Myrionecta rubra cells and plastid 16S rRNA gene and psbA sequences retained in natural cells of several Dinophysis species collected from Japanese coastal waters. A total of 715 nucleomorph sequences obtained from 134 M. rubra cells and 564 plastid 16S rRNA gene and 355 psbA sequences from 71 Dinophysis cells were determined. Almost all sequences in M. rubra and Dinophysis spp. were identical to those of Teleaulax amphioxeia, suggesting that M. rubra in Japanese coastal waters preferentially ingest T. amphioxeia. The remaining sequences were closely related to those of Geminigera cryophila and Teleaulax acuta. Interestingly, 37 plastid 16S rRNA gene sequences, which were different from T. amphioxeia and amplified from Dinophysis acuminata and Dinophysis norvegica cells, were identical to the sequence of a D. acuminata cell found in the Greenland Sea, suggesting that a widely distributed and unknown cryptophyte species is also preyed upon by M. rubra and subsequently sequestered by Dinophysis. To confirm the reliability of molecular identification of the cryptophyte Teleaulax species detected from M. rubra and Dinophysis cells, the nucleomorph and plastid genes of Teleaulax species isolated from seawaters were also analyzed. Of 19 isolates, 16 and 3 clonal strains were identified as T. amphioxeia and T. acuta, respectively, and no sequence variation was confirmed within species. T. amphioxeia is probably the primary source of prey for M. rubra in Japanese coastal waters. An unknown cryptophyte may serve as an additional source, depending on localities and seasons.

Bone Scintigraphy in Pembrolizumab-Induced Inflammatory Arthritis.

We present a novel report on the use of bone scintigraphy in pembrolizumab-induced inflammatory arthritis. A 70-year-old man with lung cancer complained about arthralgia after 7 courses of the pembrolizumab therapy. Tc-HMDP bone scintigraphy revealed symmetrically strong uptakes in the major distal joints of the upper and lower extremities, thereby clearly identifying them as the affected joints. The pattern of uptakes was not consistent with that of other pathophysiologies including bone metastases, hypertrophic osteoarthropathy, and rheumatoid arthritis. Tc-HMDP bone scintigraphy is more practical and cost-effective compared with PET to reveal the affected joints in pembrolizumab-induced inflammatory arthritis.

Anatomical Distribution of Diarrhetic Shellfish Toxins (DSTs) in the Japanese Scallop Patinopecten yessoensis and Individual Variability in Scallops and Mytilus edulis Mussels: Statistical Considerations.

Diarrhetic shellfish toxins (DSTs) are a group of phycotoxins that include okadaic acid (OA)/dinophysistoxin (DTX) analogues. At present, detailed data on the distribution of DST is insufficient, and studies of the appropriate sample sizes are lacking. This study investigated the DST frequency distribution in scallops and mussels by liquid chromatography-tandem mass spectrometry (LC/MS/MS) and a resampling analysis of existing data was carried out. The DST population-interval and the necessary sample size were also estimated. DSTs are localized in the scallop digestive-gland, and the DST concentrations in scallops were water-depth-dependent. DST concentrations in scallops and mussels showed normal distributions, but mussels tended to contain more DSTs than scallops. In the statistical resampling analysis of the acquired data on scallops and mussels, especially that using the bootstrap method, sample size was difficult to estimate when the DST variation was large. Although the DST population-interval could be statistically estimated from the sample standard deviation of three samples, the sample size corresponded to the risk management level, and the use of 13 or more samples was preferable. The statistical methods used here to analyze individual contents and estimate population content-intervals could be applied in various situations and for shellfish toxins other than DSTs.

Distribution of Diarrhetic Shellfish Toxins in Mussels, Scallops, and Ascidian.

Diarrhetic shellfish toxins (DST) are a group of phycotoxins that include Okadaic acid (OA) and structurally related toxins. In Japan, the regulatory limit of DST in shellfish for human consumption is a total OA equivalent of 0.16 mg per kg of edible tissue. Distribution and individual differences of DST in scallops collected in Aomori Prefecture were investigated. Fourteen to 20 individual scallops were divided into hepatopancreas, gonads, mantles, gills, adductor muscles, and the concentrations of diarrhetic shellfish poisoning (DSP) in each tissue were quantified by LC/MS/MS after hydrolysis. The dominant toxin in the scallops was Dinophysis toxin 1 (DTX1). More than 97% of the observed DTX1 in the scallop tissue was detected in the hepatopancreas and the average level of DTX1 was higher in mussels than the scallops. The number of individual scallops or mussels required to correctly reflect the DTX1 content of a sample group was estimated by resampling. In scallops, using 10 individuals fell within ± 20% of 30 individual's average with a probability of 99.8%. On the other hand, in the blue mussel, an average of 19 individuals fell within ± 20% of 30 individual's average with 98% probability. In addition, the analysis of the DST in ascidians collected from Miyagi Prefecture was carried out. The muscles, gills, hepatopancreas and intestines were analyzed. High concentration of both DTX1 and OA were detected in the hepatopancreas after hydrolysis. Low levels of DST were detected from other tissues, indicating that DST are primarily accumulated in the hepatopancreas in the ascidians.

Toxin Profiles of Okadaic Acid Analogues and Other Lipophilic Toxins in Dinophysis from Japanese Coastal Waters.

The identification and quantification of okadaic acid (OA)/dinophysistoxin (DTX) analogues and pectenotoxins (PTXs) in Dinophysis samples collected from coastal locations around Japan were evaluated by liquid chromatography mass spectrometry. The species identified and analyzed included Dinophysis fortii, D. acuminata, D. mitra (Phalacroma mitra), D. norvegica, D. infundibulus, D. tripos, D. caudata, D. rotundata (Phalacroma rotundatum), and D. rudgei. The dominant toxin found in D. acuminata was PTX2 although some samples contained DTX1 as a minor toxin. D. acuminata specimens isolated from the southwestern regions (Takada and Hiroshima) showed characteristic toxin profiles, with only OA detected in samples collected from Takada. In contrast, both OA and DTX1, in addition to a larger proportion of PTX2, were detected in D. acuminata from Hiroshima. D. fortii showed a toxin profile dominated by PTX2 although this species had higher levels of DTX1 than D. acuminata. OA was detected as a minor toxin in some D. fortii samples collected from Yakumo, Noheji, and Hakata. PTX2 was also the dominant toxin found among other Dinophysis species analyzed, such as D. norvegica, D. tripos, and D. caudata, although some pooled picked cells of these species contained trace levels of OA or DTX1. The results obtained in this study re-confirm that cellular toxin content and profiles are different even among strains of the same species.

High prevalence of vitamin B-12 insufficiency in patients with Crohn's disease.

BACKGROUND AND OBJECTIVES: In Crohn's disease (CD), belonging to inflammatory bowel disease, the small intestine is involved in most cases. Most frequently affected is the distal ileum, where vitamin B-12 is specifically absorbed. Therefore, malabsorption of vitamin B-12 is quite likely to occur in patients with CD. In this study, we have studied the vitamin B-12 status in CD patients. METHODS AND STUDY DESIGN: Forty eight patients with CD were evaluated for their food intake, and circulating concentrations of vitamin B-12, folic acid, and homocysteine (Hcy) as a sensitive marker for the insufficiency of these vitamins and a risk factor of atherosclerosis. RESULTS: Plasma Hcy concentration was significantly correlated with serum vitamin B-12 concentration alone, and 60.4 % of the subjects had hyperhomocysteinemia. Receiver Operating Characteristics (ROC) analysis showed that serum concentration of vitamin B-12, but not folic acid, predicted hyperhomocysteinemia. Their intake of vitamin B-12 was much higher than the Japanese RDA, but not correlated with blood concentrations of vitamin B-12 or Hcy, probably due to malabsorption. CONCLUSIONS: Vitamin B-12 insufficiency and hyperhomocysteinemia were highly prevalent in CD patients. Recently, the significance of extra-intestinal complications of CD has been increasingly recognized, and our finding is likely to be of clinical importance.

Living Anionic Polymerization of Benzofulvene: Highly Reactive Fixed Transoid 1,3-Diene.

Anionic polymerization of benzofulvene (BF, α-methyleneindene), an exomethylene monomer having a fixed transoid 1,3-diene moiety, quantitatively proceeded with sec-BuLi or diphenylmethylpotassium in THF at -78 °C for 1 h. The resulting poly(BF)s possessed the predicted molecular weights based on the molar ratios between monomer and initiators and narrow molecular weight distributions (Mw/Mn = 1.1). High anionic polymerizability of BF was realized by the fact that a well-defined diblock copolymer, poly(methyl methacrylate)-block-poly(BF), was obtained by the sequential copolymerization of BF with a low nucleophilic enolate anion of living poly(methyl methacrylate) in quantitative efficiency. NMR analyses indicated that the repeating units of poly(BF) consisted of a 1,2-addition unit (41%) and a 1,4-addition unit (59%) without a 3,4-addition unit, suggesting that the exomethylene group of BF always participated in the polymerization. Thus, BF acted as a novel polymerizable transoid 1,3-diene in the anionic polymerization.