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BackgroundThis large-scale post-marketing surveillance study (START study) evaluated the effectiveness and safety of tolvaptan in Japanese liver cirrhosis patients with hepatic edema in real-world clinical settings. Here, we present the final analysis outcomes.MethodsA prospective, multicenter, non-interventional study involving patients who received tolvaptan for the treatment of liver cirrhosis with hepatic edema with an insufficient response to conventional diuretics. The observation period was up to 6 months. Effectiveness evaluation included changes in body weight and clinical symptoms. Safety analysis included evaluation of adverse drug reactions (ADRs).ResultsCase reports of 1111 patients were collected. Of these, 1109 were included in the safety analysis and 1098 in the effectiveness analysis. The mean age was 69.4 ± 11.5 years and 695 (62.7%) patients were male. After tolvaptan treatment, a decrease in body weight from baseline was − 2.6 ± 2.7 kg on day 7 and − 3.8 ± 4.1 kg on day 14. Moreover, clinical symptoms significantly improved over the 14-day treatment. Frequently reported ADRs were thirst (6.6%), hepatic encephalopathy (2.3%), dehydration (1.5%), and hypernatremia (1.2%). A serum sodium level of ≥ 150 mEq/L was reported in five patients (0.5%). Multivariate analyses showed that the baseline blood urea nitrogen (BUN) level (cut-off value: 22.4 mg/dL) was the predictive factor for tolvaptan treatment response.ConclusionsThe results suggest that tolvaptan was effective and well-tolerated in liver cirrhosis patients with hepatic edema. In the real-world clinical setting, tolvaptan provides a useful option for the treatment of hepatic edema.

Aim Vicariance events have been proposed as a major source of lineage divergence on continental islands, whereas dispersal events followed by isolation have been proposed as the major cause on oceanic islands. However, organisms on continental islands may include taxa with characteristics similar to those on oceanic islands. Lineage divergence unassociated with the geological events that separated islands may also have occurred. This study addresses these possibilities through morphological and molecular phylogeographic analyses of land snails (Bradybaena) on continental islands. Location Samples were mainly collected on the Ryukyu and Izu Islands in Japan. Methods Molecular phylogenetic analyses using mtDNA (16S rRNA+COI) and nDNA (18S rRNA+ITS1+5.8S rRNA+ITS2+28S rRNA) were conducted for 225 individuals comprising B. circulus, B. phaeogramma and four of its subspecies endemic to the Ryukyu Islands. Shell and genital morphologies were also examined using qualitative and statistical methods. Results The Bradybaena populations examined were phylogenetically classified into six major clades whose divergence occurred during either Miocene‐Pliocene or Pliocene‐Pleistocene. Although phylogeographic patterns estimated on the basis of the 16S rRNA gene support the vicariance hypothesis for the origin of the major clades of Bradybaena, the phylogeographic patterns estimated by COI showed that these major clades resulted from diversification before the archipelagos separated from the continent. Both of these phylogeographic patterns suggest that genetic divergence occurred by dispersal from the southern to northern islands after divergence of major clades. The inferred phylogenies document parallel morphological evolution, yielding phylogenetic, morphological and taxonomic incongruences that created mosaic geographical patterns in the distribution of nominal taxa. Main conclusions Lineage diversification in endemic species on continental islands can occur before archipelago separation or subsequently via dispersal, as is seen in species on oceanic islands. Mechanisms other than vicariance should also be considered when estimating processes that created geographical patterns of genetic variations on continental islands.

In this paper, we study the nonequilibrium dynamics of the Bose-Hubbard model with the nearest-neighbor repulsion by using time-dependent Gutzwiller (GW) methods. In particular, we vary the hopping parameters in the Hamiltonian as a function of time, and investigate the dynamics of the system from the density wave (DW) to the superfluid (SF) crossing a first-order phase transition and vice versa. From the DW to SF, we find scaling laws for the correlation length and vortex density with respect to the quench time. This is a reminiscence of the Kibble-Zurek scaling for continuous phase transitions and contradicts the common expectation. We give a possible explanation for this observation. On the other hand from SF to DW, the system evolution depends on the initial SF state. When the initial state is the ground state obtained by the static GW methods, a coexisting state of the SF and DW domains forms after passing through the critical point. Coherence of the SF order parameter is lost as the system evolves. This is a phenomenon similar to the glass transition in classical systems. When the state starts from the SF with small local phase fluctuations, the system obtains a large size DW domain structure with thin domain walls.

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.

Other than hard bones and shells, it is rare for soft tissues to fossilize, but occasionally they are well-preserved in amber. Here, we focus on both modern and fossilized species of the land snail superfamily Cyclophoroidea. Phylogenetic relationships within the Cyclophoroidea were previously studied using extant species, but timing of divergence within the group remains unclear. In addition, it is difficult to observe morphological traits such as the chitinous operculum and periostracum of fossil snails due to their poor preservation potential. Here we describe nine species including a new genus and five new species of well-preserved fossil cyclophoroideans from the mid-Cretaceous Burmese amber. These fossils include not only the shell, but also the chitinous operculum and periostracum, soft body, and excrements. We present the first estimation of divergence time among cyclophoroidean families using fossil records and molecular data, suggesting extreme morphological conservatism of the Cyclophoroidea for nearly 100 million years.

Phylogenetic incongruence has frequently been encountered among different molecular markers. Recent progress in molecular phylogenomics has provided detailed and important information for evolutionary biology and taxonomy. Here we focused on the freshwater viviparid snails ( Cipangopaludina chinensis chinensis and C. c. laeta ) of East Asia. We conducted phylogenetic analyses and divergence time estimation using two mitochondrial markers. We also performed population genetic analyses using genome-wide SNPs. We investigated how and which phylogenetic patterns reflect shell morphology. The results showed these two species could be separated into four major mitochondrial clades, whereas the nuclear clusters supported two groups. The phylogenetic patterns of both mtDNA and nDNA largely reflected the geographical distribution. Shell morphology reflected the phylogenetic clusters based on nDNA. The findings also showed these two species diversified in the Pliocene to early Pleistocene era, and occurred introgressive hybridisation. The results also raise the taxonomic issue of the two species.

Understanding how population structure and demography are determined is a central theme in marine biogeography. While historical events, such as past climate change, are important determinants, the mechanisms by which they act are not well understood in many marine species. In this study, the population structure of the Japanese, marine intertidal gastropod Lunella correensis was investigated to determine whether it has been affected by past environmental changes. A genome-wide SNP analysis, L. correensis showed a genetic gradient along the coast and a weak genetic differentiation between sites in the Sea of Japan and the Pacific Ocean. Demographic inference suggests that the effective population size expanded and shrunk in response to periods of rapid warming and cooling due to past climate change. Further, ecological niche modelling suggests that the population size of L. correensis increased by advancing into the Sea of Japan during rapid warming after the Last Glacial Maximum. Notably, our analyses suggest that recent human activities may have influenced the effective population size of this species. Specifically, the period of reduction in the population size coincides with environmental changes and habitat loss associated with development along the Japanese coastal area. Thus, these results emphasize that the genetic structure and demography of marine species have been influenced by past environmental change around the Japanese Archipelago.

Background Calcareous outcrops, rocky areas composed of calcium carbonate (CaCO 3 ), 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 CaCO 3 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.

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.

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.