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Objective:. The objective of this study was to evaluate how much variation in postacute care (PAC) spending after traumatic hip fracture exists between hospitals, and to what degree this variation is explained by patient factors, hospital factors, PAC setting, and PAC intensity. Background:. Traumatic hip fracture is a common and costly event. This is particularly relevant given our aging population and that a substantial proportion of these patients are discharged to PAC settings. Methods:. It is a cross-sectional retrospective study. In a retrospective review using Medicare claims data between 2014 and 2019, we identified PAC payments within 90 days of hospitalization discharges and grouped hospitals into quintiles of PAC spending. The degree of variation present in PAC spending across hospital quintiles was evaluated after accounting for patient case-mix factors and hospital characteristics using multivariable regression models, adjusting for PAC setting choice by fixing the proportion of PAC discharge disposition across hospital quintiles, and adjusting for PAC intensity by fixing the amount of PAC spending across hospital quintiles. The study pool included 125,745 Medicare beneficiaries who underwent operative management for traumatic hip fracture in 2078 hospitals. The primary outcome was PAC spending within 90 days of discharge following hospitalization for traumatic hip fracture. Results:. Mean PAC spending varied widely between top versus bottom spending hospital quintiles ($31,831 vs $17,681). After price standardization, the difference between top versus bottom spending hospital quintiles was $8,964. Variation between hospitals decreased substantially after adjustment for PAC setting ($25,392 vs $21,274) or for PAC intensity ($25,082 vs $21,292) with little variation explained by patient or hospital factors. Conclusions:. There was significant variation in PAC payments after a traumatic hip fracture between the highest- and lowest-spending hospital quintiles. Most of this variation was explained by choice of PAC discharge setting and intensity of PAC spending, not patient or hospital characteristics. These findings suggest potential systems-level inefficiencies that can be targeted for intervention to improve the appropriateness and value of healthcare spending.

Summary: Background: Children of refugees are often exposed to the consequences of parental post-traumatic stress disorder (PTSD), potentially leaving them vulnerable to intergenerational transmission of psychopathology. The present study aimed to determine whether parental PTSD is associated with childhood psychiatric morbidity among children of refugees. Methods: This study is a two-generation nationwide cohort study using the Danish Immigration Services database. We followed up children younger than 18 years with at least one refugee parent until psychiatric contact, end of the study, their 18th birthday, emigration, or death. We excluded children if their parents were diagnosed only with psychiatric diagnoses other than PTSD or if they had received a psychiatric contact before parental PTSD diagnosis. Information on parental PTSD and offspring psychiatric morbidity was obtained from the Danish Psychiatric Central Research Register. We used Cox proportional hazards regression models to assess the risk of psychiatric contacts among children of refugees with PTSD compared with children of refugees with no psychiatric diagnosis. Findings: Between Jan 1, 1995, and Dec 31, 2015, 102 010 refugees obtained residency permission in Denmark and 62 239 biological children of refugees were born in Denmark before Dec 31, 2015. 51 793 were eligible and included in the study (median follow-up 7·15 years [IQR 3·37–11·78]); of these, 1307 (2·5%) children had a psychiatric contact. 7486 (14·5%) children of refugees were exposed to parental PTSD. Parental PTSD significantly increased the risk of psychiatric contact in offspring (hazard ratio 1·49 [95% CI 1·17–1·89] for paternal PTSD, p=0·0011; 1·55 [1·20–2·01] for maternal PTSD, p=0·00084) after adjustment for sociodemographic variables. Interpretation: Children of refugees exposed to parental PTSD are at increased risk of psychiatric morbidity. Targeted screening and interventions are necessary to prevent psychiatric morbidity and ensure access to adequate care. Funding: Section for Immigrant Medicine, Department of Infectious Diseases, Copenhagen University Hospital Hvidovre.

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 < 0.001). There were more grade 3 skin reactions and grade 3 mucositis after proton treatment compared with photons at the end of treatment, Risk Ratio (RR) 1.9 (95 % CI: 1.01-3.5, p = 0.04) and RR 1.5 (95 % CI: 1.3-1.7, p < 0.001), respectively. All differences resolved at follow up two months after treatment. There were no significant differences between groups on opioid use, use of feeding tubes, or hospitalization during the observation period., Conclusion: Proton treatment resulted in excess objective mucositis and dermatitis, which was transient and did not seem to negatively influence weight or treatment compliance and intensity. Selection bias was likely especially since NTCP models were used for selection of proton treatment and photon treated patients were matched manually. We are currently including patients in a randomized controlled trial., 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., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Poor mental health among youth in Greenland is a major challenge, childhood conditions are critical for mental health later in life. The study aimed to examine the clustering of childhood conditions by considering risk and protective factors for mental health among youth and young adults in Greenland and to explore the relationship between these clusters and mental health outcomes in youth. The study included 565 participants aged 15-34 living in Greenland. Seven indicators including childhood adversities (ACEs), childhood residence, language, and cultural indicators (protective factors) were used to define clusters via latent class analysis (LCA). The associations between clusters and mental health outcomes (satisfaction with life (Cantrill's ladder), self-esteem, self-efficacy, loneliness, psychological distress (General Health Questionnaire) and mental illness (Kessler 6)) were assessed by logistic regression. Four clusters were identified through LCA. While most participants reported positive childhoods, 40% (in two clusters) experienced ACEs. The two clusters differed as more participants in one cluster had experienced protective factors than the other. ACEs were associated with increased odds of negative aspects of mental health in youth. However, participants who faced high levels of adversity and few protective factors also had reduced odds of positive aspects of mental health in youth.

Background: Over the past decade, ultrasound utilization has increased within anesthesia and intensive care medicine, enhancing patient safety and diagnostic accuracy. However, the frequency of ultrasound usage and operator training in the Nordic countries remain unclear. This project aims to perform a survey on ultrasound availability, daily clinical use, and how ultrasound skills are trained and assessed, among anesthesiologists., Methods: This online cross-sectional survey will include anesthesiologists from the Nordic countries. The survey will adhere to the CROSS checklist. Survey items will be developed based on a formative model with a conceptual model, consisting of three main parts, including demographics, ultrasound machines and use, and skills development and assessment. The clinical relevance of items will be secured by including anesthesiologists of various levels of experience in the development of the survey. Furthermore, experienced researchers in medical education will participate in the development, contributing with relevant medical educational perspectives. Data will be summarized using a non-parametric descriptive approach. A chi-squared test will examine relevant relationships between certain answers., Results: Results will be published in a peer-reviewed journal and presented at relevant scientific conferences and meetings., Conclusion: This study may find a high availability of ultrasound machines and frequent use in the clinical departments. Despite this expected daily use of ultrasound, missing standardized structured skills acquisition and assessment could be uncovered. The results of this study may contribute to mapping various aspects of clinical ultrasound and skills development for further use in research., (© 2024 The Author(s). Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Background: Access to the neuraxial space, including lumbar punctures and neuraxial anaesthesia, is an everyday procedure in clinical practice. Traditionally these procedures rely on manual palpation technique, but ultrasound is a useful tool when patients prove challenging. Presently, there is a lack of evidence-based guidelines for technical skills acquisition, both with and without ultrasound, and likewise, competency assessment approaches vary globally. Accordingly, we aim to assess the current evidence regarding learning and assessment in neuraxial access ± $$ \pm $$ ultrasound, for future educational recommendations., Methods: This scoping review will be conducted in accordance with the Preferred Reporting Items for Systematic and Meta-Analysis (PRISMA) statement, together with the PRISMA Extension for Scoping Reviews. A systematic search strategy will be based on a PICO approach, focusing on physicians, medical students, or nurses being exposed to education, training, or assessment in procedural neuraxial access ± $$ \pm $$ ultrasound. No comparators are obligated, but outcomes should be assessable using the Kirkpatrick four levels of training evaluation. The search will be performed in Cochrane Library, Embase, Medline, Scopus, PubMed, and CINAHL. Independently, two authors will screen the studies and conflicts will be resolved by a third author. Relevant predefined data will be extracted and analysed using a descriptive approach. The quality of the studies will be assessed using the Medical Education Research Study Quality Instrument., Discussion: This scoping review will contribute by presenting gathered evidence of an overview of the different approaches to achieving education and training of technical skills in neuraxial access, and how skills are tested, which could guide research and future recommendations for skills development and assessment., (© 2024 The Author(s). Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

This case report describes laryngeal oedema occurring in a 35-year-old woman with chronic bowel-associated dermatosis-arthritis syndrome, and stenosis of the left main bronchus. The oedema was attributed to persistent cough exacerbated by delayed treatment and intubation-related irritation. Evaluations ruled out inflammatory, autoimmune, and malignant causes. Literature lacks on specific descriptions of cough-induced laryngeal oedema, emphasizing the need for a multidisciplinary approach and early intervention in complex cases to prevent severe hospitalizations in patients with known serious conditions and symptom exacerbation., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Background and Purpose: Delivery of high precision radiotherapy lymph node boosts requires detailed information on the interfraction positional variation of individual lymph nodes. In this study we characterized interfraction positional shifts of suspected malignant lymph nodes for rectal cancer patients receiving long course radiotherapy. Furthermore, we investigated parameters which could affect the magnitude of the position variation., Materials and Methods: Fourteen patients from a prospective clinical imaging study with a total of 61 suspected malignant lymph nodes in the mesorectum, presacral, and lateral regions, were included. The primary gross tumor volume (GTV p ) and all suspected malignant lymph nodes were delineated on six magnetic resonance imaging scans per patient. Positional variation was calculated as systematic and random errors, based on shifts of center-of-mass, and estimated relative to either bony structures or the GTV p using a hierarchical linear mixed model., Results: Depending on location and direction, systematic and random variations (relative to bony structures) were within 0.6-2.8 mm and 0.6-2.9 mm, respectively. Systematic and random variations increased when evaluating position relative to GTV p (median increase of 0.6 mm and 0.5 mm, respectively). Correlations with scan time-point and relative bladder volume were found in some directions., Conclusions: Using linear mixed modeling, we estimated systematic and random positional variation for suspected malignant lymph nodes in rectal cancer patients treated with long course radiotherapy. Statistically significant correlations of the magnitude of the lymph node shifts were found related to scan time-point and relative bladder volume., 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., (© 2024 The Authors.)

Background: In many countries, health care professionals are legally obliged to share information from electronic health records with patients. However, concerns have been raised regarding the sharing of notes with adolescents in mental health care, and health care professionals have called for recommendations to guide this practice., Objective: The aim was to reach a consensus among authors of scientific papers on recommendations for health care professionals' digital sharing of notes with adolescents in mental health care and to investigate whether staff at child and adolescent specialist mental health care clinics agreed with the recommendations., Methods: A Delphi study was conducted with authors of scientific papers to reach a consensus on recommendations. The process of making the recommendations involved three steps. First, scientific papers meeting the eligibility criteria were identified through a PubMed search where the references were screened. Second, the results from the included papers were coded and transformed into recommendations in an iterative process. Third, the authors of the included papers were asked to provide feedback and consider their agreement with each of the suggested recommendations in two rounds. After the Delphi process, a cross-sectional study was conducted among staff at specialist child and adolescent mental health care clinics to assess whether they agreed with the recommendations that reached a consensus., Results: Of the 84 invited authors, 27 responded. A consensus was reached on 17 recommendations on areas related to digital sharing of notes with adolescents in mental health care. The recommendations considered how to introduce digital access to notes, write notes, and support health care professionals, and when to withhold notes. Of the 41 staff members at child and adolescent specialist mental health care clinics, 60% or more agreed with the 17 recommendations. No consensus was reached regarding the age at which adolescents should receive digital access to their notes and the timing of digitally sharing notes with parents., Conclusions: A total of 17 recommendations related to key aspects of health care professionals' digital sharing of notes with adolescents in mental health care achieved consensus. Health care professionals can use these recommendations to guide their practice of sharing notes with adolescents in mental health care. However, the effects and experiences of following these recommendations should be tested in clinical practice., (© Martine Stecher Nielsen, Aslak Steinsbekk, Torunn Hatlen Nøst. Originally published in JMIR Mental Health (https://mental.jmir.org).)

Despite extensive research, targeted delivery of substances to the brain still poses a great challenge due to the selectivity of the blood-brain barrier (BBB). Most molecules require either carrier- or receptor-mediated transport systems to reach the central nervous system (CNS). These transport systems form attractive routes for the delivery of therapeutics into the CNS, yet the number of known brain endothelium-enriched receptors allowing the transport of large molecules into the brain is scarce. Therefore, to identify novel BBB targets, we combined transcriptomic analysis of human and murine brain endothelium and performed a complex screening of BBB-enriched genes according to established selection criteria. As a result, we propose the high-affinity cationic amino acid transporter 1 (SLC7A1) as a novel candidate for transport of large molecules across the BBB. Using RNA sequencing and in situ hybridization assays, we demonstrated elevated SLC7A1 gene expression in both human and mouse brain endothelium. Moreover, we confirmed SLC7A1 protein expression in brain vasculature of both young and aged mice. To assess the potential of SLC7A1 as a transporter for larger proteins, we performed internalization and transcytosis studies using a radiolabelled or fluorophore-labelled anti-SLC7A1 antibody. Our results showed that SLC7A1 internalised a SLC7A1-specific antibody in human colorectal carcinoma (HCT116) cells. Moreover, transcytosis studies in both immortalised human brain endothelial (hCMEC/D3) cells and primary mouse brain endothelial cells clearly demonstrated that SLC7A1 effectively transported the SLC7A1-specific antibody from luminal to abluminal side. Therefore, here in this study, we present for the first time the SLC7A1 as a novel candidate for transport of larger molecules across the BBB., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sarah Bau and Stephen T. Buckley are employees at Novo Nordisk. Catarina Chaves and Dominique Lesuisse are employees at Sanofi. Marijke De Bock is an employee at Janssen Pharmaceutica. Axel H. Mayer is an employee at AbbVie. German Leparc and Martin Lenter are employees at Boehringer Ingelheim Pharma. Tamas Letoha is the CEO of Pharmacoidea and Robert D. Bell is the Vice President and the Head of Research at Ascidian Therapeutics. All others declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Non-surgical management of rectal cancer relies on (chemo)radiotherapy as the definitive treatment modality. This study reports and evaluates the clinical high dose radiotherapy treatment plans delivered to patients with low resectable rectal cancer in a Danish multicenter trial., Methods: The Danish prospective multicenter phase II Watchful Waiting 2 trial (NCT02438839) investigated definitive chemoradiation for non-surgical management of low rectal cancer. Three Danish centers participated in the trial and committed to protocol-specified treatment planning and delivery requirements. The protocol specified a dose of 50.4 Gy in 28 fractions to the elective volume (CTV-/PTV-E) and a concomitant boost of 62 Gy in 28 fractions to the primary target volume (CTV-/PTV-T)., Results: The trial included 108 patients, of which 106 treatment plans were available for retrospective analysis. Dose coverage planning goals for the main target structures were fulfilled for 94% of the treatment plans. However, large intercenter differences in doses to organs-at-risk (OARs) were seen, especially for the intestines. Five patients had a V60Gy>10 cm 3 for the intestines and two patients for the bladder., Conclusion: Prescribed planning goals for target coverage were fulfilled for 94% of the treatment plans, however analysis of OAR doses and volumes indicated intercenter variations. Dose escalation to 62 Gy (as a concomitant boost to the primary tumor) introduced no substantial high dose volumes (>60 Gy) to the bladder and intestines. The treatment planning goals may be used for future prospective evaluation of highdose radiotherapy for organ preservation for low rectal cancer., 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 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Background: Response time for emergency medical service units is a key performance indicator. Studies have shown reduced response time association with improved outcome for specific critical conditions. To achieve short response time, emergency vehicles utilize lights and sirens, and crews are allowed to be non-compliant with traffic rules, posing a risk for accident. The purpose of the systematic review and meta-analysis is to provide an overview of the current body of evidence regarding the association, if any, between ambulance and helicopter response time and major complications and mortality in patients conveyed by ambulance and/or helicopter. Our secondary aim will be to enhance knowledge in the field of criteria-based dispatch to provide decision makers with evidence to optimize dispatch of limited resources., Research Questions: What is the association between overall emergency medical services unit response time and patient outcomes, major complications, and time-critical conditions? What is the internal and external validity of the included literature?, Methods: We plan the systematic review and meta-analysis to be in accordance with the Cochrane Handbook and Joanna Briggs Institute Manual for Systematic Reviews. The methodology will include formulating the review questions using a Population, Exposure, and Outcome framework. Every study design is eligible, including qualitative, quantitative, and mixed-methods designs. We will include all articles in English, Scandinavian, German, French and Portuguese in this systematic review., Results: We will publish results from the systematic review and meta-analysis in a peer-reviewed journal and we will present the results at scientific conferences and meetings. Results will also be available at www.ahrtemis.dk., Conclusion: We will base our conclusions on the findings of the review and meta-analysis., (© 2023 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Introduction: Proton treatment can potentially spare patients with H&N cancer for substantial treatment-related toxicities. The current study investigated the reproducibility of a decentralised model-based selection of patients for a proton treatment study when the selection plans were compared to the clinical treatment plans performed at the proton centre., Methods: Sixty-three patients were selected for proton treatment in the six Danish Head and Neck Cancer (DAHANCA) centres. The patients were selected based on normal tissue complication probability (NTCP) estimated from local photon and proton treatment plans, which showed a ΔNTCP greater than 5%-point for either grade 2 + dysphagia or grade 2 + xerostomia at six months. The selection plans were compared to the clinical treatment plans performed at the proton centre., Results: Of the 63 patients, 49 and 25 were selected based on an estimated benefit in risk of dysphagia and xerostomia, respectively. Eleven patients had a potential gain in both toxicities. The mean ΔNTCP changed from the local selection plan comparison to the clinical comparison from 6.9 to 5.3 %-points (p = 0.01) and 7.3 to 4.9 %-points (p = 0.03) for dysphagia and xerostomia, respectively. Volume differences in both CTV and OAR could add to the loss in ΔNTCP. 61 of the 63 clinical plans had a positive ΔNTCP, and 38 had a ΔNTCP of 5%-points for at least one of the two endpoints., Conclusion: A local treatment plan comparison can be used to select candidates for proton treatment. The local comparative proton plan overestimates the potential benefit of the clinical proton plan. Continuous quality assurance of the delineation procedures and planning is crucial in the subsequent randomised clinical trial setting., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: In the Difficult Airway Society's 2015 "cannot intubate, cannot oxygenate" guideline, the emergency cricothyroidotomy is the final option when managing an unanticipated difficult airway. How often training for maintenance of this skill is required for anesthesiologists remains unknown. We aimed to assess if specialist-trained anesthesiologists' skills improved from a brush-up intervention and if skills were retained after 3 months., Methods: In this multicenter, randomized, controlled trial, participants were randomized to either a simulation-based brush-up or no brush-up. Both groups performed a mannequin-based technical skills emergency cricothyroidotomy test twice and were assessed by a blinded rater using a structured assessment tool that included time, positioning, palpation, appropriate employment of instruments, and stepwise progression. After 3 months of non-training, participants completed identical tests of retention., Results: A total of 54 anesthesiologists were included from three hospitals in the Region of Southern Denmark. Thirty-seven percent of the participants had received skills training in emergency cricothyroidotomy in the prior 12 months. The intervention group (N = 27) performed better in the initial tests, with a mean time of 51.5 s (SD = 10.82), a total score per minute of 15.9 points (SD = 4.91), and 93% passing both initial tests compared to the control group (N = 27) with a mean time of 76.8 s (SD = 35.82), a total score per minute of 6.6 (SD = 4.68) and only 15% passing both initial tests. The intervention group managed to retain overall performance in retention tests in terms of performance time (48.9 s, p = .26), total score per minute (13.6 points, p = .094), and passing the tests (75%, p = .059)., Conclusion: Exposure to simulation-based brush-up training in emergency cricothyroidotomy improved anesthesiologists' technical performance and was overall retained after 3 months. Some loss of skill concerning specific items was observed, highlighting the need for regular training in emergency cricothyroidotomy. Simulation-based training should be prioritized to improve and maintain technical skills in infrequent high-stakes procedures., (© 2023 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Background: Blood-brain barrier (BBB) models based on primary murine, bovine, and porcine brain capillary endothelial cell cultures have long been regarded as robust models with appropriate properties to examine the functional transport of small molecules. However, species differences sometimes complicate translating results from these models to human settings. During the last decade, brain capillary endothelial-like cells (BCECs) have been generated from stem cell sources to model the human BBB in vitro. The aim of the present study was to establish and characterize a human BBB model using human induced pluripotent stem cell (hiPSC)-derived BCECs from the hIPSC line SBAD0201., Methods: The model was evaluated using transcriptomics, proteomics, immunocytochemistry, transendothelial electrical resistance (TEER) measurements, and, finally, transport assays to assess the functionality of selected transporters and receptor (GLUT-1, LAT-1, P-gp and LRP-1)., Results: The resulting BBB model displayed an average TEER of 5474 ± 167 Ω·cm 2 and cell monolayer formation with claudin-5, ZO-1, and occludin expression in the tight junction zones. The cell monolayers expressed the typical BBB markers VE-cadherin, VWF, and PECAM-1. Transcriptomics and quantitative targeted absolute proteomics analyses revealed that solute carrier (SLC) transporters were found in high abundance, while the expression of efflux transporters was relatively low. Transport assays using GLUT-1, LAT-1, and LRP-1 substrates and inhibitors confirmed the functional activities of these transporters and receptors in the model. A transport assay suggested that P-gp was not functionally expressed in the model, albeit antibody staining revealed that P-gp was localized at the luminal membrane., Conclusions: In conclusion, the novel SBAD0201-derived BBB model formed tight monolayers and was proven useful for studies investigating GLUT-1, LAT-1, and LRP-1 mediated transport across the BBB. However, the model did not express functional P-gp and thus is not suitable for the performance of drug efflux P-gp reletated studies., (© 2023. The Author(s).)

Here, we report an experimental setup to benchmark different receptors for targeted therapeutic antibody delivery at the blood-brain barrier. We used brain capillary endothelial-like cells derived from induced pluripotent stem cells (hiPSC-BECs) as a model system and compared them to colon epithelial Caco-2 cells. This approach helped to identify favourable receptors for transport into the cell layer itself or for directing transport for transcytosis across the cell layer. The sorting receptors transferrin receptor and sortilin were shown to be efficient as antibody cargo receptors for intracellular delivery to the cell layer. In contrast, the cell surface receptors CD133 and podocalyxin were identified as static and inefficient receptors for delivering cargo antibodies. Similar to in vivo studies, the hiPSC-BECs maintained detectable transcytotic transport via transferrin receptor, while transcytosis was restricted using sortilin as a cargo receptor. Based on these findings, we propose the application of sortilin as a cargo receptor for delivering therapeutic antibodies into the brain microvascular endothelium., (© 2023. The Author(s).)

Biological mechanisms to promote dietary balance remain unclear. Fibroblast growth factor 21 (FGF21) has been suggested to contribute to such potential regulation considering that FGF21 1 ) is genetically associated with carbohydrate/sugar and protein intake in opposite directions, 2 ) is secreted after sugar ingestion and protein restriction, and 3 ) pharmacologically reduces sugar and increases protein intake in rodents. To gain insight of the nature of this potential regulation, we aimed to study macronutrient interactions in the secretory regulation of FGF21 in healthy humans. We conducted a randomized, double-blinded, crossover meal study (NCT05061485), wherein healthy volunteers consumed a sucrose drink, a sucrose + protein drink, and a sucrose + fat drink (matched sucrose content), and compared postprandial FGF21 responses between the three macronutrient combinations. Protein suppressed the sucrose-induced FGF21 secretion [incremental area under the curve (iAUC) for sucrose 484 ± 127 vs. sucrose + protein -35 ± 49 pg/mL × h, P < 0.001]. The same could not be demonstrated for fat (iAUC 319 ± 102 pg/mL × h, P = 203 for sucrose + fat vs. sucrose). We found no indications that regulators of glycemic homeostasis could explain this effect. This indicates that FGF21 responds to disproportionate intake of sucrose relative to protein acutely within a meal, and that protein outweighs sucrose in FGF21 regulation. Together with previous findings, our results suggests that FGF21 might act to promote macronutrient balance and sufficient protein intake. NEW & NOTEWORTHY Here we test the interactions between sugar, protein, and fat in human FGF21 regulation and demonstrate that protein, but not fat, suppresses sugar-induced FGF21 secretion. This indicates that protein outweighs the effects of sugar in the secretory regulation of FGF21, and could suggest that the nutrient-specific appetite-regulatory actions of FGF21 might prioritize ensuring sufficient protein intake over limiting sugar intake.

Background: In the Danish Head and Neck Cancer Group (DAHANCA) 35 trial, patients are selected for proton treatment based on simulated reductions of Normal Tissue Complication Probability (NTCP) for proton compared to photon treatment at the referring departments. After inclusion in the trial, immobilization, scanning, contouring and planning are repeated at the national proton centre. The new contours could result in reduced expected NTCP gain of the proton plan, resulting in a loss of validity in the selection process. The present study evaluates if contour consistency can be improved by having access to AI (Artificial Intelligence) based contours., Materials and Methods: The 63 patients in the DAHANCA 35 pilot trial had a CT from the local DAHANCA centre and one from the proton centre. A nationally validated convolutional neural network, based on nnU-Net, was used to contour OARs on both scans for each patient. Using deformable image registration, local AI and oncologist contours were transferred to the proton centre scans for comparison. Consistency was calculated with the Dice Similarity Coefficient (DSC) and Mean Surface Distance (MSD), comparing contours from AI to AI and oncologist to oncologist, respectively. Two NTCP models were applied to calculate NTCP for xerostomia and dysphagia., Results: The AI contours showed significantly better consistency than the contours by oncologists. The median and interquartile range of DSC was 0.85 [0.78 - 0.90] and 0.68 [0.51 - 0.80] for AI and oncologist contours, respectively. The median and interquartile range of MSD was 0.9 mm [0.7 - 1.1] mm and 1.9 mm [1.5 - 2.6] mm for AI and oncologist contours, respectively. There was no significant difference in Δ NTCP., Conclusions: The study showed that OAR contours made by the AI algorithm were more consistent than those made by oncologists. No significant impact on the Δ NTCP calculations could be discerned.

Aims: No effective therapy is available in clinics to protect the heart from ischaemia/reperfusion (I/R) injury. Endothelial cells are activated after I/R, which may drive the inflammatory response by releasing ATP through pannexin1 (Panx1) channels. Here, we investigated the role of Panx1 in cardiac I/R., Methods and Results: Panx1 was found in cardiac endothelial cells, neutrophils, and cardiomyocytes. After in vivo I/R, serum Troponin-I, and infarct size were less pronounced in Panx1-/- mice, but leukocyte infiltration in the infarct area was similar between Panx1-/- and wild-type mice. Serum Troponin-I and infarct size were not different between mice with neutrophil-specific deletion of Panx1 and Panx1fl/fl mice, suggesting that cardioprotection by Panx1 deletion rather involved cardiomyocytes than the inflammatory response. Physiological cardiac function in wild-type and Panx1-/- hearts was similar. The time to onset of contracture and time to maximal contracture were delayed in Panx1-/- hearts, suggesting reduced sensitivity of these hearts to ischaemic injury. Moreover, Panx1-/- hearts showed better recovery of left ventricle developed pressure, cardiac contractility, and relaxation after I/R. Ischaemic preconditioning failed to confer further protection in Panx1-/- hearts. Panx1 was found in subsarcolemmal mitochondria (SSM). SSM in WT or Panx1-/- hearts showed no differences in morphology. The function of the mitochondrial permeability transition pore and production of reactive oxygen species in SSM was not affected, but mitochondrial respiration was reduced in Panx1-/- SSM. Finally, Panx1-/- cardiomyocytes had a decreased mitochondrial membrane potential and an increased mitochondrial ATP content., Conclusion: Panx1-/- mice display decreased sensitivity to cardiac I/R injury, resulting in smaller infarcts and improved recovery of left ventricular function. This cardioprotective effect of Panx1 deletion seems to involve cardiac mitochondria rather than a reduced inflammatory response. Thus, Panx1 may represent a new target for controlling cardiac reperfusion damage., Competing Interests: Conflict of interest: None declared, (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Adolescents in mental health care may benefit from using patient portals to access personalised information about their health and treatment. While no studies have considered the interest in using patient portals among adolescents in mental health care, factors such as patient activation, self-reported health, depressive symptoms, diagnosis, healthcare utilisation, and eHealth literacy have been found to be associated with interest in and use of patient portals in other patient groups. Therefore, the aim was to explore the associations between interest in using patient portals and patient activation, self-reported health, depressive symptoms, diagnosis, healthcare utilisation and eHealth literacy among adolescents in specialist mental health care., Methods: A cross-sectional study among adolescents between 12 and 18 years of age receiving or having received treatment at four different specialist child and adolescent mental healthcare services across Norway. The adolescents´ answers to the questionnaire were linked to data on their healthcare utilisation and ICD-10 diagnoses from the Norwegian Patient Registry. The data were analysed using descriptive statistics and bivariate tests., Results: The 53 adolescents who participated, had a mean age of 15 years and 68% of them identified as female. Two out of three (64%) were interested in using patient portals. Most of the factors were not associated with interest in using patient portals. However, adolescents with mental and behavioural disorders (F diagnoses, 75% interested) were more interested in using patient portals compared to those with symptoms and signs involving cognition, perception, emotional state, and behaviour (R diagnoses, 31% interested)., Conclusion: Except for mental health diagnosis, this study did not identify any specific factors likely to impact patient portal interest among adolescents in specialist mental health care., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: Emergency cricothyroidotomy is the final approach to establishing a secure airway. The procedure is acute and highly infrequent, making it difficult to achieve and maintain competence in the clinic. Simulation-based training in emergency cricothyroidotomy is effective but it is unknown how often training should be repeated to maintain skills. This study aimed to assess novices' retention of technical skills in emergency cricothyroidotomy after completing SBT., Methods: Novices in emergency cricothyroidotomy completed a structured, simulation-based training program and were randomized to retention tests after 1, 3, or 6 months. Participants completed two emergency cricothyroidotomy tests at end-of-training and follow-up retention testing. Test performances were video recorded and evaluated by two experienced blinded raters using a structured assessment tool. Differences in the performances and the pass/fail rates were analyzed., Results: Eighty-two medical students from two different Danish universities were included from April 2021 to February 2022. Paired t -tests showed skills decay significantly after 1 month (mean loss 6.7 points, p  < 0.001). The mean loss of points, representing the difference in global score points, from the end-of-training to retention test was 6.7 points (95% confidence interval [CI] 4.5-8.8) for the 1-month group, 8.2 points (95% CI 5.8-10.0) for the 3-months group, and 9.9 points (95% CI 8.1-11.7) for the 6-months group. Six participants in both the 1-month group (23.1%) and the 3-month group (24%) passed the first retention test, but no one in the 6-months group had a passing performance., Conclusions: Novices' technical skills performance in emergency cricothyroidotomy decay significantly already after 1 month. This initial loss of skill seems to be stable until 3 months, after which there is a further significant loss of skills. Recurring training should be implemented for the benefit of patient safety and outcomes., Competing Interests: The authors declare no conflicts of interest., (© 2023 Society for Academic Emergency Medicine.)

The intercalated disc (ID) is a highly specialized structure that connects cardiomyocytes via mechanical and electrical junctions. Although described in some detail by light microscopy in the 19th century, it was in 1966 that electron microscopy images showed that the ID represented apposing cell borders and provided detailed insight into the complex ID nanostructure. Since then, much has been learned about the ID and its molecular composition, and it has become evident that a large number of proteins, not all of them involved in direct cell-to-cell coupling via mechanical or gap junctions, reside at the ID. Furthermore, an increasing number of functional interactions between ID components are emerging, leading to the concept that the ID is not the sum of isolated molecular silos but an interacting molecular complex, an "organelle" where components work in concert to bring about electrical and mechanical synchrony. The aim of the present review is to give a short historical account of the ID's discovery and an updated overview of its composition and organization, followed by a discussion of the physiological implications of the ID architecture and the local intermolecular interactions. The latter will focus on both the importance of normal conduction of cardiac action potentials as well as the impact on the pathophysiology of arrhythmias.

Patient portals hold the potential to support patients and enhance treatment, yet some concerns exist for adults in mental health care and adolescents in general. Due to limited studies on patient portal use in adolescent mental health care, the aim was to examine the interest in and experiences with the use of patient portals among adolescents in mental health care. In a cross-sectional survey, adolescent patients in specialist mental health care across Norway were invited between April and September 2022. The questionnaire included questions on their interests in and experiences with using patient portals. Fifty-three (8,5%), adolescents between 12-18 (mean: 15) responded, of which 64 % were interested in using patient portals. Almost half of the respondents would share access to their patient portal with healthcare providers (48 %) and designated family members (43 %). One-third had used a patient portal, where 28 % had used it to change an appointment, 24 % to see their medications and 22 % to communicate with healthcare providers. The knowledge from this study can be used to inform the set-up of patient portal services for adolescents in mental health care.

Understanding the vesicular trafficking of receptors and receptor ligands in the brain capillary endothelium is essential for the development of the next generations of biologics targeting neurodegenerative diseases. Such complex biological questions are often approached by in vitro models in combination with various techniques. Here, we present the development of a stem cell-based human in vitro blood-brain barrier model composed of induced brain microvascular endothelial cells (iBMECs) on the modular µSiM (a microdevice featuring a silicon nitride membrane) platform. The µSiM was equipped with a 100 nm thick nanoporous silicon nitride membrane with glass-like imaging quality that allowed the use of high-resolution in situ imaging to study the intracellular trafficking. As a proof-of-concept experiment, we investigated the trafficking of two monoclonal antibodies (mAb): an anti-human transferrin receptor mAb (15G11) and an anti-basigin mAb (#52) using the µSiM-iBMEC-human astrocyte model. Our results demonstrated effective endothelial uptake of the selected antibodies; however, no significant transcytosis was observed when the barrier was tight. In contrast, when the iBMECs did not form a confluent barrier on the µSiM, the antibodies accumulated inside both the iBMECs and astrocytes, demonstrating that the cells have an active endocytic and subcellular sorting machinery and that the µSiM itself does not hinder antibody transport. In conclusion, our µSiM-iBMEC-human astrocyte model provides a tight barrier with endothelial-like cells, which can be used for high-resolution in situ imaging and for studying receptor-mediated transport and transcytosis in a physiological barrier.

Competing Interests: None

Background: Digitalization of health care has opened up for new ways to involve and engage patients. With this, increased attention has been put on digital patient portals. There exists some research on patient portals for adolescent patients in general and for adults in mental health care. However, no studies on patient portals for adolescents in mental health care have been identified in a recent review. The aim was therefore to explore the views on using patient portals for adolescents in mental health care among persons involved in and/or being affected by the introduction of a patient portal., Methods: A qualitative study was conducted using individual semi-structured interviews with 14 persons who were healthcare providers in child and adolescent mental health care, young representatives from the user panel, or persons affiliated with an EHR-project introducing a patient portal. The main questions addressed their views on introducing patient portals for adolescents in mental health care and how patient portals and access to clinical notes can affect them and their treatment., Results: The findings were categorised into four main themes; "Does access to a patient portal help or harm adolescents?", "Who decides access?", "Mostly a political goal" and "Need for support and competency". Informants mentioned situations in which both adolescents' and parents' access to a patient portal could help adolescents in mental health care, but also where it could potentially harm their treatment and threaten confidentiality. Most informants thought that healthcare providers should have the autonomy to determine which information should be shared with whom, but also requested guidelines to ensure equal practice and support in difficult situations. Some perceived patient portals as the result of a political decision, rather than healthcare providers´ wishes, while others described it as a necessary development towards democratization., Conclusion: The informants' views varied from thinking that a patient portal could support adolescents in mental health care, to worrying that it could be detrimental to the treatment. Informants emphasized that the management should facilitate training and support for healthcare providers in using patient portals and telehealth., (© 2023. The Author(s).)

The detailed mechanisms by which the transferrin receptor (TfR) and associated ligands traffic across brain capillary endothelial cells (BECs) of the CNS-protective blood-brain barrier constitute an important knowledge gap within maintenance and regulation of brain iron homeostasis. This knowledge gap also presents a major obstacle in research aiming to develop strategies for efficient receptor-mediated drug delivery to the brain. While TfR-mediated trafficking from blood to brain have been widely studied, investigation of TfR-mediated trafficking from brain to blood has been limited. In this study we investigated TfR distribution on the apical and basal plasma membranes of BECs using expansion microscopy, enabling sufficient resolution to separate the cellular plasma membranes of these morphological flat cells, and verifying both apical and basal TfR membrane domain localization. Using immunofluorescence-based transcellular transport studies, we delineated endosomal sorting of TfR endocytosed from the apical and basal membrane, respectively, as well as bi-directional TfR transcellular transport capability. The findings indicate different intracellular sorting mechanisms of TfR, depending on the apicobasal trafficking direction across the BBB, with the highest transcytosis capacity in the brain-to-blood direction. These results are of high importance for the current understanding of brain iron homeostasis. Also, the high level of TfR trafficking from the basal to apical membrane of BECs potentially explains the low transcytosis which are observed for the TfR-targeted therapeutics to the brain parenchyma., (© 2023. The Author(s).)

In general, optical methods for geometrical measurements are influenced by the surface properties of the examined object. In Structure from Motion (SfM), local variations in surface color or topography are necessary for detecting feature points for point-cloud triangulation. Thus, the level of contrast or texture is important for an accurate reconstruction. However, quantitative studies of the influence of surface texture on geometrical reconstruction are largely missing. This study tries to remedy that by investigating the influence of object texture levels on reconstruction accuracy using a set of reference artifacts. The artifacts are designed with well-defined surface geometries, and quantitative metrics are introduced to evaluate the lateral resolution, vertical geometric variation, and spatial-frequency information of the reconstructions. The influence of texture level is compared to variations in capturing range. For the SfM measurements, the ContextCapture software solution and a 50 Mpx DSLR camera are used. The findings are compared to results using calibrated optical microscopes. The results show that the proposed pipeline can be used for investigating the influence of texture on SfM reconstructions. The introduced metrics allow for a quantitative comparison of the reconstructions at varying texture levels and ranges. Both range and texture level are seen to affect the reconstructed geometries although in different ways. While an increase in range at a fixed focal length reduces the spatial resolution, an insufficient texture level causes an increased noise level and may introduce errors in the reconstruction. The artifacts are designed to be easily replicable, and by providing a step-by-step procedure of our testing and comparison methodology, we hope that other researchers will make use of the proposed testing pipeline.

Objectives: This study aimed to develop and gather the validity evidence for a standardised simulation-based skills test in transthoracic echocardiography and to establish a credible pass/fail score., Methods: Experts developed a virtual-reality simulator test in cardiology, medical education and simulation-based education. Thirty-six physicians with different experiences in transthoracic echocardiography completed the test at Odense University Hospital, Denmark. The performances of novice, intermediate and experienced participants were compared using the Bonferroni post hoc test. Cronbach's alpha was used to determine the internal consistency reliability of the test. The consistency of performance was analysed using the intraclass correlation coefficient. A pass/fail score was established using the contrasting groups' standard-setting method., Results: We developed a test with high consistent reliability (Alpha = .81), 95% CI [.69, .89]. In both cases, the performers' level was consistent, fitting others at the same level of experience (intraclass correlation r (35) =.81, p<.001). A pass/fail score of 48/50 points was established based on the mean test score of novice and experienced physicians., Conclusions: We developed a standardised virtual-reality simulation-based test of echocardiography skills with the ability to distinguish between participants with different levels of transthoracic echocardiography experience. This test could direct a mastery learning training program where trainees practise until they reach the pre-defined level and secure a higher level of competency to ensure quality and safety for patients.

Fucoidans are polysaccharides from brown macroalgae, showing multiple bioactivities important for bone regeneration and bone health. However, the use of fucoidans in medical applications remains sparse due to the heterogeneity in their chemical properties and unclear structure-function relationships. Innovations in extraction techniques and post processing steps are needed to produce homogeneous fucoidan molecules with tailorable bioactivities. Here, we applied enzyme-assisted extraction coupled with enzymatic hydrolysis by Fhf1 fucoidanase to generate low (LMW) and medium molecular weight (MMW) fucoidans from Fucus evanescens. In contrast to the anti-angiogenic properties of the high molecular weight fucoidan, LMW and MMW no longer suppressed the production of pro-angiogenic molecules by bone stem cells, nor impaired the formation of prevascular structures in vitro. In contrast to LMW, a pro-inflammatory response of OEC was observed after treatment with high concentrations of MMW. Thus, fucoidanase hydrolysis could be a useful tool to tailor the bioactivity of fucoidans., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Despite the high proportion of children and adolescents living in low- and middle-income countries, 95% of all specialized child and adolescent mental health resources are located in high-income countries. To strengthen child and adolescent mental health services (CAMHS), first it is necessary to complete an assessment of the available services and training programs to determine what is needed, particularly in regions with young populations, such as Southeast Europe, the Far East, and the Middle East. The aim of this article is to compare the status of child and adolescent psychiatry (CAP) training programs and the workforce in CAMHS in three geographical regions, to identify similar problems, highlight success stories, and to make recommendations for future studies., Methods: This study compared CAP training programs and CAMHS workforce using the World Psychiatric Association, CAP Section's regional studies data., Results: This study included data from 44 countries: 18 countries in the Far East, 15 countries in the Middle East, and 11 countries in Southeast Europe. There were significant differences both within, and between, the three included regions with regards to availability and infrastructure of CAP training programs. Besides Greece, all included countries reported the need for more child and adolescent psychiatrists and allied child and adolescent mental health professionals., Discussion: There is an urgent need for more qualified child and adolescent psychiatrists and allied professionals in a very large group of countries in three different geographic regions with great differences in religion, culture, and economy., (© 2021 The Authors. Asia-Pacific Psychiatry published by John Wiley & Sons Australia, Ltd.)

Parkinson's disease is mainly caused by aggregation of α-synuclein (α-syn) in the brain. Exchange of α-syn between the brain and peripheral tissues could have important pathophysiological and therapeutic implications, but the trafficking mechanism of α-syn across the blood brain-barrier (BBB) remains unclear. In this study, we therefore investigated uptake and transport mechanisms of α-syn monomers and oligomers across an in vitro BBB model system. Both α-syn monomers and oligomers were internalized by primary brain endothelial cells, with increased restriction of oligomeric over monomeric transport. To enlighten the trafficking route of monomeric α-syn in brain endothelial cells, we investigated co-localization of α-syn and intracellular markers of vesicular transport. Here, we observed the highest colocalization with clathrin, Rab7 and VPS35, suggesting a clathrin-dependent internalization, preferentially followed by a late endosome retromer-connected trafficking pathway. Furthermore, STED microscopy revealed monomeric α-syn trafficking via Rab7-decorated carriers. Knockdown of Caveolin1, VPS35, and Rab7 using siRNA did not affect monomeric α-syn uptake into endothelial cells. However, it significantly reduced transcytosis of monomeric α-syn in the luminal-abluminal direction, suggesting a polarized regulation of monomeric α-syn vesicular transport. Our findings suggest a direct role for Rab7 in polarized trafficking of monomeric α-syn across BBB endothelium, and the potential of Rab7 directed trafficking to constitute a target pathway for new therapeutic strategies against Parkinson's disease and related synucleinopathies., (© 2022. The Author(s).)

Purpose: To evaluate intravitreal 0.19 mg fluocinolone acetonide implant (FAi) (Iluvien®) for the treatment of chronic non-infectious uveitis with associated cystoid macular edema (CME)., Methods: A retrospective review of medical reports from a single Danish tertiary centre including 20 patients (20 eyes), treated with 0.19 mg FAi for non-infectious uveitic CME. The primary endpoints were change in best corrected visual acuity (BCVA) and central retinal thickness (CRT). The secondary endpoints were recurrence rate, change in systemic treatment, and intraocular pressure (IOP)., Results: Mean follow-up of the 20 eyes was 2.3 ± 1.1 years. BCVA improved at 6 (p = 0.13), 12 (p = 0.05), 18 (p = 0.03), and 24 months and CRT decreased at 6 (p = 0.004), 12 (p = 0.006), 18, and 24 months after 0.19 mg FAi. Within 18 months after implantation, four of 14 patients (28.6%) relapsed. Three of five patients discontinued systemic corticosteroids within 4 months and one patient continued with reduced dose. Five of 10 patients receiving disease-modifying antirheumatic drugs (DMARDs) at time of implantation discontinued within 1 year. No patients started new systemic treatment. Eight eyes were treated with topical IOP-lowering medication at the time of implantation, of these two later underwent trabeculectomy. There were no complications associated with previous glaucoma surgery., Conclusion: This long-term follow-up study showed that intravitreal treatment with 0.19 mg FAi should be considered in the treatment of chronic non-infectious uveitic CME in selected patients. This treatment is safe even in selected glaucoma patients and may offer reduction or cessation of local or systemic anti-inflammatory treatment., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)