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Introduction: Childhood obesity may be associated with continuous obesity into adulthood and development of obesity-related comorbidities. In adult, studies have demonstrated an association between circulating levels of uric acid (UA), body mass index (BMI), and the development of type 2 diabetes and the metabolic syndrome. The aim of the current study was to investigate the relationship between UA in children and adolescents with obesity, involved in a municipality-based lifestyle intervention.Methods: One hundred and seventy-one children (age 4-18), with a body mass index standard deviation score (BMI-SDS) of +2 or higher were included in a multifactorial lifestyle intervention study. The intervention was a collaboration between the children, parents, community healthcare workers and the regional hospital. The children who participated, were annually invited to the hospital for anthropometrics, blood samples and DEXA-scans for up to 3 years. In between, the children were seen up 8 times per year by a community healthcare worker. Eighty-nine children were included for follow-up analysis. Results: After a follow-up of 20.7 ± 9.4 months a reduction in BMI-SDS of -0.34 ± 0.53 (p < 0.01) was observed. In parallel, UA was found to be positively associated with changes in BMI-SDS. UA levels decreased in the 76 children who lost weight during the intervention, conversely, UA increased in the 23 children who gained weight during the intervention (p < 0.01 between groups).Conclusion: Interestingly, UA was found to correlate with measures of childhood obesity, and for the first time this study demonstrates a positive relationship between weight reduction in children with obesity and changes in UA.Implications for applicability: This study implies that UA may be used as a marker when assessing health conditions (i.e. BMI-SDS) in children with obesity.

The rapid repurposing of antivirals is particularly pressing during pandemics. However, rapid assays for assessing candidate drugs typically involve in vitro screens and cell lines that do not recapitulate human physiology at the tissue and organ levels. Here, we show that a microfluidic bronchial-airway-on-a-chip lined by highly differentiated human bronchial-airway epithelium and pulmonary endothelium can model viral infection, strain-dependent virulence, cytokine production, and the recruitment of circulating immune cells. In airway chips infected with influenza A, the co-administration of nafamostat with oseltamivir doubled the treatment-time window for oseltamivir. In chips infected with pseudotyped SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), clinically relevant doses of the antimalarial drug amodiaquine inhibited infection, but clinical doses of hydroxychloroquine and other antiviral drugs that inhibit the entry of pseudotyped SARS-CoV-2 in cell lines under static conditions did not. We also show that amodiaquine showed substantial prophylactic and therapeutic activities in hamsters challenged with native SARS-CoV-2. The human airway-on-a-chip may accelerate the identification of therapeutics and prophylactics with repurposing potential., One-sentence editorial summary: A microfluidic bronchial-airway-on-a-chip lined by human bronchial-airway epithelium and pulmonary endothelium can be used to rapidly identify antiviral therapeutics and prophylactics with repurposing potential.

SUMMARYSARS-CoV-2 has been found capable of inducing prolonged pathologies collectively referred to as Long-COVID. To better understand this biology, we compared the short- and long-term systemic responses in the golden hamster following either SARS-CoV-2 or influenza A virus (IAV) infection. While SARS-CoV-2 exceeded IAV in its capacity to cause injury to the lung and kidney, the most significant changes were observed in the olfactory bulb (OB) and olfactory epithelium (OE) where inflammation was visible beyond one month post SARS-CoV-2 infection. Despite a lack of detectable virus, OB/OE demonstrated microglial and T cell activation, proinflammatory cytokine production, and interferon responses that correlated with behavioral changes. These findings could be corroborated through sequencing of individuals who recovered from COVID-19, as sustained inflammation in OB/OE tissue remained evident months beyond disease resolution. These data highlight a molecular mechanism for persistent COVID-19 symptomology and characterize a small animal model to develop future therapeutics.

The 1969 geomagnetic impulse provided the first compelling evidence for rapid changes in Earth's core-generated magnetic field, taking place on timescales of a few years or less. We show here it originated at the core-mantle boundary (CMB) largely as a localized change in the field acceleration under north and central America. We find the impulse events in 1969 and 2017 involved similar amplitudes of field acceleration change with similar localized dipole structures. However in 1969 the acceleration change pattern was north-south rather than east-west oriented, and it propagated poleward rather than westward. Moreover, there was a distinctive local surge in the CMB secular variation leading up to the 1969 event. We propose the 1969 impulse resulted from hydromagnetic waves arriving at the CMB that were triggered by a convective burst near to the core surface; this event involved localized flux expulsion and inward propagating waves.

The host response to SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, demonstrates significant interindividual variability. In addition to showing more disease in males, the elderly, and individuals with underlying comorbidities, SARS-CoV-2 can seemingly afflict healthy individuals with profound clinical complications. We hypothesize that, in addition to viral load and host antibody repertoire, host genetic variants influence vulnerability to infection. Here we apply human induced pluripotent stem cell (hiPSC)-based models and CRISPR engineering to explore the host genetics of SARS-CoV-2. We demonstrate that a single-nucleotide polymorphism (rs4702), common in the population and located in the 3′ UTR of the protease FURIN, influences alveolar and neuron infection by SARS-CoV-2 in vitro. Thus, we provide a proof-of-principle finding that common genetic variation can have an impact on viral infection and thus contribute to clinical heterogeneity in COVID-19. Ongoing genetic studies will help to identify high-risk individuals, predict clinical complications, and facilitate the discovery of drugs., Graphical abstract, Brennand, Akbarian, and colleagues combine human induced pluripotent stem cell-based models and CRISPR engineering to explore the host genetics of SARS-CoV-2 in alveolar cells, intestinal cells, and neurons. A SNP(rs4702) located in the 3′ UTR of the protease FURIN influences alveolar and neuron infection by SARS-CoV-2 in vitro.

Målet for denne oppgaven har vært å designe et system som skal sjøsette og hente opp en undervannsdrone (ROV). Dette behovet ble presentert av Maritime Robotics (MR). De hadde et ønske om å utvide bruksområdet til sin Otter, som er en ubemannet båt (USV). Måten de så for seg å utvide bruksområdet på var ved å utvikle et mekanisk samspill mellom Otter og en undervannsdrone. I denne oppgaven har det blitt sett på et slikt system for en Blueye Pro ROV, levert av Blueye Robotics (BR). Prosjektet følger en 6-trinns modell, hentet fra boken The Mechanical Design Process. Disse trinnene innebærer å identifisere et behov, strukturere arbeidet, definere problemet, utvikle konsept som ender i et resultat og til slutt komme med forslag til endringer. Det har vært tett dialog mellom prosjektgruppen og MR. Bedriften satte krav til spesifikasjonene i konseptet som dannet grunnlaget for utforming av produktet. Konseptutviklingen har bestått av iterasjoner av idemyldring- og evalueringsmetoder. Idemyldringen begynte med frihåndstegninger, før de endelige tredimensjonale tegningene ble laget i CAD-programmet SolidWorks. Evalueringsprosessen har bestått av grovsorteringer, sammenligninger og tester. Utover det å designe og evaluere de ulike konseptene har prosjektgruppen gjort beregninger og analyser av de kritiske delene i systemet for å sikre riktig dimensjonering. Av det valgte konseptet ble det laget en prototype ved bruk av 3D-print, som ble brukt til å evaluere konseptet. Etter testing av prototypen ble det gjort noen endringer, før maskintegninger ble sendt til Maritime Robotics. Det ble deretter satt i gang produksjon av en full skala prototype, som ikke ble ferdig før ferdigstilling av den akademiske rapporten. Avslutningsvis diskuterer prosjektgruppen mulige forbedringspotensial og videre arbeid. Denne oppgaven tar ikke for seg kommunikasjon mellom undervannsdronen og det ubemannede fartøyet, noe som er essensielt for helheten av systemet. Alt i alt konkluderes det med at det er mulig å utvikle et system for sjøsetting og opphenting av undervanndroner, som kan monteres på Otter, men at det er behov for videre arbeid og optimalisering. The main objective of this thesis has been to design a Launch and Recovery System (LARS) for a Remote Operated Vehicle (ROV). The demand for this product was given by Maritime Robotics. They had a vision to expand the area of use for their Otter. The Otter is an Unmanned Surface Vehicle (USV). The way they envisioned expanding the use, was by developing a mechanical interaction between Otter and a ROV. In this thesis the focus has been to develop a LARS for the Blueye Pro ROV, delivered by Blueye Robotics. The project follows a 6-step model, from the book The Mechanical Design Process. These steps include identifying a need, structuring the work process, defining the problem and developing concepts that lead to a result and finally make suggestions for changes. During the entire process there has been close communication between the company and the group. The company has set requirements and specifications for the concept, which made the foundation for the evaluations. The main area of focus in this thesis is concept development, and different methods of brainstorming and evaluations have been used. SolidWorks was used to transform the two-dimensional drawings into three-dimensional drawings. For the critical components in the system calculations and analyzes have been made to ensure correct dimensioning. A 3D-printed prototype was made to evaluate the chosen concept. After testing the prototype some changes and adjustments were made before the drawings was sent to Maritime Robotics. Production of a true to size prototype begun but did not finish in time for finalizing of the thesis. Towards the end of the project the group discussed potential improvements. The thesis does not cover communication between the ROV and USV, which is essential for the system. Overall the conclusion is that it is possible to develop a concept for an Otter based Launch and Recovery system for a ROV, but that the system should be further optimized.

The SARS-CoV-2 pandemic has caused unparalleled disruption of global behavior and significant loss of life. To minimize SARS-CoV-2 spread, understanding the mechanisms of infection from all possible routes of entry is essential. While aerosol transmission is thought to be the primary route of spread, viral particles have been detected in ocular fluid, suggesting that the eye may be a vulnerable point of viral entry. To this end, we confirmed SARS-CoV-2 entry factor and antigen expression in post-mortem COVID-19 patient ocular surface tissue and observed productive viral replication in cadaver samples and eye organoid cultures, most notably in limbal regions. Transcriptional analysis of ex vivo infected ocular surface cells and hESC-derived eye cultures revealed robust induction of NF-κB in infected cells as well as diminished type I/III interferon signaling. Together these data suggest that the eye can be directly infected by SARS-CoV-2 and implicate limbus as a portal for viral entry., Graphical abstract, Eriksen et al. show that SARS-CoV-2 antigens are expressed in COVID-19 patient samples and find robust infection of cadaveric ocular surface cells. Limbus cells derived from human donors and a hPSC whole-eye differentiation model seem more prone to infection and exhibit robust chemokine production and an impaired IFN-I/-III response.

Heart injury has been reported in up to 20% of COVID-19 patients, yet the cause of myocardial histopathology remains unknown. In order to study the cause of myocardial pathology in COVID-19 patients, we used a hamster model to determine whether following infection SARS-CoV-2, the causative agent of COVID-19, can be detected in heart tissues. Here, we clearly demonstrate that viral RNA and nucleocapsid protein is present in cardiomyocytes in the hearts of infected hamsters. Interestingly, functional cardiomyocyte associated gene expression was decreased in infected hamster hearts, corresponding to an increase in reactive oxygen species (ROS). This data using an animal model was further validated using autopsy heart samples of COVID-19 patients. Moreover, we show that both human pluripotent stem cell-derived cardiomyocytes (hPSC-derived CMs) and adult cardiomyocytes (CMs) can be infected by SARS-CoV-2 and that CCL2 is secreted upon SARS-CoV-2 infection, leading to monocyte recruitment. Increased CCL2 expression and macrophage infiltration was also observed in the hearts of infected hamsters. Using single cell RNA-seq, we also show that macrophages are able to decrease SARS-CoV-2 infection of CMs. Overall, our study provides direct evidence that SARS-CoV-2 infects CMs in vivo and proposes a mechanism of immune-cell infiltration and pathology in heart tissue of COVID-19 patients.

Background To evaluate long-term effects of a multifactorial lifestyle intervention on measures of quality-of-life (QoL) in children with obesity. Methods One hundred and twenty children age 4-17 years with a BMI standard deviation score (BMI-SDS) >2 participated in a multifactorial lifestyle intervention. QoL and wellbeing were measured by a 6-item Visual Analogue Scale (VAS) throughout the intervention.Results Follow-up time was 26.4 months (13.9 SD). VAS scores decreased on bullying (0.6 vs. 0.0 median) and in motivation (10.0 vs. 9.6). QoL increased in children with a BMI-SDS reduction (0.65 (2.49 SD)) opposite children with no-change or increasing BMI-SDS who reported reduced QoL (-0.36 (1.55 SD) and -0.96 (2.27 SD)). Boys experienced reduced appetite (6.7 (2.3 SD) to 5.7 (2.6 SD)), bullying (median 0.4 vs. 0.0) and motivation (median 10.0 vs. 8.9), while girls experienced reduction in bullying (median 0.6 vs. 0.0) and an enhancement in Joy of Life compared to boys (0.73 (2.10 SD) vs. -0.04 (2.08 SD)).Conclusion Multifactorial lifestyle intervention for children with obesity induces long-term BMI-SDS reduction for the majority, and exerts significant reduction in bullying and improves QoL if weight loss is obtained and maintained.

To interfere with the biology of SARS-CoV-2, the virus responsible for the COVID-19 pandemic, we focused on restoring the transcriptional response induced by infection. Utilizing expression patterns of SARS-CoV-2-infected cells, we identified a region in gene expression space that was unique to virus infection and inversely proportional to the transcriptional footprint of known compounds characterized in the Library of Integrated Network-based Cellular Signatures. Here we demonstrate the successful identification of compounds that display efficacy in blocking SARS-CoV-2 replication based on their ability to counteract the virus-induced transcriptional landscape. These compounds were found to potently reduce viral load despite having no impact on viral entry or modulation of the host antiviral response in the absence of virus. RNA-Seq profiling implicated the induction of the cholesterol biosynthesis pathway as the underlying mechanism of inhibition and suggested that targeting this aspect of host biology may significantly reduce SARS-CoV-2 viral load.

The rising threat of pandemic viruses, such as SARS-CoV-2, requires development of new preclinical discovery platforms that can more rapidly identify therapeutics that are activein vitroand also translatein vivo. Here we show that human organ-on-a-chip (Organ Chip) microfluidic culture devices lined by highly differentiated human primary lung airway epithelium and endothelium can be used to model virus entry, replication, strain-dependent virulence, host cytokine production, and recruitment of circulating immune cells in response to infection by respiratory viruses with great pandemic potential. We provide a first demonstration of drug repurposing by using oseltamivir in influenza A virus-infected organ chip cultures and show that co-administration of the approved anticoagulant drug, nafamostat, can double oseltamivir’s therapeutic time window. With the emergence of the COVID-19 pandemic, the Airway Chips were used to assess the inhibitory activities of approved drugs that showed inhibition in traditional cell culture assays only to find that most failed when tested in the Organ Chip platform. When administered in human Airway Chips under flow at a clinically relevant dose, one drug – amodiaquine - significantly inhibited infection by a pseudotyped SARS-CoV-2 virus. Proof of concept was provided by showing that amodiaquine and its active metabolite (desethylamodiaquine) also significantly reduce viral load in both direct infection and animal-to-animal transmission models of native SARS-CoV-2 infection in hamsters. These data highlight the value of Organ Chip technology as a more stringent and physiologically relevant platform for drug repurposing, and suggest that amodiaquine should be considered for future clinical testing.

Introduction: Obesity in children and adolescents are increasing worldwide with a parallel increase in the risk of developing severe psychosocial problems, type 2 diabetes, non-alcoholic fatty liver disease, hypertension, and in adulthood overt cardiovascular disease, cancer and premature death. In Denmark 3% of children (9-13 yrs.) and 7% of adolescents (16-24 yrs.) are considered obese and it is essential to prevent and treat obesity in order to attenuate the development of obesity-related diseases. Theory and Methods: Obesity is defined as a body mass index (BMI=kg/m2) above the 99th percentile for age and sex, or an iso-BMI > 30 kg/m2. We identified 201 children age 3-17 yrs. with obesity in our outpatient clinic. The children and their families (aka patients) were included from January 2014 to December 2017 and they were referred from general practitioners and healthcare providers in the municipalities of Randers, other hospital departments, or as self-directed to our clinic. Each patient received an individual treatment plan according to the guidelines as described in the Holbaek-method. This treatment plan describes in a very structured and detailed manner the number of daily meals, contents of the meals, recommendations for grocery shopping, amount and type of activity, screen time, amount of weekly sweetened beverages, candy, chips, and daily fruit. After initial screening the patients were followed-up as a joint-venture between healthcare providers in their local community/municipality and the department of pediatrics. The patients were supported by their healthcare provider in their local community/municipality 4-5 times each year, where they were encouraged to comply to their individual treatment plan and body weight, height, waist and hip circumference, and bioimpedance were assessed. The patients were invited to the department of pediatrics once yearly where their body weight, height, waist, hip, BMI, and bioimpedance were assessed. In addition, total body fat and lean body mass was measured by a DEXA-scan. Blood samples were drawn to measure liver enzymes, thyroid function, HbA1c, fasting blood glucose, blood lipids, and electrolytes including urea. Quality of life was examined by visual analogue scales. Our criteria of success was, that at least 65% patients had obtained a reduction in z-score BMI after 2 years and/or that 90% of the patients performed exercise on a regular basis (several times each week). Results: All 201 patients have completed their participation in the project and data analyses are pending. Conclusion: We propose that this trial will assist us in the development of new knowledge in order to empower families and thereby provide better strategies to engage communities and understand, treat, and prevent obesity in children.

The emergence and spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant global morbidity, mortality, and societal disruption. A better understanding of virus-host interactions may potentiate therapeutic insights toward limiting this infection. Here we investigated the dynamics of the systemic response to SARS-CoV-2 in hamsters by histological analysis and transcriptional profiling. Infection resulted in consistently high levels of virus in the upper and lower respiratory tracts and sporadic occurrence in other distal tissues. A longitudinal cohort revealed a wave of inflammation, including a type I interferon (IFN-I) response, that was evident in all tissues regardless of viral presence but was insufficient to prevent disease progression. Bolstering the antiviral response with intranasal administration of recombinant IFN-I reduced viral disease, prevented transmission, and lowered inflammation in vivo. This study defines the systemic host response to SARS-CoV-2 infection and supports use of intranasal IFN-I as an effective means of early treatment., Graphical abstract, The host response to SARS-CoV-2 results in significant inflammation. To understand this biology, Hoagland et al. utilize infected hamsters to elucidate transcriptional footprints across tissues longitudinally, showing an inflammatory response beyond the site of acute replication. Local administration of IFN-I reduces virus load and improves immune infiltrate.

Summary Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19., Graphical Abstract, Highlights • SARS-CoV-2 infection induces low IFN-I and -III levels with a moderate ISG response • Strong chemokine expression is consistent across in vitro, ex vivo, and in vivo models • Low innate antiviral defenses and high pro-inflammatory cues contribute to COVID-19, In comparison to other respiratory viruses, SARS-CoV-2 infection drives a lower antiviral transcriptional response that is marked by low IFN-I and IFN-III levels and elevated chemokine expression, which could explain the pro-inflammatory disease state associated with COVID-19.

A study is presented on how well possible drug-molecules can be predicted with respect to their function and binding to a selection of neuro-receptors by the use of artificial neural networks. The ligands investigated in this study are chosen to be corresponding to the G protein-coupled receptors µ-opioid, serotonin 2B (5-HT 2B ) and metabotropic glutamate D5. They are selected due to the availability of pharmacological drug-molecule binding data for these receptors. Feedback and deep belief artificial neural network architectures (NNs) were chosen to perform the task of aiding drugdesign. This is done by training on structural features, selected using a “minimum redundancy, maximum relevance”-test, and testing for successful prediction of categorized binding strength. An extensive comparison of the neural network performances was made in order to select the optimal architecture. Deep belief networks, trained with greedy learning algorithms, showed superior performance in prediction over the simple feedback NNs. The best networks obtained scores of more than 90 % accuracy in predicting the degree of binding drug molecules to the mentioned receptors and with a maximal Matthew's coefficient of 0.925. The performance of 8 category networks (8 output classes for binding strength) obtained a prediction accuracy of above 60 %. After training the networks, tests were done on how well the systems could be used as an aid in designing candidate drug molecules. Specifically, it was shown how a selection of chemical characteristics could give the lowest observed IC50 values, meaning largest bio-effect pr. nM substance, around 0.03-0.06 nM. These ligand characteristics could be total number of atoms, their types etc. In conclusion, deep belief networks trained on drug-molecule structures were demonstrated as powerful computational tools, able to aid in drug-design in a fast and cheap fashion, compared to conventional pharmacological techniques.

Common variable immunodeficiency is the second most common primary immunodeficiency with a prevalence of approx. 1/10.000-50.000. The clinical challenge is early diagnosis and efficient supportive treatment. The purpose of the present article is to focus on the complexity of the disease, including the risk of a long pre-diagnostic period and to focus on the sarcoidosis-like variant and the possible impact of immunoglobulin subclass deficiency.