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Background: Liver cirrhosis leads to portal hypertension (PH) with capillarization of liver sinusoidal endothelial cells (LSECs), although drug treatment options for PH are currently limited. Sodium glucose transporter 2 inhibitors, which are antidiabetic agents, have been shown to improve endothelial dysfunction. We aimed to elucidate the effect of tofogliflozin on PH and liver fibrosis in a rat cirrhosis model. Methods: Male-F344/NSlc rats repeatedly received carbon tetrachloride (CCl4) intraperitoneally to induce PH and liver cirrhosis alongside tofogliflozin (10 or 20 mg/kg). Portal hemodynamics and hepatic phenotypes were assessed after 14 weeks. An in vitro study investigated the effects of tofogliflozin on the crosstalk between LSEC and activated hepatic stellate cells (Ac-HSC), which are relevant to PH development. Results: Tofogliflozin prevented PH with attenuated intrahepatic vasoconstriction, sinusoidal capillarization, and remodeling independent of glycemic status in CCl4-treated rats. Hepatic macrophage infiltration, proinflammatory response, and fibrogenesis were suppressed by treatment with tofogliflozin. In vitro assays showed that tofogliflozin suppressed Ac-HSC-stimulated capillarization and vasoconstriction in LSECs by enhancing the antioxidant capacity, as well as inhibited the capilliarized LSEC-stimulated contractive, profibrogenic, and proliferative activities of Ac-HSCs. Conclusions: Our study provides strong support for tofogliflozin in the prevention of liver cirrhosis-related PH.

POGZ (Pogo transposable element derived with ZNF domain) is known to function as a regulator of gene expression. While variations in the POGZ gene have been associated with intellectual disabilities and developmental delays in humans, the exact pathophysiological mechanisms remain unclear. To shed light on this, we created two lines of conditional knockout mice for Pogz, one specific to excitatory neurons (Emx1-Pogz mice) and the other to inhibitory neurons (Gad2-Pogz mice) in the brain. Emx1-Pogz mice showed a decrease in body weight, similar to total Pogz knockout mice. Although the two lines did not display significant morphological abnormalities in the telencephalon, impaired POGZ function affected the electrophysiological properties of both excitatory and inhibitory neurons differently. These findings suggest that these mouse lines could be useful tools for clarifying the precise pathophysiological mechanisms of neurodevelopmental disorders associated with POGZ gene abnormalities.

C20H18N4O4, orthorhombic, Pbca (no. 61), a = 7.670(4) Å, b = 15.679(8) Å, c = 29.170(17) Å, V = 3508(3) Å3, Z = 8, Rgt(F) = 0.0497, wRref(F2) = 0.1379, T = 243(2) K.

Carbapenemase-producing Enterobacterales cause healthcare-associated infections but modes of transmission are not well understood. Here, the authors find evidence of transmission without direct patient contact, indicating presence of undetected environmental reservoirs, whilst half of the transmission events are likely due to plasmid-mediated transmission.

Abstract The leaves and twigs of Lindera spp. have long been used as a herbal medicine and toothpicks in Japan. However, little is known about individual variations in the extractives of these species, because many previous studies have not distinguished extractives between individuals. In this study, we investigated the extractives of L. umbellata at the individual level. The detailed identification of the inter- and intra-individual variations in the major terpenoids and flavonoids in native L. umbellata may greatly contribute to the development of cultivation techniques and the effective use of forest resources. The contents of major components of L. umbellata, including four terpenoids (1,8-cineole, linalool, geraniol, and geranyl acetate) and five low-molecular-weight phenolics (pinocembrin chalcone, pinocembrin, pinostrobin chalcone, pinostrobin, and 5,6-dehydrokawain), were analyzed in leaves and twigs seasonally (June, August, and October). The compositions of the major terpenoids were strongly dependent on the properties of each individual and were generally independent of leaves and twigs. Moreover, geranyl acetate was characteristically present in the twigs of some individuals. As new findings regarding linalool, some individuals showed characteristic enantiomeric excesses, presumably because of biotic factors, and the proportion of these enantiomers was kept constant in each individual, regardless of the season. The total phenolic contents in leaves were more than twice those detected in twigs, and the leaves tended to contain more chalcones and twigs more flavanones. Furthermore, the contents of chalcones (pinocembrin chalcone vs. pinostrobin chalcone) and flavanones (pinocembrin vs. pinostrobin) were positively correlated in both leaves and twigs. The coefficient of variation (CV) clearly showed that the content of the major terpenoids was determined by inter-individual rather than intra-individual differences. Although the results obtained in this study should at present only be applicable to a limited population native to specific regions, our findings provide key knowledge in considering the sustainable use of L. umbellata.

S Abbas Raza,1,* Morton Brian Keith,2,* Kar Chai Koh3,* 1Shaukat Khanum Cancer Hospital & Research Center and National Hospital, Lahore, Pakistan; 2Northbridge Medical Practice, Northbridge, New South Wales, Australia; 3Poliklinik Kepong Baru, Kuala Lumpur, Malaysia*These authors contributed equally to this workCorrespondence: Kar Chai Koh, Poliklinik Kepong Baru, Jalan Ambong Kiri Satu, Kepong Baru, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, 52100, Malaysia, Email drcaseysurf@gmail.comPurpose: Pain is considered a major clinical and socioeconomic problem worldwide. Delayed gastric emptying rates allegedly influence the suitability of pain-relief medications in patient populations such as the elderly and individuals with diabetes. Faster pain relief was reportedly achieved by using a fast-dissolving paracetamol (FD-APAP) formulation. This study aims to gain insights to healthcare professionals’ (HCPs) perspectives towards using FD-APAP in addressing barriers of pain relief in patient populations susceptible to delayed gastric emptying rates.Patients and Methods: A two-step modified Delphi consensus study was conducted among a panel of 10 general practitioners (GPs) and four endocrinologists. The first step comprises in-depth discussions around evidence relevant to FD-APAP for pain management in patient populations with delayed gastric emptying rates (elderly/diabetics). The second step (a survey) was based on the summarized input from the first step. Consensus was accepted upon ≥ 70% agreement. Perspectives on pain management by FD-APAP for elderly patients were explored among GPs, while those for diabetic patients were explored among GPs and endocrinologists.Results: Consensus was achieved, whereby all panel members found FD-APAP to be favorable and relevant for pain management in the elderly and the diabetic patient populations. GPs additionally raised the consensus on the importance of considering comorbidities associated with diabetes while having minimal complications during pain management.Conclusion: The panel found the faster disintegration and absorption of FD-APAP relevant and useful for patients with delayed gastric emptying, wherein, pain in the elderly and those with diabetes could be treated effectively with limited side-effects.Keywords: fast-dissolving paracetamol, consensus, delayed gastric emptying, pain relief, elderly, diabetics

During development, astrocytes are generated from radial glia, and migrate to the cortical plate, but the process of astrocyte migration during development is not fully understood. Here the authors labelled cells derived from the cortical ventricular zone in the late stages of cortical plate development in mice, and identified a migration mode in which cells move rapidly and almost at random within the intermediate zone and the cortical plate.

Abstract Background Among various complications of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), renal complications, namely COVID-19-associated kidney injuries, are related to the mortality of COVID-19. Methods In this retrospective cross-sectional study, we measured the sphingolipids and glycerophospholipids, which have been shown to possess potent biological properties, using liquid chromatography-mass spectrometry in 272 urine samples collected longitudinally from 91 COVID-19 subjects and 95 control subjects without infectious diseases, to elucidate the pathogenesis of COVID-19-associated kidney injuries. Results The urinary levels of C18:0, C18:1, C22:0, and C24:0 ceramides, sphingosine, dihydrosphingosine, phosphatidylcholine, lysophosphatidylcholine, lysophosphatidic acid, and phosphatidylglycerol decreased, while those of phosphatidylserine, lysophosphatidylserine, phosphatidylethanolamine, and lysophosphatidylethanolamine increased in patients with mild COVID-19, especially during the early phase (day 1–3), suggesting that these modulations might reflect the direct effects of infection with SARS-CoV-2. Generally, the urinary levels of sphingomyelin, ceramides, sphingosine, dihydrosphingosine, dihydrosphingosine l-phosphate, phosphatidylcholine, lysophosphatidic acid, phosphatidylserine, lysophosphatidylserine, phosphatidylethanolamine, lysophosphatidylethanolamine, phosphatidylglycerol, lysophosphatidylglycerol, phosphatidylinositol, and lysophosphatidylinositol increased, especially in patients with severe COVID-19 during the later phase, suggesting that their modulations might result from kidney injuries accompanying severe COVID-19. Conclusions Considering the biological properties of sphingolipids and glycerophospholipids, an understanding of their urinary modulations in COVID-19 will help us to understand the mechanisms causing COVID-19-associated kidney injuries as well as general acute kidney injuries and may prompt researchers to develop laboratory tests for predicting maximum severity and/or novel reagents to suppress the renal complications of COVID-19.

The optimal allocation of energy storage capacity is an important issue for integrated energy systems (IES). To reduce the impact of volatility and intermittency of renewable energy sources, the impact of volatility needs to be smoothed out by rational allocation of energy storage. To address the above issues, this paper proposes a method for the optimal allocation of source storage capacity considering integrated demand response(IDR). Firstly, the basic mechanism of IES based on energy hub(EH) is constructed, and the model and coupling relationship of equipment components in the system are introduced. The IDR model is built to optimize the load curve according to the real-time market tariff scheme, and then the confidence interval method is used to analyze the scenery uncertainty in IES and determine the scenery output curve under different confidence levels. On this basis, a bi-level optimization model is built that takes into account both source and storage capacity allocation and operational optimization. The upper-level planning model takes into account the uncertainty of wind power and photovoltaic output, and solves the allocation scheme of energy storage intending to minimize the total planning cost; the lower-level operation optimization model takes into account the output constraints of each unit and optimizes the output of the equipment to minimize the operation cost. Finally, it is verified that considering IDR can reasonably optimize the allocation of the system’s source storage capacity and reduce the system’s investment and operating costs.

A wind power curtailment consumption strategy using electric vehicles (EVs) based on individual differential evolution quantum particle swarm optimization algorithm (IDE-QPSO) is proposed, with the objective of reducing the system’s wind curtailment in order to further improve the wind power consumption rate while effectively reducing wind power output fluctuation and amplitude. EV aggregators act as charging tariff setters, releasing dynamic time-of-use tariffs (DTOU) for EV clusters to respond to based on wind curtailment data accounted for by the dispatch center. This method first establishes an electric vehicle charging load model based on the travel chain theory and residents’ travel rules, then establishes an EV users autonomous response model based on the sensitivity of electric vehicle users to the charging prices. Second, a multi-objective optimization function is established based on the aforementioned model, which integrates wind power curtailment consumption and minimizes wind power output fluctuation and amplitude, and it is solved using an improved quantum particle swarm optimization algorithm. Finally, adequate simulation experiments show that this strategy can effectively smooth out the fluctuation of wind power output and improve the wind power consumption rate.

Background The rapid spread of the coronavirus disease 2019 (COVID-19) pandemic demonstrates the value of regional cooperation in infectious disease prevention and control. We explored the literature on regional infectious disease control bodies, to identify lessons, barriers and enablers to inform operationalisation of a regional infectious disease control body or network in southeast Asia.Methods We conducted a scoping review to examine existing literature on regional infectious disease control bodies and networks, and to identify lessons that can be learned that will be useful for operationalisation of a regional infectious disease control body such as the Association of Southeast Asian Nations (ASEAN) Center for Public Health Emergency and Emerging Diseases.Results Of the 57 articles included, 53 (93%) were in English, with two (3%) in Spanish and one (2%) each in Dutch and French. Most were commentaries or review articles describing programme initiatives. Sixteen (28%) publications focused on organisations in the Asian continent, with 14 (25%) focused on Africa, and 14 (25%) primarily focused on the European region. Key lessons focused on organisational factors, diagnosis and detection, human resources, communication, accreditation, funding, and sustainability. Enablers and constraints were consistent across regions/organisations. A clear understanding of the regional context, budgets, cultural or language issues, staffing capacity and governmental priorities, is pivotal. An initial workshop inclusive of the various bodies involved in the design, implementation, monitoring or evaluation of programmes is essential. Clear governance structure, with individual responsibilities clear from the beginning, will reduce friction. Secure, long-term funding is also a key aspect of the success of any programme.Conclusion Operationalisation of regional infectious disease bodies and networks is complicated, but with extensive groundwork, and focus on organisational factors, diagnosis and detection, human resources, communication, accreditation, funding, and sustainability, it is achievable. Ways to promote success are to include as many stakeholders as possible from the beginning, to ensure that context-specific factors are considered, and to encourage employees through capacity building and mentoring, to ensure they feel valued and reduce staff turnover.

Abstract Because captive-bred animals gradually adapt to artificial rearing environments due to evolving life history traits, such individuals sometimes show lessened performance in natural environments. The lateral line system, one of the principal sensory organs of fishes, varies according to habitat environments, sometimes differing even within the same species. A reduction in lateral line elements may also occur in successive generations of captive-bred fish. Such a reduction, involving neuromasts over the entire body, was examined for the first time in captive-bred masu salmon Oncorhynchus masou masou. The total number of neuromasts in captive-bred fish was ca. 10% lower than in wild-caught and F1 fishes, suggesting that the system in captive-bred fish had reduced in number due to domestication. Furthermore, differences in total neuromast numbers between captive-bred and wild fish were greater than between anadromous and fluvial populations of the species. The lower number of neuromasts could be one of the reasons behind the lower survival of captive-bred fish in natural environments.

Wenjia Chen,1 Mohsen Sadatsafavi,2 Trung N Tran,3 Ruth B Murray,4 Chong Boon Nigel Wong,1 Nasloon Ali,4,5 Cono Ariti,4,5 Esther Garcia Gil,6 Anthony Newell,5,7 Marianna Alacqua,8 Mona Al-Ahmad,9 Alan Altraja,10 Riyad Al-Lehebi,11,12 Mohit Bhutani,13 Leif Bjermer,14 Anne Sofie Bjerrum,15 Arnaud Bourdin,16 Lakmini Bulathsinhala,4,5 Anna von Bülow,17 John Busby,18 Giorgio Walter Canonica,19,20 Victoria Carter,4,5 George C Christoff,21 Borja G Cosio,22 Richard W Costello,23 J Mark FitzGerald,24 João A Fonseca,25 Kwang Ha Yoo,26 Liam G Heaney,27 Enrico Heffler,19,20 Mark Hew,28,29 Ole Hilberg,30 Flavia Hoyte,31,32 Takashi Iwanaga,33 David J Jackson,34,35 Rupert C Jones,36 Mariko Siyue Koh,37,38 Piotr Kuna,39 Désirée Larenas-Linnemann,40 Sverre Lehmann,41 Lauri A Lehtimäki,42,43 Juntao Lyu,5,7 Bassam Mahboub,44,45 Jorge Maspero,46,47 Andrew N Menzies-Gow,48 Concetta Sirena,49 Nikolaos Papadopoulos,50,51 Andriana I Papaioannou,52 Luis Pérez de Llano,53,54 Diahn-Warng Perng,55,56 Matthew Peters,57 Paul E Pfeffer,58,59 Celeste M Porsbjerg,17 Todor A Popov,60 Chin Kook Rhee,61 Sundeep Salvi,62 Camille Taillé,63 Christian Taube,64 Carlos A Torres-Duque,65 Charlotte S Ulrik,66 Seung Won Ra,67 Eileen Wang,31,32 Michael E Wechsler,68 David B Price4,5,69 1Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore; 2Respiratory Evaluation Sciences Program, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada; 3AstraZeneca, Gaithersburg, MD, USA; 4Optimum Patient Care, Cambridge, UK; 5Observational and Pragmatic Research Institute, Singapore, Singapore; 6AstraZeneca, Barcelona, Spain; 7Optimum Patient Care, Queensland, VIC, Australia; 8AstraZeneca, Cambridge, UK; 9Microbiology Department, Faculty of Medicine, Kuwait University, Al-Rashed Allergy Center, Ministry of Health, Kuwait City, Kuwait; 10Department of Pulmonology, University of Tartu and Lung Clinic, Tartu University Hospital, Tartu, Estonia; 11Department of Pulmonology, King Fahad Medical City, Riyadh, Saudi Arabia; 12College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; 13Department of Medicine, Division of Pulmonary Medicine, University of Alberta, Western Canada, AB, Canada; 14Department of Clinical Sciences, Respiratory Medicine and Allergology, Skåne University Hospital, Lund University, Lund, Sweden; 15Department of Respiratory Medicine and Allergy, Aarhus University Hospital, Jutland, Aarhus, Denmark; 16PhyMedExp, Univ Montpellier, CNRS, INSERM, CHU Montpellier, Montpellier, France; 17Respiratory Research Unit, Bispebjerg University Hospital, Copenhagen, Denmark; 18Centre for Public Health, Queen’s University Belfast, Belfast, Northern Ireland; 19Personalized Medicine, Asthma and Allergy, Humanitas Clinical and Research Center IRCCS, Milan, Italy; 20Department of Biomedical Sciences, Humanitas University, Milan, Italy; 21Medical University-Sofia, Faculty of Public Health, Sofia, Bulgaria; 22Son Espases University Hospital-IdISBa-Ciberes, Mallorca, Spain; 23Department of Respiratory Medicine, Clinical Research Centre, Smurfit Building Beaumont Hospital, RCSI, Dublin, Ireland; 24Department of Medicine, the University of British Columbia, Vancouver, BC, Canada; 25Comunity Health, Information and Decision Sciences Department (MEDCIDS) & Center for Health Technology and Services Research (CINTESIS), Faculty of Medicine of University of Porto, Porto, Portugal; 26KonKuk University School of Medicine in Seoul, Seoul, Korea; 27Wellcome-Wolfson Centre for Experimental Medicine, Queen’s University Belfast, Belfast, Northern Ireland; 28Allergy, Asthma & Clinical Immunology Service, Alfred Health, Melbourne, VIC, Australia; 29Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; 30Medical Department, Vejle University Hospital, Jutland, Vejle, Denmark; 31Department of Medicine, Division of Allergy and Clinical Immunology, National Jewish Health, Denver, CO, USA; 32Department of Internal Medicine, Division of Allergy & Clinical Immunology, University of Colorado School of Medicine, Aurora, CO, USA; 33Center for General Medical Education and Clinical Training, Kindai University Hospital, Osakasayama, Japan; 34UK Severe Asthma Network and National Registry, Guy’s and St Thomas’ NHS Trust, London, UK; 35School of Immunology & Microbial Sciences, King’s College London, London, UK; 36Research and Knowledge Exchange, Plymouth Marjon University, Plymouth, UK; 37Respiratory & Critical Care Medicine, Singapore General Hospital, Singapore, Singapore; 38SingHealth Duke-NUS Lung Centre, Singapore, Singapore; 39Division of Internal Medicine, Asthma and Allergy Medical University of &Lstrok;ód&zacute;, &Lstrok;ód&zacute;, Poland; 40Directora Centro de Excelencia en Asma y Alergia, Hospital Médica Sur, Ciudad de México, Mexico; 41Section of Thoracic Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway; 42Allergy Centre, Tampere University Hospital, Tampere, Finland; 43Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; 44College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 45Rashid Hospital, Dubai Health Authority, Dubai, United Arab Emirates; 46Clinical Research for Allergy and Respiratory Medicine, CIDEA Foundation, Buenos Aires, Argentina; 47University Career of Specialists in Allergy and Clinical Immunology at the Buenos Aires University School of Medicine, Buenos Aires, Argentina; 48Royal Brompton & Harefield Hospitals, London, UK; 49Severe Asthma Network in Italy (SANI), Milano, Italy; 50Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester, UK; 51Allergy Department, 2nd Pediatric Clinic, University of Athens, Athens, Greece; 52 2nd Respiratory Medicine Department, National and Kapodistrian University of Athens Medical School, Attikon University Hospital, Athens, Greece; 53Pneumology Service, Lucus Augusti University Hospital, EOXI Lugo, Lugo, Spain; 54Biodiscovery Research Group, Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain; 55Division of Clinical Respiratory Physiology Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan; 56COPD Assembly of the Asian Pacific Society of Respirology Hongo, Bunkyo-ku, Tokyo, Japan; 57Department of Thoracic Medicine, Concord Hospital, Sydney, NSW, Australia; 58Department of Respiratory Medicine, Barts Health NHS Trust, London, UK; 59Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 60University Hospital ”sv. Ivan Rilski”, Sofia, Bulgaria; 61Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul, South Korea; 62Pulmocare Research and Education Foundation, Pune, India; 63Department of Respiratory Diseases, Bichat Hospital, AP-HP Nord-Université de Paris, Paris, France; 64Department of Pulmonary Medicine, University Medical Center Essen-Ruhrlandklinik, Essen, Germany; 65CINEUMO, Respiratory Research Center, Fundación Neumológica Colombiana, Bogotá, Colombia; 66Department of Respiratory Medicine, Copenhagen University Hospital-Hvidovre, Hvidovre, Denmark; 67Department of Internal Medicine, Division of Pulmonology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea; 68Department of Medicine, NJH Cohen Family Asthma Institute, National Jewish Health, Denver, CO, USA; 69Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UKCorrespondence: David B Price, Observational and Pragmatic Research Institute, 22 Sin Ming Lane, &num;06 Midview City, Singapore, Singapore, 573969, Tel +65 3105 1489, Email dprice@opri.sgBackground: Many severe asthma patients with high oral corticosteroid exposure (HOCS) often do not initiate biologics despite being eligible. This study aimed to compare the characteristics of severe asthma patients with HOCS who did and did not initiate biologics.Methods: Baseline characteristics of patients with HOCS (long-term maintenance OCS therapy for at least 1 year, or ≥ 4 courses of steroid bursts in a year) from the International Severe Asthma Registry (ISAR; https://isaregistries.org/), who initiated or did not initiate biologics (anti-lgE, anti-IL5/5R or anti-IL4R), were described at the time of biologic initiation or registry enrolment. Statistical relationships were tested using Pearson’s chi-squared tests for categorical variables, and t-tests for continuous variables, adjusting for potential errors in multiple comparisons.Results: Between January 2015 and February 2021, we identified 1412 adult patients with severe asthma from 19 countries that met our inclusion criteria of HOCS, of whom 996 (70.5%) initiated a biologic and 416 (29.5%) did not. The frequency of biologic initiation varied across geographical regions. Those who initiated a biologic were more likely to have higher blood eosinophil count (483 vs 399 cells/μL, p=0.003), serious infections (49.0% vs 13.3%, p< 0.001), nasal polyps (35.2% vs 23.6%, p< 0.001), airflow limitation (56.8% vs 51.8%, p=0.013), and uncontrolled asthma (80.8% vs 73.2%, p=0.004) despite greater conventional treatment adherence than those who did not start a biologic. Both groups had similar annual asthma exacerbation rates in the previous 12 months (5.7 vs 5.3, p=0.147).Conclusion: Around one third of severe HOCS asthma patients did not receive biologics despite a similar high burden of asthma exacerbations as those who initiated a biologic therapy. Other disease characteristics such as eosinophilic phenotype, serious infectious events, nasal polyps, airflow limitation and lack of asthma control appear to dictate biologic use.Keywords: severe asthma, biologics, real-world, treatment pattern, patient characteristics

Carbon-ion radiotherapy (CIRT) for prostate cancer is both safe and efficacious; beam range calculations use relative stopping power ratio, which is derived from computed tomography (CT) values. However, hip prostheses are made of high atomic number materials and show severe artifacts on CT images. Therefore, it is not possible to accurately calculate dose distribution for CIRT in patients with prostate cancer with hip prostheses. Here, we describe the management of a 77-year-old man with prostate cancer who had previously undergone bilateral hip replacement. CIRT, in combination with androgen deprivation therapy, was recommended as definitive treatment for prostate cancer. Planning CT, magnetic resonance (MRI), and CT images with metal artifact reduction (MAR) were acquired for CIRT planning. MRI and MAR images were superimposed on the planning CT to delineate target volume and organs at risk. The radiation treatment plan consisted of a total dose of 51.6 Gy (relative biological effect) to be delivered in 12 fractions over 3 weeks, and the patient was irradiated in the supine and prone positions with a vertical beam, on alternating days. CIRT was completed as scheduled. No adverse events were observed during treatment or at 3 months after treatment initiation. While we show that CIRT may be a treatment option for patients with prostate cancer with bilateral hip prostheses, further studies are needed to evaluate treatment efficacy and late toxicity and to determine how CIRT can be administered to patients with prostate cancer with bilateral hip prostheses.

Hyung Joon Yim,1,&ast; Ji Hoon Kim,2,&ast; Yong Kyun Cho,3 Young Oh Kweon,4 Hyun Chin Cho,5 Jae Seok Hwang,6 Changhyeong Lee,7 Moon Soo Koh,8 Yang-Hyun Baek,9 Young-Min Park,10 Jeong-Hoon Lee,11 Seung Up Kim,12 Min-Kyu Kang,13 Neung Hwa Park,14 June Sung Lee,15 Young Eun Chon,16 Gab Jin Cheon,17 Hee Bok Chae,18 Joo Hyun Sohn,19 Young-Suk Lim20 1Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Seoul, Korea; 2Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea; 3Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea; 4Department of Internal Medicine, Kyungpook National University, School of Medicine, Daegu, Korea; 5Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Korea; 6Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea; 7Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea; 8Department of Internal Medicine, Dongguk University Ilsan Hospital, College of Medicine, Dongguk University, Goyang, Korea; 9Department of Gastroenterology, DongA University College of Medicine, Busan, Korea; 10Department of Internal Medicine, Bundang Jesaeng General Hospital, Seongnam, Korea and Hepatology Center, Bundang Jesaeng General Hospital, Seongnam, Korea; 11Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea; 12Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea, and Yonsei Liver Center, Severance Hospital, Seoul, Korea; 13Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea; 14Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea; 15Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea; 16Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea; 17Department of Medicine, GangNeung Asan Hospital, Ulsan University College of Medicine, Gangwon-do, Korea; 18Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea; 19Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea, and Hanyang University Guri Hospital, Guri, Korea; 20Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea&ast;These authors contributed equally to this workCorrespondence: Young-Suk Lim, Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, 43-Gil 88, Olympic-Ro, Songpa-Gu, Seoul, Korea, Tel +82-2-3010-3190, Fax +82-2-485-5782, Email limys@amc.seoul.krPurpose: Tenofovir disoproxil (TD), modified from tenofovir disoproxil fumarate (TDF), was developed as a salt-free formulation, removing fumarate to improve the ease of oral intake by reducing the tablet’s size. We evaluated the maintenance of antiviral effects and overall safety profile of TD 245 mg after switching from TDF 300 mg in patients with chronic hepatitis B (CHB).Patients and Methods: CHB patients with HBV-DNA < 69 IU/mL after ≥ 24 weeks of TDF therapy were enrolled. The primary efficacy endpoint was the HBV-DNA suppression rate (HBV-DNA < 69 IU/mL) at week 48; We evaluated the non-inferiority (10% margin) of TD to TDF in terms of efficacy. Safety was assessed based on adverse events (AEs), laboratory tests, bone mineral density, and renal function abnormalities.Results: Overall, 189 subjects were randomized in a 2:1 ratio, and 117 and 66 subjects in the TD and TDF groups, respectively, completed the study. In the per-protocol set, the HBV-DNA suppression rate at week 48 was 99.1% and 100% in the TD and TDF groups, respectively. The lower limit of the 97.5% one-sided confidence interval for the intergroup difference in HBV-DNA suppression rate was − 2.8%, which was greater than the prespecified margin of non-inferiority. The changes in creatinine clearance from baseline to week 48 was significantly less in the TD group and in the TDF group; − 0.8 ± 9.8 versus − 2.4 ± 12.8 mL/min, respectively (P=0.017).Conclusion: TD was non-inferior to TDF for maintaining viral suppression in CHB patients, showing the less decline of renal function.Keywords: viral DNA, bone density, antiviral agents, viral suppression

In children with haemophilia (CwH), central venous access devices (CVADs) are frequently placed to aid in the delivery of factor concentrates. In those who develop inhibitors, CVADs also allow for easy venous access and facilitation of immune tolerance therapy.

This study aimed to examine the sleep habits in pairs of Japanese high school students and their mothers in the summer and autumn. Nineteen pairs of high school students and their mothers participated in this study. Wrist actigraphy, subjective sleep evaluations, and bedroom environmental measurements (temperature, humidity, and light) were performed for a duration of one week. The results of a split-plot analysis of variance revealed no significant difference in the actigraphically evaluated time spent in bed (TIB) between the seasons and between the mothers and students. The TIB was approximately 6 h on weekdays, and significantly lengthened to approximately 7 h on weekends (p < 0.05). The average sleep efficiency values recorded were higher than 90%. The mothers showed significantly advanced sleep phases compared to those of the students (p < 0.05). In addition, the waking time on Monday morning was significantly correlated between the mothers and students in the summer and autumn (p < 0.05). A perceived sleep loss “almost every day” or “several times per week” was reported by approximately half of the mothers and students in each season. The students occasionally fell into nocturnal sleep with the room light turned on. These results suggest that sleep hygiene education considering life habit characteristics is required to ensure sufficient sleep time.

Background: Athletes have changes that can mimic pathological cardiomyopathy. Methods: Echocardiographic study of 50 male, female athletes (MA, FA) and non-athletes (MNA, FNA) age 18 to 30 years. These athletes participate in sports with predominantly endurance component. All participants exhibit no known medical illnesses or symptoms. Results: MA have thicker wall (IVSd) than MNA. No MA have IVSd > 1.2 cm and no FA have IVSd > 1.0 cm. Left ventricle internal dimension (LVIDd), left ventricle end diastolic volume index (LVEDVi) is bigger in athletes. None have LVIDd > 5.8 cm. Right ventricle fractional area change (FAC) is lower in athletes. (MA vs MNA, p = 0.013, FA vs FNA, p = 0.025). Athletes have higher septal and lateral e’ (Septal e’; MA 13.57 ± 2.66 cm/s vs MNA 11.46 ± 2.93 cm/s, p 1.2 cm and/or LVIDd > 5.8 cm. There is no difference in GLS, RVFWS and GCS but athletes have smaller LArS and LAbS.

Small insects with flapping wings, such as bees and flies, have flexible wings with veins, and their compliant motion enhances flight efficiency and robustness. This study investigated the effects of integrating wing veins into soft wings for micro-flapping aerial vehicles. Prototypes of soft wings, featuring various wing areas and vein patterns in both the wing-chord and wing-span directions, were fabricated and evaluated to determine the force generated through flapping. The results indicated that the force is not solely dependent upon the wing area and is influenced by the wing vein pattern. Wings incorporating wing-chord veins produced more force compared to those with wing-span veins. In contrast, when the wing area was the specific wing area, wings with crossed wing veins, comprising both wing-span veins and wing-chord veins, produced more force. Although wing-chord veins tended to exert more influence on the force generated than the wing-span veins, the findings suggested that a combination of wing-span and wing-chord veins may be requisite, depending upon the wing area.

Summary: Bioconversion of lignin-related aromatic compounds relies on robust catabolic pathways in microbes. Sphingobium sp. SYK-6 (SYK-6) is a well-characterized aromatic catabolic organism that has served as a model for microbial lignin conversion, and its utility as a biocatalyst could potentially be further improved by genome-wide metabolic analyses. To this end, we generate a randomly barcoded transposon insertion mutant (RB-TnSeq) library to study gene function in SYK-6. The library is enriched under dozens of enrichment conditions to quantify gene fitness. Several known aromatic catabolic pathways are confirmed, and RB-TnSeq affords additional detail on the genome-wide effects of each enrichment condition. Selected genes are further examined in SYK-6 or Pseudomonas putida KT2440, leading to the identification of new gene functions. The findings from this study further elucidate the metabolism of SYK-6, while also providing targets for future metabolic engineering in this organism or other hosts for the biological valorization of lignin.

Owing to their complex structural design and control system, musculoskeletal robots struggle to execute complicated tasks such as turning with their limited range of motion. This study investigates the utilization of passive toe joints in the foot slip-turning motion of a musculoskeletal robot to turn on its toes with minimum movements to reach the desired angle while increasing the turning angle and its range of mobility. The different conditions of plantar intrinsic muscles (PIM) were also studied in the experiment to investigate the effect of actively controlling the stiffness of toe joints. The results show that the usage of toe joints reduced frictional torque and improved rotational angle. Meanwhile, the results of the toe-lifting angle show that the usage of PIM could contribute to preventing over-dorsiflexion of toes and possibly improving postural stability. Lastly, the results of ground reaction force show that the foot with different stiffness can affect the curve pattern. These findings contribute to the implementations of biological features and utilize them in bipedal robots to simplify their motions, and improve adaptability, regardless of their complex structure.

Abstract A cryptic lineage is a genetically diverged but morphologically unrecognized variant of a known species. Clarifying cryptic lineage evolution is essential for quantifying species diversity. In sympatric cryptic lineage divergence compared with allopatric divergence, the forces of divergent selection and mating patterns override geographical isolation. Introgression, by supplying preadapted or neutral standing genetic variations, can promote sympatric cryptic lineage divergence via selection. However, most studies concentrated on extant species introgression, ignoring the genetic legacy of introgression from extinct or unsampled lineages (“ghost introgression”). Cycads are an ideal plant for studying the influence of ghost introgression because of their common interspecific gene flow and past high extinction rate. Here, we utilized reference‐based ddRADseq to clarify the role of ghost introgression in the evolution of a previously identified sympatric cryptic lineage in Cycas revoluta. After re‐evaluating the evolutionary independency of cryptic lineages, the group‐wise diverged single‐nucleotide polymorphisms among sympatric and allopatric lineages were compared and functionally annotated. Next, we employed an approximate Bayesian computation method for hypothesis testing to clarify the cryptic lineage evolution and ghost introgression effect. SNPs with the genomic signatures of ghost introgression were further annotated. Our results reconfirmed the evolutionary independency of cryptic lineage among C. revoluta and demonstrated that ghost introgression to the noncryptic lineage facilitated their divergence. Gene function related to heat stress and disease resistance implied ecological adaptation of the main extant populations of C. revoluta.

Summary: The endoplasmic reticulum (ER) maintains an oxidative redox environment that is advantageous for the oxidative folding of nascent polypeptides entering the ER. Reductive reactions within the ER are also crucial for maintaining ER homeostasis. However, the mechanism by which electrons are supplied for the reductase activity within the ER remains unknown. Here, we identify ER oxidoreductin-1α (Ero1α) as an electron donor for ERdj5, an ER-resident disulfide reductase. During oxidative folding, Ero1α catalyzes disulfide formation in nascent polypeptides through protein disulfide isomerase (PDI) and then transfers the electrons to molecular oxygen via flavin adenine dinucleotide (FAD), ultimately yielding hydrogen peroxide (H2O2). Besides this canonical electron pathway, we reveal that ERdj5 accepts electrons from specific cysteine pairs in Ero1α, demonstrating that the oxidative folding of nascent polypeptides provides electrons for reductive reactions in the ER. Moreover, this electron transfer pathway also contributes to maintaining ER homeostasis by reducing H2O2 production in the ER.

Summary: Synaptic vesicle (SV) clusters, which reportedly result from synapsin’s capacity to undergo liquid-liquid phase separation (LLPS), constitute the structural basis for neurotransmission. Although these clusters contain various endocytic accessory proteins, how endocytic proteins accumulate in SV clusters remains unknown. Here, we report that endophilin A1 (EndoA1), the endocytic scaffold protein, undergoes LLPS under physiologically relevant concentrations at presynaptic terminals. On heterologous expression, EndoA1 facilitates the formation of synapsin condensates and accumulates in SV-like vesicle clusters via synapsin. Moreover, EndoA1 condensates recruit endocytic proteins such as dynamin 1, amphiphysin, and intersectin 1, none of which are recruited in vesicle clusters by synapsin. In cultured neurons, like synapsin, EndoA1 is compartmentalized in SV clusters through LLPS, exhibiting activity-dependent dispersion/reassembly cycles. Thus, beyond its essential function in SV endocytosis, EndoA1 serves an additional structural function by undergoing LLPS, thereby accumulating various endocytic proteins in dynamic SV clusters in concert with synapsin.

Background: Approaches to the prescription behavior of broad-spectrum antibiotics, including preauthorization and prospective audit and feedback (PAF), are a focus of antimicrobial stewardship (ASP). However, preprescription behavior, such as blood-culture collection before empiric prescription, is understudied and merits more attention given its influence on the usage of broad-spectrum antibiotics. At the University of Tokyo Hospital, carbapenems are subject to PAF, which has resulted in a compensatory increase in piperacillin-tazobactam use. To evaluate the inherent preprescription behavior associated with a broad-spectrum antibiotic, we investigated the initial blood-culture collection practices upon hospitalization in patients who were continued on empiric piperacillin-tazobactam. Methods: A retrospective observational study was conducted at the University of Tokyo Hospital, a tertiary-care hospital in Tokyo, Japan. Patients who were administered piperacillin-tazobactam on the day of hospitalization between April 2016 and December 2017 were included. Patients aged

Background Zooplankton plays an important role in the marine ecosystem. A high level of taxonomic expertise is necessary for accurate species identification based on morphological characteristics. As an alternative method to morphological classification, we focused on a molecular approach using 18S and 28S ribosomal RNA (rRNA) gene sequences. This study investigates how the accuracy of species identification by metabarcoding improves when taxonomically verified sequences of dominant zooplankton species are added to the public database. The improvement was tested by using natural zooplankton samples. Methods rRNA gene sequences were obtained from dominant zooplankton species from six sea areas around Japan and registered in the public database for improving the accuracy of taxonomic classifications. Two reference databases with and without newly registered sequences were created. Comparison of detected OTUs associated with single species between the two references was done using field-collected zooplankton samples from the Sea of Okhotsk for metabarcoding analysis to verify whether or not the newly registered sequences improved the accuracy of taxonomic classifications. Results A total of 166 sequences in 96 species based on the 18S marker and 165 sequences in 95 species based on the 28S marker belonging to Arthropoda (mostly Copepoda) and Chaetognatha were registered in the public database. The newly registered sequences were mainly composed of small non-calanoid copepods, such as species belonging to Oithona and Oncaea. Based on the metabarcoding analysis of field samples, a total of 18 out of 92 OTUs were identified at the species level based on newly registered sequences in the data obtained by the 18S marker. Based on the 28S marker, 42 out of 89 OTUs were classified at the species level based on taxonomically verified sequences. Thanks to the newly registered sequences, the number of OTUs associated with a single species based on the 18S marker increased by 16% in total and by 10% per sample. Based on the 28S marker, the number of OTUs associated with a single species increased by 39% in total and by 15% per sample. The improved accuracy of species identification was confirmed by comparing different sequences obtained from the same species. The newly registered sequences had higher similarity values (mean >0.003) than the pre-existing sequences based on both rRNA genes. These OTUs were identified at the species level based on sequences not only present in the Sea of Okhotsk but also in other areas. Discussion The results of the registration of new taxonomically verified sequences and the subsequent comparison of databases based on metabarcoding data of natural zooplankton samples clearly showed an increase in accuracy in species identification. Continuous registration of sequence data covering various environmental conditions is necessary for further improvement of metabarcoding analysis of zooplankton for monitoring marine ecosystems.

An analysis of the measured macroscopic withinwafer variations for threshold voltage (Vth) and on-current (Ion) over several technology generations (180 nm, 100 nm and 65 nm) is reported. It is verified that the dominant microscopic variations of the MOSFET device can be extracted quantitatively from these macroscopic variation data by applying the surface-potential compact model Hiroshima University STARC IGFET model 2 (HiSIM2), which is presently brought into industrial application. Only a small number of microscopic parameters, representing substrate doping (NSUBC), pocket-implantation doping (NSUBP), carrier-mobility degradation due to gate-interface roughness (MUESR1) and channel-length variation during the gate formation (XLD) are found sufficient to quantitatively reproduce the measured macroscopic within-wafer variations of Vth and Ion for all channel length Lg and all technology generations. Quantitative improvements from 180 nm to 65 nm are confirmed to be quite large for MUESR1 (about 70%) and Lmin(XLD) (55%) variations, related to the gate-oxide interface and the gate-stack structuring, respectively. On the other hand, doping-related technology advances, which are reflected by the variation magnitudes of NSUBC (30%) and NSUBP (25%), are found to be considerably smaller. Furthermore, specific combinations of extreme microscopic parameter-variation values are able to represent the boundaries of macroscopic fabrication inaccuracies for Vth and Ion. These combinations are found to remain identical, not only for all Lg of a given technology node, but also for all investigated technologies with minimum Lg of 180 nm, 100 nm and 65 nm.

C28H28O7, triclinic, P1‾ $P\overline{1}$ (no. 2), a = 11.0746(18) Å, b = 11.4312(17) Å, c = 11.552(2) Å, α = 77.148(8)°, β = 62.164(8)°, γ = 67.858(8)°, V = 1195.9(4) Å3, Z = 2, R gt(F) = 0.0522, wRref (F 2) = 0.1862, T = 223(2) K.

C20H14O3, triclinic, P1‾ $P\overline{1}$ (no. 2), a = 8.3085(10) Å, b = 8.3918(8) Å, c = 12.1359(14) Å, α = 91.691(5)°, β = 107.708(5)°, γ = 113.607(5)°, V = 727.42(14) Å3, Z = 2, R gt(F) = 0.0471, wRref (F 2) = 0.1235, T = 223(2) K.

C21H16O4, monoclinic, P21/n (no. 14), a = 13.531(6) Å, b = 8.390(3) Å, c = 14.288(5) Å, β = 95.322(15)°, V = 1615.1(11) Å3, Z = 4, Rgt (F) = 0.0588, wRref (F 2) = 0.1795, T = 243(2) K.

Household transmission is a primary source of SARS-CoV-2 spread. We used COVID-19 epidemiologic investigation data and viral genome analysis data collected in the city of Kyoto, Japan, during January 2020–June 2021 to evaluate the effects of different settings and viral strains on SARS-CoV-2 transmission. Epidemiologic investigations of 5,061 COVID-19 cases found that the most common category for close contact was within households (35.3%); this category also had the highest reverse transcription PCR positivity. The prevalent viral lineage shifted from B.1.1.214 in the third wave to the Alpha variant in the fourth wave. The proportion of secondary cases associated with households also increased from the third to fourth waves (27% vs. 29%). Among 564 contacts from 206 households, Alpha variant was significantly associated with household transmission (odds ratio 1.52, 95% CI 1.06–2.18) compared with B.1.1.214. Public health interventions targeting household contacts and specific variants could help control SARS-CoV-2 transmission.

Ian JY Wee,1 Fiona NN Moe,1 Rehena Sultana,2 Reiko WT Ang,1 Pearly PS Quek,3 Brian Kim Poh Goh,1 Chung Yip Chan,1 Peng Chung Cheow,1 Alexander YF Chung,1 Prema Raj Jeyaraj,1 Ye Xin Koh,1 Peter OP Mack,1 London Lucien PJ Ooi,1 Ek Khoon Tan,1 Jin Yao Teo,1 Juinn Huar Kam,1 Jacelyn SS Chua,1 Ashley WY Ng,1 Jade SQ Goh,1 Pierce KH Chow1,4 1Department of Hepatopancreatobiliary and Transplantation Surgery, Singapore General Hospital and National Cancer Centre Singapore, Singapore, Singapore; 2Center of Quantitative Medicine, Duke-NUS Medical School, Singapore, Singapore; 3Ministry of Health Holdings, Singapore, Singapore; 4Surgery Academic Clinical Program, Duke-NUS Medical School, Singapore, SingaporeCorrespondence: Pierce KH Chow, Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore, Tel +65 6576 2151, Email pierce.chow@duke-nus.edu.sgObjective: We aimed to prognosticate survival after surgical resection of HCC stratified by stage with amalgamation of the modified Barcelona Clinic Liver Cancer (BCLC) staging system and location of tumour.Methods: This single-institutional retrospective cohort study included patients with HCC who underwent surgical resection between 1st January 2000 to 30th June 2016. Participants were divided into 6 different subgroups: A-u) Within MC with Unilobar lesions; A-b) Within MC + Bilobar lesions; B1-u) Out of MC + within Up-To-7 + Unilobar lesions; B1-b) Out of MC + within Up-to-7 + Bilobar lesions; B2-u) Out of MC + Out of Up-To-7 + Unilobar lesions; B2-b) Out of MC + Out of Up-To-7 + Bilobar lesions. A separate survival analysis was conducted for solitary HCC lesions according to three subgroups: A-S (Within MC); B1-S (Out of MC + within Up-To-7); B2-S (Out of MC + out of Up-To-7).Results: A total of 794 of 1043 patients with surgical resection for HCC were analysed. Groups A-u (64.6%), A-b (58.4%) and B1-u (56.2%) had 5-year cumulative overall survival (OS) rates above 50% after surgical resection and median OS exceeding 60 months (P = 0.0001). The 5-year cumulative recurrence-free survival rates (RFS) were 40.4% (group A-u), 38.2% (group A-b), 36.3% (group B1-u), 24.6% (group B2-u), and 7.3% (group B2-b)(P=0.0001). For solitary lesions, the 5-year OS for the subgroups were A-S (65.1%), B1-S (56.0%) and B2-S (47.1%) (P = 0.0003). Compared to A-S, there was also a significant trend towards relatively poorer OS as the lesion sizes increased in B1-S (HR 1.46, 95% CI 1.03– 2.08) and B2-S (HR 1.65, 95% CI 1.25– 2.18).Conclusion: We adopted a novel approach combining the modified BCLC B sub-classification and dispersion of tumour to show that surgical resection in intermediate stage HCC can be robustly prognosticated. We found that size prognosticates resection outcomes in solitary tumours.Keywords: hepatocellular carcinoma, surgical resection, Barcelona clinic liver cancer

Abstract Abdominal aortic aneurysm (AAA) is a lethal disease, but no beneficial therapeutic agents have been established to date. Previously, we found that AAA formation is suppressed in microRNA (miR)-33-deficient mice compared with wild-type mice. Mice have only one miR-33, but humans have two miR-33 s, miR-33a and miR-33b. The data so far strongly support that inhibiting miR-33a or miR-33b will be a new strategy to treat AAA. We produced two specific anti-microRNA oligonucleotides (AMOs) that may inhibit miR-33a and miR-33b, respectively. In vitro studies showed that the AMO against miR-33b was more effective; therefore, we examined the in vivo effects of this AMO in a calcium chloride (CaCl2)-induced AAA model in humanized miR-33b knock-in mice. In this model, AAA was clearly improved by application of anti-miR-33b. To further elucidate the mechanism, we evaluated AAA 1 week after CaCl2 administration to examine the effect of anti-miR-33b. Histological examination revealed that the number of MMP-9-positive macrophages and the level of MCP-1 in the aorta of mice treated with anti-miR-33b was significantly reduced, and the serum lipid profile was improved compared with mice treated with control oligonucleotides. These results support that inhibition of miR-33b is effective in the treatment for AAA.

Abstract The intrinsic cardiovascular regulatory system (β, 0.00013–0.02 Hz) did not adapt to microgravity after a 6-month spaceflight. The infraslow oscillation (ISO, 0.01–0.10 Hz) coordinating brain dynamics via thalamic astrocytes plays a key role in the adaptation to novel environments. We investigate the adaptive process of a healthy astronaut during a 12-month-long spaceflight by analyzing heart rate variability (HRV) in the LF (0.01–0.05 Hz) and MF1 (0.05–0.10 Hz) bands for two consecutive days on four occasions: before launch, at 1-month (ISS01) and 11-month (ISS02) in space, and after return to Earth. Alteration of β during ISS01 improved during ISS02 (P = 0.0167). During ISS01, LF and MF1 bands, reflecting default mode network (DMN) activity, started to increase at night (by 43.1% and 32.0%, respectively), when suprachiasmatic astrocytes are most active, followed by a 25.9% increase in MF1-band throughout the entire day during ISS02, larger at night (47.4%) than during daytime. Magnetic declination correlated positively with β during ISS01 (r = 0.6706, P

The aim of this paper was to report the cases of 3 consecutive patients with mitogen-activated protein kinase kinase inhibitor (MEKi)-associated retinopathy with characteristic multiple serous retinal detachments (SRDs). A functional analysis of the retinal pigment epithelium was performed in 2 patients by electro-oculography (EOG). In all 3 patients, SRD lesions were observed in the posterior pole including the fovea of both eyes. Interestingly, neither obvious leakage in fluorescein/indocyanine angiography nor abnormal fundus autofluorescence was associated. SRDs and associated cystoid macular edema in one case rapidly resolved with the cessation of MEKi but recurred quickly after treatment resumption. In EOG tests, three of four eyes with multiple SRDs showed a marked decrease in the light-peak-to-dark-trough ratio (LP:DT ratio). The LP:DT ratio in EOG reflects the transepithelial potential of the retinal pigment epithelium, suggesting the involvement of disrupted tight junctions and impaired active transport of fluid/ions in MEKi-associated retinopathy. The latter may be the major cause of SRDs as we observed that fluid leakage in angiography was absent in the areas of the patients' SRDs.

Abstract Background In recent years, behaviourally driven policies such as nudges have been increasingly implemented to steer desired outcomes in public health. This study examines the different nudges and the socio-demographic characteristics and lifestyle behaviours that are associated with public acceptance of lifestyle nudges. Methods The study used data from the nationwide Knowledge, Attitudes and Practices study (KAP) on diabetes in Singapore. Three types of nudges arranged in increasing order of intrusiveness were examined: (1) information government campaigns, (2) government mandated information and (3) default rules and choice architecture. Acceptance was assessed based upon how much respondents ‘agreed’ with related statements describing heathy lifestyle nudges. Multivariable linear regressions were performed with socio-demographics and lifestyle behaviours using scores calculated for each nudge. Results The percentage of respondents who agreed to all statements related to each nudge were: 75.9% (information government campaigns), 73.0% (government mandated information), and 33.4% (default rules and choice architecture). Respondents of Malay/Others ethnicity (vs. Chinese) were more likely to accept information government campaigns. Respondents who were 18 – 34 years old (vs 65 years and above), female, of Malay/Indian ethnicity (vs Chinese), were sufficiently physically active, and with a healthier diet based on the DASH (Dietary Approach to Stop Hypertension) score were more likely to accept nudges related to government mandated information. Respondents of Malay/Indian ethnicity (vs Chinese), and who had a healthier diet were more likely to accept default rules and choice architecture. Conclusion Individuals prefer less intrusive approaches for promoting healthy lifestyle. Ethnicity and lifestyle behaviours are associated with acceptance of nudges and should be taken into consideration during the formulation and implementation of behaviourally informed health policies.

Abstract Aims There is a scarcity of data on the post‐discharge prognosis in acute heart failure (AHF) patients with a low‐income but receiving public assistance. The study sought to evaluate the differences in the clinical characteristics and outcomes between AHF patients receiving public assistance and those not receiving public assistance. Methods and results The Kyoto Congestive Heart Failure registry was a physician‐initiated, prospective, observational, multicentre cohort study enrolling 4056 consecutive patients who were hospitalized due to AHF for the first time between October 2014 and March 2016. The present study population consisted of 3728 patients who were discharged alive from the index AHF hospitalization. We divided the patients into two groups, those receiving public assistance and those not receiving public assistance. After assessing the proportional hazard assumption of public assistance as a variable, we constructed multivariable Cox proportional hazard models to estimate the risk of the public assistance group relative to the no public assistance group. There were 218 patients (5.8%) receiving public assistance and 3510 (94%) not receiving public assistance. Patients in the public assistance group were younger, more frequently had chronic coronary artery disease, previous heart failure hospitalizations, current smoking, poor medical adherence, living alone, no occupation, and a lower left ventricular ejection fraction than those in the no public assistance group. During a median follow‐up of 470 days, the cumulative 1 year incidences of all‐cause death and heart failure hospitalizations after discharge did not differ between the public assistance group and no public assistance group (13.3% vs. 17.4%, P = 0.10, and 28.3% vs. 23.8%, P = 0.25, respectively). After adjusting for the confounders, the risk of the public assistance group relative to the no public assistance group remained insignificant for all‐cause death [hazard ratio (HR), 0.97; 95% confidence interval (CI), 0.69–1.32; P = 0.84]. Even after taking into account the competing risk of all‐cause death, the adjusted risk within 180 days in the public assistance group relative to the no public assistance group remained insignificant for heart failure hospitalizations (HR, 0.93; 95% CI, 0.64–1.34; P = 0.69), while the adjusted risk beyond 180 days was significant (HR, 1.56; 95% CI, 1.07–2.29; P = 0.02). Conclusions The AHF patients receiving public assistance as compared with those not receiving public assistance had no significant excess risk for all‐cause death at 1 year after discharge or a heart failure hospitalization within 180 days after discharge, while they did have a significant excess risk for heart failure hospitalizations beyond 180 days after discharge. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02334891 (NCT02334891) and https://upload.umin.ac.jp/cgi‐open‐bin/ctr_e/ctr_view.cgi?recptno=R000017241 (UMIN000015238)

In this paper, we prove a new point-sphere incidence bound in vector spaces over finite fields. More precisely, let $P$ be a set of points and $S$ be a set of spheres in $\mathbb{F}_q^d$. Suppose that $|P|, |S|\le N$, we prove that the number of incidences between $P$ and $S$ satisfies \[ I(P, S)\le N^2q^{-1}+q^{\frac{d-1}{2}}N, \] under some conditions on $d, q$, and radii. This improves the known upper bound $N^2q^{-1}+q^{\frac{d}{2}}N$ in the literature. As an application, we show that for $A\subset \mathbb{F}_q$ with $q^{1/2}\ll |A|\ll q^{\frac{d^2+1}{2d^2}}$, one has \[ \max \left\lbrace |A+A|,~|dA^2|\right\rbrace \gg \frac{|A|^d}{q^{\frac{d-1}{2}}}. \] This improves earlier results on this sum-product type problem over arbitrary finite fields.

Understanding the association between subjective emotional experiences and physiological signals is of practical and theoretical significance. Previous psychophysiological studies have shown a linear relationship between dynamic emotional valence experiences and facial electromyography (EMG) activities. However, whether and how subjective emotional valence dynamics relate to facial EMG changes nonlinearly remains unknown. To investigate this issue, we re-analyzed the data of two previous studies that measured dynamic valence ratings and facial EMG of the corrugator supercilii and zygomatic major muscles from 50 participants who viewed emotional film clips. We employed multilinear regression analyses and two nonlinear machine learning (ML) models: random forest and long short-term memory. In cross-validation, these ML models outperformed linear regression in terms of the mean squared error and correlation coefficient. Interpretation of the random forest model using the SHapley Additive exPlanation tool revealed nonlinear and interactive associations between several EMG features and subjective valence dynamics. These findings suggest that nonlinear ML models can better fit the relationship between subjective emotional valence dynamics and facial EMG than conventional linear models and highlight a nonlinear and complex relationship. The findings encourage emotion sensing using facial EMG and offer insight into the subjective–physiological association.

Sila[1]ferrocenophane bearing a 9-silafluorenylidene moiety (1) as a bridging unit was synthesized and isolated as a stable crystalline compound. Sila[1]ferrocenophane 1, which was newly obtained in this study, was characterized by spectroscopic analyses, a single-crystal X-ray diffraction (SC-XRD) analysis, and electrochemical measurements. Due to the characteristic 9-silafluorenyl moiety, 1 exhibited large electron affinity and a slightly higher oxidation potential relative to that of ferrocene. In addition, 1 was found to undergo ring-opening polymerization (ROP) triggered by thermolysis at a lower temperature relative to that of Ph2Sifc (1′, fc = 1,1′-ferrocenylidene). It also underwent ROP through reduction by KC8 to give the corresponding polymeric compound. The DFT calculations suggested that one-electron reduction of 1 would promote ring-opening polymerization, as shown in the experimental results.

It has been suggested that the effect of coronavirus disease 2019 (COVID-19) booster vaccination in patients with B-cell non-Hodgkin’s lymphoma (B-NHL) is inferior to that in healthy individuals. However, differences according to histological subtype or treatment status are unclear. In addition, there has been less research on patients who subsequently develop breakthrough infections. We investigated the effects of the first COVID-19 booster vaccination for patients with B-NHL and the clinical features of breakthrough infections in the Omicron variant era. In this study, B-NHL was classified into two histological subtypes: aggressive lymphoma and indolent lymphoma. Next, patients were subdivided according to treatment with anticancer drugs at the start of the first vaccination. We also examined the clinical characteristics and outcomes of patients who had breakthrough infections after a booster vaccination. The booster effect of the COVID-19 mRNA vaccine in patients with B-NHL varied considerably depending on treatment status at the initial vaccination. In the patient group at more than 1 year after the last anticancer drug treatment, regardless of the histological subtype, the booster effect was comparable to that in the healthy control group. In contrast, the booster effect was significantly poorer in the other patient groups. However, of the 213 patients who received the booster vaccine, 22 patients (10.3%) were infected with COVID-19, and 18 patients (81.8%) had mild disease; these cases included the patients who remained seronegative. Thus, we believe that booster vaccinations may help in reducing the severity of Omicron variant COVID-19 infection in patients with B-NHL.

We present an [O/Fe] ratio of a luminous galaxy GN-z11 at z = 10.60 derived with the deep public JWST/NIRSpec data. We fit the medium-resolution grating (G140M, G235M, and G395M) data with the model spectra consisting of BPASS-stellar and Cloudy -nebular spectra in the rest-frame UV wavelength ranges with Fe absorption lines, carefully masking the other emission and absorption lines in the same manner as previous studies conducted for lower-redshift ( z ∼ 2–6) galaxies with oxygen abundance measurements. We obtain an Fe-rich abundance ratio $[{\rm{O}}/\mathrm{Fe}]=-{0.37}_{-0.22}^{+0.43}$ , which is confirmed with the independent deep prism data as well as by the classic 1978 index method. This [O/Fe] measurement is lower than that measured for star-forming galaxies at z ∼ 2–3. Because z = 10.60 is an early epoch after the Big Bang (∼430 Myr) and the first star formation (likely ∼200 Myr), it is difficult to produce Fe by Type Ia supernovae (SNe Ia), which requires sufficient delay time for white-dwarf formation and gas accretion. The Fe-rich abundance ratio in GN-z11 suggests that the delay time is short or that the major Fe enrichment is not accomplished by SNe Ia but by bright hypernovae (BrHNe) and/or pair-instability supernovae (PISNe), where the yield models of BrHNe and PISNe explain Fe, Ne, and O abundance ratios of GN-z11. The [O/Fe] measurement is not too low to rule out the connection between GN-z11 and globular clusters (GCs) previously suggested by the nitrogen abundance but rather supports the connection with a GC population at high [N/O] if a metal dilution process exists.

Some supernovae (SNe) are powered by the collision of the SN ejecta with dense circumstellar matter (CSM). Their emission spectra show characteristic line shapes of combined broad emission and narrow P Cygni lines, which should closely relate to the CSM structure and the mass-loss mechanism that creates the dense CSM. We quantitatively investigate the relationship between the line shape and the CSM structure by Monte Carlo radiative transfer simulations, considering two representative cases of dense CSM formed by steady and eruptive mass loss. Comparing the H α emission between the two cases, we find that a narrow P Cygni line appears in the eruptive case but does not appear in the steady case due to the difference in the velocity gradient in the dense CSM. We also reproduce the blueshifted photon excess observed in some Type IIn SNe, which is formed by photon transport across the shock wave, and find the relationship between the velocity of the shocked matter and the amount of blueshift of the photon excess. We conclude that the presence or absence of narrow P Cygni lines can distinguish the mass-loss mechanism and suggest high-resolution spectroscopic observations with λ /Δ λ ≳ 10 ^4 after the light-curve peak for applying this diagnostic method.

Halal tourism has increased and become a key tourism industry following the COVID-19 pandemic. Although this industry suffered greatly during the pandemic, it has made a promising return after the outbreak ended. Understanding how to sustain the tourism business in this recovering industry is critical. This study attempts to build a model of a sustainable strategy for the halal tourism industry from the tourist’s perspective, i.e., the tourists’ experience and their pleasure with the visit, by employing innovation and environmental concern as the determinants. Data from 442 inbound tourists visiting various Indonesian tourism destinations were used in this study. Using Partial Least Squares modelling, this study discovers that innovation and environmental concern are significant determinants of tourist experiences in tourism destinations, with innovation having a higher influence. Subsequently, tourist satisfaction is highly influenced by the attraction and halal products and services. Thus, this analysis implies that destination innovation and tourist concern for the environment are critical variables for the sustainable development of halal tourism.

To analyze various types of cold formability in TRIP-aided polygonal ferrite (TPF), annealed martensite (TAM), and bainitic ferrite (TBF) steels, the effects of the mean normal stress on the strain-hardening, strain-induced martensite transformation, and void-formation behaviors were investigated. The strain-hardening behavior was influenced by positive mean normal stress and was hardly influenced by zero and negative mean normal stresses in all steels. Positive mean normal stress promoted the strain-induced martensitic transformation behavior, especially in TBF steel due to the high mechanical stability of the retained austenite. The void-formation behavior was also promoted by positive mean normal stress, especially in TPF steel. These behaviors were also related to the microstructural properties, such as the matrix structure, retained austenite characteristics, and second phase.

We present gas-phase elemental abundance ratios of thirteen local extremely metal-poor galaxies (EMPGs), including our new Keck/LRIS spectroscopy determinations together with 33 James Webb Space Telescope z ∼ 4–10 star-forming galaxies in the literature, and compare chemical evolution models. We develop chemical evolution models with the yields of core-collapse supernovae (CCSNe), Type Ia SNe, hypernovae (HNe), and pair-instability supernovae (PISNe), and compare the EMPGs and high- z galaxies in conjunction with dust depletion contributions. We find that high Fe/O values of EMPGs can (cannot) be explained by PISN metal enrichments (CCSN/HN enrichments even with the mixing-and-fallback mechanism enhancing iron abundance), while the observed Ar/O and S/O values are much smaller than the predictions of the PISN models. The abundance ratios of EMPGs can be explained by the combination of Type Ia SNe and CCSNe/HNe whose inner layers of argon and sulfur mostly fallback, which are comparable to the Sculptor stellar chemical abundance distribution, suggesting that early chemical enrichment has taken place in the EMPGs. Comparing our chemical evolution models with the star-forming galaxies at z ∼ 4–10, we find that the Ar/O and S/O ratios of the high- z galaxies are comparable to those of the CCSN/HN models, while the majority of high- z galaxies do not have constraints good enough to rule out contributions from PISNe. The high N/O ratio recently reported in GN-z11 cannot be explained even by rotating PISNe, but could be reproduced by the winds of rotating Wolf–Rayet stars that end up as a direct collapse.