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Abstract Background Varoglutamstat (formerly PQ912) is a small molecule that inhibits the activity of the glutaminyl cyclase to reduce the level of pyroglutamate-A-beta (pGluAB42). Recent studies confirm that pGluAB42 is a particular amyloid form that is highly synaptotoxic and plays a significant role in the development of AD. Methods This paper describes the design and methodology behind the phase 2b VIVIAD-trial in AD. The aim of this study is to evaluate varoglutamstat in a state-of-the-art designed, placebo-controlled, double-blind, randomized clinical trial for safety and tolerability, efficacy on cognition, and effects on brain activity and AD biomarkers. In addition to its main purpose, the trial will explore potential associations between novel and established biomarkers and their individual and composite relation to disease characteristics. Results To be expected early 2023 Conclusion This state of the art phase 2b study will yield important results for the field with respect to trial methodology and for the treatment of AD with a small molecule directed against pyroglutamate-A-beta. Trial registration ClinicalTrials.gov Identifier: NCT04498650

Objective: Dual amylin and calcitonin receptor agonists (DACRAs) are novel therapeutic agents that not only improve insulin sensitivity but also work as an adjunct to established T2DM therapies. DACRAs are currently administered once daily, though it is unknown whether DACRAs with increased plasma half-life can be developed as a once-weekly therapy. Methods: The in vitro potencies of the KBP-066A and KBP-066 (non-acylated) were assessed using reporter assays. Acylation functionality was investigated by a combination of pharmacokinetics and acute food intake in rats. in vivo efficacies were investigated head-to-head in obese (HFD) and T2D (ZDF) models. Results: In in vitro, KBP-066A activated the CTR and AMY-R potently, with no off-target activity. Acylation functionality was confirmed by acute tests, as KBP-066A demonstrated a prolonged PK and PD response compared to KBP-066. Both compounds induced potent and dose-dependent weight loss in the HFD rat model. In ZDF rats, fasting blood glucose/fasting insulin levels (tAUC) were reduced by 39%/50% and 36%/47% for KBP-066 and KBP-066A, respectively. This effect resulted in a 31% and 46% vehicle-corrected reduction in HbA1c at the end of the study for KBP-066 and KBP-066A, respectively. Conclusions: Here, we present pre-clinical data on an acylated DACRA, KBP-066A. The in vivo efficacy of KBP-066A is significantly improved compared to its non-acylated variant regarding weight loss and glycemic control in obese (HFD) and obese diabetic rats (ZDF). This compendium of pre-clinical studies highlights KBP-066A as a promising, once-weekly therapeutic agent for treating T2DM and obesity.

Two Doppler imaging systems (DIS) or wide-field imaging Fabry-Perot interferometers (FPI), have recently been commissioned, one at the Auroral Station, Adventdalen, Longyearbyen, Svalbard, and the second at the IRF, Kiruna, Sweden. These instruments can provide wide-field (600 * 800 km) images of neutral wind flows in the upper thermosphere, by measuring the Doppler shift of the atomic oxygen forbidden near 630 nm, which is emitted from an altitude of approximately 240 km. From the instrument in Svalbard, at mid-winter, it is possible to observe the dayside polar cusp and the polar cap throughout the entire day, whereas from Kiruna, the night-time auroral oval is observable during the hours of darkness. Measurements of thermospheric dynamics from the DIS can be used in conjunction with observations of ionospheric plasma flows and thermal plasma densities by the EISCAT-Svalbard radar (ESR) and by EISCAT, along with other complementary observations by co-located instruments such as the auroral large-scale imaging system (ALIS). Such combined data sets will allow a wide range of scientific studies to be performed concerning the dynamical response of the thermosphere and ionosphere, and the important energetic and momentum exchange processes resulting from their complex interactions. These processes are particularly important in the immediate vicinity of the polar cusp and within the auroral oval. Early results from Svalbard in late 1995 will be discussed. The DIS in Kiruna observed two interesting geomagnetic disturbances in early 1997, the minor geomagnetic storm of 10, 11 January, and the disturbed period from 7–10 February. During these events, the thermospheric wind response showed some interesting departures from the average behaviour, which we attribute to the result of strong and variable Lorenz forcing (ion drag) and Joule and particle heating during these geomagnetic disturbances.Key words. Ionosphere (Polar ionosphere) · Meteorology and atmospheric dynamics (thermospheric dynamics; instruments and techniques).

The lidar measurements at Verhnetulomski observatory (68.6°N, 31.8°E) at Kola peninsula detected a considerable increase of stratospheric aerosol concentration after the solar proton event of GLE (ground level event) type on the 16/02/84. This increase was located at precisely the same altitude range where the energetic solar protons lost their energy in the atmosphere. The aerosol layer formed precipitated quickly (1–2 km per day) during 18, 19, and 20 February 1984, and the increase of R(H) (backscattering ratio) at 17 km altitude reached 40% on 20/02/84. We present the model calculation of CN (condensation nuclei) altitude distribution on the basis of an ion-nucleation mechanism, taking into account the experimental energy distribution of incident solar protons. The meteorological situation during the event was also investigated.

In this article, we discuss how quantum physics and relativity can be taught in upper secondary school, in ways that promote conceptual understanding and philosophical reflections. We present the ReleQuant project, in which web-based teaching modules have been developed. The modules address competence aims in the Norwegian national curriculum for physics (final year of upper secondary education), which is unique in that it includes general relativity, entangled photons and the epistemological consequences of modern physics. These topics, with their high demands on students’ understanding of abstract and counter-intuitive concepts and principles, are challenging for teachers to teach and for students to learn. However, they also provide opportunities to present modern physics in innovative ways that students may find motivating and relevant both in terms of modern technological applications and in terms of contributions to students’ intellectual development. Beginning with these challenges and opportunities, we briefly present previous research and theoretical perspectives with relevance to student learning and motivation in modern physics. Based on this, we outline the ReleQuant teaching approach, where students use written and oral language and a collaborative exploration of animations and simulations as part of their learning process. Finally, we present some of the first experiences from classroom tests of the quantum physics modules. [ABSTRACT FROM AUTHOR]

The use of electronic audience response systems (ARS) in undergraduate science instruction is increasing. In this article, we argue for combining such a teaching approach with a more active use of student small-group discussions, demonstrating with examples from a Norwegian physics course how 'talking physics' is central to the development of understanding and can be used to enhance learning in ARS classrooms. [ABSTRACT FROM AUTHOR]

In this paper we describe a teaching approach focusing on modelling in physics, emphasizing scientific reasoning based on empirical data and using the notion of multiple representations of physical phenomena as a framework. We describe modelling activities from a project (PHYS 21) and relate some experiences from implementation of the modelling approach in Norwegian upper secondary physics classrooms. [ABSTRACT FROM AUTHOR]

Science teacher knowledge and skills have been thoroughly discussed by researchers; however, less is known about how teachers themselves conceptualise their professional qualities. We asked first and final-year pre-service science teachers and in-service physics teachers to describe the knowledge and skills needed to be a good science/physics teacher. Data was collected through a one-item questionnaire, followed by interviews. Using thematic coding with inductively defined codes as well as codes derived from theoretical perspectives on teacher knowledge and skills (notably the Refined Consensus Model of PCK), we found that all respondent groups emphasised science content knowledge as important. In-service teachers also often described external factors such as working conditions. First-year pre-service teachers put more emphasis on pedagogical skills and personality traits, whereas final-year pre-service teachers expressed a more integrated view of science teacher knowledge and skills. Further, we discuss the need for teacher education to focus on integrating science content knowledge and pedagogical knowledge through articulating aspects of PCK, and on giving pre- and in-service teachers arenas for professional development and for research-based discussions of teaching and learning.

Quantum physics and relativity are demanding for teachers and students, but have the potential for students to experience physics as fascinating and meaningful. Project ReleQuant engaged in educational design research to improve teaching and learning in these topics in Norwegian upper secondary schools. The paper focuses on the first cycle of development of a teaching module on quantum physics and how design principles were developed. We construct the design principles by reviewing relevant research literature and conducting three pilot studies. The process resulted in the following principles for designing the quantum physics teaching module: 1) clarify how quantum physics breaks with classical physics; 2) use simulations of phenomena that cannot be experienced directly; 3) provide students to use written and oral language; 4) address and discuss wave-particle duality and the uncertainty

Athletes' stories about their experiences in elite sport inevitably evoke the notion of meaning, a concept, which has appeared in many shapes and forms within sport psychology. Qualitative scholarship, for example, has generated a large literature base on the meaning of experience (i.e., implicit meaning) in elite sport. However, the experience of meaning(fulness) (i.e., existential meaning) has received less scholarly attention and has rarely been the explicit study object. To assist theorizing and the empirical investigation of meaning and purpose in elite sport in these early stages, we take stock of the emerging body of literature in sport psychology. The article has three parts: Firstly, we distinguish between implicit and existential meaning to delineate our study object. Secondly, we introduce psychological theory to show how existential meaning can be conceptualized (e.g., dimensions, sources, crisis of meaning). Thirdly, we analyzed 23 studies in a narrative review approach to understand how meaning (n = 17) and purpose (n = 6) in elite sport have been understood, and what we know about these concepts empirically. The current scholarship revealed itself heterogenous in terms of study designs, methodologies, theoretical frameworks, and conceptualizations of meaning and purpose. Findings are discussed in eight overarching themes (e.g., moments when meaning and purpose are questioned; as mechanism and indicator of growth following adversity) to map the reviewed literature comprehensibly and to provide a foundation for applied work. The article concludes by highlighting unresolved issues and proposing future directions for studying and applying existential meaning in elite sport., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Parkinson's Disease (PD) is a progressive neurodegenerative condition, which is highly heterogeneous upon diagnosis. Brain extracellular matrix (ECM) accounts for 10-20 % of the total brain volume and is responsible for the physical organization of neuronal and glia cells. Blood-based biomarkers quantifying ECM fragments holds the potential as diagnostic and prognostic biomarkers. Here we evaluated the serum ECM biomarkers C1M, C4M, TUM, SPARC-M and BGM in healthy donors and patients diagnosed with PD. The biomarkers were able to separate between healthy donors and PD patients with an AUC up to 0.926. These pathologically relevant biomarkers could be used as biomarkers in clinical management., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Numerous factors have been identified that potentially influence athletes' mental health. Given the predominant focus in the literature on athletes' mental health risk factors, our study aimed to explore elite athletes' perceptions of factors associated with their mental health and thriving based on the combination of holistic developmental and ecological approaches., Methods: Seven Danish international elite athletes representing diverse sports were interviewed twice. The initial interview delved into their retrospective perspectives on career and mental health development, while the subsequent interview, conducted two months later, centered on recent events., Results: Thematic analysis yielded a map outlining four overarching themes. Elite sport was perceived as a (1) relentless performance context marked by rigorous demands, which evoked (2) personal reactions among athletes characterized by heightened expectations, self-blame, and anxiety. In response to these challenging demands, athletes have cultivated (3) coping resources and strategies over the course of their careers, such as self-reflection, emphasis on recovery, planning and prioritization skills, and passion for their sport. Nonetheless, the development of these resources and strategies was a gradual process, often informed by past experiences of mental health difficulties during adolescence. Additionally, they have found support for their mental health within a (4) nurturing environment consisting of supportive coaching, camaraderie among teammates, guidance from experts, and caring relationships., Discussion: The findings of this study highlight the complex interplay of factors affecting mental health and emphasize the need for creating supportive environments that help athletes manage the intense demands of elite sport., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Küttel, Storm, Stambulova and Henriksen.)

Purpose: Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus and a leading cause of chronic kidney disease and end-stage renal disease. One potential mechanism underlying cellular dysfunction contributing to kidney disease is aberrant protein post-translational modifications. Lysine acetylation is associated with cellular metabolic flux and is thought to be altered in patients with diabetes and dysfunctional renal metabolism., Experimental Design: A novel extraction and LC-MS/MS approach was adapted to quantify sites of lysine acetylation from formalin-fixed paraffin-embedded (FFPE) kidney tissue and from patients with DKD and non-diabetic donors (n = 5 and n = 7, respectively)., Results: Analysis of FFPE tissues identified 840 total proteins, with 225 of those significantly changing in patients with DKD. Acetylomic analysis quantified 289 acetylated peptides, with 69 of those significantly changing. Pathways impacted in DKD patients revealed numerous metabolic pathways, specifically mitochondrial function, oxidative phosphorylation, and sirtuin signaling. Differential protein acetylation in DKD patients impacted sirtuin signaling, valine, leucine, and isoleucine degradation, lactate metabolism, oxidative phosphorylation, and ketogenesis., Conclusions and Clinical Relevance: A quantitative acetylomics platform was developed for protein biomarker discovery in formalin-fixed and paraffin-embedded biopsies of kidney transplant patients suffering from DKD., (© 2024 Wiley‐VCH GmbH.)

Background: Rehabilitation following traumatic knee injury often focuses primarily on physical aspects. Lack of knowledge of psychological factors and appropriate strategies may be a barrier to meeting treatment recommendations to address these factors., Purpose: The aim of this study was to investigate whether, and to what extent, Scandinavian physical therapists address psychological factors in treatment of physically active people with traumatic knee injury., Study Design: Cross-sectional online survey study., Methods: This 32-item study-specific online survey examined physical therapists' use of goal-setting, imagery, and arousal regulation to address psychological factors during rehabilitation following traumatic knee injury., Results: Results from n=143 physical therapists indicate that they consider it very important to use goal-setting (median 4 [IQR 1]), imagery (median 4 [IQR 1]), and stress management (median 4 [IQR 1]) during rehabilitation on a scale of 1 (lowest) to 5 (highest). Goal-setting was used by n=143 (100%); imagery by n=67 (47%), and arousal regulation by 76 (53%). Lack of knowledge was the most commonly cited reason for not using imagery (n=61; 43%) and arousal regulation (n=55; 38%). Participants rated workshops, courses, or formal education as the most useful methods of learning to use psychological skills training in clinical work., Conclusion: Goal-setting is commonly used by Scandinavian physical therapists. However, only approximately half of participants report using imagery and/or arousal regulation in knee injury rehabilitation. This may indicate that best-evidence recommendations for treatment are not being met. Future research should explore methods for providing education and practical strategies for encouraging clinical use of psychological interventions., Level of Evidence: 3., Competing Interests: The authors declare no conflicts of interest., (© The Author(s).)

It is an open question to which degree compassion-noticing, engaging with, and acting to alleviate suffering in self and others-is (considered) advantageous in elite sports. Addressing this question, we herein provide insights into high-performance coaches' perceptions on the role of compassion in elite sports environments. Specifically, 12 coaches working at the highest level of their respective sport (in Denmark) partook in semi-structured interviews focusing on the utilization, implications, as well as barriers for implementing compassion in elite sports environments. Following a thematic analysis, three themes comprising various subthemes were identified and discussed. The first theme - Benefits of compassion - focuses on coaches' perception of the use and implications of compassion and comprises four subthemes: Compassion is important when times are tough; Compassion stimulates human connection; Compassion fosters unity in competitive environments; and Compassion promotes performance. The second theme - Increasing compassionate competence - focuses on how a compassionate approach can flourish and comprises three subthemes: Reflection; Awareness and knowledge; and Keeping up with the times. The third theme - Barriers to compassion - focuses on barriers to implementing and enhancing compassion in elite sports environments and comprises four subthemes: Compassion is soft; Power dynamics can stand in the way; Requires prioritization; and Performance outcome orientation. We conclude that while compassion (beyond self-compassion) can be beneficial in elite sports, coaches still perceive barriers for successful implementation, and that research should further investigate the outcomes and consequences of compassion in the elite sport context., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: Dual amylin and calcitonin receptor agonists (DACRAs) are therapeutic candidates in the treatment of obesity with beneficial effects on weight loss superior to suppression of food intake. Hence, suggesting effects on energy expenditure by possibly targeting mitochondria in metabolically active tissue., Methods: Male rats with HFD-induced obesity received a DACRA, KBP-336, every third day for 8 weeks. Upon study end, mitochondrial respiratory capacity (MRC), - enzyme activity, - transcriptional factors, and -content were measured in perirenal (pAT) and inguinal adipose tissue. A pair-fed group was included to examine food intake-independent effects of KBP-336., Results: A vehicle-corrected weight loss (23.4 ± 2.8%) was achieved with KBP-336, which was not observed to the same extent with the food-restricted weight loss (12.4 ± 2.8%) (P < 0.001). Maximal coupled respiration supported by carbohydrate and lipid-linked substrates was increased after KBP-336 treatment independent of food intake in pAT (P < 0.01). Moreover, oligomycin-induced leak respiration and the activity of citrate synthase and β-hydroxyacetyl-CoA-dehydrogenase were increased with KBP-336 treatment (P < 0.05). These effects occurred without changes in mitochondrial content in pAT., Conclusions: These findings demonstrate favorable effects of KBP-336 on MRC in adipose tissue, indicating an increased energy expenditure and capacity to utilize fatty acids. Thus, providing more mechanistic insight into the DACRA-induced weight loss., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for the treatment of type 2 diabetes and obesity due to their beneficial effects on body weight, glucose control, and insulin action. However, how the metabolic benefits are maintained after long-lasting treatment is unknown. This study investigates the long-term anti-obesity and anti-diabetic treatment efficacy of the DACRA KBP-336 alone and combined with the GLP-1 analog semaglutide. Zucker diabetic Sprague Dawley (ZDSD) rats with obesity and diabetes received KBP-336 (4.5 nmol/kg Q3D), semaglutide (50 nmol/kg Q3D), or the combination for 7 mo, and the treatment impact on body weight, food intake, glucose control, and insulin action was evaluated. Furthermore, serum levels of the cardiac fibrosis biomarker endotrophin were evaluated. KBP-336, semaglutide, and the combination lowered body weight significantly compared with the vehicle, with the combination inducing a larger and more sustained weight loss than either monotherapy. All treatments resulted in reduced fasting blood glucose levels and HbA1c levels and improved glucose tolerance compared with vehicle-treated rats. Furthermore, all treatments protected against lost insulin secretory capacity and improved insulin action. Serum levels of endotrophin were significantly lowered by KBP-336 compared with vehicle. This study shows the benefit of combining KBP-336 and semaglutide to obtain significant and sustained weight loss, as well as improved glucose control. Furthermore, KBP-336-driven reductions in circulating endotrophin indicate a clear reduction in the risk of complications. Altogether, KBP-336 is a promising candidate for the treatment of obesity and type 2 diabetes both alone and in combination with GLP-1 analogs. NEW & NOTEWORTHY These studies describe the benefit of combining dual amylin and calcitonin receptor agonists (DACRA) with semaglutide for long-term treatment of obesity and type 2 diabetes. Combination treatment induced sustained weight loss and improved glucose control. A DACRA-driven reduction in a serological biomarker of cardiac fibrosis indicated a reduced risk of complications. These results highlight DACRAs as a promising candidate for combination treatment of obesity and type 2 diabetes and related long-term complications.

Background: Despite the extensive research to provide a disease-modifying osteoarthritis drug (DMOAD), there is still no approved DMOAD. Dual amylin and calcitonin receptor agonists (DACRA) can provide metabolic benefits along with antinociceptive and potential structural preserving effects. In these studies, we tested a DACRA named KBP-336 on a metabolic model of OA in meniscectomised (MNX) rats., Methods: We evaluated KBP-336's effect on pain-like symptoms in Sprague Dawley (SD) rats on high-fat diet (HFD) that underwent meniscectomy using the von Frey test to measure the 50% paw withdrawal threshold (PWT) and analyzed using one-way ANOVA. Short in vivo studies and in vitro cell receptor expression systems were used to illustrate receptor pharmacology., Results: After 30 weeks on HFD, including an 8-week treatment, female MNX animals receiving KBP-336 4.5 nmol/Kg/72 h had lower body weight and smaller adipose tissues than their vehicle-treated counterparts. After 20 weeks on HFD, including an 8-week treatment, male rats receiving KBP-336 had lower body weight than the vehicle group. In both the female and male rats, the MNX groups on KBP-336 treatment had a higher PWT than the vehicle-treated MNX group. Aiming to identify the receptor influencing pain alleviation, KBP-336 was compared to the long-acting human calcitonin (hCTA). Single-dose studies on 12-week-old male rats showed that hCTA lowers CTX-I without affecting food intake, confirming its calcitonin receptor selectivity. On the metabolic OA model with 18 weeks of HFD, including 6-week treatment, hCTA at 100 nmol/Kg/24 h and KBP-336 at 0.5, 1.5, and 4.5 nmol/Kg/72 h produced significantly higher PWT in MNX animals compared to MNX animals on vehicle treatment. hCTA and KBP-336 at 0.5 nmol/Kg did not affect body weight and fat tissues., Conclusion: Overall, KBP-336 improved the pain observed in the metabolic OA model. Calcitonin receptor activation proved to be essential in this antinociceptive effect., (© 2024. The Author(s).)

Background: During the initial wave of the COVID-19 pandemic, there was a surprisingly low incidence of SARS-CoV-2 among People Who Use Drugs (PWUD) in Oslo, Norway, despite their heightened vulnerability regarding risk of infection and severe courses of the disease.This study aims to investigate the seroprevalence of SARS-CoV-2 antibodies among PWUD, their antibody responses to relevant virus infections and COVID-19 mRNA vaccines, and their vaccination coverage compared to the general population., Methods: Conducted as a prospective cohort study, data was collected from residents in six institutions for homeless PWUD and users of a low-threshold clinic for opioid agonist treatment. Ninety-seven participants were recruited for SARS-CoV-2 seroprevalence analysis. Additional two participants with known positive SARS-CoV-2 test results were recruited for further analyses. Twenty-five participants completed follow-up. Data included questionnaires, nasal swabs and blood samples. Data on vaccination coverage was obtained from the National Vaccine Register. Serologic methods included detection of antibodies to relevant virus proteins, neutralizing antibodies to SARS-CoV-2, antibodies to the full-length spike protein, and receptor-binding domain from SARS-CoV-2., Results: Among PWUD, antibodies to SARS-CoV-2 were detected in 2 out of 97 samples before vaccines against SARS-CoV-2 were available, comparable to a 2.8% frequency in population-based screening. Levels of serum antibodies to seasonal coronaviruses and Epstein-Barr-Virus (EBV) in PWUD were similar to population-based levels. After the second vaccine dose, binding and neutralizing antibody levels to SARS-CoV-2 in PWUD were comparable to controls. Eighty-four of PWUD received at least one dose of COVID-19 mRNA vaccine, compared to 89% in the general population., Conclusion: Results indicate that PWUD did not exhibit increased SARS-CoV-2 seroprevalence or elevated serum antibodies to seasonal coronaviruses and EBV. Moreover, vaccine responses in PWUD were comparable to controls, suggesting that vaccination is effective in conferring protection against SARS-CoV-2 also in this population., (© 2024. The Author(s).)

Background and Purpose: Insulin therapies for Type 1 diabetes (T1D) have limitations, such as glucose fluctuations, hypoglycaemia, and weight gain. Only pramlintide is approved with insulin. However, its short half-life limits efficacy, requiring multiple daily injections and increasing hypoglycaemia risk. New strategies are needed to improve glycaemic control. Dual amylin and calcitonin receptor agonists are potent insulin sensitizers developed for Type 2 diabetes (T2D) as they improve glucose control, reduce body weight, and attenuate hyperglucagonemia. However, it is uncertain if they could be used to treat T1D., Experimental Approach: Sprague Dawley rats received a single intravenous injection of streptozotocin (STZ) (50 mg·kg -1 ) to induce T1D. Humulin (1 U/200 g·day -1 or 2 U/200 g·day -1 ) was continuously infused, while half of the rats received additional KBP-336 (4.5 nmol·kg -1 Q3D) treatment. Bodyweight, food intake, and blood glucose were monitored throughout the study. An oral glucose tolerance test was performed during the study., Key Results: Treatment with Humulin or Humulin + KBP-336 improved the health of STZ rats. Humulin increased body weight in STZ rats, but KBP-336 attenuated these increases and maintained a significant weight loss. The combination exhibited greater blood glucose reductions than Humulin-treated rats alone, reflected by improved HbA1c levels and glucose control. The combination prevented hyperglucagonemia, reduced amylin levels, and increased pancreatic insulin content, indicating improved insulin sensitivity and beta-cell preservation., Conclusion and Implications: The insulin sensitizer KBP-336 lowered glucagon secretion while attenuating insulin-induced weight gain. Additionally, KBP-336 may prevent hypoglycaemia and improve insulin resistance, which could be a significant advantage for individuals with T1D seeking therapeutic benefits., (© 2024 British Pharmacological Society.)

Our overview covers several key areas related to recent results obtained for collagen type VI and endotrophin (ETP). (1) An introduction to the history of ETP, including how it was identified, how it is released, and its function and potential receptors. (2) An introduction to the collagen family, with a focus on what differentiates collagen type VI from an evolutionary standpoint. (3) An overview of collagen type VI, the 6 individual chains (COL6A1, A2, A3, A4, A5, and A6), their differences and similarities, as well as their expression profiles and function. (4) A detailed analysis of COL6A3, including the cleaved product endotrophin, and what separates it from the other 5 collagen 6 molecules, including its suggested function based on insights gained from knockout and gain of function mouse models. (5) The pathology of ETP. What leads to its presence and release and what are the consequences thereof? (6) Functional implications of circulating ETP. Here we review the data with the functional roles of ETP in mind. (7) We propose that ETP is a mediator for fibrotic (or fibroinflammatory) disorders. Based on what we know about ETP, we have to consider it as a target for the treatment of fibrotic (or fibroinflammatory) disorders. What segment(s) of the patient population would most dramatically respond to an ETP-targeted intervention? How can we find the population that would profit most from an intervention? We aim to present a broad overview over the ETP field at large, providing an assessment of where the future research efforts need to be placed to tap into the vast potential of ETP, both as a marker and as a target in different diseases., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

People who use drugs (PWUD) are at a high risk of contracting and developing severe coronavirus disease 2019 (COVID-19) and other infectious diseases due to their lifestyle, comorbidities, and the detrimental effects of opioids on cellular immunity. However, there is limited research on vaccine responses in PWUD, particularly regarding the role that T cells play in the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we show that before vaccination, PWUD did not exhibit an increased frequency of preexisting cross-reactive T cells to SARS-CoV-2 and that, despite the inhibitory effects that opioids have on T-cell immunity, standard vaccination can elicit robust polyfunctional CD4 + and CD8 + T-cell responses that were similar to those found in controls. Our findings indicate that vaccination stimulates an effective immune response in PWUD and highlight targeted vaccination as an essential public health instrument for the control of COVID-19 and other infectious diseases in this group of high-risk patients., Competing Interests: Authors MG, RS, ST, BM and TC were employed by company NEC OncoImmunity AS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gainullin, Federico, Røkke Osen, Chaban, Kared, Alirezaylavasani, Lund-Johansen, Wildendahl, Jacobsen, Sarwar Anjum, Stratford, Tennøe, Malone, Clancy, Vaage, Henriksen, Wüsthoff and Munthe.)

Objective: Dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonists are therapeutic agents with an interesting liver-specific mode of action suitable for metabolic complications. In this study, dual GLP-1 and glucagon receptor agonist OXM-104 is compared head-to-head with the once-daily dual GLP-1 and glucagon receptor agonist cotadutide and GLP-1 receptor agonist semaglutide to explore the metabolic efficacy of OXM-104., Methods: The in vitro potencies of OXM-104, cotadutide and semaglutide were assessed using reporter assays. In addition, in vivo efficacy was investigated using mouse models of diet-induced obesity (DIO mice), diabetes (db/db mice) and diet-induced NASH mice (MS-NASH)., Results: OXM-104 was found to only activate the GLP-1 and glucagon with no cross-reactivity at the (GIP) receptor. Cotadutide was also found to activate the GLP-1 and glucagon receptors, whereas semaglutide only showed activity at the GLP-1 receptor. OXM-104, cotadutide, and semaglutide elicited marked reductions in body weight and improved glucose control. In contrast, hepatoprotective effects, i.e., reductions in steatosis and fibrosis, as well as liver fibrotic biomarkers, were more prominent with OXM-104 and cotadutide than those seen with semaglutide, demonstrated by an improved NAFLD activity score (NAS) by OXM-104 and cotadutide, underlining the importance of the glucagon receptor., Conclusion: These results show that dual GLP-1 and glucagon receptor agonism is superior to GLP-1 alone. OXM-104 was found to be a promising therapeutic candidate for the treatment of metabolic complications such as obesity, type 2 diabetes and NASH., Competing Interests: Declaration of competing interest Morten A. Karsdal and Kim Henriksen own stock in Nordic Bioscience A/S. All authors are employed by Nordic Bioscience A/S., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Serum-measured fragments of Tau cleaved by ADAM-10 (Tau-A) and Caspase-3 (Tau-C) have been found linked to change in cognitive function and risk of dementia., Objectives: 1) To determine the discriminatory abilities of Tau-A, and Tau-C in subjects with either mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or AD dementia compared to a control group. 2) To determine if there is a relation between Tau-A, and Tau-C and established cerebrospinal fluid (CSF) markers of AD- β-Amyloid1-42 (AB42), Phosphorylated-tau-181 (p-tau), and total-tau. 3) To determine if Tau-A and Tau-C are associated with progression rate from MCI due to AD to AD dementia., Design: Cross-sectional and a substudy using a retrospective cohort design., Setting: Memory clinic derived subjects contributing to the Danish Dementia Biobank., Participants: Cognitively unimpaired subjects (n=49), patients with mild cognitive impairment (MCI) due to AD (n=45), and Alzheimer's dementia (n=52)., Measurements: Competitive enzyme-linked immunosorbent assay (ELISA)-measured serum levels of Tau-A, and Tau-C., Results: The ratio between Tau-A and Tau-C differed between the three groups (p=0.015). Age- and sex-adjusted Tau-A differed between groups with lower ratios being associated with more severe disease (p=0.023). Tau-C was trending towards significant correlation to CSF-levels of AB42 (Pearson correlation coefficient 0.164, p=0.051). Those with Tau-C-levels in the 2nd quartile had a hazard ratio (HR) of 2.91 (95% CI 1.01 - 8.44, p=0.04) of progression compared to those in the 1st quartile. Those in the 3rd quartile was found to have a borderline significant (p=0.055) HR of 2.63 (95% CI 0.98 - 7.05) when compared to those in the lowest quartile., Conclusions: Tau-A and the ratio between Tau-A and Tau-C showed significant differences between groups and were correlated to CSF-AB42. Tau-C values in the middle range were associated with faster progression from MCI to dementia. This pilot study adds to the mounting data suggesting serum-measured Tau-A and Tau-C as biomarkers useful in relation to diagnosis and progression rate in AD but need further validation., Competing Interests: Nordic Bioscience holds a patent on the assays for measuring serum Tau-A and Tau-C. The principal investigator’s PhD-study is funded by the Danish Research Fund which has close economic ties to Nordic Bioscience A/S. Kim Henriksen and Morten A. Karsdal are employees of Nordic Bioscience and hold shares in the company

Background and Objectives: Diabetes and especially insulin resistance are associated with an increased risk of developing cognitive dysfunction, making anti-diabetic drugs an interesting therapeutic option for the treatment of neurodegenerative disorders. Dual amylin and calcitonin receptor agonists (DACRAs) elicit beneficial effects on glycemic control and insulin sensitivity. However, whether DACRAs affect cognition is unknown., Design and Intervention: Zucker Diabetic Fatty rats were treated with either the DACRA KBP-336 (4.5 nmol/kg Q3D), the amylin analog AM1213 (25 nmol/kg QD), or vehicle for 18 weeks. Further, the efficacy of a late KBP-336 intervention was evaluated by including a group starting treatment on day 30. Glucose control and tolerance were evaluated throughout the study and spatial learning and memory were evaluated by Morris Water Maze after 17 weeks of treatment., Results: When evaluating spatial learning, rats receiving KBP-336 throughout the study performed significantly better than AM1213, vehicle, and late intervention KBP-336. Both KBP-336 and AM1213 treatments improved spatial memory compared to the vehicle. The overall performance in the cognitive tests was reflected in the treatment efficacy on glycemic control, where KBP-336 was superior to AM1213., Conclusion: In summary, the DACRA KBP-336 ameliorates diabetes-induced spatial learning and memory impairment in diabetic rats. Further, KBP-336 improves long-term glycemic control superior to the amylin analog AM1213. Taken together, KBP-336 is, due to its anti-diabetic and insulin-sensitizing properties, a promising candidate for the treatment of cognitive impairments., Competing Interests: MAK and KH own stock in Nordic Bioscience A/S. All authors are employed by Nordic Bioscience A/S

Forkhead box A1 (FoxA1) + regulatory T cells (T regs ) exhibit distinct characteristics from FoxP3 + T regs while equally effective in exerting anti-inflammatory properties. The role of FoxP3 + T regs in vivo has been challenged, motivating a better understanding of other T regs in modulating hyperactive immune responses. FoxA1 + T regs are generated on activation of the transcription factor FoxA1 by interferon-β (IFNβ), an anti-inflammatory cytokine. T cell activation, expansion, and function hinge on metabolic adaptability. We demonstrated that IFNβ promotes a metabolic rearrangement of FoxA1 + T regs by enhancing oxidative phosphorylation and mitochondria clearance by mitophagy. In response to IFNβ, FoxA1 induces a specific transcription variant of adenosine 5'-monophosphate-activated protein kinase (AMPK) γ2 subunit, PRKAG2.2. This leads to the activation of AMPK signaling, thereby enhancing mitochondrial respiration and mitophagy by ULK1-BNIP3. This IFNβ-FoxA1-PRKAG2.2-BNIP3 axis is pivotal for their suppressive function. The involvement of PRKAG2.2 in FoxA1 + T reg , not FoxP3 + T reg differentiation, underscores the metabolic differences between T reg populations and suggests potential therapeutic targets for autoimmune diseases.

Dual amylin and calcitonin receptor agonists (DACRAs) are effective treatments for obesity and type 2 diabetes (T2D). They provide beneficial effects on body weight, glucose control, and insulin action. However, whether DACRAs protect against diabetes-related kidney damage remains unknown. We characterize the potential of long-acting DACRAs (KBP-A, Key Bioscience Peptide-A) as a treatment for T2D-related pathological alterations of the kidney extracellular matrix (ECM) in Zucker diabetic fatty rats (ZDF). We examined levels of endotrophin (profibrotic signaling molecule reflecting collagen type VI formation) and tumstatin (matrikine derived from collagen type IVα3) in serum and evaluated kidney morphology and collagen deposition in the kidneys. We included a study in obese Sprague-Dawley rats to further investigate the impact of KBP-A on ECM biomarkers. In ZDF vehicles, levels of endotrophin and tumstatin increased, suggesting disease progression along with an increase in blood glucose levels. These rats also displayed damage to their kidneys, which was evident from the presence of collagen formation in the medullary region of the kidney. Interestingly, KBP-A treatment attenuated these increases, resulting in significantly lower levels of endotrophin and tumstatin than the vehicle. Levels of endotrophin and tumstatin were unchanged in obese Sprague-Dawley rats, supporting the relation to diabetes-related kidney complications. Furthermore, KBP-A treatment normalized collagen deposition in the kidney while improving glucose control. These studies confirm the beneficial effects of DACRAs on biomarkers associated with kidney fibrosis. Moreover, these antifibrotic effects are likely associated with improved glucose control, highlighting KBP-A as a promising treatment of T2D and its related late complications. NEW & NOTEWORTHY These studies describe the beneficial effects of using a dual amylin and calcitonin receptor agonist (DACRA) for diabetes-related kidney complications. DACRA treatment reduced levels of serological biomarkers associated with kidney fibrosis. These reductions were further reflected by reduced collagen expression in diabetic kidneys. In general, these results validate the use of serological biomarkers while demonstrating the potential effect of DACRAs in treating diabetes-related long-term complications.

Introduction: Although serum amyloid A (AA) amyloid may occasionally show nonspecific staining by immunofluorescence (IF), the correct diagnosis can usually be determined by integrating pathologic features and clinical scenario, and using AA amyloid immunohistochemistry (IHC) and/or mass spectrometry. A recent mass spectrometry-based study described false-positive Ig IF staining in a subset of AA amyloid cases., Methods: We sought to delineate clinicopathologic features of AA amyloid with Ig-dominant staining by using a retrospective review., Results: AA amyloid with Ig-dominant staining was identified in 10 patients from 5 institutions, representing 1.2% to 4% of AA amyloid kidney biopsies. Evidence of a monoclonal protein was documented in 0% to 2.7% of patients with AA amyloid screened for inclusion, but 30% of those with Ig-dominant staining. The patient population had equal sex distribution and presented at median age of 68.5 years with nephrotic proteinuria and kidney impairment. Etiologies of AA amyloid included injection drug use (30%), autoimmune disease (20%), and chronic infection (10%); 40% had no identified clinical association. On biopsy, heavy chain (co)dominant staining by IF (in 80%), discordant distribution in Ig staining (in 20%), tubulointerstitial nephritis (in 30%), and/or crescents (in 10%) were present. Two of 3 patients with paraproteinemia had concordant heavy and/or light chain dominant staining within the AA amyloid. Two cases were initially misdiagnosed as Ig-associated amyloidosis., Conclusion: We describe the morphologic spectrum of AA amyloidosis with Ig-dominant staining which may have clinical, laboratory, and pathologic overlap with amyloid light chain (AL), amyloid heavy chain, and heavy and light chain (AHL) amyloidosis., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Objective: Long-acting dual amylin and calcitonin receptor agonists (DACRAs) hold great promise as potential treatments for obesity and its associated comorbidities. These agents have demonstrated beneficial effects on body weight, glucose control, and insulin action mirroring the effects observed with glucagon-like peptide-1 (GLP-1) agonist treatment. Strategies aimed at enhancing and prolonging treatment efficacy include treatment sequencing and combination therapy. Here, we sought to investigate the impact of switching between or combining treatment with the DACRA KBP-336 and the GLP-1 analog semaglutide in fed rats with obesity induced by a high-fat diet (HFD)., Methods: Two studies were performed in which HFD-induced obese Sprague Dawley rats were switched between treatment with KBP-336 (4.5 nmol/kg, Q3D) and semaglutide (50 nmol/kg, Q3D) or a combination of the two. Treatment efficacy on weight loss and food intake was evaluated, and glucose tolerance was assessed by oral glucose tolerance tests., Results: KBP-336 and semaglutide monotherapy resulted in a similar reduction in body weight and food intake. Treatment sequencing resulted in continuous weight loss and all monotherapies resulted in similar weight loss independent of the treatment regimen (P < 0.001 compared to vehicle). The combination of KBP-336 and semaglutide significantly improved the weight loss compared to either monotherapy alone (P < 0.001), which was evident in the adiposity at the study end. All treatments improved glucose tolerance, with the KBP-effect on insulin sensitivity as the dominant response., Conclusions: These findings highlight KBP-336 as a promising anti-obesity therapy both alone, in treatment sequencing, and in combination with semaglutide or other incretin-based therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 Elsevier B.V. All rights reserved.)

Dual amylin and calcitonin receptor agonists (DACRAs) are known to induce significant weight loss as well as improve glucose tolerance, glucose control, and insulin action in rats. However, to what extent DACRAs affect insulin sensitivity beyond that induced by weight loss and if DACRAs affect glucose turnover including tissue-specific glucose uptake is still unknown. Hyperinsulinemic glucose clamp studies were carried out in pre-diabetic ZDSD and diabetic ZDF rats treated with either the DACRA KBP or the long-acting DACRA KBP-A for 12 days. The glucose rate of disappearance was assessed using 3- 3 H glucose and tissue-specific glucose uptake was evaluated using 14 C-2-deoxy-D-glucose ( 14 C-2DG). In diabetic ZDF rats, KBP treatment significantly reduced fasting blood glucose and improved insulin sensitivity independent of weight loss. Furthermore, KBP increased the rate of glucose clearance, likely by increasing glucose storage, but without altering the endogenous glucose production. This was confirmed in pre-diabetic ZDSD rats. Direct assessment of tissue-specific glucose uptake showed, that both KBP and KBP-A significantly increased glucose uptake in muscles. In summary, KBP treatment significantly improved insulin sensitivity in diabetic rats and markedly increased glucose uptake in muscles. Importantly, in addition to their well-established weight loss potential, the KBPs have an insulin-sensitizing effect independent of weight loss, highlighting DACRAs as promising agents for the treatment of type 2 diabetes and obesity., Competing Interests: Declaration of Competing Interest MAK and KH own stock in Nordic Bioscience A/S. All authors are employed by Nordic Bioscience A/S., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: EndoC-βH5 is a newly established human beta-cell model which may be superior to previous model systems. Exposure of beta cells to pro-inflammatory cytokines is widely used when studying immune-mediated beta-cell failure in type 1 diabetes. We therefore performed an in-depth characterization of the effects of cytokines on EndoC-βH5 cells., Methods: The sensitivity profile of EndoC-βH5 cells to the toxic effects of interleukin-1β (IL-1β), interferon γ (IFNγ) and tumor necrosis factor-α (TNFα) was examined in titration and time-course experiments. Cell death was evaluated by caspase-3/7 activity, cytotoxicity, viability, TUNEL assay and immunoblotting. Activation of signaling pathways and major histocompatibility complex (MHC)-I expression were examined by immunoblotting, immunofluorescence, and real-time quantitative PCR (qPCR). Insulin and chemokine secretion were measured by ELISA and Meso Scale Discovery multiplexing electrochemiluminescence, respectively. Mitochondrial function was evaluated by extracellular flux technology. Global gene expression was characterized by stranded RNA sequencing., Results: Cytokines increased caspase-3/7 activity and cytotoxicity in EndoC-βH5 cells in a time- and dose-dependent manner. The proapoptotic effect of cytokines was primarily driven by IFNγ signal transduction. Cytokine exposure induced MHC-I expression and chemokine production and secretion. Further, cytokines caused impaired mitochondrial function and diminished glucose-stimulated insulin secretion. Finally, we report significant changes to the EndoC-βH5 transcriptome including upregulation of the human leukocyte antigen ( HLA ) genes, endoplasmic reticulum stress markers, and non-coding RNAs, in response to cytokines. Among the differentially expressed genes were several type 1 diabetes risk genes., Conclusion: Our study provides detailed insight into the functional and transcriptomic effects of cytokines on EndoC-βH5 cells. This information should be useful for future studies using this novel beta-cell model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Frørup, Gerwig, Svane, Mendes Lopes de Melo, Henriksen, Fløyel, Pociot, Kaur and Størling.)

There is an unmet need for nonalcoholic steatohepatitis (NASH) therapeutics, considering the increase in global obesity. Dual GLP-1/glucagon (GCG) receptor agonists have shown beneficial effects in circumventing the pathophysiology linked to NASH. However, dual GLP-1/GCG receptor agonists as a treatment of metabolic diseases need delicate optimization to maximize metabolism effects. The impacts of increased relative GLP-1/GCG receptor activity in NASH settings must be addressed to unleash the full potential. In this study, we investigated the potential of OXM-104 and OXM-101, two dual GLP-1/GCG receptor agonists with different receptor selectivity in the setting of NASH, to establish the relative receptor activities leading to the best metabolic outcome efficacies to reduce the gap between surgery and pharmacological interventions. We developed dual GLP-1/GCG receptor agonists with selective agonism. Despite the improved metabolic effects of OXM-101, we explored a hyperglycemic risk attached to increased relative GCG receptor agonism. Thirty-eight days of treatment with a dual GLP-1/GCG receptor agonist, OXM-104, with increased GLP-1 receptor agonism in obese NASH mice was found to ameliorate the development of NASH by lowering body weight, improving liver and lipid profiles, reducing the levels of the fibrosis marker PRO-C4, and improving glucose control. Similarly, dual GLP-1/GCG receptor agonist OXM-101 with increased relative GCG receptor agonism ameliorated NASH by eliciting dramatic body weight reductions to OXM-104, reflected in the improvement of liver and lipid enzymes and reduced PRO-C4 levels. Optimizing dual GLP-1/GCG agonists with increased relative GCG receptor agonism can provide the setting for future agonists to treat obesity, type 2 diabetes, and NASH without having a hyperglycemic risk. SIGNIFICANT STATEMENT: There is an unmet need for nonalcoholic steatohepatitis (NASH) therapeutics, considering the increase in global obesity. Dual GLP-1/glucagon (GCG) receptor agonists have shown beneficial effects in circumventing the pathophysiology linked to NASH. Therefore, this study has examined OXM-104 and OXM-101, two dual GLP-1/GCG receptor agonists in the setting of NASH, to establish the relative receptor activities leading to the best metabolic outcome efficacies to reduce the gap between surgery and pharmacological interventions., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

During the last decade, talent identification and development research that favours an individual perspective has been complemented by a focus on young athletes' social environments, termed "athletic talent development environments" (ATDEs). Two major lines of research have created a foundation for an ecological vision of talent development as the mutual accommodation between athletes and their ATDEs and of career development as an athlete's journey through various athletic and non-athletic environments. The Talent Development Environment Questionnaire allows the quantitative screening of athletes' environments, while the holistic ecological approach (HEA) promotes in-depth qualitative case studies of ATDEs. In this chapter, we focus mainly on the HEA, including: (a) two models that combine to illustrate an ATDE; (b) a summary of empirical case studies of successful environments in various sports and countries, culminating in a set of shared features of ATDEs that promote athletes' wellbeing and athletic and personal development; (c) an overview of recent trends within HEA (e.g. interorganisational collaboration in talent development) and (d) recommendations for coaches and sport psychology consultants, emphasising the importance of integrating efforts across the whole environment and building strong and coherent organisational cultures. In the discussion, we elaborate on developing the HEA discourse and point to future challenges for researchers and practitioners., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Henriksen and Stambulova.)

Objective: The gut hormone glucose-dependent insulinotropic polypeptide (GIP) is an important regulator of glucose and bone metabolism. In rodents, the naturally occurring GIP variant, GIP(1-30)NH2, has shown similar effects as full-length GIP (GIP(1-42)), but its effects in humans are unsettled. Here, we investigated the actions of GIP(1-30)NH2 compared to GIP(1-42) on glucose and bone metabolism in healthy men and in isolated human pancreatic islets., Methods: Nine healthy men completed three separate three-step glucose clamps (0-60 minutes at fasting plasma glucose (FPG) level, 60-120 minutes at 1.5× FPG, and 120-180 minutes at 2× FPG) with infusion of GIP(1-42) (4 pmol/kg/min), GIP(1-30)NH2 (4 pmol/kg/min), and saline (9 mg/mL) in randomised order. Blood was sampled for measurement of relevant hormones and bone turnover markers. Human islets were incubated with low (2 mmol/L) or high (20 mmol/L) d-glucose with or without GIP(1-42) or GIP(1-30)NH2 in three different concentrations for 30 minutes, and secreted insulin and glucagon were measured., Results: Plasma glucose (PG) levels at FPG, 1.5× FPG, and 2× FPG were obtained by infusion of 1.45 g/kg, 0.97 g/kg, and 0.6 g/kg of glucose during GIP(1-42), GIP(1-30)NH2, and saline, respectively (P = .18), and were similar on the three experimental days. Compared to placebo, GIP(1-30)NH2 resulted in similar glucagonotropic, insulinotropic, and carboxy-terminal type 1 collagen crosslinks-suppressing effects as GIP(1-42). In vitro experiments on human islets showed similar insulinotropic and glucagonotropic effects of the two GIP variants., Conclusions: GIP(1-30)NH2 has similar effects on glucose and bone metabolism in healthy individuals and in human islets in vitro as GIP(1-42)., Competing Interests: Conflicts of interest: L.S.K., K.H., S.S., N.C.B., K.S.J., and J.S. have nothing to disclose. L.S.G. is a co-founder of Antag Therapeutics. B.H. is a co-founder of Bainan Biotech. J.J.H. has served on scientific advisory panels for and/or has received speaker honoraria from Novo Nordisk and MSD/Merck, is co-founder and board member of Antag Therapeutics, and co-founder of Bainan Biotech. M.M.R. is co-founder of Antag Therapeutics, co-founder and board member of Bainan Biotech and Synklino. F.K.K. has served on scientific advisory panels and/or been part of speaker's bureaus for; served as a consultant to and/or received research support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Sanofi, and Zealand Pharma; and is a co-founder of and minority shareholder in Antag Therapeutics. F.K.K. is on the editorial board of EJE and was not involved in the review or editorial process for this paper, on which he is listed as an author., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pharmacotherapies for obesity and type 2 diabetes (T2D) are thought to bridge the gap between lifestyle modification and the weight loss obtained with bariatric surgery. Although the effect of monotherapies, namely amylin and glucagon-like peptide-1 receptor (GLP-1R) agonists, has shown great potential, combination therapy is now becoming a strategy to optimize efficacy for weight management while minimizing adverse effects. This study investigated a dual amylin and calcitonin receptor agonist (DACRA); KBP-066A in combination with the GLP-1R agonist semaglutide or the sodium-glucose co transporter-2 inhibitor (SGLT2i) empagliflozin for anti-obesity and anti-diabetic treatment. The effect of KBP-066A, semaglutide, and empagliflozin alone and in combination was studied with respect to their impact on body weight, food intake, and glucose metabolism in high-fat diet (HFD) and Zucker diabetic fatty (fa/fa) (ZDF) rats. Treatment with KBP-066A and semaglutide lowered body weight by 13% and 9.7%. In contrast, a combination of both KBP-066A + semaglutide reduced body weight by 21% in HFD rats demonstrating superiority compared to monotherapies alone. A combination of KBP-066A with semaglutide or empagliflozin significantly lowered fasting blood glucose, and HbA1C (%) levels in ZDF rats. The complementary action by KBP-066A to GLP-1R agonist and SGLT2i on BW, food intake and glucose control endorsed the potential of DACRAs as an add-on therapy to therapeutic options for T2D and obesity., Competing Interests: Declaration of competing interest MAK and KH own stock in Nordic Bioscience A/S. All authors are employed by Nordic Bioscience A/S., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Disease modifying treatments for dementia are only just surfacing, and their development is still significantly hindered by the lack of validated tools for identification of subjects with subclinical disease. Much interest has been taken in developing accessible non-invasive serum biomarkers of neurodegeneration. Recent studies have identified caspase-3-cleaved tau (Tau-C), and ADAM-10 cleaved tau (Tau-A) as possible markers of preclinical neurodegenerative disease., Objectives: To explore if serum levels of Tau-A and Tau-C change as a consequence of neurodegeneration., Design and Setting: Cohort study with measurement of biomarkers and genome sequencing at baseline with follow-up after an average of 14 years., Participants: Postmenopausal Danish women from the Prospective Epidemiological Risk Factor (PERF) cohort (n=4968) Methods: Genotyping data was used to perform a Mendelian randomization analysis of serum levels of Tau-A and Tau-C in relation to a diagnosis of dementia at follow-up. A dementia diagnosis was defined as a composite of an all-cause dementia diagnosis derived from the Danish National Health registries, a self-reported diagnosis of dementia and/or cognitive test scores suggestive of dementia. Serum levels of Tau-A and Tau-C were measured blinded in samples from baseline in a CAP certified lab. The association with dementia was assessed using bi-directional one- and two- sample Mendelian randomization., Results: A lead single nucleotide polymorphism (SNP) was identified for Tau-A (rs10414043) and Tau-C (rs429358), respectively were identified. Both were located in the APOE/C1 cluster on chromosome 19. APOE and EPOC1 variants were associated with lower levels of Tau-A and Tau-C levels - effect size -0.13, 95%CI [-0.17 - -0.09] log2 (ng/mL), p=7.05e-11 for rs10414043 association with Tau-A and effect size -0.12, 95%CI [-0.15 - -0.08] log2 (ng/mL), p=2e-11 for rs429358 association with Tau-C. When incorporating genetic data from a larger genetic study we found that Alzheimer's disease was marginally associated with a decreased Tau-A and Tau-C levels (Odds Ratio 0.97, 95%CI [0.93 - 1.00]. No association was found in the forward Mendelian randomization analysis., Conclusions: By combining genotype data with serum measurements of the novel biomarkers Tau-A and Tau-C, we conclude that Tau-A and Tau-C levels change because of neurodegeneration. We also conclude that lower serum-values of the biomarkers are associated with the presence of genetic variants commonly found in individuals suffering from late-onset Alzheimer's Dementia. These findings add to the growing data pointing towards Tau-A and Tau-C as valuable biomarkers for neurodegeneration., Competing Interests: Dr. Axelsen has no conflict of interests. Dr. Bager and Dr. Henriksen are both full-time employees of Nordic Bioscience A/S and both hold stocks in the company, Dr. Tang was previously employed at Nordic Bioscience A/S. Dr. Bihlet is a full-time employee and shareholder of Sanos Group A/S and its subsidiary NBCD A/S. Prof Karsdal is the CEO of Nordic Bioscience A/S and holds stock in the company. Nordic Bioscience holds a patent on the assays for detecting Tau-A and Tau-C.

Cagrilintide is a novel long-acting amylin receptor agonist, which has shown a potent induction of weight loss. Interestingly, cagrilintide is a Dual Amylin and Calcitonin Receptor Agonist (DACRA) derived from an amylin backbone. Another class of long-acting DACRAs exists, namely the KBPs. These are salmon calcitonin-based and have shown preclinical potential; however, how and if they differentiate from amylin-derived molecules remain to be studied. Here, we compare cagrilintide to the DACRA KBP-336 with respect to receptor activation balance in vitro and using metabolic in vivo models. Peptide potencies were assessed using receptor-specific assays in vitro and in vivo. In vivo efficacies on body weight and glucose homeostasis were investigated head-to-head in high-fat diet (HFD) fed obese and T2D (ZDF) rat models. Both peptides activate the amylin and the calcitonin receptor in vitro and in vivo, with KBP-336 being more potent, and showing a CTR bias. KBP-336 and cagrilintide induced a potent and dose-dependent weight loss in HFD rats, with the highest dose of KBP-336 being superior to cagrilintide. In diabetic ZDF rats, DACRA treatment improved fasting blood glucose, HbA1c levels, and insulin action, with KBP-336 being superior to cagrilintide in improving glucose control. In summary, both KBP-336 and cagrilintide are DACRAs, however with KBP-336 being biased towards the CTR resulting in a different receptor activation balance. Interestingly, KBP-336 showed superior long-term efficacy on both weight loss and glucose control, supporting relevance of the receptor balance, and highlighting KBP-336 as a promising agent for the treatment of obesity and T2D., Competing Interests: Conflict of interest statement MAK and KH own stock in Nordic Bioscience A/S. All authors are employed by Nordic Bioscience A/S., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Dual Amylin and Calcitonin Receptor Agonists (DACRAs) are treatment candidates for obesity and type 2 diabetes. Recently, a once-weekly DACRA (KBP-A) showed promise, potentially due to its different exposure profile compared to daily DACRA (KBP). Parathyroid hormone, a G-protein-coupled receptor (GPCR) class B agonist, is an example of the exposure profile being critical to the effect. Since KBP and KBP-A also activate GPCR class B, we compared the effects of injection to continuous infusion of short-acting KBP and long-acting KBP-A in obese and diabetic rats to shed light on the role of exposure profiles., Methods: To explore the metabolic benefits of dose optimization, the following dosing profiles were compared in High Fat Diet (HFD)-fed Sprague-Dawley rats and diabetic Zucker Diabetic Fatty (ZDF) rats: (1) KBP dosed once-daily by injection or by continuous infusion in HFD and ZDF rats; (2) KBP injected once-daily and KBP-A injected once every 3rd day (Q3D) in HFD rats; (3) KBP-A injected Q3D or by infusion in ZDF rats., Results: KBP and KBP-A, delivered by either injection or infusion, resulted in similar weight and food intake reductions in HFD rats. In ZDF rats, injection of KBP improved glucose control significantly compared to infusion, while delivery of KBP-A by injection and continuous infusion was comparable in terms of glucose control., Conclusion: different dosing profiles of KBP and KBP-A had no impact on metabolic benefits in HFD rats. In diabetic ZDF rats, KBP by injection instead of infusion was superior, while for KBP-A the effects were similar., Competing Interests: M.A.K. and K.H. own stock in Nordic Bioscience. M.A.K. and K.H. hold patent in KBP-042, KBP-088, KBP-088A and KBP-066A. N.S. holds patent in KBP-066A. All authors are employed by Nordic Bioscience A/S.

Background: Previous studies have indicated the utility of the ADAM10-generated fragment of tau, Tau-A, as marker of neuronal damage. However, the sensitivity of the ELISA-based system was limited., Objectives: We utilized the extensive dynamic range of electrochemiluminescence compared to colorimetric assessment to improve the sensitivity of the Tau-A assay and investigate Tau-A levels after brain injury., Methods: We converted the Tau-A competitive ELISA to a competitive electrochemiluminescence-based immunoassay, Tau-A ECLIA, and compared the methods by measuring serum samples in a TBI (n = 40) and a stroke cohort (n = 64)., Results: The Tau-A ECLIA was technically robust. Only 1% of the samples was below the detection limit in the ECLIA compared to 10.6% in the ELISA . Tau-A measured in both assays could discriminate between patients with a TBI and non-trauma controls (ELISA: p = 0.0005, ECLIA: p = 0.0002). The increased dynamic range of the Tau-A ECLIA also allowed discrimination between healthy controls from patients with hemorrhagic ( p = 0.0172) and severe ischemic stroke ( p = 0.0118) respectively, as well as patients with mild ischemic stroke from severe ( p = 0.0445)., Conclusions: The Tau-A ECLIA was characterized by dynamic range compared to the ELISA, which facilitated a better separation between the patient groups. Tau-A warrants further investigation as a neuronal injury associated marker.

Thrombotic microangiopathies (TMAs) have in common a terminal phenotype of microangiopathic hemolytic anemia with end-organ dysfunction. Thrombotic thrombocytopenic purpura results from von Willebrand factor multimerization, Shiga toxin-mediated hemolytic uremic syndrome causes toxin-induced endothelial dysfunction, while atypical hemolytic uremic syndrome results from complement system dysregulation. Drug-induced TMA, rheumatological disease-induced TMA, and renal-limited TMA exist in an intermediate space that represents secondary complement activation and may overlap with atypical hemolytic uremic syndrome clinically. The existence of TMA without microangiopathic hemolytic features, renal-limited TMA, represents an undiscovered syndrome that responds incompletely and inconsistently to complement blockade. Hematopoietic stem cell transplant-TMA represents another more resistant form of TMA with different therapeutic needs and clinical course. It has become apparent that TMA syndromes are an emerging field in nephrology, rheumatology, and hematology. Much work remains in genetics, molecular biology, and therapeutics to unravel the puzzle of the relationships and distinctions apparent between the different subclasses of TMA syndromes., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Despite endorsements for greater use of systems approaches and reports from national consensus bodies calling for closer engineering/health care partnerships to improve care delivery, there has been a scarcity of effort of actually engaging the design and engineering disciplines in patient safety projects. The article describes a grant initiative undertaken by the Agency for of Healthcare Research and Quality that brings these disciplines together to test new ideas that could make health care safer., Methods: Collectively known as patient safety learning laboratories, grantee teams engage in phase-based activities that parallel a systems engineering process-problem analysis, design, development, implementation, and evaluation-to gain an in-depth understanding of related patient safety problems, generate fresh ideas and rapid prototypes, develop the prototypes, ensure that developed components are implemented as an integrated working system, and evaluate the system in a simulated or clinical setting., Findings: Obstacles are described that can derail the best of intentions in deploying the systems engineering methodology. Based on feedback received from project teams, lessons learned are emerging that find considerable variation among project teams in deploying the methodology and a longer than anticipated amount of time in bringing team members from different disciplines together where they learn to communicate and function as a team., Conclusions: Three narratives are generated in terms of what success might look like. Much is yet to be learned about the limitations and successes of the ongoing learning laboratory initiative, which should be relevant to the broader scale interest in learning health systems., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

There is a need for antidiabetic agents successfully targeting insulin sensitivity and treating obesity control at the same time. The aim of this first-in-human study was (a) to evaluate safety and tolerability, (b) to evaluate pharmacokinetics and (c) to assess indications of receptor engagement of single ascending doses of KBP-042, a dual amylin and calcitonin receptor agonist (DACRA) that has shown promising preclinical data, with superior activity in terms of typical amylin-induced responses including reduction of food intake, weight loss and gluco-regulatory capacities. A randomised double-blind placebo-controlled single ascending dose study was performed with six dose levels of KBP-042 (5, 7.5, 10, 20, 20 (evening), 40 ug) in healthy male adults. KBP-042 or placebo was administered as a single dose after an overnight fast, followed by a standardized lunch after 4 hours. KBP-042 was associated with dose-dependent complaints of nausea and vomiting, with a lack of tolerability at doses of 20 μg and above. Doses of 5-40 μg KBP-042 behaved according to a linear pharmacokinetic profile. Indications of target receptor engagement were observed at the level of glucose control and lowering of bone resorption, compared to placebo. The results of this study showed that doses up to 40 μg were safe, although tolerability was not present at the highest doses. The study confirmed target receptor engagement at the studied doses., (© 2021 British Pharmacological Society.)

Objectives: There is a need for precision medicine and an unspoken promise of an optimal approach for identification of the right patients for value-based medicine based on big data. However, there may be a misconception that measurement of proteins is more valuable than measurement of fewer selected biomarkers. In population-based research, variation may be somewhat eliminated by quantity. However, this fascination of numbers may limit the attention to and understanding of the single. This review highlights that protein measurements (with collagens as examples) may mean different things depending on the targeted epitope - formation or degradation of tissues, and even signaling potential of proteins., Design and Methods: PubMed was searched for collagen, neo-epitope, biomarkers., Results: Ample examples of assays with specific epitopes, either pathological such as HbA1c, or domain specific such as pro-peptides, which total protein arrays would not have identified were evident., Conclusions: We suggest that big data may be considered as the funnel of data points, in which most important parameters will be selected. If the technical precision is low or the biological accuracy is limited, and we include suboptimal quality of biomarkers, disguised as big data, we may not be able to fulfill the promise of helping patients searching for the optimal treatment. Alternatively, if the technical precision of the total protein quantification is high, but we miss the functional domains with the most considerable biological meaning, we miss the most important and valuable information of a given protein. This review highlights that measurements of the same protein in different ways may provide completely different meanings. We need to understand the pathological importance of each epitope quantified to maximize protein measurements., (Copyright © 2021 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Capillary deposition of C4d is an important marker of antibody-mediated rejection (AMR) following heart transplantation (HT). There are two immunopathologic assay methods for detecting C4d: frozen-tissue immunofluorescence (IF) and paraffin immunohistochemistry (IHC). The clinical significance of discrepancy between the results of IF and IHC has not been understood., Methods and Results: We reviewed 2187 biopsies from 142 HT recipients who had biopsies with assessment of both IF and IHC staining. Among them, 103 (73%) patients had negative IF and IHC C4d staining (Negative Group) and 32 (23%) patients had positive IF but negative IHC staining (Discordant Group). At the time of positive biopsy, 6 (19%) Discordant patients had graft dysfunction, compared to 5 (5%) Negative patients (p = .022). Cumulative incidence of cellular rejection at 1 year was comparable (31% vs. 29%, p = .46); however, cumulative incidence of AMR was significantly higher in the Discordant group (21% vs. 4%, p = .004). Overall 1-year survival was comparable (90% vs. 96%, p = .24); however, freedom from heart failure (HF) was significantly lower in the Discordant group (70% vs. 96%, p < .001)., Conclusion: The Discordant group showed higher rates of graft dysfunction, AMR and HF admission than the Negative group., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Therapies for metabolic diseases are numerous, yet improving insulin sensitivity beyond that induced by weight loss remains challenging. Therefore, search continues for novel treatment candidates that can stimulate insulin sensitivity and increase weight loss efficacy in combination with current treatment options. Calcitonin gene-related peptide (CGRP) and amylin belong to the same peptide family and have been explored as treatments for metabolic diseases. However, their full potential remains controversial., Scope of Review: In this article, we introduce this rather complex peptide family and its corresponding receptors. We discuss the physiology of the peptides with a focus on metabolism and insulin sensitivity. We also thoroughly review the pharmacological potential of amylin, calcitonin, CGRP, and peptide derivatives as treatments for metabolic diseases, emphasizing their ability to increase insulin sensitivity based on preclinical and clinical studies., Major Conclusions: Amylin receptor agonists and dual amylin and calcitonin receptor agonists are relevant treatment candidates, especially because they increase insulin sensitivity while also assisting weight loss, and their unique mode of action complements incretin-based therapies. However, CGRP and its derivatives seem to have only modest if any metabolic effects and are no longer of interest as therapies for metabolic diseases., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Weight loss therapy is becoming more and more important, and two classes of molecules, namely amylin receptor and GLP-1 receptor agonists, have shown promise in this regard. Interestingly, these molecules have several overlapping pharmacological effects, such as suppression of gastric emptying, reduction of glucagon secretion and weight loss in common; however, they also have distinct effects on prandial insulin secretion. Hence, a combination of these two mechanisms is of significant interest., Methods: In this study, we investigated the add-on potential of the dual amylin and calcitonin receptor agonist (DACRA) KBP-089 in combination with the GLP-1 receptor agonist liraglutide as obesity treatment in high-fat diet (HFD) fed rats., Results: Increasing doses of KBP-089 and liraglutide alone and in combination were studied with respect to their effects on body weight, food intake and glucose metabolism during a 9-week intervention study conducted in HFD rats. Further, the gastric emptying rate during an oral glucose tolerance was assessed. Treatment with KBP-089 and liraglutide dose-dependently lowered body weight 15% (at 2.5 μg/kg/day) and 7% (at 400 μg/kg/day) in HFD rats, respectively, while the combination resulted in a 21% body weight reduction, which was mirrored by reduction in fat depot sizes. Gastric emptying and glucose metabolism were improved, primarily by KBP-089, although liraglutide led to a reduction in fasting plasma glucagon., Conclusion: DACRAs complement GLP-1 on food intake, body weight, and glucose tolerance indicating the potential for an add-on therapy.

Objectives: Menopause is often characterized by detrimental metabolic changes, such as obesity, insulin resistance, and impaired glucose tolerance, often requiring treatment. KeyBioscience Peptides (KBPs) are Dual Amylin and Calcitonin Receptor Agonists which have shown promising metabolic effects in rats. The objective of this study was to investigate the in vivo effect of KBP on the metabolic health in a model driven by unhealthy diet, age, and menopause., Methods: Female Sprague Dawley rats were fed a high-fat diet (HFD) for 3 months before the initiation of the study. At 6 months of age the rats were randomized into groups (n = 12) and subjected to ovariectomy surgery and treatment with KBP: (1) Lean-Sham, (2) HFD-Sham, (3) Lean-OVX, (4) HFD-OVX, (5) HFD-OVX-KBP (10 μg/kg/d), (6) HFD-OVX-KBP (20 μg/kg/d), (7) HFD-OVX-EE2 (30 μg/d 17a-ethynylestradiol). Body weight, food intake, oral glucose tolerance tests (OGTTs), subcutaneous fat, visceral fat, liver weight, and uterus weight were assessed during the 6-month study. Statistical analyses were conducted by one-way ANOVA with Tukey post-hoc test for multiple comparisons., Results: Combination of OVX and HFD led to significant induction of obesity (31% weight increase, P < 0.001) and insulin resistance (13% increase in tAUCglucose during OGTT P < 0.01) compared with the relevant control groups (P < 0.05), and this could be completely rescued by EE2 therapy confirming the model system (P < 0.05).Treatment of OVX-HFD rats with KBP for 26 weeks led to a significant reduction in body weight (13%, P < 0.001) in the high dose and 9% (P < 0.01) in the low dose, with corresponding improvements in fat depot sizes, all compared with HFD-OVX controls. As expected, food intake was suppressed, albeit mainly in the first 2 weeks of treatment, resulting in a reduction of overall caloric intake by 6.5% (P < 0.01) and 12.5% (P < 0.001) in the low and high doses respectively. Furthermore, treatment with KBP reduced the weight of visceral and subcutaneous fat tissues. Finally, KBP treatment significantly improved glucose tolerance, assessed using OGTTs at weeks 8, 16, and 24., Conclusions: The data presented here clearly indicate a positive and sustained effect of KBP treatment on body weight loss, fat depot size, and improved glucose tolerance, illustrating the potential of KBPs as treatments for metabolic complications of overweight and menopause., Competing Interests: Financial disclosure/conflicts of interest: M.A.K., A-C.B.J., and K.H. are employees of Nordic Bioscience A/S which is a company involved in the discovery and development of biochemical biomarkers and novel therapeutic peptides, including KBPs. A.K. and D.R. are former employees of Nordic Bioscience A/S. M.A.K. and K.H. hold patents on KBPs. M.A.K., A.-C.B.J., and K.H. hold stocks in Nordic Bioscience A/S., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.)