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Transit through the carbon liquid phase has significant consequences for the subsequent formation of solid nanocarbon detonation products. We report dynamic measurements of liquid carbon condensation and solidification into nano-onions over ∽200 ns by analysis of time-resolved, small-angle X-ray scattering data acquired during detonation of a hydrogen-free explosive, DNTF (3,4-bis(3-nitrofurazan-4-yl)furoxan). Further, thermochemical modeling predicts a direct liquid to solid graphite phase transition for DNTF products ~200 ns post-detonation. Solid detonation products were collected and characterized by high-resolution electron microscopy to confirm the abundance of carbon nano-onions with an average diameter of ∽10 nm, matching the dynamic measurements. We analyze other carbon-rich explosives by similar methods to systematically explore different regions of the carbon phase diagram traversed during detonation. Our results suggest a potential pathway to the efficient production of carbon nano-onions, while offering insight into the phase transformation kinetics of liquid carbon under extreme pressures and temperatures.

Background: People with dual diagnosis die prematurely compared to the general population, and general practice might serve as a setting in the healthcare system to mend this gap in health inequity. However, little is known about which interventions that have been tested in this setting., Aim: To scope the literature on interventions targeting patients with dual diagnosis in a general practice setting, the outcomes used, and the findings., Design and Setting: A scoping review of patients with dual diagnosis in general practice., Methods: From a predeveloped search string, we used PubMed (Medline), PsychInfo, and Embase to identify scientific articles on interventions. Studies were excluded if they did not evaluate an intervention, if patients were under 18 years of age, and if not published in English. Duplicates were removed and all articles were initially screened by title and abstract and subsequent fulltext were read by two authors. Conflicts were discussed within the author group. A summative synthesis of the findings was performed to present the results., Results: Seven articles were included in the analysis. Most studies investigated integrated care models between behavioural treatment and primary care, and a single study investigated the delivery of Cognitive Behavioral treatment (CBT). Outcomes were changes in mental illness scores and substance or alcohol use, treatment utilization, and implementation of the intervention in question. No studies revealed significant outcomes for patients with dual diagnosis., Conclusion: Few intervention studies targeting patients with dual diagnosis exist in general practice. This calls for further investigation of the possibilities of implementing interventions targeting this patient group in general practice., (© 2024. The Author(s).)

The oncogene PIM2 is upregulated in several malignancies but has never been investigated in mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma (CTCL). PIM2 is a well-known oncogene and is regulated by cell signaling pathways like the JAK/STAT- and NF-kB-pathway, key regulators in the pathogenesis of CTCL. The aim of this study was to examine the role of PIM2 in MF. PIM2 gene expression was measured in 81 formalin-fixed paraffin-embedded skin biopsies from patients with MF and 46 control biopsies from healthy skin (HS) and benign inflammatory skin disease (BID). Validation of PIM2 protein expression was performed on selected biopsies with immunohistochemical staining. We found a significant difference in gene expression levels between both early stage MF and HS (p < 0.0001), and BID (p < 0.0001). In addition, the PIM2 gene expression was higher in advanced-stage MF compared to early stage disease (p = 0.0001). No significant difference in gene expression levels was found between patients with and without disease progression. In conclusion, we found PIM2 expression is significantly increased in MF compared to controls, and in advanced-stage MF compared to early stage MF. These findings could potentially have diagnostic value in discriminating early stage MF from BID., (© 2024 Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

This study aimed to explore the experiences and perspectives of people with osteoarthritis attending the "Osteoarthritis School" (OA School) in Nuuk, Greenland to generate insights and lessons that can inform the development of self-management education and exercise interventions for people with other lifestyle conditions in a Greenland context. We conducted a qualitative interpretive description (ID) study based on ten semi-structured interviews with people with hip or knee osteoarthritis. Interviews were audio-recorded, transcribed, and coded. Using ID, we identified three themes: 1) perceptions and experiences of how the OA School intervention was organised (time and place); 2) perspectives and experiences of the education and exercise components (social factors, motivation, and education); and 3) significant change stories (physical and mental improvements and increased knowledge of OA). Social and organisational factors, such as working out with peers and the time and place of the intervention, influenced the participants' acceptance of the OA School intervention. Knowledge from this study will help us gain insight into what to address when developing future self-management education and exercise interventions in the Greenlandic healthcare system.

Non-communicable diseases such as chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2D) represent major challenges for health systems all over the world. In an interview study, we explored patient experiences and perspectives of being diagnosed and living with COPD or T2D in Greenland. Participants ( n  = 24) were selected by purposeful sampling and recruited by phone. We conducted individual semi-structured interviews at the National Hospital in Nuuk and the four regional hospitals. Interviews were audio-recorded, transcribed verbatim, and analysed using interpretive description. Three themes emerged: shock and shame on receiving the diagnosis, coping with a changed life, and varying needs for care and communication. We found that being diagnosed with COPD or T2D required a rapid change in the participants' everyday lives and lifestyle behaviours. Some self-managed their disease well and were able to transfer their knowledge and integrate it into their daily lives, while others struggled to make lifestyle changes. Additionally, living with COPD or T2D could be related to silence and shame. The findings contribute to a better understanding of living with COPD or T2D in the Arctic region and the development of future, culturally-adapted patient education initiatives.

Introduction: Shared decision making (SDM) has become a crucial element on the political agenda and represents a vital aspect of modern healthcare. However, successful implementation of SDM highly depends on the attitude of clinicians towards SDM. The overall aim of our study was to explore the experience of oncologists and nurses with SDM using the Decision Helper, an in-consultation decision aid, at four Danish radiotherapy departments., Methods: Semi-structured interviews were conducted with 20 clinicians. The participants were selected using purposive sampling to include nurses and oncologists, male and female, with different levels of experience with SDM and clinical work. The analysis was a data-driven, iterative process with inductive coding of all interviews and meaning condensation., Results: Two main themes emerged: "Using the Decision Helper changes the consultation" and "Change of attitude among Danish oncologists." Each of the two themes included four elaborative subthemes, which are reported with supporting citations in this paper. In brief, the use of SDM and the Decision Helper should ideally be adjusted to the individual patient and depends highly on the oncologist. The participants described ambitions towards "making the right decision for this patient at this time." The healthcare system, however, has pitfalls that may hinder SDM, e.g., rigid interpretation of guideline-based recommendations., Conclusion: Using an in-consultation Decision Helper has the potential for individualized, structured patient engagement in decision making. There is a need for patient decision aids in clinical guidelines to ensure patient engagement in decision making., Competing Interests: Disclosure The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Partial breast irradiation (PBI)has beenthe Danish Breast Cancer Group(DBCG) standard for selected breast cancer patients since 2016 based onearlyresults from the DBCG PBI trial.During trial accrual, respiratory-gated radiotherapy was introduced in Denmark. This study aims to investigate the effect of respiratory-gating on mean heart dose (MHD)., Patients and Methods: From 2009 to 2016 the DBCG PBI trial included 230 patientswith left-sided breast cancer receiving external beam PBI, 40 Gy/15 fractions/3 weeks.Localization of the tumor bed on the planning CT scan, the use of respiratory-gating, coverage of the clinical target volume (CTV), and doses to organs at risk were collected., Results: Respiratory-gating was used in 123 patients (53 %). In 176 patients (77 %) the tumor bed was in the upper and in 54 patients (23 %) in the lower breast quadrants. The median MHD was 0.37 Gy (interquartile range 0.26-0.57 Gy), 0.33 Gy (0.23-0.49 Gy) for respiratory-gating, and 0.49 Gy (0.31-0.70 Gy) for free breathing, p < 0.0001. MHD was < 1 Gy in 206 patients (90 %) and < 2 Gy in 221 patients (96 %). Respiratory-gating led to significantly lower MHD for upper-located, but not for lower-located tumor beds, however, all MHD were low irrespective of respiratory-gating. Respiratory-gating did not improve CTV coverage or lower lung doses., Conclusions: PBI ensured a low MHD for most patients. Adding respiratory-gating further reduced MHD for upper-located but not for lower-located tumor beds but did not influence target coverage or lung doses. Respiratory-gating is no longer DBCG standard for left-sided PBI., Competing Interests: Declaration of competing interest KWH and BVO are supported by the Novo Nordisk Foundation. BVO is supported by the Danish Cancer Society., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Shared decision making (SDM) is a patient engaging process advocated especially for preference-sensitive decisions, such as adjuvant treatment after breast cancer. An increasing call for patient engagement in decision making highlights the need for a systematic SDM approach. The objective of this trial was to investigate whether the Decision Helper (DH), an in-consultation patient decision aid, increases patient engagement in decisions regarding adjuvant whole breast irradiation., Material and Methods: Oncologists at four radiotherapy units were randomized to practice SDM using the DH versus usual practice. Patient candidates for adjuvant whole breast irradiation after breast conserving surgery for node-negative breast cancer were eligible. The primary endpoint was patient-reported engagement in the decision process assessed with the Shared Decision Making Questionnaire (SDM-Q-9) (range 0-100, 4 points difference considered clinical relevant). Other endpoints included oncologist-reported patient engagement, decisional conflict, fear of cancer recurrence, and decision regret after 6 months., Results: Of the 674 included patients, 635 (94.2%) completed the SDM-Q-9. Patients in the intervention group reported higher level of engagement (median 80; IQR 68.9 to 94.4) than the control group (71.1; IQR 55.6 to 82.2; p < 0.0001). Oncologist-reported patient engagement was higher in the invention group (93.3; IQR 82.2 to 100) compared to control group (73.3; IQR 60.0 to 84.4) (p < 0.0001)., Conclusion: Patient engagement in medical decision making was significantly improved with the use of an in-consultation patient decision aid compared to standard. The DH on adjuvant whole breast irradiation is now recommended as standard of care in the Danish guideline., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: A low incidence of eosinophilic esophagitis (EoE) in children in the North Denmark Region (NDR) were measured in 2007-2017. Few of the children diagnosed before 2017 were treated to remission suggesting a lack of awareness. While there currently are no guidelines for treating EoE in Denmark, a new English guideline was published in 2022 renewing focus on the disease., Objective: The aim of this study was to measure the difference of current Danish clinical practice for treatment and follow-up of EoE children in the NDR with the new English guideline from the British Society of Gastroenterology (BSG) and the British Society of Pediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN)., Methods: This retrospective, register-based DanEoE cohort study included 31 children diagnosed with EoE between 2007 and 2021 in NDR. Medical records were reviewed and information about treatment and follow-up were collected., Results: In 32% of the children with EoE in the NDR, first-line treatment corresponded with the new English guideline. One in 6 children were never started on any treatment even though treatment always is recommended. Histologic evaluation within 12 weeks as recommended was performed in 13% of the children., Conclusions: In Denmark focus on improving EoE treatment and follow-up for children is needed, as there is a significant difference between current clinical practice and the recommendations in the new English guideline., (© 2024. The Author(s).)

Non-alcoholic steatohepatitis (NASH) is emerging as a major cause of hepatocellular carcinoma (HCC), however, it is not resolved if compounds in late-stage clinical development for NASH may have additional therapeutic benefits in NASH-driven HCC (NASH-HCC). Here, we profiled monotherapy with semaglutide (glucagon-like-receptor-1 receptor agonist) and lanifibranor (pan-peroxisome proliferator-activated receptor agonist) in a diet-induced obese (DIO) mouse model of NASH-HCC. Disease progression was characterized in male C57BL/6 J mice fed the GAN (Gubra Amylin NASH) diet high in fat, fructose and cholesterol for 12-72 weeks (n = 15 per group). Other GAN DIO-NASH-HCC mice fed the GAN diet for 54 weeks and with biopsy-confirmed NASH (NAFLD Activity Score ≥ 5) and advanced fibrosis (stage F3) received vehicle (n = 16), semaglutide (30 nmol/kg, s.c., n = 15), or lanifibranor (30 mg/kg, p.o., n = 15) once daily for 14 weeks. GAN DIO-NASH-HCC mice demonstrated progressive NASH, fibrosis and HCC burden. Tumors presented with histological and molecular signatures of poor prognostic HCC. Consistent with clinical trial outcomes in NASH patients, both lanifibranor and semaglutide improved NASH while only lanifibranor reduced fibrosis in GAN DIO-NASH-HCC mice. Notably, only semaglutide reduced tumor burden in GAN DIO-NASH-HCC mice. In conclusion, the GAN DIO-NASH-HCC mouse is a clinical translational model of NASH-HCC. Semaglutide improves both NASH and tumor burden in GAN DIO-NASH-HCC mice, highlighting the suitability of this preclinical model for profiling novel drug therapies targeting NASH-HCC., (© 2023. The Author(s).)

The aim was to test the internal consistency of the Greenlandic version of the COPD Assessment Test (CAT) questionnaire and to estimate the symptom burden in patients with chronic obstructive pulmonary disease (COPD) in Greenland using the CAT questionnaire. A Greenlandic version of the CAT questionnaire was developed including forward translation, reconciliation, backwards translation, and pilot test. Afterwards, a cross-sectional study of patients with COPD was conducted. The internal consistency assessed by the Cronbach α coefficient was 0.823 for the Greenlandic version of the questionnaire ( n  = 103). The CAT was negatively correlated to spirometry values and current smoking. In the cross-sectional study ( n  = 250), 81.1% of the patients experienced a high symptom burden (≥10). The main CAT score was 17 (range 0-38). The CAT was used in 9 out of 17 towns in Greenland. The Greenlandic version of the CAT questionnaire demonstrated a good internal consistency. We observed a high burden of symptoms associated with reduced lung function and active smoking status among patient diagnosed with COPD in Greenland. The questionnaire can be used in clinical practice for assessment of symptom burden in patients with COPD in Greenland and may help to increase focus on symptom control and quality of care.

The aim of this study was to estimate prevalence of patients with asthma in Greenland according to age, gender and residence and to investigate the associated quality of care. The study was performed as a cross-sectional study with data extracted from the Greenlandic electronical medical record. A total of 870 patients aged 12 years or above were diagnosed with asthma at the end of 2022, corresponding to a prevalence of 1.9%. In 2020, the total prevalence was 0.2%. The prevalence of patients aged 12 years or above with asthma was highest among patients in Nuuk (3.3%) compared with patients in the remaining parts of Greenland (1.1%). More women than men were diagnosed with asthma, and the prevalence increased with age from 20 to 59 years. The prevalence of current smokers was high among the asthma population. The quality of care was significantly higher among patients living in Nuuk for all process indicators compared with patients from the remaining parts of Greenland. The prevalence of asthma in Greenland is low compared to other comparable populations and might be underestimated. Initiatives supporting increased focus on diagnosing asthma are thus warranted.

We report a case of a 58-year-old man with recurrent unprovoked deep vein thrombosis (DVT) and severe immune thrombocytopenia (ITP) with a platelet count of 19 × 10 9 /L. We further review studies reporting venous thromboembolism (VTE) in patients with severe ITP (≤ 35 × 10 9 /L) and identified 14 patients highlighting VTE risk factors and management of these patients. The present case had several risk factors for VTE (previous DVT, obesity, heterozygosity for factor V Leiden mutation, and previous splenectomy). The patient was initially treated with low-molecular-weight heparin followed by long-term apixaban treatment. The literature review together with our case demonstrates that VTE in severe ITP (≤ 35 × 10 9 /L) can occur in patients with VTE risk factors and antithrombotic management of these patients can be achieved without bleeding depending on severity of thrombocytopenia either by full or reduced dose of anticoagulation together with ITP therapy., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: People with a severe mental illness (SMI) have shorter life expectancy and poorer quality of life compared to the general population. Most years lost are due to cardiovascular disease, respiratory disease, and various types of cancer. We co-designed an intervention to mitigate this health problem with key stakeholders in the area, which centred on an extended consultations for people with SMI in general practice. This study aimed to1) investigate general practitioners' (GPs) experience of the feasibility of introducing extended consultations for patients with SMI, 2) assess the clinical content of extended consultations and how these were experienced by patients, and 3) investigate the feasibility of identification, eligibility screening, and recruitment of patients with SMI., Methods: The study was a one-armed feasibility study. We planned that seven general practices in northern Denmark would introduce extended consultations with their patients with SMI for 6 months. Patients with SMI were identified using practice medical records and screened for eligibility by the patients' GP. Data were collected using case report forms filled out by practice personnel and via qualitative methods, including observations of consultations, individual semi-structured interviews, a focus group with GPs, and informal conversations with patients and general practice staff., Results: Five general practices employing seven GPs participated in the study, which was terminated 3 ½ month ahead of schedule due to the COVID-19 pandemic. General practices attempted to contact 57 patients with SMI. Of these, 38 patients (67%) attended an extended consultation, which led to changes in the somatic health care plan for 82% of patients. Conduct of the extended consultations varied between GPs and diverged from the intended conduct. Nonetheless, GPs found the extended consultations feasible and, in most cases, beneficial for the patient group. In interviews, most patients recounted the extended consultation as beneficial., Discussion: Our findings suggest that it is feasible to introduce extended consultations for patients with SMI in general practice, which were also found to be well-suited for eliciting patients' values and preferences. Larger studies with a longer follow-up period could help to assess the long-term effects and the best implementation strategies of these consultations., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: To evaluate the feasibility and fidelity of implementing and assessing the SOFIA coordinated care program aimed at lowering mortality and increasing quality of life in patients with severe mental illness by improving somatic health care in general practice., Design: A cluster-randomised, non-blinded controlled pilot trial., Setting: General Practice in Denmark., Intervention: The SOFIA coordinated care program comprised extended structured consultations carried out by the GP, group-based training of GPs and staff, and a handbook with information on signposting patients to relevant municipal, health, and social initiatives., Patients: Persons aged 18 years or older with a diagnosis of psychotic, bipolar, or severe depressive disorder., Main Outcome Measures: We collected quantitative data on the delivery, recruitment and retention rates of practices and patients, and response rates of questionnaires MMQ and EQ-5D-5 L., Results: From November 2020 to March 2021, nine practices were enrolled and assigned in a 2:1 ratio to the intervention group (n = 6) or control group (n = 3). Intervention group practices included 64 patients and Control practices included 23. The extended consultations were delivered with a high level of fidelity in the general practices; however, thresholds for collecting outcome measures, and recruitment of practices and patients were not reached., Conclusion: Our findings suggest that delivering the coordinated care program in a fully powered trial in primary care is likely feasible. However, the recruitment methodology requires improvement to ensure sufficient recruitment and minimize selective inclusion., Trial Registration: The date of pilot trial protocol registration was 05/11/2020, and the registration number is NCT04618250., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Although failure to establish a vascular network has been associated with many skeletal disorders, little is known about what drives development of vasculature in the intracortical bone compartments. Here, we show that intracortical bone resorption events are coordinated with development of the vasculature. We investigated the prevalence of vascular structures at different remodeling stages as well as their 3D organization using proximal femoral cortical bone from 5 girls and 6 boys (aged 6-15 years). A 2D analysis revealed that non-quiescent intracortical pores contained more vascular structures than quiescent pores (p < 0.0001). Type 2 pores, i.e., remodeling of existing pores, had a higher density of vascular structures than type 1 pores, i.e., de novo created pores (p < 0.05). Furthermore, pores at the eroded-formative remodeling stage, had more vascular structures than pores at any other remodeling stage (p < 0.05). A 3D reconstruction of an intracortical remodeling event showed that osteoclasts in the advancing tip of the cutting cone as well as preosteoclasts in the lumen expressed vascular endothelial growth factor-A (VEGFA), while VEGFA-receptors 1 and 2 mainly were expressed in endothelial cells in the adjacent vasculature. Consequently, we propose that the progression of the vascular network in intracortical remodeling events is driven by osteoclasts expressing VEGFA. Moreover, the vasculature is continuously reconfigured according to the demands of the remodeling events at the surrounding bone surfaces., Competing Interests: Declaration of competing interest The following research grants have been received: However, none of our founders had any role in conceptualization, analysis, or interpretation of the study and I can, as last author of the submitted manuscript declare that none of the authors have any personal financial interest to declare in connection this manuscript., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Aims: OxLDL modulates innate and adaptive immunity, and extracellular vesicles (EVs) released from both non-immune and immune cells are proposed key players in atherosclerosis development. In the present study, we aimed to investigate EVs expressing markers related to adaptive immunity-driven inflammation and endothelial activation/dysfunction in hypercholesterolemic patients., Methods: EVs were phenotyped in thirty patients with familial hypercholesterolemia (FH) and twenty-three healthy controls using the Extracellular Vesicle (EV) Array with antibodies targeting proteins expressed on B and T cells, and endothelial cells., Results: FH patients had a higher atherosclerotic burden, as determined by the mean carotid intima-media thickness (IMT) (0.64 ± 0.12 mm vs. 0.58 ± 0.07 mm; p = 0.033), higher oxLDL levels (p < 0.0001), and showed increased levels of EV-specific markers: CD9 (p = 0.017), CD63 (p = 0.045), CD81 (p = 0.003), Annexin V (p = 0.018), and EV markers related to adaptive/lymphocyte immunity: CD28 (p = 0.034), CD4 (p = 0.049), CD152 (p = 0.029), LFA-1 (p = 0.024), and endothelial function: CD62E (p = 0.032), CD144 (p = 0.018), tPA (p = 0.017), CD31 (p = 0.024). Linear regression revealed a positive relationship between carotid IMT and several of the increased markers observed within the FH group, including CD9 (β = 0.33; p = 0.022), CD63 (β = 0.35; p 225 = 0.026), CD28 (β = 0.37; p = 0.026), CD4 (β = 0.40; p = 0.025), CD152 (β = 0.41; p = 0.017), LFA-1 (β = 0.42; p = 0.014) and CD62E (β = 0.38; p = 0.024)., Conclusion: EVs associated with adaptive immunity and endothelial dysfunction are elevated in FH patients, and several markers related to a higher atherosclerotic burden., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Fibroblast growth factor 21 (FGF21) plays a key role in hepatic lipid metabolism and long-acting FGF21 analogs have emerged as promising drug candidates for the treatment of nonalcoholic steatohepatitis (NASH). It remains to characterize this drug class in translational animal models that recapitulate the etiology and hallmarks of human disease. To this end, we evaluated the long-acting FGF21 analog PF-05231023 in the GAN (Gubra Amylin NASH) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH. Male C57BL/6J mice were fed the GAN diet high in fat, fructose, and cholesterol for 34 wk before the start of the study. GAN DIO-NASH mice with biopsy-confirmed NAFLD Activity Score (NAS ≥5) and fibrosis (stage ≥F1) were biweekly administered with PF-05231023 (10 mg/kg sc) or vehicle (sc) for 12 wk. Vehicle-dosed chow-fed C57BL/6J mice served as healthy controls. Pre-to-post liver biopsy histopathological scoring was performed for within-subject evaluation of NAFLD Activity Score (NAS) and fibrosis stage. Terminal endpoints included quantitative liver histology and transcriptome signatures as well as blood and liver biochemistry. PF-05231023 significantly reduced body weight, hepatomegaly, plasma transaminases, and plasma/liver lipids in GAN DIO-NASH mice. Notably, PF-05231023 reduced both NAS (≥2-point improvement) and fibrosis stage (1-point improvement). Improvements in NASH and fibrosis severity were supported by reduced quantitative histological markers of steatosis, inflammation, and fibrogenesis as well as improvements in disease-associated liver transcriptome signatures. In conclusion, PF-05231023 reduces NASH and fibrosis severity in a translational biopsy-confirmed mouse model of NASH, supporting development of FGF21 analogs for the treatment of NASH. NEW & NOTEWORTHY It is unclear if long-acting FGF21 analogs have antifibrotic efficacy in NASH. We therefore profiled the clinically relevant FGF21 analog PF-05231023 in a translational diet-induced obese and biopsy-confirmed mouse model of NASH. We found PF-05231023 to exert hepatoprotective effects as indicated by notable improvements in plasma markers and histological hallmarks of NASH, including improved fibrosis stage. Collectively, the present study supports the continued exploration of long-acting FGF21 analogs for the treatment of NASH and other fibrotic diseases.

The aim of this study was to estimate the prevalence of patients diagnosed with chronic obstructive pulmonary disease (COPD) according to age, gender, and residence in Greenland and to investigate the associated quality of care. The study was performed as an observational cross-sectional study using data on patients diagnosed with COPD, extracted from the electronical medical record (EMR) in Greenland. The total prevalence of patients aged 20-79 years diagnosed with COPD in Greenland in 2022 was 2.2%. The prevalence was significantly higher in the capital Nuuk compared to the remaining parts of Greenland (2.4% vs. 2.0%, respectively). Significantly more women than men were diagnosed with COPD, but the lung function of men was found to be significantly reduced/impaired compared to women. The prevalence of patients aged 40 years or above was 3.8%. The quality of care was significantly higher among patients living in Nuuk compared to the remaining parts of Greenland for eight out of ten quality indicators. The prevalence of COPD in Greenland is lower than in other comparable populations and might be underestimated. Continued focus on early detection of new cases and initiatives to improve and expand monitoring of quality-of-care measurements, including both additional clinical and patient reported outcomes, are recommended.

Background: With increasing survival rates following out-of-hospital cardiac arrest (OHCA), knowledge on return to everyday life, including return to work, should be getting increasing attention., Objectives: To i) describe patterns of labor market affiliation up to 12 months after discharge among a workforce population and to, ii) investigate the association between clinical and sociodemographic characteristics, self-reported health at discharge and a composite endpoint of prolonged sick leave and leaving the workforce after 3 and 12 months., Methods: Data from the national survey, DenHeart, were used, including measures of self-reported health: HeartQoL and the Hospital Anxiety and Depression Scale (HADS), combined with register-based follow-up., Results: During the study period, n = 572 OHCA patients were discharged from five Heart centres, n = 184 were part of the workforce. At discharge, 60% were on paid sick leave, and 20% at 12 months. Age (per one year older) increased the odds of experiencing the composite endpoint at 3 and 12 months (3 months: OR 1.06 95%CI 1.03-1.10, 12 months: OR 1.06 95%CI 1.03-1.09) among the total population (n = 184). Self-reported health at discharge was not associated with the endpoint., Conclusion: One-fifth of the OHCA survivors at a working-age prior to the OHCA was still on paid sick leave after 12 months. Increasing age was the only characteristic associated with a composite endpoint of prolonged sick leave or leaving the workforce at 3 and 12 months after discharge. With increasing survival rates, healthcare professionals need to support the population in resuming daily life, including returning to the workforce, when relevant., Competing Interests: Declaration of Competing Interest None, (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Prolonged icterus is an important and common problem in neonatology and accurate determination of the different bilirubin species, including differentiation between delta-bilirubin and mono- and di-conjugated bilirubin, is useful for diagnostic purposes. However, most bilirubin measurements routinely performed in the clinical laboratory are hampered by the lack of separation of the four bilirubin fractions (unconjugated bilirubin, mono-conjugated bilirubin, di-conjugated bilirubin, and delta-bilirubin). Herein, we propose a high-performance liquid chromatography-based method, independent of commercially available standards or reliable molar absorption coefficients, for the determination of bilirubin fractions in blood samples from icteric patients. The method is a robust and reliable candidate for a semi-automatized setup for measuring the various bilirubin fractions in a specialized laboratory handling samples from clinics with expertise in biliary disease.

Purpose: On the basis of low risk of local recurrence in elderly patients with breast cancer after conservative surgery followed by whole breast irradiation (WBI), the Danish Breast Cancer Group initiated the noninferiority external-beam partial breast irradiation (PBI) trial (ClinicalTrials.gov identifier: NCT00892814). We hypothesized that PBI was noninferior to WBI regarding breast induration., Methods: Patients operated with breast conservation for relatively low-risk breast cancer were randomly assigned to WBI versus PBI, and all had 40 Gy/15 fractions. The primary end point was 3-year grade 2-3 breast induration., Results: In total, 865 evaluable patients (434 WBI and 431 PBI) were enrolled between 2009 and 2016. Median follow-up was 5.0 years (morbidity) and 7.6 years (locoregional recurrence). The 3-year rate of induration was 9.7% for WBI and 5.1% for PBI ( P = .014). Large breast size was significantly associated with induration with a 3-year incidence of 13% (WBI) and 6% (PBI) for large-breasted patients versus 6% (WBI) and 5% (PBI) for small-breasted patients. PBI showed no increased risk of dyspigmentation, telangiectasia, edema, or pain, and patient satisfaction was high. Letrozole and smoking did not increase the risk of radiation-associated morbidity. Sixteen patients had a locoregional recurrence (six WBI and 10 PBI; P = .28), 20 patients had a contralateral breast cancer, and eight patients had distant failure (five WBI and three PBI). A nonbreast second cancer was detected in 73 patients (8.4%), and there was no difference between groups., Conclusion: External-beam PBI for patients with low-risk breast cancer was noninferior to WBI in terms of breast induration. Large breast size was a risk factor for radiation-associated induration. Few recurrences were detected and unrelated to PBI.

Purpose: The Danish Breast Cancer Group Internal Mammary Node study demonstrated improved 8-year overall survival (OS) with internal mammary node irradiation (IMNI) in patients with node-positive early breast cancer. Here, we present long-term results from the Danish Breast Cancer Group Internal Mammary Node study cohort., Patients and Methods: This nationwide, prospective cohort study allocated patients with node-positive early breast cancer to adjuvant radiotherapy with or without IMNI depending on cancer laterality. Patients with right-sided cancer received IMNI. Patients with left-sided cancer were treated without IMNI because of risk of radiation-induced heart disease. Other treatment was independent of laterality. The primary study end point was OS. Secondary end points were distant recurrence and breast cancer mortality. Analyses were by intention to treat., Results: During 2003-2007, 3,089 women were allocated to IMNI (right-sided, n = 1,491) or no IMNI (left-sided, n = 1,598). With a median follow-up of 14.8 years, 589 patients with and 701 patients without IMNI had died. The corresponding 15-year OS rates were 60.1% and 55.4%. The adjusted hazard ratio (HR) for death was 0.86 (95% CI, 0.77 to 0.96; P = .007) in favor of IMNI. The 15-year risk of developing distant recurrence was 35.6% (523 recurrences) and 38.6% (602 recurrences) with vs. without IMNI (adjusted HR, 0.88 [95% CI, 0.79 to 0.99; P = .04]). The 15-year breast cancer mortality with IMNI was 31.7% (467 deaths) compared with 33.9% (537 deaths) without IMNI (adjusted HR, 0.88 [95% CI, 0.78 to 1.00; P = .05]). The distribution of other deaths was similar across groups., Conclusion: In patients with node-positive early breast cancer treated with IMNI or without IMNI depending on breast cancer laterality, IMNI reduced the risk of distant recurrence and death from breast cancer, thereby improving long-term survival.

This study aimed to estimate the age- and sex specific prevalence of patients using antihypertensive medication in Greenland, and compared the quality of care between patients with and without a diagnosis for hypertension. The study was a cross-sectional study comparing patients using antihypertensive medication in 2020 (6,629 patients) and 2021 (7,008 patients), respectively. For data from 2021, patients with a medical diagnosis code were identified. Data was obtained from the Greenlandic electronic medical record. The population of Greenland was used as background population. Quality of care was evaluated based on suggested indicators by international guidelines and goals from Steno Diabetes Centre Greenland. The prevalence of patients aged ≥20 years using antihypertensive medication had increased from 16.7% in 2020 to 17.5% in 2021. The prevalence increased by age and was higher among women compared to men. In 2021, the prevalence of patients aged ≥20 years with a medical diagnosis code for hypertension was 7.9%. The use of antihypertensive medication in Greenland is common. The associated quality of care was low. However, process indicators were significantly improved when patients had a medical diagnosis code. Future focus must be on initiating initiatives ensuring that more patients are registered with a medical diagnosis code.

Purpose: The relation between breast induration grade 2-3 at 3 years after radiation therapy and irradiated breast volume was investigated for patients in the Danish Breast Cancer Group (DBCG) Partial Breast Irradiation (PBI) trial. METHODS Treatment plan data was obtained from the Danish radiotherapy plan database. Dosimetric parameters for breast and organs at risk were determined. Breast induration data was obtained from the DBCG database. The volume of the whole breast (CTVp&#95;breast) treated to various dose levels was determined for treatment plans in both arms. Logistic regression was used to assess the frequency of induration on breast volume irradiated to ≥40 Gy. RESULTS PBI and WBI was given to 433 and 432 patients, respectively. Median and interquartile ranges (IQR) for CTVp&#95;breast were 710 mL (467-963 mL; PBI) and 666 mL (443-1012 mL; WBI) (p = 0.98). Median and IQR for CTVp&#95;breast treated to ≥40 Gy was 24.9% (18.6-32.6%; PBI) and 59.8% (53.6-68.5%; WBI). Grade 2-3 induration was observed in 5% (PBI) and 10% (WBI) of the patients. A dose-response relationship was established between irradiated breast volume and frequency of breast induration. From the model, 5% and 10% risks of breast induration were observed for ≥40 Gy delivered to CTVp&#95;breast volumes of 177 mL (95%CI, 94-260 mL) and 426 mL (95%CI, 286-567 mL), respectively. CONCLUSION The frequency of breast induration increased significantly with increasing irradiated breast volume, strongly favouring small volumes and PBI. Thus, treated breast volume - not the breast size itself - is the risk factor for induration. This is the first report directly linking the 40 Gy irradiated breast volume to breast induration., (Copyright © 2022 Elsevier B.V. All rights reserved.)

We investigate the sensitivity and potential of a synergistic experiment-theory X-ray Raman spectroscopy (XRS) methodology on revealing and following the static and dynamic electronic structure of high explosive molecular materials. We show that advanced ab-initio theoretical calculations accounting for the core-hole effect based on the Bethe-Salpeter Equation (BSE) approximation are critical for accurately predicting the shape and the energy position of the spectral features of C and N core-level spectra. Moreover, the incident X-ray dose typical XRS experiments require can induce, in certain unstable structures, a prominent radiation damage at room temperature. Upon developing a compatible cryostat module for enabling cryogenic temperatures ([Formula: see text] 10 K) we suppress the radiation damage and enable the acquisition of reliable experimental spectra in excellent agreement with the theory. Overall, we demonstrate the high sensitivity of the recently available state-of-the-art X-ray Raman spectroscopy capabilities in characterizing the electronic structure of high explosives. At the same time, the high accuracy of the theoretical approach may enable reliable identification of intermediate structures upon rapid chemical decomposition during detonation. Considering the increasing availability of X-ray free-electron lasers, such a combined experiment-theory approach paves the way for time-resolved dynamic studies of high explosives under detonation conditions., (© 2022. The Author(s).)

Eosinophilic oesophagitis (EoE) is a clinicopathological condition characterised by symptoms of oesophageal dysfunction and eosinophilic inflammation. The EoE incidence is increasing rapidly as described in this review. In Denmark, EoE among children is significantly underdiagnosed. Untreated EoE is associated with low quality of life, and development of complications. EoE is effectively treated with proton pump inhibitors, diet, or topical corticosteroids. However, evaluation of the treatment response requires histological samples, since conflicting symptoms and histology is observed in 40%.

Cellular senescence is an important factor in aging and many age-related diseases, but understanding its role in health is challenging due to the lack of exclusive or universal markers. Using neural networks, we predict senescence from the nuclear morphology of human fibroblasts with up to 95% accuracy, and investigate murine astrocytes, murine neurons, and fibroblasts with premature aging in culture. After generalizing our approach, the predictor recognizes higher rates of senescence in p21-positive and ethynyl-2'-deoxyuridine (EdU)-negative nuclei in tissues and shows an increasing rate of senescent cells with age in H&E-stained murine liver tissue and human dermal biopsies. Evaluating medical records reveals that higher rates of senescent cells correspond to decreased rates of malignant neoplasms and increased rates of osteoporosis, osteoarthritis, hypertension and cerebral infarction. In sum, we show that morphological alterations of the nucleus can serve as a deep learning predictor of senescence that is applicable across tissues and species and is associated with health outcomes in humans., (© 2022. The Author(s).)

The strictly regulated bone remodeling process ensures that osteoblastic bone formation is coupled to osteoclastic bone resorption. This coupling is regulated by a panel of coupling factors, including clastokines promoting the recruitment, expansion, and differentiation of osteoprogenitor cells within the eroded cavity. The osteoprogenitor cells on eroded surfaces are called reversal cells. They are intermixed with osteoclasts and become bone-forming osteoblast when reaching a critical density and maturity. Several coupling factors have been proposed in the literature, but their effects and expression pattern vary between studies depending on species and experimental setup. In this study, we investigated the mRNA levels of proposed secreted and membrane-bound coupling factors and their receptors in cortical bone remodeling events within the femur of healthy adolescent human controls using high-sensitivity RNA in situ hybridization. Of the proposed coupling factors, human osteoclasts showed mRNA-presence of LIF , PDGFB , SEMA4D , but no presence of EFNB2 , and OSM . On the other hand, the osteoblastic reversal cells proximate to osteoclasts presented with LIFR , PDGFRA and PLXNB1 , but not PDGFRB , which are all known receptors of the proposed coupling factors. Although EFNB2 was not present in mature osteoclasts, the mRNA of the ligand-receptor pair EFNB2:EPHB4 were abundant near the central blood vessels within intracortical pores with active remodeling. EPHB4 and SEMA4D were also abundant in mature bone-forming osteoblasts. This study highlights that especially LIF:LIFR , PDGFB:PDGFRA , SEMA4D:PLXNB1 may play a critical role in the osteoclast-osteoblast coupling in human remodeling events, as they are expressed within the critical cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Borggaard, Nielsen, Delaisse, Andreasen and Andersen.)

Background: The standard in Denmark for treating breast cancer patients receiving loco-regional irradiation is tangential 3D Conformal RadioTherapy (3DCRT), treated in deep inspiration breath-hold (DIBH). Treating with Volumetric Modulated Arc Therapy (VMAT) may reduce the treatment time, which is particularly important for DIBH treatments. The VMAT should be performed without increased dose to the heart, lung, and contralateral breast. This study compares VMAT and 3DCRT for left-sided breast cancer patients with intramammary lymph node involvement., Material and Methods: Twenty left-sided breast cancer patients were included. VMAT and tangential plans were created for all patients, with a prescription dose of 50 Gy. The tangential plans used 6 MV and for larger breast combined with 18 MV. The VMAT plans utilised two 6 MV fields in a butterfly configuration. Dose planning was done in Pinnacle 3 16.0 using the Auto-Planning module for the VMAT plans. Comparison of the plans was based on: mean doses, metrics provided by DBCG guidelines, dose-volume histograms and required number of breath-holds for treatment delivery in DIBH., Results: For most OAR, the doses were similar for VMAT and 3DCRT. The target coverage was comparable, with VMAT having a statistically significant improved dose homogeneity of the target volumes. Less than half the number of breath-hold was required for VMAT compared to 3DCRT. Mean gamma pass rates (3 mm and 3%) from ArcCHECK of the VMAT plans was 98.4% (range 96.6-99.8%)., Conclusion: Automatic VMAT planning of left-sided breast cancer patients with lymph node involvement can produce dose distributions comparable to those of tangential 3DCRT, while reducing the number of breath-holds in DIBH by more than a factor of two. The reduction in breath-holds is beneficial for patient comfort and reduces the risk of intra-fraction patient motion.

Purpose: We investigated risk of myocardial infarction (MI) associated with the content of linoleic acid (LA) in adipose tissue, a biomarker of long-term dietary intake of LA and a marker of endogenous LA exposure., Methods: Between 1993 and 1997, 57,053 middle-aged subjects were included in the Danish Diet, Cancer and Health cohort. We performed a case-cohort study that included a random sample of the full cohort (n = 3167) and all incident MI cases appearing during 16 years of follow-up (n = 2819). Information on incident MI cases was obtained by linkage with Danish nationwide registries. Adipose tissue biopsies were taken from the buttocks of the participants, and their fatty acid composition was determined using gas chromatography. HRs (hazard ratios) with 95% confidence intervals (CIs) were used to describe the associations between content of LA in adipose tissue and the risk of MI. HRs were calculated using weighted Cox proportional hazards regression with robust variance., Results: After adjustment for established risk factors of MI, adipose tissue content of LA was not associated with the risk of MI in men and women combined (quintiles 5 versus 1, HR, 1.03 (95% CI, 0.85-1.25), P-trend = 0.970) or in men and women separately (quintiles 5 versus 1, HR, 1.05 (95% CI, 0.83-1.33), P-trend = 0.871 and quintiles 5 versus 1, HR, 0.99 (95% CI 0.72-1.37), P-trend = 0.928, respectively). Investigating the association between LA and MI with a shorter, 5- or 10-year duration of follow-up provided similar results., Conclusion: Content of LA in adipose tissue was not associated with the risk of MI., (© 2021. Springer-Verlag GmbH, DE part of Springer Nature.)

Background: People with severe mental illness (SMI) have an increased risk of premature mortality, predominantly due to somatic health conditions. Evidence indicates that primary and tertiary prevention and improved treatment of somatic conditions in patients with SMI could reduce this excess mortality. This paper reports a protocol designed to evaluate the feasibility of a coordinated co-produced care program (SOFIA model, a Danish acronym for Severe Mental Illness and Physical Health in General Practice) in the general practice setting to reduce mortality and improve quality of life in patients with severe mental illness., Methods: The SOFIA pilot trial is designed as a cluster randomized controlled trial targeting general practices in two regions in Denmark. We aim to include 12 practices, each of which is instructed to recruit up to 15 community-dwelling patients aged 18 and older with SMI. Practices will be randomized by a computer in a ratio of 2:1 to deliver a coordinated care program or usual care during a 6-month study period. A randomized algorithm is used to perform randomization. The coordinated care program includes educational training of general practitioners and their clinical staff educational training of general practitioners and their clinical staff, which covers clinical and diagnostic management and focus on patient-centered care of this patient group, after which general practitioners will provide a prolonged consultation focusing on individual needs and preferences of the patient with SMI and a follow-up plan if indicated. The outcomes will be parameters of the feasibility of the intervention and trial methods and will be assessed quantitatively and qualitatively. Assessments of the outcome parameters will be administered at baseline, throughout, and at end of the study period., Discussion: If necessary the intervention will be revised based on results from this study. If delivery of the intervention, either in its current form or after revision, is considered feasible, a future, definitive trial to determine the effectiveness of the intervention in reducing mortality and improving quality of life in patients with SMI can take place. Successful implementation of the intervention would imply preliminary promise for addressing health inequities in patients with SMI., Trial Registration: The trial was registered in Clinical Trials as of November 5, 2020, with registration number NCT04618250 . Protocol version: January 22, 2021; original version., (© 2021. The Author(s).)

Detonation nanodiamond (DND) is known to form aggregates that significantly reduce their unique nanoscale properties and require postprocessing to separate. How and when DND aggregates is an important question that has not been answered experimentally and could provide the foundation for approaches to limit aggregation. To answer this question, time-resolved small-angle X-ray scattering was performed during the detonation of high-explosives that are expected to condense particulates in the diamond, graphite, and liquid regions of the carbon phase diagram. DND aggregation into low fractal dimension structures could be observed as early as 0.1 μs, along with a separate scattering population also observed from an explosive that produces primarily graphitic products. A counterexample is the case of a high-explosive that produces nano-onions, where no hierarchical scattering was observed for at least 10 μs behind the detonation front. These results suggest that DND aggregation occurs on time scales comparable to particle formation.

High-resolution flow cytometers (hFCM) are used for the detection of extracellular vesicles (EV) in various biological fluids. Due to the increased sensitivity of hFCM, new artifacts with the potential of interfering with data interpretation are introduced, such as detection of antibody aggregates. The aim of this study was to investigate the extent of aggregates in labels commonly used for the characterization of EVs by hFCM. Furthermore, we aimed to compare the efficacy of centrifugation and filtering treatments to remove aggregates, as well as to quantify the effect of the treatments in reducing aggregates. For this purpose, we labeled phosphate buffered saline (PBS) with fluorescently conjugated protein labels and antibodies after submitting them to 5, 10, or 30 min centrifugation, filtering or washed filtering. We investigated samples by hFCM and quantified the amount of aggregates found in PBS labeled with untreated and pre-treated labels. We found a varying amount of aggregates in all labels investigated, and further that filtering is most efficient in removing all but the smallest aggregates. Filtering protein labels can reduce the extent of aggregates; however, how much remains depends on the specific labels and their combination. Therefore, it is still necessary to include appropriate controls in a hFCM study of EVs.

Bacterial type II toxin-antitoxin (TA) modules encode a toxic protein that downregulates metabolism and a specific antitoxin that binds and inhibits the toxin during normal growth. In non-typeable Haemophilus influenzae, a common cause of infections in humans, the vapXD locus was found to constitute a functional TA module and contribute to pathogenicity; however, the mode of action of VapD and the mechanism of inhibition by the VapX antitoxin remain unknown. Here, we report the structure of the intact H. influenzae VapXD complex, revealing an unusual 2:1 TA molecular stoichiometry where a Cas2-like homodimer of VapD binds a single VapX antitoxin. VapX consists of an oligonucleotide/oligosaccharide-binding domain that docks into an asymmetrical cavity on the toxin dimer. Structures of isolated VapD further reveal how a symmetrical toxin homodimer adapts to interacting with an asymmetrical antitoxin and suggest how a primordial TA system evolved to become part of CRISPR-Cas immunity systems., Competing Interests: Declarations of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)