Tele-education by an orthopedic specialist increased the confidence in orthopedics of a general practitioner at a rural solo-practice clinic.

Objective: General practitioners in rural clinics are required to deal with musculoskeletal problems, but they often lack the confidence. We aim to confirm changes in their confidence in orthopedic practices after using tele-education. Materials and Methods: We conducted tele-education in orthopedic practices from June 1, 2022, to November 30, 2022. Using a teleconference system, the first author, an orthopedic specialist, provided tele-education training to an independent general practitioner in a rural clinic. We adopted a 7-point Likert scale to assess the general practitioner's confidence levels. In pre- and post-research, the counts and confidence levels in the scale were assessed for 18 types of orthopedic practices each month. Furthermore, we interviewed the general practitioner to examine the factors influencing their confidence. Results: The confidence levels increased for all measurement items. The most experienced orthopedic practice was "Advising on daily care for musculoskeletal problems", with confidence levels increasing from 3 to 6. The least experienced orthopedic practice was "Manipulative reduction of radial head subluxation", with confidence levels increasing from 4 to 5. The factors that influenced the change in confidence levels were regular feedback and unrestricted availability of consultations. Conclusion: Tele-education in orthopedics may enhance general practitioners' confidence in orthopedic practices.

Utilization of and barriers to a telemedicine system at a rural general hospital in Japan: a mixed methods study.

Objective: The initial and operational costs of telemedicine are major barriers to its adoption. We aimed to investigate and identify the barriers to adopting a telemedicine system in a Japanese rural general hospital without incurring setup and operational costs. Materials and Methods: Our study was conducted between May and August 2018, and included six general practitioners working at a rural general hospital. We extracted data collected from messages (date and time, sender and recipient, and counts and contents of messages) and conducted semi-structured interviews, which were then analyzed using quantitative and qualitative methods. Results: We quantitatively analyzed the total counted of the 179 messages. The total counts recorded for each physician were 56 (A), 20 (B), 3 (C), 74 (D), 5 (E), and 21 (F). The mean monthly counts were 2.17 (May), 8.50 (June), 11.50 (July), and 7.67 (August). Interview data from the six physicians yielded 13 codes that included various points of dissatisfaction acting as barriers to using our system, which we grouped into mental and physical barriers. Mental barriers included suspicion of carrying, feelings of isolation, and loss, whereas physical barriers included portability, user authentication, internet speed, group chat system, notice, search image, typing, chat system, print facility, and limited function. Conclusion: The representative barriers to introducing a telemedicine system at a rural general hospital in Japan without initial and running costs could be classified as feelings of isolation and suspicion of carrying (mental barriers); and notice, portability, and user authentication (physical barriers). Continued investigation in this area is warranted, and solutions to these barriers could improve the shortage of medical staff in the context of declining birth rates and aging populations in Japan.

Strategies to Address Current Challenges in Real-World Evidence Generation in Japan.

The generation of real-world evidence (RWE), which describes patient characteristics or treatment patterns using real-world data (RWD), is rapidly growing more popular as a tool for decision-making in Japan. The aim of this review was to summarize challenges to RWE generation in Japan related to pharmacoepidemiology, and to propose strategies to address some of these challenges. We first focused on data-related issues, including the lack of transparency of RWD sources, linkage across different care settings, definitions of clinical outcomes, and the overall assessment framework of RWD when used for research purposes. Next the study reviewed methodology-related challenges. As lack of design transparency impairs study reproducibility, transparent reporting of study design is critical for stakeholders. For this review, we considered different sources of biases and time-varying confounding, along with potential study design and methodological solutions. Additionally, the implementation of robust assessment of definition uncertainty, misclassification, and unmeasured confounders would enhance RWE credibility in light of RWD source-related limitations, and is being strongly considered by task forces in Japan. Overall, the development of guidance for best practices on data source selection, design transparency, and analytical methods to address different sources of biases and robustness in the process of RWE generation will enhance credibility for stakeholders and local decision-makers.

Changes in renal function over time in outpatients with eGFR ≥ 30 mL/min/1.73 m2: implication for timing of renal function testing before contrast-enhanced CT imaging.

PURPOSE: To evaluate the associations between comorbidities and kidney function decline at 6-month and 1-year follow-up in outpatients with initial estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2. MATERIALS AND METHODS: Outpatients aged 18 and older with confirmed diagnosis, who had eGFR ≥ 30 mL/min/1.73 m2 measured between April 2017 and March 2019, were included in this retrospective observational study. Of them, 30,595 included outpatients had 6-month eGFR test and 27,698 included outpatients had 1-year eGFR test. The outpatients were further divided into two groups based on initial eGFR: between 30 and 59 and ≥ 60 mL/min/1.73 m2. Impaired renal function was defined as eGFR declined to below 30 mL/min/1.73 m2. The comorbidities with P values less than 0.1 identified in univariable logistic regression models were entered into the multivariable analysis with backward selection, thereby identifying comorbidities that increased the risk of eGFR decline at 6-month and 1-year follow-up. RESULTS: Outpatients with initial eGFR between 30 and 59 mL/min/1.73 m2 were 175.94 times more likely to have eGFR decline at 6 months, and were 94.10 times more likely to have eGFR decline at 1 year, compared with their corresponding initial eGFR ≥ 60 counterparts. Multivariable logistic regression analyses disclosed that chronic kidney disease, hypertension, and heart failure were independent risk factors for eGFR decline in outpatients with initial eGFR between 30 and 59 mL/min/1.73 m2. CONCLUSIONS: Outpatients with initial eGFR ≥ 60 mL/min/1.73 m2 might not need routine eGFR test prior to contrast-enhanced CT scan for 1 year. In addition, chronic kidney disease, hypertension, and heart failure increased the risk of declined renal function, particularly, in outpatients with initial eGFR between 30 and 59 mL/min/1.73 m2.

Validation of algorithms to identify colorectal cancer patients from administrative claims data of a Japanese hospital.

BACKGROUND: Administrative claims data are a valuable source for clinical studies; however, the use of validated algorithms to identify patients is essential to minimize bias. We evaluated the validity of diagnostic coding algorithms for identifying patients with colorectal cancer from a hospital's administrative claims data. METHODS: This validation study used administrative claims data from a Japanese university hospital between April 2017 and March 2019. We developed diagnostic coding algorithms, basically based on the International Classification of Disease (ICD) 10th codes of C18-20 and Japanese disease codes, to identify patients with colorectal cancer. For random samples of patients identified using our algorithms, case ascertainment was performed using chart review as the gold standard. The positive predictive value (PPV) was calculated to evaluate the accuracy of the algorithms. RESULTS: Of 249 random samples of patients identified as having colorectal cancer by our coding algorithms, 215 were confirmed cases, yielding a PPV of 86.3% (95% confidence interval [CI], 81.5-90.1%). When the diagnostic codes were restricted to site-specific (right colon, left colon, transverse colon, or rectum) cancer codes, 94 of the 100 random samples were true cases of colorectal cancer. Consequently, the PPV increased to 94.0% (95% CI, 87.2-97.4%). CONCLUSION: Our diagnostic coding algorithms based on ICD-10 codes and Japanese disease codes were highly accurate in detecting patients with colorectal cancer from this hospital's claims data. The exclusive use of site-specific cancer codes further improved the PPV from 86.3 to 94.0%, suggesting their desirability in identifying these patients more precisely.

An Attempt to Replicate Randomized Trials of Diabetes Treatments Using a Japanese Administrative Claims and Health Checkup Database: A Feasibility Study.

BACKGROUND: Use of real-world evidence (RWE) has been limited for evaluating effectiveness because of the lack of confidence in its reliability. Examining whether a rigorously designed observational study using real-world data (RWD) can reproduce the results of a randomized controlled trial (RCT) will provide insights into the implementation of high-quality RWE studies that can produce valid conclusions. OBJECTIVE: We aimed to replicate published RCTs using a Japanese claims and health checkup database and examine whether the emulated RWE studies' results agree with those of the original RCTs. METHODS: We selected three RCTs on diabetes medications for replication in patients with type 2 diabetes. The study outcome was either the change or percentage change in HbA1c levels from baseline. We designed three observational studies using the RWD to mimic the critical study elements of the respective RCTs as closely as possible. We performed 1:1 propensity score nearest-neighbor matching to balance the groups for potential confounders. The differences in outcomes between the groups and their 95% confidence intervals (CIs) were calculated in each RWE study, and the results were compared with those of the RCT. RESULTS: Patient characteristics, such as age, sex, and duration of diabetes, differed between the RWE studies and RCTs. In Trial 1 emulation, the percentage changes in HbA1c levels were larger in the treatment group than in the comparator group (difference -6.21, 95% confidence interval (CI) -11.01 to -1.40). In Trial 2, the change in HbA1c level was larger in the treatment group (difference -0.01; 95% CI -0.25 to 0.23), and in Trial 3, it was smaller in the treatment group (difference 0.46; 95% CI -0.01 to 0.94). These results did not show regulatory or estimate agreement with the RCTs. CONCLUSIONS: None of the three emulated RWE studies using this claims and health checkup database reproduced the same conclusions as the RCTs. These discrepancies could largely be attributed to design differences between RWE studies and RCTs, primarily due to the lack of necessary data in the database. This particular RWD source may not be the best fit for evaluating treatment effects using laboratory data as the study outcome.

Taxonomic insights and evolutionary history in East Asian terrestrial slugs of the genus Meghimatium.

East Asia, specifically the Japanese Archipelago, is a biodiversity hotspot of both vertebrates and invertebrates. Mollusks represent a burst of species diversity in this region due to the effects of biotic and abiotic factors on their morphological traits, such as shell shape and size. However, the evolutionary history of terrestrial slugs in East Asia remains unknown. In the present study, we investigated the molecular phylogeny of terrestrial slugs of the genus Meghimatium. This genus includes three described and eight undescribed species, and our study used all except for two. Based on phylogeny and the species delimitation tests, the genus Meghimatium was split into many putative species, suggesting higher species diversity than previously thought based on morphological and anatomical studies and that almost undescribed species may be inappropriate. Therefore, morphological traits, such as body size and colour, conventionally considered for classification may easily vary or be similar across geographic region. Moreover, the divergence time of this genus is almost concordant with the geographical time scale of the formation of the Japanese mainland. Our findings suggest that molecular phylogenetics helps classify Japanese Meghimatium slugs, but comprehensive taxonomic revisions using multi-locus analyses are needed.

Phylogenomic analyses reveal incongruences between divergence times and fossil records of freshwater snails in East Asia.

Fossils provide important insight into our understanding of phylogenetic history by serving as calibration points for divergence time estimation. However, uncertainties in the fossil record due to parallel evolution and convergent evolution can critically affect estimates of node ages. Here, we compare and contrast estimates of phylogenetic divergence with geologic and fossil history for two freshwater snail genera of the family Viviparidae in East Asia (Cipangopaludina and Margarya). Cipangopaludina species are commonly widely distributed species in East Asia, but extant Margarya species are endemic to the ancient lakes in Yunnan, China. According to some previous studies, parallel evolution or convergent evolution of shell morphology has occurred in the family several times which may affect divergence time estimation using fossil records. In this study, we used SNP data derived from ddRAD-seq loci to investigate population demographic history of both genera. Our results show a common pattern of lake endemic lineages diversifying from widely distributed lineages in the Miocene, and multiple colonization to a single ancient lake occurred in the Pleistocene. Our results indicate substantial incongruence among estimated phylogenomic divergence times, some fossil records, and formation ages of ancient lakes. These findings suggest some fossil records may be misidentified in these groups and highlight the need to carefully evaluate geological evidence and fossil records when using these for divergence time estimation.

Validation of Algorithms to Identify Bone Metastases Using Administrative Claims Data in a Japanese Hospital.

BACKGROUND: Validated coding algorithms are essential to generate high-quality, real-world evidence from claims data studies. OBJECTIVE: We aimed to evaluate the validity of the algorithms to identify patients with bone metastases using claims data from a Japanese hospital. PATIENTS AND METHODS: This study used administrative claims data and electronic medical records at Juntendo University Hospital from April 2017 to March 2019. We developed two candidate claims-based algorithms to detect bone metastases, one based on diagnosis codes alone (Algorithm 1) and the other based on the combination of diagnosis and imaging test codes (Algorithm 2). Of the patients identified by Algorithm 1, 100 patients were randomly sampled. Among these 100 patients, 88 patients met the conditions of Algorithm 2; further, 12 additional patients were randomly sampled from those identified by Algorithm 2, thus obtaining a total of 100 patients for Algorithm 2. They were evaluated for their true diagnosis using the patient chart review as the gold standard. The positive predictive value (PPV) was calculated to assess the accuracy of each algorithm. RESULTS: For Algorithm 1, 82 patients were analyzed after excluding 18 patients without diagnostic imaging reports. Of these, 69 patients were true positive by chart review, resulting in a PPV of 84.1% (95% confidence interval (CI) 74.5-90.6). For Algorithm 2, 92 patients were analyzed after excluding eight patients whose diagnoses were not judged by chart review. Of these, 76 patients were confirmed positive by chart review, yielding a PPV of 82.6% (95% CI 73.4-89.1). CONCLUSION: Both claims-based algorithms yielded high PPVs of approximately 85%, with no improvement in PPV by adding imaging test conditions. The diagnosis code-based algorithm is sufficient and valid for identifying bone metastases in this Japanese hospital.

Evaluation of simulation-based ultrasound education using a bladder simulator for medical students in Japan: a prospective observational study.

PURPOSE: This study aimed to investigate the usefulness of ultrasound education for medical students using a bladder simulator. METHODS: This prospective observational study included volunteer fifth- and sixth-year medical students. An intravesical urine volume measurement simulator and a pocket-sized hand-held ultrasound device were used. The ultrasound education comprised pre-learning, briefing, simulation, debriefing, and learning summary. The simulation consisted of two tests: bladder simulator cube evaluation and scenario-based clinical application. A self-rated confidence score of 0-10 points along with reasons for the scores was recorded before and after the ultrasound education. RESULTS: Twelve participants (median age, 23 years; female, 75%) met the inclusion criteria and were examined. Participants' bladder simulator cube evaluation and scenario-based clinical application test results were good, and the educational difficulty level was appropriate. The mean confidence scores for main unit operation, probe control, image acquisition, image evaluation and clinical application before the ultrasound education were 1.0, 1.8, 1.3, 0.8 and 0.1 points, respectively. The mean confidence scores after the ultrasound education were 5.8, 5.9, 5.4, 5.5 and 5.1, respectively, with significant increases for all items (p < 0.01). The positive impression categories that affected confidence scores after ultrasound education were related to device operation, image acquisition, image evaluation, clinical application and learning. CONCLUSION: Ultrasound education using a bladder simulator increases confidence scores by imparting competencies related to device operation, image acquisition, image evaluation and clinical application, and it improves students' learning impression. This is a useful method for introductory ultrasound education for medical students.

Impact of "time zero" of Follow-Up Settings in a Comparative Effectiveness Study Using Real-World Data with a Non-user Comparator: Comparison of Six Different Settings.

BACKGROUND: Time-related bias can lead to misleading conclusions. Properly setting the "time zero" of follow-up is crucial for avoiding these biases. However, the time-zero setting is challenging when comparing users and non-users of a study drug because the latter do not have a time point for starting treatment. OBJECTIVE: This methodological study aimed to illustrate the impact of different time-zero settings on effect estimates in a comparative effectiveness study using real-world data with a non-user comparator. METHODS: Data for type 2 diabetes patients were extracted from an administrative claims database, and the onset of diabetic retinopathy (study outcome) was compared between users (treatment group) and non-users (non-use group) of lipid-lowering agents. We applied six time-zero settings to the same dataset. The adjusted hazard ratio (HR) for the outcome was estimated using a Cox regression model in each time-zero setting, and the obtained results were compared among the settings. RESULTS: Of the six settings, three (study entry date [SED] vs SED [naïve approach], treatment initiation [TI] vs SED, TI vs Matched [random order]) showed that the treatment had a reduced risk of the outcome (HR [95% CI]: 0.65 [0.61-0.69], 0.92 [0.86-0.97], and 0.76 [0.71-0.82], respectively), one (TI vs Random) had an increased risk (HR [95% CI]: 1.52 [1.40-1.64]) , and two (SED vs SED [cloning method], and TI vs Matched [systematic order]) had neither increased nor decreased risk (HR [95% CI]: 0.95 [0.93-1.13], and 0.99 [0.93-1.07], respectively). CONCLUSIONS: This study demonstrates that different time-zero settings can lead to different conclusions, even if the same dataset is analyzed for the same research question, probably because improper settings can introduce bias. To minimize such biases, researchers should carefully define time zero, particularly when designing a non-user comparator study using real-world data.

De novo genome assembly and genome skims reveal LTRs dominate the genome of a limestone endemic Mountainsnail (Oreohelix idahoensis).

BACKGROUND: Calcareous outcrops, rocky areas composed of calcium carbonate (CaCO3), often host a diverse, specialized, and threatened biomineralizing fauna. Despite the repeated evolution of physiological and morphological adaptations to colonize these mineral rich substrates, there is a lack of genomic resources for calcareous rock endemic species. This has hampered our ability to understand the genomic mechanisms underlying calcareous rock specialization and manage these threatened species. RESULTS: Here, we present a new draft genome assembly of the threatened limestone endemic land snail Oreohelix idahoensis and genome skim data for two other Oreohelix species. The O. idahoensis genome assembly (scaffold N50: 404.19 kb; 86.6% BUSCO genes) is the largest (~ 5.4 Gb) and most repetitive mollusc genome assembled to date (85.74% assembly size). The repetitive landscape was unusually dominated by an expansion of long terminal repeat (LTR) transposable elements (57.73% assembly size) which have shaped the evolution genome size, gene composition through retrotransposition of host genes, and ectopic recombination. Genome skims revealed repeat content is more than 2-3 fold higher in limestone endemic O. idahoensis compared to non-calcareous Oreohelix species. Gene family size analysis revealed stress and biomineralization genes have expanded significantly in the O. idahoensis genome. CONCLUSIONS: Hundreds of threatened land snail species are endemic to calcareous rock regions but there are very few genomic resources available to guide their conservation or determine the genomic architecture underlying CaCO3 resource specialization. Our study provides one of the first high quality draft genomes of a calcareous rock endemic land snail which will serve as a foundation for the conservation genomics of this threatened species and for other groups. The high proportion and activity of LTRs in the O. idahoensis genome is unprecedented in molluscan genomics and sheds new light how transposable element content can vary across molluscs. The genomic resources reported here will enable further studies of the genomic mechanisms underlying calcareous rock specialization and the evolution of transposable element content across molluscs.

Resolving species-level diversity of Beringiana and Sinanodonta mussels (Bivalvia: Unionidae) in the Japanese archipelago using genome-wide data.

Accurate species identification is of primary importance in ecology and evolutionary biology. For a long time, the unionid mussels Beringiana and Sinanodonta have puzzled researchers trying to unravel their diversity because of their poorly discernible morphologies. A recent study conducted species delineation of unionid mussels based on mitochondrial DNA variation, opening up a new avenue to grasp species diversity of the mussels. However, mtDNA-based classification may not align with species boundaries because mtDNA is prone to introgression and incomplete lineage sorting that cause discordance between species affiliation and gene phylogeny. In this study, we evaluated the validity of the mtDNA-based classification of unionid mussels Beringiana and Sinanodonta in Japan using mitochondrial sequence data, double digest restriction site-associated DNA library (ddRAD) sequencing, and morphological data. We found significant inconsistencies in the mitochondrial and nuclear DNA phylogenies, casting doubt on the reliability of the mtDNA-based classification in this group. In addition, nuclear DNA phylogeny revealed that there are at least two unionid lineages hidden in the mtDNA phylogeny. Although molecular dating technique indicates that Beringiana and Sinanodonta diverged >35 million years ago, their shell morphologies are often indistinguishable. Specifically, morphological analyses exhibited the parallel appearance of nearly identical ball-like shell forms in the two genera in Lake Biwa, which further complicates species identification and the morphological evolution of unionid mussels. Our study adds to a growing body of literature that accurate species identification of unionid mussels is difficult when using morphological characters alone. Although mtDNA-based classification is a simple and convenient way to classify unionid mussels, considerable caution is warranted for its application in ecological and evolutionary studies.

Uncovering overlooked diversity using molecular phylogenetic approach: A case of Japanese sphaeriid clams (Bivalvia: Sphaeriidae).

Revealing the species and lineage diversity of a taxon is important for many biological studies of wildlife. In recent decades, DNA-based approaches have been widely utilised to elucidate the diversity of taxa, especially those that are difficult to distinguish based on morphological traits. This study focused on freshwater clams (Sphaeriidae) in Japan, a biodiversity hotspot of freshwater molluscs. Molecular phylogenetic approaches, including divergence time estimation, species delimitation, rarefaction, and biogeographic area estimation, were used to reveal the nature of the species diversity and its formation process, which are largely unknown. Our delimitation and rarefaction analyses suggest that Japanese sphaeriid clams consist of at least 18 delimitated lineages. This lineage diversity is relatively high compared to other Japanese freshwater molluscs, and in addition, the majority of the Japanese lineage appears to have high endemicity despite the possibility of long-distance dispersal in sphaeriid clams. Our biogeographical analyses suggest that this diversity may be due to the combination of colonisation, during the period when Japan was connected to the continent, and the relatively recent dispersal. Our results highlight the overlooked biodiversity of Japan and provide a basis for further Japanese sphaeriid research, including conservation perspectives.

Species identification of introduced veronicellid slugs in Japan.

Reliable identification of species is important for protecting native ecosystems against the invasion of non-native species. DNA barcoding using molecular markers, such as the mitochondrial cytochrome oxidase subunit 1 (COI) gene, helps researchers distinguish species. In this study, we focused on introduced veronicellid slugs in the Ryukyu Islands and some greenhouses on mainland Japan. Some veronicellids are medium-to-high risk pest species for humans. Identifying veronicellid species by their external morphology is difficult and unreliable because there is substantial overlap between intraspecific variation and interspecific differentiation. Therefore, internal morphologies such as male genitalia have been the primary traits used to distinguish veronicellids. To identify introduced veronicellid slugs in Japan to the species level, we used morphological assessment of male genitalia and DNA barcoding of the standard COI gene fragment. We also conducted species-delimitation analyses based on the genetic data. The results showed that five evolutionarily significant units, corresponding to four nominal species inhabit the Ryukyu Islands, of which two species were also found in the greenhouses of mainland Japan, including the first record of Sarasinula plebeia in Japan. The presence of non-native slug species could increase the transmission of parasites in Japan.

Context and Considerations for Use of Two Japanese Real-World Databases in Japan: Medical Data Vision and Japanese Medical Data Center.

In Japan, an increasing interest in real-world evidence for hypothesis generation and decision-making has emerged in order to overcome limitations and restrictions of clinical trials. We sought to characterize the context and concrete considerations of when to use Medical Data Vision (MDV) and JMDC databases, the main Japanese real-world data (RWD) sources accessible by pharmaceutical companies. Use cases for these databases, and related issues and considerations, were identified and summarized based on a literature search and experience-based knowledge. Studies conducted using MDV or JMDC were mostly descriptive in nature, or explored potential risk factors by evaluating associations with a target outcome. Considerations such as variable ascertainment at different time points, including issues relating to treatment identification and missing data, were highlighted for these two databases. Although several issues were commonly shared (e.g., only month of event occurrence reported), some database-specific issues were also identified and need to be accounted for. In conclusion, MDV and JMDC present limitations that are relatively typical of RWD sources, though some of them are unique to Japan, such as the identification of event occurrence and the inability to track patients visiting different healthcare settings. Addressing study design and careful result interpretation with respect to the specificities and uniqueness of the Japanese healthcare system is of particular importance. This aspect is especially relevant with respect to the growing global interest of conducting RWD studies in Japan.

Structure-activity relationship studies on an antitumor marine macrolide using aplyronine a-swinholide A hybrid.

An aplyronine A-swinholide A hybrid, consisting of the macrolactone part of aplyronine A and the side chain part of swinholide A, was designed, synthesized, and biologically evaluated. This hybrid induced protein-protein interactions between two major cytoskeletal proteins actin and tubulin in the same manner as aplyronine A, and exhibited potent cytotoxicity and actin-depolymerizing activity. The importance of the methoxy group in the N,N,O-trimethylserine ester was clarified by the structure-activity relationship studies of the amino acid moiety by using the hybrid analogs. Furthermore, the comparison of the actin-depolymerizing activities between the side chain analogs of aplyronine A and swinholide A showed that the side chain analog of swinholide A had much weaker actin-depolymerizing activity than that of aplyronine A.

Tolerability of the Intravenously Administered Tolvaptan Prodrug, OPC-61815, in Patients With Congestive Heart Failure Who Have Difficulty With, or Are Incapable of, Oral Intake (TRITON-HF)　- A Phase III, Multicenter, Open-Label Trial.

BACKGROUND: OPC-61815, a prodrug of tolvaptan, is an injectable aquaretic drug. This study evaluated the tolerability of OPC-61815 in patients with congestive heart failure (CHF) who had difficulty with, or were incapable of, oral intake in a multicenter, uncontrolled, open-label Phase III study.Methods and Results: Forty-five patients were enrolled at 30 Japanese sites. OPC-61815 infusion was administered once daily; the 8 mg initial dose could be increased to 16 mg if the dose escalation criteria were met. Patients were treated for up to 5 days. Thirty-eight patients maintained the 8-mg dose and 7 had a dose increase to 16 mg; 41 completed the trial (34 completed early). One patient had mild hypernatremia. No significant safety concerns were observed with OPC-61815 administration at a starting dose of 8 mg and with dose escalation in accordance with the protocol-specified criteria. Treatment resulted in weight decrease (-3.01 kg); improvement or disappearance rates for other CHF symptoms (including edema, dyspnea, orthopnea, pulmonary congestion, and rales) indicated that treatment was effective. Urine excretion was increased 0-1 h after OPC-61815 administration and reached a maximum level at 1-2 h. CONCLUSIONS: The tolerability of once daily (up to 5 days) intravenous OPC-61815 (8 mg or 16 mg) was confirmed in patients with CHF who had difficulty with, or were incapable of, oral intake.

Patterns of diversification of the operculate land snail genus Cyclophorus (Caenogastropoda: Cyclophoridae) on the Ryukyu Islands, Japan.

The Ryukyu Islands, an island chain in southwestern Japan, originated from land masses that separated from the Eurasian continent due to the formation of sea barriers about 1.55 million years ago. In this study, we investigated the phylogenetic relationships of the operculate land snail genus Cyclophorus (Caenogastropoda: Cyclophoridae) in the Ryukyu Archipelago and surrounding regions based on DNA sequence data. According to our results, all studied Cyclophorus specimens from Japan form a monophyletic group containing eight subclades. Six of these subclades were found only on the Ryukyu Islands. On most islands of the Ryukyu Archipelago, no more than one Cyclophorus subclade was recorded, which may be due to limited ecological niche space and competition. No subclade was found to occur on both sides of the Watase Line, a regional zoogeographical boundary. Divergence times were estimated based on a time-calibrated phylogeny. We found that multiple splits among the Japanese Cyclophorus subclades predate the emergence of major sea barriers in the Ryukyu Archipelago. Vicariance due to sea barrier formation, as assumed for many other taxa from the region, was thus likely not the main driver for subclade divergence in these snails. Instead, certain geographical features might have shaped the diversification of subclades prior to sea barrier formation. Given that Cyclophorus populations were also present on islands that have never been connected to other land masses, the snails must have colonized them via oversea dispersal. As not all nominal taxa corresponded to monophyletic groups, our molecular phylogenetic approach revealed that a taxonomic revision of the Japanese Cyclophorus fauna is necessary. The eight subclades may be regarded as potential species-level groups based on COI p-distances. A canonical discriminant analysis using shell morphological data revealed slight differences among the subclades.