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Sodium-glucose cotransporter 2 (SGLT2) is imporant in glucose reabsorption. SGLT2 inhibitors suppress renal glucose reabsorption, therefore reducing blood glucose levels in patients with type 2 diabetes. We and others have developed several SGLT2 inhibitors starting from phlorizin, a natural product. Using cryo-electron microscopy, we present the structures of human (h)SGLT2-MAP17 complexed with five natural or synthetic inhibitors. The four synthetic inhibitors (including canagliflozin) bind the transporter in the outward conformations, while phlorizin binds it in the inward conformation. The phlorizin-hSGLT2 interaction exhibits biphasic kinetics, suggesting that phlorizin alternately binds to the extracellular and intracellular sides. The Na + -bound outward-facing and unbound inward-open structures of hSGLT2-MAP17 suggest that the MAP17-associated bundle domain functions as a scaffold, with the hash domain rotating around the Na + -binding site. Thus, Na + binding stabilizes the outward-facing conformation, and its release promotes state transition to inward-open conformation, exhibiting a role of Na + in symport mechanism. These results provide structural evidence for the Na + -coupled alternating-access mechanism proposed for the transporter family., (© 2023. The Author(s).)

The prognosis of tetralogy of Fallot with pulmonary atresia (TOF/PA) is mainly determined by the development of major aorto-pulmonary collateral arteries (MAPCAs) that provide pulmonary blood perfusion. TOF/PA can be managed conservatively until adulthood in patients with adequate, but not excessive perfusion via MAPCAs. To the best of our knowledge, this is the first report of a patient with unrepaired TOF/PA who eventually developed descending aortic dissection (AD), and survived with medical treatment. A 46-year-old woman was referred to our hospital by her local cardiologist with exertional dyspnea. A three-dimensional (3-D) computed tomography (CT) performed prior to presentation showed a dilated thoracic aorta, three well-developed MAPCAs, and a patent ductus arteriosus (PDA), whereas the 3-D CT performed at presentation revealed a descending AD with the entry site at the proximal part of the thoracic descending aorta, and neither the MAPCAs nor the PDA originated from the area of the AD. The patient was treated medically and was discharged thereafter. In this case, 3D-CT taken 9 months prior to the dissection showed no involvement of MAPCAs in the dissection area and was useful to make a decision of conservative therapy., Learning Objective: Few systematic studies have addressed patients with tetralogy of Fallot with pulmonary atresia (TOF/PA) who survived more than 20 years due to optimal control of pulmonary blood flow depending on the development of major aorto-pulmonary collateral arteries (MAPCAs). We report a patient with unrepaired TOF/PA who developed descending aortic dissection (AD) in her forties. Three-dimensional computed tomography was useful for diagnosing and choosing a treatment plan by identifying the involvement of MAPCAs within the region of the AD., Competing Interests: The authors declare that there is no conflict of interest., (© 2023 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

MND-2119 is a self-emulsifying formulation of highly purified eicosapentaenoic acid ethyl ester (EPA-E) designed to be administered once daily due to improved absorption compared with the nonself-emulsifying formulation. In these studies, MND-2119 was administered to healthy adult males in single or multiple doses. In the single administration study, MND-2119 (0.5-4 g) was administered under fed and fasted conditions to evaluate MND-2119 pharmacokinetics and safety under these conditions. This study showed that C max and AUC 0-72h of plasma EPA concentration after single administration were higher under fed conditions than under fasted conditions, for all doses. In the multiple administration study, subjects received either MND-2119 (0.5-4 g) immediately after breakfast or EPA-E (0.9 g) immediately after breakfast and dinner for 11 days to compare pharmacokinetics and safety of MND-2119 to EPA-E. In this study, the rate of rise in C min of the plasma EPA concentration with MND-2119 decreased from days 6 to 8 after administration and was thought to have reached a steady state on day 11. The mean C ss,max of MND-2119 administered as 1 g once daily, and the mean C ss,min and the mean AUC ss,0-24h of MND-2119 administered as 2 g once daily were higher than those of EPA-E administered as 0.9 g twice daily. No safety-related issues occurred in either study. These results suggest that MND-2119 administered once daily may achieve equivalent or higher plasma EPA concentrations compared to the nonself-emulsifying formulation administered twice daily., (© 2022, The American College of Clinical Pharmacology.)

Background: In Japan, eicosapentaenoic acid ethyl ester (EPA-E) is administered twice-daily or three-times-daily for dyslipidemia. We have developed MND-2119, a novel self-emulsifying formulation of highly purified EPA-E, which can be administered once-daily., Objective: The objective of this study was to assess non-inferiority in the efficacy of MND-2119 in patients with hypertriglyceridemia compared with highly purified EPA-E., Methods: In this multicenter, 12-week, double-blind study, patients with high triglyceride (TG levels between ≥ 150 and < 500 mg/dL) undergoing lifestyle modification were randomized to MND-2119 2 g/day (n=145), MND-2119 4 g/day (n=145), EPA-E 1.8 g/day (n=145) or EPA-E 2.7 g/day (n=145). The primary endpoint was percentage change in TG levels from baseline to end of treatment., Results: MND-2119 2, 4 g/day and EPA-E 1.8, 2.7 g/day reduced TG levels from baseline by -10.09%, -15.51%, -9.30%, and -8.80%, respectively. The TG reduction rate of MND-2119 2 g/day was non-inferior to that of EPA-E 1.8 g/day (LS mean difference: -0.42, 95%CI: -5.76 to 4.91). Moreover, the TG reduction rate of MND-2119 4 g/day was superior to that of MND-2119 2 g/day (LS mean difference: -5.74, 95%CI: -10.59 to -0.89). There were no remarkable safety differences between MND-2119 2 g/day and EPA-E 1.8 g/day and between MND-2119 4 g/day and EPA-E 2.7 g/day., Conclusion: Non-inferiority of MND-2119 2 g/day to EPA-E 1.8 g/day for efficacy, and superiority of MND-2119 4 g/day over MND-2119 2 g/day for efficacy were verified. MND-2119 was safe and well tolerated., Competing Interests: Declaration of Competing Interest Takuya Mori, Koichi Hayashi, and Yuichi Yokoyama are employed by Mochida Pharmaceutical Co., Ltd., (Copyright © 2022. Published by Elsevier Inc.)

Background: In Japan, eicosapentaenoic acid ethyl ester (EPA-E) is administered twice-daily or three-times-daily for dyslipidemia. We have developed MND-2119, a novel self-emulsifying formulation of highly purified EPA-E which can be administered once-daily., Objective: The objective of this study was to investigate the safety and efficacy of long-term administration of MND-2119 in hypertriglyceridemia patients., Methods: In this multicenter, 52-week, open-label study, patients with high triglyceride (TG) (TG levels between ≥ 150 and < 500 mg/dL) undergoing lifestyle modification were randomized to MND-2119 2 g/day (n=61) or MND-2119 4 g/day (n=61)., Results: The incidence of adverse events in MND-2119 2 g/day and MND-2119 4 g/day was 70.5% and 62.3%, respectively, and the incidence of adverse drug reactions was 9.8% and 8.2%, respectively. There were no notable problems in the safety assessments of both treatment groups. By Week 4, TG levels had decreased from baseline in both groups, and the TG reducing effect continued up to Week 52 (mean percentage change from baseline in TG at Week 52 [two-sided 95% confidence interval]: MND-2119 2 g/day: -16.71% [-26.61, -6.81], MND-2119 4 g/day: -21.01% [-27.86, -14.16]). In both groups, plasma EPA concentration at Week 4 was maintained up until Week 52 and the plasma EPA concentration at Week 52 was 200.5 ± 54.7 μg/mL in MND-2119 2 g/day and 308.6 ± 98.6 μg/mL in MND-2119 4 g/day., Conclusion: Long-term administration of MND-2119 was not associated with any safety-related problems. TG levels decreased by Week 4, and the TG reducing effect continued up to Week 52., Competing Interests: Declarations of interest T.M and Y.Y are employed by Mochida Pharmaceutical Co., Ltd. This study was supported by Mochida Pharmaceutical Co., Ltd. K.M has acted as the medical expert of this study and has received research/grant support from Mochida Pharmaceutical Co., Ltd., (Copyright © 2022. Published by Elsevier Inc.)

The snailfish Osteodiscus abyssicola sp. nov. is described from a single specimen collected off the Pacific coast of Hokkaido, northern Japan, at a depth of 4,6714,744 m. It is distinguished from all currently recognized congeners by the following combination of characters: vertebrae 49; dorsal-fin rays 44; anal-fin rays 39; principal caudal-fin rays 8; pyloric caeca 5; mouth horizontal; teeth on both jaws simple and sharp, without cusps; upper and lower jaw symphyses without diastema; cephalic pore sizes moderate, similar to or slightly larger than nostril; gill slit extending ventrally to 2nd pectoral-fin ray base; pectoral fin notched; mandibular symphysis to center of anus 101.6% head length (HL); posterior edge of pelvic disk to center of anus 15.5% HL; epural 1, reduced; epipleural ribs absent. An emended diagnosis and key to the species of Osteodiscus are provided.

Background: Recent research has led to the development of many information technology-supported systems for health care control, including systems estimating nutrition from images of meals. Systems that capture data about eating and exercise are useful for people with diabetes as well as for people who are simply on a diet. Continuous monitoring is key to effective dietary control, requiring systems that are simple to use and motivate users to pay attention to their meals. Unfortunately, most current systems are complex or fail to motivate. Such systems require some manual inputs such as selection of an icon or image, or by inputting the category of the user's food. The nutrition information fed back to users is not especially helpful, as only the estimated detailed nutritional values contained in the meal are typically provided., Objective: In this paper, we introduce healthiness of meals as a more useful and meaningful general standard, and present a novel algorithm that can estimate healthiness from meal images without requiring manual inputs., Methods: We propose a system that estimates meal healthiness using a deep neural network that extracts features and a ranking network that learns the relationship between the degrees of healthiness of a meal using a dataset prepared by a human dietary expert. First, we examined whether a registered dietitian can judge the healthiness of meals solely by viewing meal images using a small dataset (100 meals). We then generated ranking data based on comparisons of sets of meal images (850 meals) by a registered dietitian's viewing meal images and trained a ranking network. Finally, we estimated each meal's healthiness score to detect unhealthy meals., Results: The ranking estimated by the proposed network and the ranking of healthiness based on the dietitian's judgment were correlated (correlation coefficient 0.72). In addition, extracting network features through pretraining with a publicly available large meal dataset enabled overcoming the limited availability of specific healthiness data., Conclusions: We have presented an image-based system that can rank meals in terms of the overall healthiness of the dishes constituting the meal. The ranking obtained by the proposed method showed a good correlation to nutritional value-based ranking by a dietitian. We then proposed a network that allows conditions that are important for judging the meal image, extracting features that eliminate background information and are independent of location. Under these conditions, the experimental results showed that our network achieves higher accuracy of healthiness ranking estimation than the conventional image ranking method. The results of this experiment in detecting unhealthy meals suggest that our system can be used to assist health care workers in establishing meal plans for patients with diabetes who need advice in choosing healthy meals., (©Kyoko Sudo, Kazuhiko Murasaki, Tetsuya Kinebuchi, Shigeko Kimura, Kayo Waki. Originally published in JMIR Formative Research (http://formative.jmir.org), 26.10.2020.)

A new snailfish, Paraliparis flammeus , is described on the basis of 18 specimens collected off the Pacific coast of Tohoku District, northern Japan at depths of 422-890 m. The new species is distinguished from 28 species of Paraliparis described from the North Pacific by the following combination of characters: mouth oblique; uppermost pectoral-fin base below horizontal through posterior margin of maxillary; 60-63 vertebrae, 54-58 dorsal-fin rays, 50 or 51 anal-fin rays, six principal caudal-fin rays, and 17-20 pectoral-fin rays. A maximum likelihood tree based on 106 COI gene sequences (492 bp) of Paraliparis recovered a monophyletic group comprising P. flammeus , Paraliparis cephalus , and Paraliparis dipterus . Paraliparis cephalus is similar to P. flammeus in having an oblique mouth, but it has four caudal-fin rays (vs six rays) and the uppermost pectoral-fin base above a horizontal through the maxillary posterior margin. Paraliparis dipterus differs from P. flammeus in having a horizontal mouth, 12-14 pectoral-fin rays, and lacking pyloric caeca (present in P. flammeus ). Paraliparis flammeus is most similar to the eastern North Pacific Paraliparis mento in having an oblique mouth and the uppermost pectoral-fin base below a horizontal through the posterior margin of the maxillary. However, P. flammeus differs from P. mento in having six caudal-fin rays (vs five rays) and greater preanal length (29.9-35.3% SL vs 26.7-28.5% SL). A poorly known species, Paraliparis mandibularis , previously known from only two specimens collected from Tosa Bay, southern Japan, is redescribed based on the holotype and seven newly collected specimens. It is also similar to the new species but has 27-30 pectoral-fin rays and a shorter pectoral-fin lower lobe (13.8-15.9% SL in P. mandibularis vs 16.7-23.4% SL in P. flammeus )., (Yoshiaki Kai, Kenta Murasaki, Ryo Misawa, Atsushi Fukui, Eisuke Morikawa, Yoji Narimatsu.)

Background: Recent clinical trials' findings have revealed the therapeutic noninferiority of direct oral anticoagulant (DOAC) to standard therapy with vitamin K antagonist (VKA) in patients with pulmonary thromboembolism (PTE). However, few studies have quantitatively analyzed thrombus reduction in the pulmonary artery., Methods: This observational study included 38 symptomatic PTE patients with stable hemodynamics. All patients received an intravenous heparin bolus followed by continual heparin injections immediately after the PTE diagnosis. The heparin was discontinued after edoxaban therapy began in the DOAC group (n = 22) or after the therapeutic range for the prothrombin time-international normalized ratio was achieved in the VKA group (n = 16). The thrombus volumes in the pulmonary arteries were quantitatively analyzed using contrast-enhanced computed tomography scans, and they were compared at baseline and at 2 weeks after admission., Results: The pulmonary thrombus volumes declined in the VKA and DOAC groups from 7.9 to 4.2 cm 3 (P = 0.048) and from 7.1 to 3.7 cm 3 (P < 0.01), respectively, and the thrombus reduction rates did not differ significantly between the groups (-34% vs. -64%, respectively; P = 0.38). The fibrinogenolysis parameter changes during the14 days after admission were similar in both groups. Compared with the VKAgroup, the average hospital stay was 9days shorter in the DOAC group. There were no in-hospital deaths, and 1 case experienced major bleeding in the VKA group., Conclusions: In relation to pulmonary artery thrombus volume reduction, DOAC monotherapy for PTE may be comparable with standard therapy involving VKAs., (Copyright © 2020 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background: In "real-world" practice, anticoagulant therapy is indicated for patients whose clinical profiles are not addressed in randomized clinical trials. We assessed the effectiveness and safety of dabigatran versus warfarin in "real-world" Japanese patients with non-valvular atrial fibrillation (NVAF)., Methods: Among 613 NVAF patients who initiated dabigatran or warfarin therapy during the period between 2011 and 2013, 362 patients were included in the study after propensity score adjustment. The median follow-up period was 1.3 years. The effectiveness and safety outcomes were thromboembolism and major bleeding, respectively., Results: The propensity-matched hazard ratios of thromboembolism and major bleeding with dabigatran were 1.03 (95% CI: 0.12-8.04, p =0.971) and 0.15 (95% CI: 0.01-0.90, p =0.037), respectively., Conclusions: The ability of dabigatran to prevent thromboembolism is comparable to that of warfarin; however, the major bleeding rate is lower with dabigatran in "real-world" NVAF patients.

Background: Non-vitamin K antagonist oral anticoagulants (NOACs) show a favorable balance between efficacy and safety compared with warfarin for patients with non-valvular atrial fibrillation (NVAF). In "real-world" practice, however, NOAC adherence and persistence among patients are not clear. The aim of this study is to evaluate NOAC and warfarin persistence in Japanese patients with NVAF who newly started these drugs., Methods: We retrospectively studied 401 patients with NVAF who had newly started NOACs during the first 18 months after our hospital adopted their use (197 dabigatran, 107 rivaroxaban, 102 apixaban) and 200 patients with NVAF who had newly started warfarin during the same period. The endpoint was drug discontinuation for each drug., Results: During the follow-up period (up to a maximum of 24 months), 113 (28%) patients who had newly started NOACs and 33 (17%) patients who had newly started warfarin discontinued the drug. The persistence rates of patients prescribed NOACs was lower than that of patients prescribed warfarin at 3, 6, and 12 months (85% versus 93%, 79% versus 88%, and 70% versus 82%, respectively). One-tenth of patients who had newly started NOACs discontinued the drug by their own decision. Drug adverse events, worsening renal dysfunction, and patient desire were the major causes of NOAC discontinuation., Conclusions: The rate of persistence of prescribed NOACs was significantly lower than that of warfarin in Japanese patients with NVAF.