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Ruth Plummer,1 Alastair Greystoke,1 Gregory Naylor,2 Debashis Sarker,3,4 ANM Kaiser Anam,4 Hans Prenen,5 Laure-Anne Teuwen,5 Eric Van Cutsem,6 Jeroen Dekervel,6 Beate Haugk,1 Thomas Ness,1 Sujata Bhoi,7 Malene Jensen,7 Tom Morris,7 Pia Baumann,7 Niclas Sjögren,8 Karin Tunblad,7 Hans Wallberg,7 Fredrik Öberg,7 Thomas R Jeffry Evans2 1Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK; 2Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK; 3School of Cancer and Pharmaceutical Sciences, King’s College London, London, UK; 4Department of Medical Oncology, Guy’s Hospital, London, UK; 5Department of Oncology, Antwerp University Hospital, Edegem, Belgium; 6Department of Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium; 7Medivir AB, Huddinge, Sweden; 8SDS Life Science, Stockholm, SwedenCorrespondence: Pia Baumann, Medivir AB, Box 1086, SE-141 22, Huddinge, Sweden, Tel +46 739163897, Email pia.baumann@medivir.comPurpose: To evaluate safety, preliminary efficacy, pharmacokinetics, and pharmacodynamics, of fostroxacitabine bralpamide (fostrox, MIV-818), a novel oral troxacitabine nucleotide prodrug designed to direct exposure to the liver, while minimizing systemic toxicity.Patients and Methods: Fostrox monotherapy was administered in an open-label, single-arm, first-in-human, phase 1a/1b study, in patients with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, or solid tumor liver metastases. The first part (1a) consisted of intra/inter-patient escalating doses (3 mg to 70 mg) QD for up to 5 days, and the second part (1b), doses of 40 mg QD for 5 days, in 21-day cycles. Safety and tolerability were evaluated by the Safety Review Committee, and efficacy was assessed every 6 weeks with CT or MRI using RECIST 1.1 and mRECIST.Results: Nineteen patients were treated with fostrox. Most common adverse events (AEs) were hematological and increased AST. Grade 3 treatment related AEs (TRAE) were seen in 53% of the patients, with transient neutropenia and thrombocytopenia as the most common. No grade 5 AE was observed. Recommended Phase 2 dose of fostrox was 40 mg QD for 5 days in 21-day cycles. Preliminary efficacy showed a clinical benefit rate in the liver of 53% and stable disease (SD) as best response in 10 patients. Liver targeting with fostrox was confirmed with higher exposure of troxacitabine and its metabolites in liver compared to plasma. Systemic exposure of fostrox was generally low with troxacitabine as main analyte. Biopsies demonstrated tumor-selective, drug-induced DNA damage.Conclusion: The phase 1a/1b monotherapy study of fostrox, in patients with liver tumors, showed a tumor selective effect in the liver and that 40 mg QD for 5 days in 21-day cycles is safe and tolerable. Safety and preliminary efficacy in patients with advanced HCC supports clinical development of fostrox in combination with other modes of action in HCC.Keywords: phase 1, fostrox, hepatocellular carcinoma, nucleotide prodrug, pharmacokinetics, pharmacodynamics

Background and aimsDetailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis.Approach and resultsA targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p

Martin L Kårhus,1,* Anne-Marie Ellegaard,1,* Matilde Winther-Jensen,2 Susanne Hansen,2 Filip K Knop,1,3,4,* Line L Kårhus2,* 1Center for Clinical Metabolic Research, Copenhagen University Hospital – Herlev and Gentofte, Hellerup, Denmark; 2Center for Clinical Research and Prevention, Copenhagen University Hospital – Bispebjerg and Frederiksberg, Frederiksberg, Denmark; 3Steno Diabetes Center Copenhagen, Herlev, Denmark; 4Department of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark*These authors contributed equally to this workCorrespondence: Anne-Marie Ellegaard; Line L Kårhus, Email anne.marie.gade.ellegaard@regionh.dk; line.lund.kaarhus@regionh.dkObjective: Bile acid diarrhea (BAD) is a socially debilitating disease with frequent bowel movements, urgency, and fecal incontinence as the main symptoms. It is caused by excessive bile acid levels in the colon and is most commonly treated with bile acid sequestrants. It is estimated that 1– 2% of the population suffers from the disease, but only a fraction of these are properly diagnosed with the gold standard ⁷⁵selenium-homotaurocholic acid (SeHCAT) test. Here, we use nationwide registries to describe the demographic characteristics of individuals suffering from BAD in Denmark.Methods: Since the International Classification of Diseases diagnosis code for BAD was not used until 2021, we identified the BAD population by referral to SeHCAT testing followed by a prescription of a bile acid sequestrant (colestyramine, colestipol or colesevelam) within 365 days. The study period was from 2003 to 2021.Results: During the study period, a total of 5264 individuals with BAD were identified with large differences between the five regions in Denmark. The number of prescriptions of colestyramine and colesevelam, the number of SeHCAT tests, and the number of individuals diagnosed with BAD increased during the study period. The BAD population had more co-morbidities and more health care contacts as well as lower levels of education and income compared with age- and sex-matched controls from the general population.Conclusion: Using the Danish registries, we identified a BAD population, which seems to be inferior in health care and socio-economic parameters compared with the Danish general population.Keywords: Bile acid diarrhea, epidemiology, nationwide registries

Compact active transponders (CATs) – also termed electronic corner reflectors – are compact electronic devices designed to receive, actively amplify and re-transmit a radar signal, e.g. a C-band radar signal received from a Sentinel-1 satellite. CATs can potentially be useful for a number of purposes, e.g. if co-located with geodetic infrastructure. However, CATs have only recently become commercially available, and therefore, the usability and long-term performance of CATs are not well known. In this study, two CATs are tested under realistic operating conditions for a period of 14 months, from July 2020 to September 2021. The displacement time series of the CATs are determined from a persistent scatterers interferometric synthetic aperture radar processing of four tracks of Sentinel-1A/-1B data with a passive corner reflector (CR) as the spatial reference. The displacement time series of the CATs are evaluated against a ground truth established from repeated levellings between the CR and the CATs. Based on the results of this study, it is found that a sudden vertical displacement of a CAT can be determined with an accuracy better than 1 cm, possibly a few millimetres. Furthermore, it is found that the mean vertical velocity of a CAT, calculated from 14 months of interferometric synthetic aperture radar displacement time series, can be determined with an accuracy of a few mm/year. Finally, the line of sight (LoS) phase error is generally found to be moderately correlated with temperature, with an instrument-specific linear relationship between LoS error and temperature ranging between approx. 0.1 and 0.2 mm/°C. This correlation between LoS phase error and temperature can in principle be used for instrument-specific calibrations, which is a topic that should be addressed in future studies.

Although active learning improves student outcomes in science, technology, engineering, and mathematics (STEM) programs, it may provoke anxiety in some students. We examined whether two psychological variables, social anxiety (psychological distress relating to the fear of negative evaluation by others) and academic self-efficacy (confidence in one's ability to overcome academic challenges), interact with student perceptions of evidence-based instructional practices (EBIPs) and associate with their final grades in a STEM-related course. Human anatomy and physiology students in community college courses rated various EBIPs for their perceived educational value and their capacity to elicit anxiety (N = 227). In general, practices causing students the most anxiety (e.g., cold calling) were reported by students as having the least educational value. When controlling for students' self-reported grade point averages, socially anxious students rated several EBIPs as more anxiety inducing, whereas high-efficacy students reported less anxiety surrounding other EBIPs. Furthermore, mediation analysis revealed that individual differences in academic self-efficacy at the beginning of the term explained some of the negative association between students' social anxiety levels and final grades in the course. Our results, obtained in a community college context, support a growing body of evidence that social anxiety and academic self-efficacy are linked with how students perceive and perform in an active-learning environment.

The susceptibility of air quality, weather, terrestrial ecosystems, and climate to human activities was investigated in a tropical environment.

Evidence-based teaching is a highly complex skill, requiring repeated cycles of deliberate practice and feedback to master. Despite existing well-characterized frameworks for practice-based training in K-12 teacher education, the major principles of these frameworks have not yet been transferred to instructor development in higher educational contexts, including training of graduate teaching assistants (GTAs). We sought to determine whether a practice-based training program could help GTAs learn and use evidence-based teaching methods in their classrooms. We implemented a weekly training program for introductory biology GTAs that included structured drills of techniques selected to enhance student practice, logic development, and accountability and reduce apprehension. These elements were selected based on their previous characterization as dimensions of active learning. GTAs received regular performance feedback based on classroom observations. To quantify use of target techniques and levels of student participation, we collected and coded 160 h of video footage. We investigated the relationship between frequency of GTA implementation of target techniques and student exam scores; however, we observed no significant relationship. Although GTAs adopted and used many of the target techniques with high frequency, techniques that enforced student participation were not stably adopted, and their use was unresponsive to formal feedback. We also found that techniques discussed in training, but not practiced, were not used at quantifiable frequencies, further supporting the importance of practice-based training for influencing instructional practices.

Background: The negative consequences of prescription opioid misuse and opioid use disorder make it relevant to identify factors associated with this problem in individuals with chronic pain. This cross‐sectional study aimed at identifying subgroups of people with chronic pain based on their psychological profiles, prescription opioid misuse, craving, and withdrawal. Methods: The sample comprised 185 individuals with chronic pain. We performed hierarchical cluster analysis on impulsivity, anxiety sensitivity, pain acceptance, pain intensity, opioid misuse, craving, and withdrawal. Results: The four‐cluster solution was the optimal one. Misuse, craving, and anxiety sensitivity were higher among people in the Severe‐problems cluster than among people in the other three clusters. Withdrawal was the highest in the High‐withdrawal cluster. Impulsivity was higher among people in the Severe‐problems and High‐withdrawal clusters than those in the Moderate‐problems and Mild‐problems clusters. Pain acceptance was higher among people in the Mild‐problems cluster than among people in the other three clusters. Anxiety sensitivity and misuse were higher among people in the Moderate‐problems cluster than among people in the Mild‐problems cluster. Conclusions: These results support that impulsivity, anxiety sensitivity, and pain acceptance are useful constructs to identify subgroups of people with chronic pain according to their level of prescription opioid misuse, craving, and withdrawal. The results of this study may help in selecting the early intervention most suitable for each of the identified profiles. Significance: The psychological profile of individuals with chronic pain, prescription opioid misuse, craving, and withdrawal is characterized by fearing anxiety‐related symptoms due to the catastrophic interpretation of such symptoms and reacting impulsively to negative moods. In contrast, participants with high pain acceptance had less prescription opioid misuse, craving, and withdrawal. The profiles identified in this study could help clinicians select targets for intervention among profiles with similar needs and facilitate early interventions to prevent opioid misuse onset or aggravation. [ABSTRACT FROM AUTHOR]