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This study investigates the co-creation process between course facilitators and students while the course takes place at recovery colleges (RCs), emphasising the synergistic partnership where individuals with lived experience of mental health issues collaborate with professionals in course delivery. This paper focuses on understanding the dynamics of these interactions from the students’ perspectives and the dynamic shifts between the private realm and the public space. We conducted a qualitative study inspired by critical ethnography, collecting data from participatory observations in RCs at two locations and focus group interviews with students. Goffman’s dramaturgical approach guided us in examining social interactions in RC as theatrical performances with students playing specific roles, managing impressions, and navigating the front and backstage of their lives. During the analysis, we separated the data into front- and backstage contexts where we identified moments where students were actively performing a social role and moments revealing more authentic sides of themselves. We demonstrate that a RC is a stage where students can test their performance and adapt to their audience’s reactions. Uncertainty about their roles, social scripts, and the audience’s reactions lead them to switch between front- and backstage appearances, either performing a role or revealing their authentic sides. While exploring appearances, students develop social scripts aligning with their roles as performers and audience, eventually promoting security by mutual understanding of appropriate appearances. Emotional support, collaborative relationships, and group dynamics were critical factors in fostering an environment conducive to authentic participation. Challenges persist, such as vulnerability, recognizing the value of personal contributions, and establishing personal boundaries. Safety within the college environment was paramount for genuine engagement in co-creation, leading to personal and collective benefits for mental health services. The study suggests an in-depth investigation into the structural and power dynamics that shape such interactive processes within RCs.

Background: Immunological mechanisms have been implicated in the development of mental disorders, and interestingly, case reports have suggested that hematopoietic stem cell transplantation (HSCT) can both transmit and cure psychotic disorders by replacing immune progenitor cells. Methods: Using Danish registers, we followed patients who received HSCT from donors with a psychiatric diagnosis or psychotropic medication use. We assessed risk of incident mental disorders or psychotropic medication use compared with recipients with unaffected donors. We identified 464 donor-recipient pairs (51.3% male recipients). All donor-recipient pairs were related. Results: Receiving HSCT from a donor with a psychiatric history was not significantly associated with incident psychiatric diagnoses (hazard rate ratio [HRR] 2.79, 95% CI, 0.83–9.39; p = .098) or incident use of psychotropics (HRR 1.43, 95% CI, 0.91–2.24; p = .118). Subgroup analysis showed an increased risk of antipsychotic use, which remained significant after adjusting for confounders (HRR 4.73, 95% CI, 1.26–17.78; p = .021); however, this was based on a small number of cases. For depression and antidepressant use, data were available to perform a meta-analysis of our and one additional study, which showed no significant difference (HRR 1.24, 95%, CI 0.66–2.35). Conclusions: Receiving HSCT from a donor with a psychiatric history did not affect risk of mental disorders. An increased risk of antipsychotic use was observed only in subgroup analyses; however, the exploratory nature of the study, the limited sample size, and family relationship between donors and recipients do not allow for causal conclusions, and external replication studies are warranted.

Background: Radicular pain is the most predominant symptom among adults with Lyme neuroborreliosis (LNB) but the duration preceding and following diagnosis remains unknown. We aimed to investigate whether patients with LNB have increased obtainment of analgesics before and after diagnosis and for how long. Methods: We performed a nationwide, population-based, matched cohort study (2009–2021). all Danish residents with LNB (positive Borrelia burgdorferi intrathecal antibody index test and cerebrospinal fluid pleocytosis) were included. To form a comparison cohort, individuals from the general population were randomly extracted and matched 10:1 to patients with LNB on age and sex. Outcomes were obtainment of simple analgesics, antiepileptics, tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, tramadol, and other opioids. We calculated monthly and six-monthly proportions of individuals with obtainment of analgesics and absolute risk differences. Results: 1,056 patients with LNB and 10,560 comparison cohort members were included. An increased proportion of patients with LNB obtained analgesics from 3 months before study inclusion, especially simple analgesics, tramadol, and other opioids. Within the 0–1-month period after study inclusion, patients with LNB most frequently obtained simple analgesics (15 %), antiepileptics (11 %), and tramadol (10 %). Thereafter, obtainment of analgesics declined within a few months. A slightly larger proportion of patients with LNB obtained antiepileptics up to 2.5 years after diagnosis. Conclusions: Up to 3 months preceding diagnosis, LNB was preceded by increased obtainment of analgesics, which suggests diagnostic delay. Importantly, most patients with LNB did not obtain analgesics after the immediate disease course, although obtainment remained more frequent up to 2.5 years after.

Objective: Our primary objectives are to assess whether intraarticular corticosteroid injections are superior to saline injections with regards to thumb base pain after 4 weeks, and to compare the efficacy of steroid injections, saline injections, and an occupational therapy intervention on thumb base pain after 12 weeks in people with painful inflammatory osteoarthritis (OA) of the first carpometacarpal (CMC-1) joint. Design: In this three-armed, double-blind, randomized multicenter trial, 354 participants with painful inflammatory CMC-1 OA from six Norwegian hospitals are recruited. Participants are randomized 1:1:1 to intraarticular steroid or saline injections in the CMC-1 joint or a multimodal occupational therapy intervention. The primary outcomes are thumb base pain measured on a numeric rating scale (NRS, range: 0–10) after 4 weeks and 12 weeks. Key secondary outcomes include synovitis by Magnetic Resonance Imaging (MRI) after 4 weeks and hand function by the Measure of Activity Performance of the Hand (MAP-Hand) questionnaire after 12 and 24 weeks. Other secondary outcomes are synovitis by clinical examination and ultrasound, measures of pain, function, stiffness, and health-related quality of life, and direct and indirect costs. Adverse events are recorded at each visit. The duration of the randomized controlled trial is 24 weeks, followed by an 80-week open-label observational phase to investigate the long-term efficacy and safety of repeated steroid injections and the occupational therapy intervention. Conclusions: The results from this trial will have important clinical implications and influence future guidelines on OA management of the CMC-1 joint. Clinical trial registration: EU-CT 2023-505254-17-00, NCT06084364.

Background and purpose: As preparation for a national randomized study comparing proton radiotherapy to photon radiotherapy, DAHANCA 35, we performed a non-randomized pilot study to investigate patient selection, logistics, planning, and treatment delivery. With the present study, as a comprehensive safety analysis, we want to compare toxicity during and up to two months after therapy to a historically matched group of patients treated with photon radiotherapy. Materials and methods: 62 patients treated with protons were matched to 124 patients who received photon treatment outside a protocol. Available data were retrieved from the DAHANCA database. Patients were matched on treatment centre, concurrent chemotherapy, tumour site, stage, p16 status for oropharynx cancers. Selection of patients for proton therapy was based on comparative treatment plans with a NTCP reduction for dysphagia and xerostomia at six months. Results: Baseline characteristics between groups were well balanced, except for the type of drug used concurrently; more photon patients received Carboplatin (21.2 % vs 5.8 %, p = 0.01). Proton therapy was associated with significantly less weight loss at the end of treatment, mean weight loss of 3 % for protons and 5 % for photons (p

The clinical presentation of CD21 deficiency in 2 siblings caused by a novel mutation in the CD21 gene is reported, and the frequency of this mutation in the Danish population is explored. Successful treatment with IgG replacement in both patients with CD21 deficiency is also reported.

In this study, an experimental assessment of the performance of carbon black nanofluids in a direct absorption solar collector was conducted. Unlike traditional direct absorption solar collectors, the laboratory setup in the present work utilized stationary nanofluids for solar absorption, which later heated a secondary fluid (water). This approach enabled the elimination of the need for pumping nanofluids within the system, thus reducing pumping costs and maintenance requirements. The efficiency of various nanoparticle concentrations was investigated and evaluated under identical conditions. Among the six nanofluids examined in the experimental analysis, ranging from 0.0015 to 0.05 wt.%, the most effective concentration was found to be 0.01 wt.% with a thermal enhancement of 42%, as compared to the reference distilled water values.

Converting arable land to permanent grassland may favor SOC sequestration and thus climate change mitigation. We studied a field experiment on coarse sand soil that during 1894–1997 was under arable rotation with various nutrient treatments (unfertilized, mineral fertilizer, animal manure), leading to topsoils with different SOC contents. In 1998, the treatments stopped, and a semi-natural grassland has been established with topsoil sampled seven times during the following 26 years. Introduction of grassland increased topsoil SOC content linearly at a rate of 0.30 ± 0.01 Mg C ha−1 yr−1, unaffected by pre-conversion SOC level and with no sign of steady state. By mitigating the loss of SOC associated with continued arable cropping, the overall benefit of this land conversion becomes 0.39 Mg C ha−1 yr−1 during the period 1998 to 2023.

Background: Lyme borreliosis is a tick-borne disease caused by the bacterium Borrelia burgdorferi (Bb) sensu lato complex. Previous studies have suggested an association between Lyme borreliosis and heart failure, which have been suggested to be a possible manifestation of Lyme carditis. We aimed to investigate the risk of heart failure among individuals tested for serum Bb antibodies, and serum Bb seropositive individuals. Methods: We performed a matched nationwide cohort study (Denmark, 1993–2020) and included 52,200 Bb seropositive individuals, and two age- and sex-matched comparison cohorts: 1) 104,400 Bb seronegative comparison cohort members, and 2) 261,000 population controls. We investigated the risk associated with 1) being tested for serum Bb antibodies, and 2) being Bb seropositive. Outcomes were: 1) a composite of heart failure, cardiomyopathy, and/or myocarditis diagnosis, and 2) redemption of cardiovascular medicine used for treatment of heart failure. We calculated short-term odds ratios (aOR) (within 1 month) and long-term hazard rates (aHR) (after 1 month) adjusted for age, sex, diabetes, pre-existing heart failure, and kidney disease. Results: Compared with the population controls, individuals tested for Bb antibodies, regardless of the test result, had increased short-term risk of heart failure, cardiomyopathy, and myocarditis (aOR 8.3, 95 %CI: 6.7–10.2), and both increased short- and long-term risk of redemption of cardiovascular medicine (aOR 4.3, 95 %CI: 3.8–4.8, aHR 1.13, 95 % CI: 1.11–1.15). The Bb seropositive individuals had no increased short- or long-term risk of any outcome compared with Bb seronegative comparison cohort members. Conclusions: In conclusion, Bb antibody tests seemed to be performed in the diagnostic work-up of heart failure, but Bb seropositivity was not associated with heart failure.

Aim: To determine whether targeting mild hypercapnia (PaCO2 7 kPa) would yield improved cerebral blood flow and metabolism compared to normocapnia (PaCO2 5 kPa) with and without targeted temperature management to 33 °C (TTM33) in a porcine post-cardiac arrest model. Methods: 39 pigs were resuscitated after 10 minutes of cardiac arrest using cardiopulmonary bypass and randomised to TTM33 or no-TTM, and hypercapnia or normocapnia. TTM33 was managed with intravasal cooling. Animals were stabilized for 30 minutes followed by a two-hour intervention period. Hemodynamic parameters were measured continuously, and neuromonitoring included intracranial pressure (ICP), pressure reactivity index, cerebral blood flow, brain-tissue pCO2 and microdialysis. Measurements are reported as proportion of baseline, and areas under the curve during the 120 min intervention period were compared. Results: Hypercapnia increased cerebral flow in both TTM33 and no-TTM groups, but also increased ICP (199% vs. 183% of baseline, p = 0.018) and reduced cerebral perfusion pressure (70% vs. 84% of baseline, p

Introduction: Patients with failure after primary radiotherapy (RT) for head and neck squamous cell carcinoma (HNSCC) have a poor prognosis. This study investigates pattern of failure after primary curatively intended IMRT in a randomized controlled trial in relation to HPV/p16 status. Material and methods: Patients with HNSCC of the oral cavity, oropharynx (OPSCC), hypopharynx or larynx were treated with primary curative IMRT (+/-cisplatin) and concomitant nimorazole between 2007 and 12. Of 608 patients, 151 had loco-regional failure within five years, from whom 130 pairs of scans (planning-CT and diagnostic failure scan) were collected and deformably co-registered. Point of origin-based pattern of failure analysis was conducted, including distance to CTV1 and GTV, and estimated dose coverage of the point of origin. Results: Of 130 patients with pairs of scans, 104 (80 %) had at least one local or regional failure site covered by 95 % of prescribed dose and 87 (67 %) of the failures had point of origin within the high-dose CTV (CTV1). Of failures from primary p16 + OPSCC, the majority of both mucosal (84 %) and nodal (61 %) failures were covered by curative doses. For p16− tumors (oral cavity, OPSCC p16neg, hypopharynx and larynx), 75 % of mucosal and 66 % of nodal failures were high-dose failures. Conclusion: Radioresistance is the primary cause of failure after RT for HNSCC irrespective of HPV/p16 status. Thus, focus on predictors for the response to RT is warranted to identify patients with higher risk of high-dose failure that might benefit from intensified treatment regimens.

Background & Aims: Cognitive dysfunction is an increasingly recognised manifestation of metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanistic link remains unclear. The aim of this study was to investigate the hypothesis that experimental MASLD leads to cognitive dysfunction via systemic inflammation and neuroinflammation. Methods: Twenty male Sprague Dawley rats were randomised to a high-fat high-cholesterol (HFHC) diet to induce MASLD, or a standard diet (n = 10/group), for 16 weeks. Assessments included: MASLD severity (histology), neurobehaviour, inflammation (liver, plasma and cerebrospinal fluid), brain microglia and astrocyte activation, and synaptic density. Results: The HFHC diet induced MASLD with extensive steatosis and lobular inflammation without fibrosis. Several plasma cytokines were elevated (CXCL1, IL-6, IL-17, MIP-1α, MCP-1, IL-10; all p

Aim: Compare lung injury and hemodynamic effects in synchronized ventilations (between two chest compressions) vs. unsynchronized ventilations during cardiopulmonary resuscitation (CPR) in a porcine model of cardiac arrest. Methods: Twenty pigs were randomized to either synchronized or unsynchronized group. Ventricular fibrillation was induced electrically and left for 1.5 minutes. Four minutes of basic chest compression:ventilation (30:2) CPR was followed by eight minutes of either synchronized or unsynchronized ventilations (10/min) during continuous compressions before defibrillation was attempted. Aortic, right atrial and intracerebral pressures, carotid and cerebral blood flow and cardiac output were measured. Airway monitoring included capnography and respiratory function monitor. Macro- and microscopic lung injuries were assessed post-mortem. Results: There were no significant differences between groups in any of the measured hemodynamic variables or inspiration time (0.4 vs. 1.0 s, p = 0.05). The synchronized ventilation group had lower median peak inspiratory airway pressure (57 vs. 94 cm H2O, p

Introduction: Renal functional response (RFR) is the acute increase in glomerular filtration rate (GFR) after a protein load. Low RFR is a marker of single nephron hyperfiltration. Low birth weight (LBW) is associated with reduced number of nephrons, lower kidney function, and smaller kidneys in adults. In the present study, we investigate the associations among LBW, kidney volume, and RFR. Methods: We studied adults aged 41 to 52 years born with either LBW (≤2300 g) or normal birth weight (NBW; 3500–4000 g). GFR was measured using plasma clearance of iohexol. A stimulated GFR (sGFR) was measured on a separate day after a protein load of 100 g using a commercially available protein powder, and RFR was calculated as delta GFR. Kidney volume was estimated from magnetic resonance imaging (MRI) images using the ellipsoid formula. Results: A total of 57 women and 48 men participated. The baseline mean ± SD GFR was 118 ± 17 ml/min for men and 98 ± 19 ml/min for women. The overall mean RFR was 8.2 ± 7.4 ml/min, with mean RFR of 8.3 ± 8.0 ml/min and 8.1 ± 6.9 ml/min in men and women, respectively (P = 0.5). No birth-related variables were associated with RFR. Larger kidney volume was associated with higher RFR, 1.9 ml/min per SD higher kidney volume (P = 0.009). Higher GFR per kidney volume was associated with a lower RFR, −3.3ml/min per SD (P < 0.001). Conclusion: Larger kidney size and lower GFR per kidney volume were associated with higher RFR. Birth weight was not shown to associate with RFR in mainly healthy middle-aged men and women.

Summary: Background: Hand hygiene (HH) by healthcare workers (HCWs) is one of the most important measures to prevent hospital-acquired infections. However, HCWs struggle to adhere to HH guidelines. We aimed to investigate the effect of a non-resource intensive intervention with group and individual feedback on HCWs HH in a real-life clinical practice during the COVID-19 pandemic. Methods: In 2021, an 11-month prospective, interventional study was conducted in two inpatient departments at a Danish university hospital. An automated hand hygiene monitoring system (Sani Nudge™) was used to collect data. HH opportunities and alcohol-based hand rub events were measured. Data were provided as HH compliance (HHC) rates. We compared HHC across 1) a baseline period, 2) an intervention period with weekly feedback in groups, followed by 3) an intervention period with weekly individual feedback on emails, and 4) a follow-up period. Results: We analyzed data from physicians (N=65) and nurses (N=109). In total, 231,022 hygiene opportunities were analyzed. Overall, we observed no significant effect of feedback, regardless of whether it was provided to the group or individuals. We found a trend toward a higher HHC in staff restrooms than in medication rooms and patient rooms. The lowest HHC was found in patient rooms. Conclusions: The automated hand hygiene monitoring system enabled assessment of the interventions. We found no significant effect of group or individual feedback at the two departments. However, other factors may have influenced the results during the pandemic, such as time constraints, workplace culture, and the degree of leadership support.

The Climate Change Act recently enacted in Germany highlights the urgency of understanding the future demand for renewable fuels. In this study, we combine technological progress and socio-economic pathways in an energy system analysis to assess future renewable fuel demands in Germany. We apply the whole-system optimisation model, TIMES, to investigate transition pathways with varying electrification levels and socio-economic developments. The results show that renewable fuels demand varies between 388 PJ and 1310 PJ depending on the electrification rates. Furthermore, our findings demonstrate that considering socio-economic aspects and behavioural change, as represented by different Shared-Socio-economic Pathways, can significantly alter the demand for renewable fuels within a narrower yet still noteworthy range compared to the electrification scenarios. This provides country-level evidence highlighting the often-overlooked influence of social developments on demand projections. Consequently, it becomes crucial to prioritize the consideration of the climate mitigation potential arising from socioeconomic-induced changes in demand patterns within the broader framework of energy efficiency measures.

Purpose: Effective leadership across all areas of radiation oncology (RO) is vital to fully realise the benefits of radiation therapy in cancer care. We report outcomes of a novel interdisciplinary leadership program designed for RO professionals under a global joint society initiative. Methods: The Foundations of Leadership in RO (FLiRO) program was designed for aspiring RO leaders. Initially delivered in a blended learning format, it was adapted to fully virtual in 2021. It comprised a webinar tutorial, on-line modules and homework followed by ‘live’ in-person/virtual workshops over an approximately 6-week period. Topics included personal awareness, effective teamwork, quality improvement skills, leading change and conflict management. An immediate post-program online survey was performed using Likert scales to measure self-reported educational value, interaction with others and the likely application of learning to practice. Open comments were invited. Results: 170 participants from 36 countries and 6 continents took part from 2018 to 2021 (99 doctors, 36 physicists, 32 radiation therapists/RTTs and 3 others). 141 (83%) participants responded to the post-program survey. Average weightings for responders’ views on whether pre-determined learning objectives were met ranged from 4.30 to 4.61 on a 5-point scale (1 = ‘not met at all’ and 5 = completely met). For the question addressing potential value of learning for application to their workplace, 124 of 130 (95%) of responders indicated that FLIRO would be ‘very useful’ or ‘extremely useful’. Conclusion: Initial evaluation of the FLiRO program supports its continuation and expansion with ongoing evolution based on emerging evidence around leadership education and participant feedback.

Introduction: During the COVID-19 pandemic the ESTRO School who provides international non-profit postgraduate education in Radiation Oncology and related disciplines, including Medical Physics and Radiation Technology, had to close down all live educational activities and turn online, although having only limited experience. The paper describes the experience, discusses the limitations and benefits of online education and suggests directions for the future. Materials and methods: Data about format and feedback from attendees and faculty members from the course activities held in 2019, 2020 and 2021 were made available from the ESTRO School. Results: In 2020, all but two out of thirty live courses that happened before the lockdown were canceled. Among the 18 courses scheduled in the second half of the year, seven went online with a short notice. Each course planned their activities quite differently, from compressed courses with consecutive full days online program to courses over several weeks with a few hours online a week. Both numbers of participants and different nationalities were higher than live courses in 2019 for the seven courses happening online, and courses were well evaluated by participants and faculties. Roughly-one-third of participants would prefer online courses in the future. Discussion: Although online education was well received by the majority, pros and cons exist and especially the personal discussions and networking were missed. Online education and live education are not comparable but can complement each other. Careful balancing these activities in the future is important and strategies for online andragogy are needed.

The field of radiation oncology is rapidly advancing through technological and biomedical innovation backed by robust research evidence. However, cancer professionals are notoriously time-poor, meaning there is a need for high quality, accessible and tailored oncologic education programs. While traditional teaching methods including lectures and other in-person delivery formats remain important, digital learning (DL) has provided additional teaching options that can be delivered flexibly and on-demand from anywhere in the world.While evidence of this digital migration has been evident for some time now, it has not always been met with the same enthusiasm by the teaching community, in part due to questions about its pedagogical effectiveness. Many of these reservations have been driven by a rudimentary utilisation of the medium and inexperience with digital best-practice. With increasing familiarity and understanding of the medium, increasingly sophisticated and pedagogically-driven learning solutions can be produced.This article will review the application of immersive digital learning tools in radiation oncology education. This includes first and second-generation Virtual Reality (VR) environments and Augmented Reality (AR). It will explore the data behind, and best-practice application of, each of these tools as well as giving practical tips for educators who are looking to implement (or refine) their use of these learning methods. It includes a discussion of how to match the digital learning methods to the content being taught and ends with a horizon scan of where the digital medium may take us in the future. This article is the second in a two-part series, with the companion piece being on Screen-Based Digital Learning Methods in Radiation Oncology.Overall, the digital space is well-placed to cater to the evolving educational needs of oncology learners. Further uptake over the next decade is likely to be driven by the desire for flexible on demand delivery, high-yield products, engaging delivery methods and programs that are tailored to individual learning needs. Educational programs that embrace these principles will have unique opportunities to thrive in this space.

Summary: Mechanistically, the symptomatology and disease progression of non-alcoholic fatty liver disease (NAFLD) remain poorly understood, which makes therapeutic progress difficult. In this review, we focus on the potential importance of decreased urea cycle activity as a pathogenic mechanism. Urea synthesis is an exclusive hepatic function and is the body’s only on-demand and definitive pathway to remove toxic ammonia. The compromised urea cycle activity in NAFLD is likely caused by epigenetic damage to urea cycle enzyme genes and increased hepatocyte senescence. When the urea cycle is dysfunctional, ammonia accumulates in liver tissue and blood, as has been demonstrated in both animal models and patients with NAFLD. The problem may be augmented by parallel changes in the glutamine/glutamate system. In the liver, the accumulation of ammonia leads to inflammation, stellate cell activation and fibrogenesis, which is partially reversible. This may be an important mechanism for the transition of bland steatosis to steatohepatitis and further to cirrhosis and hepatocellular carcinoma. Systemic hyperammonaemia has widespread negative effects on other organs. Best known are the cerebral consequences that manifest as cognitive disturbances, which are prevalent in patients with NAFLD. Furthermore, high ammonia levels induce a negative muscle protein balance leading to sarcopenia, compromised immune function and increased risk of liver cancer. There is currently no rational way to reverse reduced urea cycle activity but there are promising animal and human reports of ammonia-lowering strategies correcting several of the mentioned untoward aspects of NAFLD. In conclusion, the ability of ammonia-lowering strategies to control the symptoms and prevent the progression of NAFLD should be explored in clinical trials.

Biliary atresia (BA) is a rare congenital liver disease with unknown etiology, and it is the most common indication for liver transplantation in children. As BA infants suffer from intestinal malabsorption and neurodevelopmental deficits, it is necessary to identify optimal medical and nutritional strategies using appropriate neonatal animal models. We aim to determine the feasibility of using newborn piglets with surgically induced cholestasis (bile duct ligation (BDL)) to mimic clinical features of BA. Six piglets were subjected to abdominal surgery on day 4 after birth. The bile ducts were ligated, and the piglet were followed for up to 12 days. On day 12 the piglets were subjected to a hepatobiliary scintigraphy using the tracer radiolabeled Technetium(99m-tc)-mebrofenin, and blood samples were collected for biochemical profiling. Of the six piglets, hepatobiliary scintigraphy verified that two piglets (BDL) had no excretion of bile into the duodenum, i.e. full cholestasis with a hepatic extraction fraction of 84–87% and clearance time of 230–318 min. One piglet (SHAM) had bile excretion to the duodenum. In accordance with this, the BDL piglets had steatorrhea, and increased levels of bilirubin and gammaglutamyl transferase (GGT). The last three piglets were euthanized due to bile leakage or poor growth. Surgically induced cholestasis in young piglets, may offer an animal model that displays clinical characteristics of biliary atresia, including malabsorption, hyperbilirubinaemia, increased GGT and reduced hepatic excretory function. Following refinement, this animal model may be used to optimize feeding strategies to secure optimal nutrition and neurodevelopment for neonatal cholestasis/BA patients.

Background: Intracranial tumors are commonly approached through a craniotomy, and the bone flap is later reattached with plates and screws. The gap created around the bone flap may cause the skin to submerge, potentially influencing the facial and head aesthetic appearance. The aim of this study was to examine patient satisfaction with cosmetic outcome after craniotomy for intracranial tumor resection. Methods: In a prospective questionnaire-based study, patients were asked to report their degree of satisfaction with the scar and overall cosmetic appearance, and the extent of change to their facial appearance using 0–10 rating scales. The questionnaire was sent six months after surgery to patients undergoing first-time craniotomy for tumor resection at either of two neurosurgical departments. Results: Of the 70 patients included in the study, 49 (70%) completed the questionnaire. Median scores were 9.3 for satisfaction with the scar and 9.0 for overall cosmetic satisfaction (a score of 10 reflected highest satisfaction). The median score was 1.7 for degree of change in facial appearance (a score of 0 reflected no change). However, 24.5% of patients reported major alterations to facial appearance. Satisfaction levels were similar by age, sex, and tumor type, but patients with occipital craniotomies were less satisfied with the overall cosmetic result than those with temporal craniotomies. Conclusion: Most patients were satisfied with the cosmetic outcome of the craniotomy, but a considerable proportion reported major facial alterations. While the level of overall cosmetic satisfaction did not differ according to age, sex, or tumor type, the location of the craniotomy seemed to be a factor in satisfaction with the aesthetic outcome. Further studies are needed to investigate how the cosmetic result from craniotomy could be improved from the patient's perspective.

Background and purpose: Interactive segmentation seeks to incorporate human knowledge into segmentation models and thereby reducing the total amount of editing of auto-segmentations. By performing only interactions which provide new information, segmentation performance may increase cost-effectively. The aim of this study was to develop, evaluate and test feasibility of a deep learning-based single-cycle interactive segmentation model with the input being computer tomography (CT) and a small amount of information rich contours. Methods and Materials: A single-cycle interactive segmentation model, which took CT and the most cranial and caudal contour slices for each of 16 organs-at-risk for head-and-neck cancer as input, was developed. A CT-only model served as control. The models were evaluated with Dice similarity coefficient, Hausdorff Distance 95th percentile and average symmetric surface distance. A subset of 8 organs-at-risk were selected for a feasibility test. In this, a designated radiation oncologist used both single-cycle interactive segmentation and atlas-based auto-contouring for three cases. Contouring time and added path length were recorded. Results: The medians of Dice coefficients increased with single-cycle interactive segmentation in the range of 0.004 (Brain)–0.90 (EyeBack_merged) when compared to CT-only. In the feasibility test, contouring time and added path length were reduced for all three cases as compared to editing atlas-based auto-segmentations. Conclusion: Single-cycle interactive segmentation improved segmentation metrics when compared to the CT-only model and was clinically feasible from a technical and usability point of view. The study suggests that it may be cost-effective to add a small amount of contouring input to deep learning-based segmentation models.

Background: Depression represents the second leading cause of years lived with disability worldwide.1 However, 30 % of patients do not achieve remission after treatment with anti-depressants.2 Effective and fast-acting treatments are needed.Our meta-analysis of placebo-controlled randomized controlled trials measuring effects of anti-inflammatory compounds on depressive symptoms showed that glucocorticoids – although the current evidence is weak – displayed the largest effect size (SMD = 0.90; 95 % CI: 0.36 to 1.44), equivalent to more than double the effect of current anti-depressants, in as little as 1-14 days.3 However, the included studies had only a limited number of patients (nTotal=59) and inadequate reporting of safety outcomes.4,5 Objectives: The DEXA-PSYCH Study will investigate the acute effect and safety of oral dexamethasone compared to placebo as augmentation in treatment of moderate to severe depression. Design: Investigator-initiated, double-blind, parallel-group, superiority, randomized, placebo-controlled clinical trial. Study population: 300 patients from the Mental Health Services in The Capital Region of Denmark will be randomized. Patient from diagnosed with non-psychotic, recurrent or single episode moderate to severe depression are eligible. Exclusion criteria include, but are not limited to, diagnosis of a psychotic disorder, personality disorder, bipolar disorder (or a family history thereof) or disorders that are relative contraindications for treatment with glucocorticoids, including diabetes. Intervention: Orally administered dexamethasone at 4 mg/day for 4 days and subsequently 2 mg/day for 3 days as add-on to treatment as usual (TAU). Outcomes: The primary outcome is change from baseline (day 0) on the Montgomery-Asberg Depression Rating Scale (MADRS10) at day 7. Key secondary outcomes include effects on remission rates, quality of life, suicidal ideation and psychiatric hospitalizations as well as suicide attempts. Safety outcomes and all-cause discontinuation will be reported. Statistics: The primary outcome will be analyzed through a Mixed Model for Repeated Measurements (MMRM) in an intention-to-treat analysis.

The risk of ovarian, tubal, and peritoneal cancer is related to germline pathogenic variants, and over time, the number of known disease-associated genes has increased significantly. This study reviews the literature regarding the topic from a historical perspective. The aim is to present a timeline of the knowledge gained from the early 1900s until today. The findings are put into perspective by looking at the current gene panel used for screening for suspected hereditary ovarian cancer in Denmark compared to what is known internationally. In 1929, the first familial ovarian cancer incidents were registered, and in 1950, the involvement of a genetic component was suggested for the first time. During the 1970s, several studies reported an accumulation of ovarian cancer in certain families, and during this time, it was discovered that ovarian cancer was linked to both breast cancer and colorectal cancer. The inheritance of cancer disposition has been thoroughly investigated, leading to the discovery of the BRCA genes in the 1990s. Furthermore, new studies based on new genetic technologies have revealed several genes with germline pathogenic variants that increase the risk of ovarian cancer. The identification of these pathogenic variants has led to preventive measures and specific treatment of women with genetic disposition to ovarian cancer. In Denmark, consensus is to include at least ten genes in the screening panel for hereditary ovarian cancer, and in the future additional genes will probably be added.

Access to information about risk factors of violence for patients admitted to acute psychiatric wards may be sparse. This prospective study from three acute wards explored associations between items scored “Don't know” and violence during hospital stays (N ​= ​1435) and the first three months after discharge (N ​= ​461) when using a violence risk screening tool (Violence risk screening - 10; V-RISK-10). When V-RISK-10 was scored at admission and “Don't know” was weighted 0 or 1, the area under the curve of the receiver operating characteristics (AUC) was 0.79 and 0.82 for inpatient violence and 0.79 and 0.80 for post-discharge violence. “Don't know” scored at admission was significantly associated with inpatient violence for eight risk items and with violence after discharge for seven items. Numbers of “Don't know” scores decreased substantially at discharge. A substantial proportion of those scores seemed to change into “Maybe/moderate” or “Yes”. There were some differences in single items in the associations of “Don't know” with violence and the distribution of scores. Findings indicate that items scored “Don't know” at the time of admission may be associated with violence during hospital stay and after discharge. More research is needed to elaborate these findings.

Summary: Here, we describe a series of protocols detailing the steps for evaluating SARS-CoV-2 infection in models of the human eye. Included are protocols for whole eye organoid differentiation, SARS-CoV-2 infection, and processing organoids for single-cell RNA sequencing. Additional protocols describe how to dissect and culture adult human ocular cells from cadaver donor eyes and how to compare infection of SARS-CoV-2 and the presence of SARS-CoV-2 entry factors using qPCR, immunofluorescence, and plaque assays.For complete details on the use and execution of this protocol, please refer to Eriksen et al. (2021).

Objectives: Faecal immunochemical tests (FIT) for the detection of haemoglobin are widely used in the diagnostic pathway of colorectal cancer (CRC) in patients presenting with lower abdominal symptoms. Several quantitative immunochemical tests are available, however only a few tests are available on high throughput automated analyzers. Here we report the analytical and clinical evaluation of the Sentinel-FOB Gold assay on the Roche Cobas 8000 automated system. Design: and Methods: The assessment of the analytical performance of the assay on the Roche Cobas analyzer comprised determination of imprecision, accuracy, limit of detection, linearity, carryover and prozone effect. In the clinical evaluation part of the study 163 patients presenting for coloscopy with lower abdominal symptoms were included in the study. Diagnostic accuracy and optimal cutoff of the FIT-assay were determined by comparing faecal haemoglobin (f-Hb) concentrations with coloscopy findings as reference. Results: We confirmed good analytical performance of the assay on the Roche Cobas system. Patients with CRC had significant higher f-Hb concentrations than patients with non-advanced adenomas and patients with normal findings by coloscopy. When applying a cutoff of 10 μg/g the sensitivity and specificity were 96.2% and 51.8%, respectively for CRC and 84.6% and 57.7% for CRC and advanced adenoma. Conclusion: The Sentinel-FOB Gold assay is appropriate for application on the automated Roche Cobas 8000 analyzer. The assay shows good analytical performance on the system. With regard to early detection of significant colorectal diseases a cutoff of 10 μg/g seems to be optimal.

Optical particle counters (OPCs) based on the light extinction measurement scheme are widely used in the industry for monitoring the level of wear debris in lubricating oil systems. In this work it is investigated how model-based size estimation and OPC output data can be correlated. Spherical metal coated 5–20 μm diameter particles were used in a laboratory oil system and monitored using an OPC. The raw OPC output data were extracted with the purpose of estimating the true particle size. Distribution parameters has been deducted from detected minima in output signals for each particle diameter using a half-normal fit centered at the detected kernel peak. Experiments with different sized particles showed that signal minima amplitude distributions differ between particle diameters thus, clearly showing the discrimination ability of the OPC. Furthermore, to obtain OPC based true size determination, the apparent absorption coefficient of the micrometer sized particles must be considered. Thus, reducing the maximum deviation between true and OPC determined diameter to 13%.

This paper studies the design of a mid-scale maritime supply chain for distribution of liquefied natural gas (LNG) from overseas sourcing locations, via a storage located at the coast, before transporting the LNG on land to industrial customers. The case company has signed contracts with a number of initial customers and expect that there will be more customers and increased demand in the years to come. However, it is currently uncertain whether and when new contracts will be signed. To capture this uncertainty with regard to which and how many future customers there will be, which directly affects the demand, we propose a multi-stage stochastic programming model, which maximizes the expected profits of the supply chain. The model aims at aiding decisions concerning the import of LNG, investments in floating storage units and customer distribution systems, and it has been applied on a real case study for distributing LNG to customers in a Brazilian state. It is shown that explicitly considering uncertainty in the modeling of this problem is very important, with a Value of Stochastic Solution of 13.2%, and that there are significant economies of scale in this supply chain. Most importantly, the multi-stage stochastic programming model and the analysis presented in this paper provided valuable decision support and managerial insights for the case company in its process of setting up the LNG supply chain.

The Fusarium mycotoxin deoxynivalenol (DON) and its modified forms are present in most samples of grain and grain-based products. Due to the widespread presence of DON in these highly consumed food commodities, nearly all individuals are exposed to DON. Previous estimates of the dietary DON intake in Norway indicated that children’s dietary intake is close to or exceed the TDI of 1 µg/kg bw/day for the sum of DON and three modified forms. One aim of the current study was to determine whether the concentrations of DON in morning urine differ between population groups like men, women, children, vegetarians, and pregnant women. An additional aim was to compare a set of models for estimating the dietary intake of DON based on urinary DON concentrations and also compare these models with DON-intakes estimated using food consumption data. DON and metabolites were detected in the morning urine from 256 out of 257 individuals and with concentrations in similar range as reported from other countries. Children have higher urinary DON-concentration than adults and elderly. The urinary DON-concentration in pregnant women and vegetarians did not differ from other adults. The estimated intake of DON was higher for children than for other age groups on a body weight basis. The correlations between different models for estimating DON-intake based on urinary concentration as well as based on individual food consumption were good (0.79–0.99), but with some outliers. We conclude that Norwegians are exposed to DON in the same range as reported from other countries and that children have a higher exposure than adults. Furthermore, we conclude that intake estimates based on urinary DON concentration is a useful tool for evaluation of the exposure at population level, but due to outliers, the estimates for individuals are uncertain. There are also uncertainties in intake estimates both from food consumption and from urinary DON concentration, and we could not conclude on which approach provides the most accurate exposure estimate.

Summary: In this Personal View, we examine how the Convention on the Rights of Persons with Disabilities and lived experiences of disability can deepen understanding of four key features of climate-resilient development: social justice and equity as normative goals; the ethical underpinnings of social choices; the inequitable relations that drive marginalisation; and the ways in which society navigates uncertainty through inclusive and contestatory politics. A disability lens not only helps to understand how marginalisation generates vulnerability; it also helps to elaborate the ethic of solidarity as underpinning social choices and steering development towards climate-resilient pathways. Social justice concerns non-discrimination and equitable participation in everyday informal arenas, as well as formal decision making processes. The resilience knowledges of disabled people help to rethink sustainable development by expounding human interdependence and everyday problem solving in the face of uncertainties. They also contribute to opening up climate change decision making and knowledge processes in ways crucial to engendering transformative change. Embracing human diversity by recognising dignity and capacity is required to counter othering and marginalisation, ensure human wellbeing and planetary health, and achieve socially just development. As such, solidarity is not just a normative goal, but also a means of building climate-resilient development.

A deep eutectic solvent (DES) is a eutectic system consisting of hydrogen bond donor and acceptor has been suggested as a promising formulation strategy for poorly soluble drugs. A DES consisting of choline chloride and levulinic acid in a 1:2 molar ratio was used to formulate a liquid solution of the model drug aprepitant. This formulation was tested in vitro (drug release and permeability) and in vivo (rat model) and compared with the performance of amorphous aprepitant and the commercial aprepitant nanocrystalline formulation. In this study a DES formulation is compared for the first time directly to other established enabling formulations. The in vitro drug release study demonstrated that the DES formulation and the amorphous form both were able to induce an apparent supersaturation followed by subsequent drug precipitation. To mitigate the risk of precipitation, HPMC was predissolved in the dissolution medium, which successfully reduced the degree of precipitation. In line with the results from the release study, an in vitro permeation study showed superior permeation of the drug from the DES formulation and from the amorphous form compared to the nanocrystalline formulation. However, the promising in vitro findings could not be directly translated into an increased in vivo performance in rats compared to the nanocrystalline formulation. Whilst the DES formulation (34 ± 4%) showed a higher oral bioavailability compared to amorphous aprepitant (20 ± 4%), it was on par with the oral bioavailability obtained from the nanocrystalline formulation (36 ± 2%).

Summary: Hospital infection control measures against COVID-19 may come into conflict with patients' need for support. In Norway, some hospitals have restricted access for partners of women giving birth. We investigated the incidence rate of SARS-CoV-2 among birthing parents compared to similarly aged women and men in the general population; and the additional risk posed by allowing partners in. Birthing parents often shared infection status and had a slightly lower incidence rate than the general population in the peripartum period. They should not be considered a high-risk group for SARS-CoV-2 infections.

Background: Patients with adult congenital heart disease (ACHD) have many risk factors for chronic pain such as prior cardiac interventions and adult comorbidities. However, the prevalence of chronic pain has not been well described in this population. We sought to determine the prevalence of pain in a large international cohort of patients with ACHD. Methods: Data from the APPROACH-IS dataset was utilized for this study which includes 4028 patients with ACHD from 15 different countries. The prevalence of pain was assessed under the health status patient reported outcome domain utilizing the EuroQol-5D 3 level version tool. Multivariable logistic regression was used to assess differences across countries in pain, taking into account country-level random effects for clustering across observations within each country. Results: A total of 3832 patients with ACHD met the study criteria, median age 32 years [IQR 25, 42], 52.6% females. The prevalence of at least moderate pain was reported by 28.9% (95% CO 27.5 ​= ​30.3%) of participants. Pain was associated with country of origin, age, gender, background, education and marital status as well as several clinical variables including disease complexity, cardiac device presence, history of heart failure, psychiatric conditions and presence of other medical conditions. Those with pain had lower levels of perceived health and a lower quality of life score. Conclusion: Pain in patients with ACHD is common, impacting nearly one-third of patients. Given the far reaching implications of pain in patients with ACHD, further study of pain characteristics and treatment management appear warranted.

The aim of this study is to generate a first global overview of pressures and methods used to assess the environmental quality of rivers and streams using macroinvertebrates. In total, 314 peer-review studies were reviewed, published in the period 1997 – 2018, from developing economies in Africa, South-Central America, Mexico and Southern Asia. To establish a global perspective, the results from the literature review were compared to other compiled datasets, biomonitoring manuals, environmental surveys and literature reviews from Europe, North America and Australasia. The literature review from the developing economies showed that sampling was most usual during baseflow, using kick- or Surber sampling, with taxonomical identification levels mostly to genus or family. Assessments were most often done using metrics (singular and multimetrics; > 70% of the applications) and were based on community attributes related to richness and dominance (58% of studies), sensitivity (40%), diversity by heterogeneity (32%) and functional traits (25%). Within each category, the most used metrics were the richness and dominance of Ephemeroptera, Plecoptera and Trichoptera (EPT), Biological Monitoring Working Party scoring systems (BMWP/ASPT), Shannon-Wiener diversity and feeding traits. Overall, 92% of the reviewed studies reported that the use of macroinvertebrates, at least in some of their responses, was successful in detecting degradation of environmental quality in the investigated rivers. Given the many similarities in applied methods worldwide, at present, we consider that a global assessment of riverine environmental quality can be feasible by using family level identifications of macroinvertebrate samples. We propose a global common metric (multimetric), comprising three of the most common river assessment metrics from the reviewed literature, but also elsewhere, namely the BMWP/ASPT, Shannon-Wiener diversity and richness of EPT. Recent concerns regarding the global state of nature and consequences for freshwater communities, as reported by the intergovernmental science-policy platform on biodiversity and ecosystem services (IPBES), emphasize the urgent need for such a synthesis.

Post-menopausal osteoporosis is characterized by a negative imbalance between bone formation and bone resorption resulting in a net bone loss, increasing the risk of fracture. One of the earliest interventions to protect against this was hormonal replacement therapy (HRT).Bone strength depends on both the amount and quality of bone, the latter including compositional / material and structural properties. Bone compositional / material properties are greatly dependent on both patient-, and tissue-age.Raman spectroscopy is an analytical tool ideally suited for the determination of bone compositional / material properties as a function of tissue age as it is capable of analyzing areas ~1 × 1 μm2 in tetracycline labeled bone forming areas. Using such analysis of humeri from an ovariectomized primate animal model, we reported that loss of estrogen results in alteration in the mineralization regulation mechanisms by osteoid organic matrix attributes at actively forming bone surfaces. In the present work, we used Raman microspectroscopic techniques to compare osteoid and youngest mineralized tissue composition, as well as relationships between osteoid organic matrix quality and quality attributes of the earliest mineralized tissue in paired iliac crest biopsies obtained from early postmenopausal women before and after two years of HRT therapy. Significant correlations between osteoid proteoglycans, sulfated proteoglycans, pyridinoline, and earliest mineralized tissue mineral content were observed, suggesting that in addition to changes in bone turnover rates, HRT affects the osteoid composition, mineralization regulation mechanisms, and potentially fibrillogenesis.

Reepithelialisation is fundamental to wound healing, but our current understanding largely relies on cellular and animal studies. The aim of the present randomised double-blind three-arm controlled trial was to correlate genuine epidermal wound healing with key proteins and topical zinc treatment in humans. Sixty wounds were produced using deroofed suction blisters in 30 healthy volunteers and randomised to topical zinc sulphate (n = 20), placebo (n = 20), or control (n = 20) treatment for 4 days. All wounds with perilesional skin were processed for automatic immunostaining of paraffin tissue sections with monoclonal antibodies against Ki-67, metallothionein (MT) and matrix metalloproteinase (MMP)-1. Protein expression was quantified by automated digital image analysis. Epidermal Ki-67 and MT labelling indices were increased in keratinocytes in the neoepidermis (∼1.1 mm) and at the wound edge (0.5 mm) compared to normal skin. Increased MMP-1 immunostaining was restricted to the neoepidermis. MT was robustly upregulated in the upper dermis of the wounds. Zinc treatment enhanced MMP-1 expression beneath the neoepidermis via paracrine mechanisms and MT under the neoepidermis and in the nonepithelialised wound bed via direct actions of zinc as indicated by the induction of MT2A mRNA but not MMP-1 mRNA in cultured normal human dermal fibroblasts by zinc sulphate. The present human study demonstrates that quantitative immunohistochemistry can identify proteins involved in reepithelialisation and actions of external compounds. Increased dermal MT expression may contribute to the anti-inflammatory activities of zinc and increased MMP-1 levels to promote keratinocyte migration.

Field-based monitoring of deer food availability and browsing on recruiting forest trees is a necessary but labour-intensive task. We explored how such estimates from a low-resolution multipurpose national forest inventory (NFI) (plot density 0.3 km−2) corresponded with estimates from local inventories that specifically and in greater detail monitor the availability of deer food and browsing intensity (LFI) (plot density 2–3 km−2).We used NFI and LFI data from 16 moose Alces alces ranges (mean area 276 ± SE 69 km2) in southern Norway. Only the height segment 30–130 cm of browsable trees could be obtained from the NFI data, while moose can browse trees from 30 to 300 cm in height. According to the LFI, the browse species did not have similar proportions of their browsable stems below 130 cm. Using only the stems from heights of 30–130 cm overestimated the availability of RAS (rowan, aspen and sallow) relative to birch (silver birch and downy birch) and Scots pine.The browsable biomass per stem of each species also varied between ranges, which introduces uncertainty to the food availability estimates that are based on stems only. Nevertheless, the NFI density of stems at 30–130 cm heights can be a useful index for species-specific comparisons of browse availability across ranges, because the variations between ranges in stem densities outweighed the biomass variations per stem. The NFI and LFI estimates of the species-specific densities of stems at 30–130 cm heights were significantly related and close to isometric (1:1), especially for RAS and pine.We did not find strong relationships between NFI and LFI in the browsing intensity (i.e. proportion of shoots that were browsed during the winter). The explained variation was only 11% (R2) for RAS (p = 0.281) and 32% for pine (p = 0.028). This was likely due to the small sample sizes of browsed trees in the NFI and methodological differences between the NFI and LFI in how browsing intensity is estimated. Conclusions: Using data from national forest inventories can be an efficient but low-resolution way to monitor browse availability for deer, provided that the monitoring includes the full range of tree heights reachable for the deer (e.g., 30–300 cm for moose). It is also a prerequisite that the number of NFI plots is sufficient to cover the spatial variability of the area. Regarding browsing intensities, adjustments in both the NFI and LFI approaches are needed to make the two monitoring schemes more comparable.

Objective: Glucagon is well known to regulate blood glucose but may be equally important for amino acid metabolism. Plasma levels of amino acids are regulated by glucagon-dependent mechanism(s), while amino acids stimulate glucagon secretion from alpha cells, completing the recently described liver-alpha cell axis. The mechanisms underlying the cycle and the possible impact of hepatic steatosis are unclear. Methods: We assessed amino acid clearance in vivo in mice treated with a glucagon receptor antagonist (GRA), transgenic mice with 95% reduction in alpha cells, and mice with hepatic steatosis. In addition, we evaluated urea formation in primary hepatocytes from ob/ob mice and humans, and we studied acute metabolic effects of glucagon in perfused rat livers. We also performed RNA sequencing on livers from glucagon receptor knock-out mice and mice with hepatic steatosis. Finally, we measured individual plasma amino acids and glucagon in healthy controls and in two independent cohorts of patients with biopsy-verified non-alcoholic fatty liver disease (NAFLD). Results: Amino acid clearance was reduced in mice treated with GRA and mice lacking endogenous glucagon (loss of alpha cells) concomitantly with reduced production of urea. Glucagon administration markedly changed the secretion of rat liver metabolites and within minutes increased urea formation in mice, in perfused rat liver, and in primary human hepatocytes. Transcriptomic analyses revealed that three genes responsible for amino acid catabolism (Cps1, Slc7a2, and Slc38a2) were downregulated both in mice with hepatic steatosis and in mice with deletion of the glucagon receptor. Cultured ob/ob hepatocytes produced less urea upon stimulation with mixed amino acids, and amino acid clearance was lower in mice with hepatic steatosis. Glucagon-induced ureagenesis was impaired in perfused rat livers with hepatic steatosis. Patients with NAFLD had hyperglucagonemia and increased levels of glucagonotropic amino acids, including alanine in particular. Both glucagon and alanine levels were reduced after diet-induced reduction in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR, a marker of hepatic steatosis). Conclusions: Glucagon regulates amino acid metabolism both non-transcriptionally and transcriptionally. Hepatic steatosis may impair glucagon-dependent enhancement of amino acid catabolism.

The E0 transition depopulating the first-excited 0+ state in 24Mg has been observed for the first time, and the E0 transition strength determined by electron-positron pair and γ-ray spectroscopy measurements performed using the Super-e pair spectrometer. The E0 transition strength is ρ2×103=380(70). A two-state mixing model implies a deformation of the first-excited 0+ state of β2≈1 and a change in the mean-square charge radius of Δ〈r2〉≈1.9fm2, which suggests a significant shape change between the ground state and first-excited 0+ state in 24Mg. The observed E0 strength gives direct evidence of shape coexistence and superdeformation in 24Mg, bringing this nucleus into line with similar behaviour in nearby N=Z nuclei. This result agrees with recent theoretical work on the cluster nature of 24Mg and has potential ramifications for nuclear reactions of astrophysical importance.

Summary: Background: Dietary advice remains the cornerstone of prevention and management of type 2 diabetes (T2D). However, understanding the efficacy of dietary interventions is confounded by the challenges inherent in assessing free living diet. Here we profiled dietary metabolites to investigate glycaemic deterioration and cardiometabolic risk in people at risk of or living with T2D. Methods: We analysed data from plasma collected at baseline and 18-month follow-up in individuals from the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohort 1 n = 403 individuals with normal or impaired glucose regulation (prediabetic) and cohort 2 n = 458 individuals with new onset of T2D. A dietary metabolite profile model (Tpred) was constructed using multivariable regression of 113 plasma metabolites obtained from targeted metabolomics assays. The continuous Tpred score was used to explore the relationships between diet, glycaemic deterioration and cardio-metabolic risk via multiple linear regression models. Findings: A higher Tpred score was associated with healthier diets high in wholegrain (β=3.36 g, 95% CI 0.31, 6.40 and β=2.82 g, 95% CI 0.06, 5.57) and lower energy intake (β=-75.53 kcal, 95% CI -144.71, -2.35 and β=-122.51 kcal, 95% CI -186.56, -38.46), and saturated fat (β=-0.92 g, 95% CI -1.56, -0.28 and β=–0.98 g, 95% CI -1.53, -0.42 g), respectively for cohort 1 and 2. In both cohorts a higher Tpred score was also associated with lower total body adiposity and favourable lipid profiles HDL-cholesterol (β=0.07 mmol/L, 95% CI 0.03, 0.1), (β=0.08 mmol/L, 95% CI 0.04, 0.1), and triglycerides (β=-0.1 mmol/L, 95% CI -0.2, -0.03), (β=-0.2 mmol/L, 95% CI -0.3, -0.09), respectively for cohort 1 and 2. In cohort 2, the Tpred score was negatively associated with liver fat (β=-0.74%, 95% CI -0.67, -0.81), and lower fasting concentrations of HbA1c (β=-0.9 mmol/mol, 95% CI -1.5, -0.1), glucose (β=-0.2 mmol/L, 95% CI -0.4, -0.05) and insulin (β=-11.0 pmol/mol, 95% CI -19.5, -2.6). Longitudinal analysis showed at 18-month follow up a higher Tpred score was also associated lower total body adiposity in both cohorts and lower fasting glucose (β=-0.2 mmol/L, 95% CI -0.3, -0.01) and insulin (β=-9.2 pmol/mol, 95% CI -17.9, -0.4) concentrations in cohort 2. Interpretation: Plasma dietary metabolite profiling provides objective measures of diet intake, showing a relationship to glycaemic deterioration and cardiometabolic health. Funding: This work was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115,317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013) and EFPIA companies.

Background: Blood-brain barrier (BBB) pathology may be associated with mental disorders. The aim of this systematic review and meta-analysis is to identify, evaluate and summarize available evidence on whether potential biomarkers of BBB pathology are altered in patients with schizophrenia spectrum disorders, major depression and bipolar disorder compared to healthy controls. Methods: The primary outcome is blood S100B, while secondary outcomes include biomarkers in blood and/or cerebrospinal fluid, i.e. albumin ratio, fibrinogen, immunoglobulin G, glial fibrillary acidic protein, amyloid beta (Aβ), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases, endothelial glycocalyx constituents, and cell adhesion molecules (CAMs). A systematic search in PubMed, Embase and PsycINFO resulted in 131 eligible studies, of which 93 were included in the meta-analysis. Meta- and subgroup analyses were undertaken using random-effects modelling. The protocol was a priori registered on PROSPERO (CRD42020152721). Results: S100B was increased in schizophrenia spectrum disorders (24 studies; 1107 patients; standardized mean difference (SMD) ​= ​0.82; 95% confidence interval (CI) ​= ​0.51 to 1.13; I2 ​= ​90%), major depression (13 studies; 584 patients; SMD ​= ​0.57; 95% CI ​= ​0.31 to 0.83; I2 ​= ​73%) and bipolar disorder (4 studies; 142 patients; SMD ​= ​0.55; 95% CI ​= ​0.16 to 0.94; I2 ​= ​48%). Similarly, numerous secondary outcomes, including albumin ratio, fibrinogen, Aβ, MMPs and CAMs, were altered. Results of the included studies varied considerably, and important confounders were often not accounted for. Conclusions: The findings implicate occurrence of BBB pathology in patients with schizophrenia spectrum disorders, major depression and bipolar disorder compared to healthy controls. However, definite conclusions cannot be drawn, mainly because the investigated biomarkers are indirect measures of BBB pathology.

Background: The Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. Methods and results: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012–2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P

BACKGROUND: Additional prognostic markers are needed for better treatment stratification of stage II colon cancer (CC). We investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) in a true population-based cohort of patients with stage II CC. MATERIAL AND METHODS: A total of 573 patients were included. Tumor blocks representing the deepest invasive part of the primary tumor were used for analysis. CD3+ and CD8+ TILs at the invasive front were evaluated by immunohistochemistry on whole tumor sections. The invasive area was manually outlined, and Visiopharm Integrator System software was used for quantification. Data were dichotomized for comparison with clinical data. The prognostic value was investigated in Cox proportional-hazard models for recurrence-free survival (RFS) and overall survival (OS). RESULTS: Low CD3+ or CD8+ TILs were significantly associated with poor RFS and OS (P = .0021 and P ≤ .0009, respectively, log-rank test). In multiple Cox regression analysis, low CD3+ and CD8+ TILs were associated with reduced RFS with hazard ratio (HR) = 1.386 (95% CI 1.039-1.850), P = .026, and HR = 1.394 (95% CI 1.029-1.890), P = .032, respectively, independent of age, T-stage, localization, perforation, and microsatellite instability (MSI). In the subgroups of patients with low CD3+ or CD8+ TILs, there was no difference in survival between patients with MSI and microsatellite-stable tumors, (P = .821 and P = .907, respectively). CONCLUSION: Low CD3+ and CD8+ TILs in the invasive area are both related to inferior prognosis of stage II CC, and we recommend either of these parameters to be considered as additional high-risk factor.

Introduction: Radiotherapy education can be very different across Europe, despite the publication of the ESTRO core curricula in 2011. The purpose of the current study is to map the different RO European education systems, to report their perceived quality and to understand what could be improved to better teach RO. Methods: An online survey consisting of 30 questions was sent to RO professionals under 40 years of age via email and social media. Clinicians, radiobiologists, physicists and radiation therapists (RTTs) were invited to answer questions regarding (1) demographics data, (2) duration, (3) organization, (4) content, (5) quality and potential improvements of national education programs. Results: Four hundred and sixty three questionnaires were received from 34 European countries. All disciplines were represented: 45% clinicians (n = 210), 29% physicists (n = 135), 24% RTTs (n = 108) and 2% radiobiologists (n = 10). Male and female participants were well-balanced in each speciality, except for radiobiologists (80% males). Median age was 31.5 years old (range 21–40). A large range of the duration of the National RO education programs was observed: median = 9 years (range: 3–15). In half of the surveyed countries the European Credit Transfer System (ECTS), that facilitates mobility for trainees, has been implemented. Participants declared only a minority of countries have implemented the ESTRO Core Curriculum (n = 5). A quarter of participants indicated that their national education program is insufficient. Conclusion: This is the first study to examine the different RO education systems in Europe. Large differences in organization and duration of national education programs have been found, along with perceived quality across Europe within each speciality. These results show the necessity of a discussion on how to move forward in this diversity of education programs and the potential contribution that the ESTRO may fulfil.