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Prostate cancer (PCa) is a major public health concern for men globally and the most commonly diagnosed cancer among men in the European Union (EU). Despite large trials suggesting benefits from early detection of PCa, risks of overdiagnosis and overtreatment are evident. In 2022, the EU Commission proposed introducing prostate-specific antigen (PSA) testing for men in an organised setting, in combination with magnetic resonance imaging (MRI) scanning as a follow-up test to minimise these risks. PRostate cancer Awareness and Initiative for Screening Europe (PRAISE-U) is a pilot study evaluating the implementation of a risk-stratified population-based approach to PCa screening in Ireland, Lithuania, Poland, and two areas in Spain (Galicia and Manresa) for feasibility, efficacy, and cost effectiveness. As per the protocol designed for the pilots, men aged 50–69 yr residing within the catchment area of the study sites will be invited to participate. Those consenting to participate will undergo PSA testing, and men with PSA >3 ng/ml will undergo risk stratification before MRI and, if necessary, after MRI before undergoing biopsy. A collaborative user board comprising health care professionals, patients, and decision-makers will be formed to provide stakeholder input throughout the study. PRAISE-U will be evaluated on three major pillars: analysis of clinical and programme outcomes, psychosocial impact, and cost effectiveness. A set of key performance indicators (KPIs) has been developed to be piloted in the PRAISE-U pilot sites. The KPIs will serve to assess the performance and outcomes of risk-stratified PCa screening at each site. A REDCap database will be used to collect and manage pseudoanonymised data from the pilot sites. Ethics approval was obtained from each pilot site. The PRAISE-U pilot implementation is expected to commence in the 3rd quarter of 2024 for 12 mo and provide valuable data on the implementation outcomes of a risk-stratified screening approach across Europe. The findings is expected to inform the development of an optimised screening strategy with an acceptable benefit to harm ratio.

Abstract Background Colorectal cancer (CRC) screening can reduce both CRC incidence and mortality, and faecal immunochemical testing (FIT)-based screening programmes are therefore now being implemented in many countries. However, social inequality in FIT-based screening participation is well documented, and initiatives to address this challenge are understudied. We explored the perceptions of CRC screening and the perceived barriers and facilitators towards FIT-based CRC screening among men visiting a drop-in centre for people with severe social problems in Denmark. Methods The study was a qualitative interview study. Participants were sixteen men visiting a drop-in centre in Denmark. A local staff member provided supplementary information and assisted with the recruitment process. The interviews were transcribed verbatim, followed by an inductive content analysis. Results The men were often dealing with health and social problems, and they often had low self-esteem. At first, they stated that they did not think much about cancer and their own risk of being diagnosed with it. They argued that they had little time, energy, and resources to participating in, for example, CRC screening programmes, and barriers to participating were facts of life such as comorbidity and cognitive difficulties. Further, they were not sure how to participate, and some misunderstood the concept of screening. However, during the interviews, the main part of the participants became very keen to participate, and they suggested that in the future, they could receive regular information about cancer screening in face-to-face interactions with someone who cared and was interested in helping them. Conclusion Men in a vulnerable position visiting a drop-in centre were interested in CRC screening. If we intervene in a way that meets the needs among these vulnerable citizens, it may contribute to reducing social inequality in FIT-based CRC screening programmes.

This study aimed to develop and test MyPL, a questionnaire that measures self-reported physical literacy (PL) among children and adolescents. First, the item pool was developed and adapted, and face validity was tested with cognitive interviewing. Then, factor structures were identified through multidimensional scaling and exploratory factor analyses in a sample of 951 children (ages 7-13). Then, the identified models were tested using confirmatory factor analyses (CFA) within a sample of 2861 children (ages 7-12) and a sample of 1518 children (ages 13-15). Finally, measurement invariance and predictive validity were investigated. CFA showed that the identified physical activity (PA) environment-based models fitted better with the data than the domain-derived model. Reliability analyses showed that the internal consistency of the total PL scale was good and that, the reliability of the identified scales, except the cognitive scale, of the two models based on PA environments was satisfactory. Additionally, MyPL also showed measurement invariance across gender. This study suggests that the type of PA and the environment in which PA occur is important to consider when designing PL measurement tools. This study indicated that MyPL can be used to measure children and young people's PL in large surveys.

Abstract Understanding the relationship between the structure of chemical reaction networks and their reaction dynamics is essential for unveiling the design principles of living organisms. However, while some network-structural features are known to relate to the steady-state characteristics of chemical reaction networks, mathematical frameworks describing the links between out-of-steady-state dynamics and network structure are still underdeveloped. Here, we characterize the out-of-steady-state behavior of a class of artificial chemical reaction networks consisting of the ligation and splitting reactions of polymers. Within this class, we examine minimal networks that can convert a given set of sources (e.g., nutrients) to a specified set of targets (e.g., biomass precursors). By exploring the dynamics of the models with a simple setup, we find three distinct types of relaxation dynamics after perturbation from a steady-state: exponential-, power-law-, and plateau-dominated. We computationally show that we can predict this out-of-steady-state dynamical behavior from just three features computed from the network’s stoichiometric matrix, namely, (1) the rank gap, determining the existence of a steady-state; (2) the left null-space, being related to conserved quantities in the dynamics; and (3) the stoichiometric cone, dictating the range of achievable chemical concentrations. We further demonstrate that these three quantities relates to the type of relaxation dynamics of combinations of our minimal networks, larger networks with many redundant pathways, and a real example of a metabolic network. The relationship between the topological features of reaction networks and the relaxation dynamics presented here are useful clues for understanding the design of metabolic reaction networks as well as industrially useful chemical production pathways.

Stig Holm Ovesen,1,2 Søren Helbo Skaarup,3 Rasmus Aagaard,4 Hans Kirkegaard,1 Bo Løfgren,1,5 Michael Dan Arvig,6– 8 Bo Martin Bibby,9 Stefan Posth,10 Christian B Laursen,11,12 Jesper Weile1,2 1Research Center for Emergency Medicine, Department of Clinical Medicine, Aarhus University Hospital and Aarhus University, Aarhus, Denmark; 2Emergency Department, Horsens Regional Hospital, Horsens, Denmark; 3Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark; 4Department of Anesthesiology, Aarhus University Hospital, Aarhus, Denmark; 5Department of Internal Medicine, Randers Regional Hospital, Randers, Denmark; 6Emergency Department, Slagelse Hospital, Slagelse, Denmark; 7Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; 8Department of Regional Health Research, University of Southern Denmark, Odense, Denmark; 9Department of Biostatistics, Aarhus University, Aarhus, Denmark; 10Emergency Department, Odense University Hospital, Odense, Denmark; 11Department of Respiratory Medicine, Odense University Hospital, Odense, Denmark; 12Odense Respiratory Research Unit (ODIN), Department of Clinical Research, University of Southern Denmark, Odense, DenmarkCorrespondence: Stig Holm Ovesen, Research Center for Emergency Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, J103, Aarhus, 8200, Denmark, Email stigholm@clin.au.dkPurpose: Point-of-care ultrasound (POCUS) helps emergency department (ED) physicians make prompt and appropriate decisions, but the optimal diagnostic integration and potential clinical benefits remain unclear. We describe the protocol and statistical analysis plan for a randomized controlled trial. The objective is to determine the effect of a POCUS-driven diagnostic pathway in adult dyspneic ED patients on the proportion of patients having a hospital stay of less than 24 hours when compared to the standard diagnostic pathway.Patients and Methods: This is a multicenter, randomized, investigator-initiated, open-labeled, pragmatic, controlled trial. Adult ED patients with chief complaint dyspnea are eligible. Patients are randomized (1:1) to the POCUS-driven diagnostic pathway or standard diagnostic pathway, with 337 patients in each group. The primary outcome is the proportion of patients having a hospital stay (from ED arrival to hospital discharge) of less than 24 hours. Key secondary outcomes include hospital length-of-stay, 72-hour revisits, and 30-day hospital-free days.Conclusion: Sparse evidence exists for any clinical benefit from a POCUS-integrated diagnostic pathway. The results from this trial will help clarify the promising signals for POCUS to influence patient care among ED patients with dyspnea.Keywords: focused lung ultrasound, focused cardiac ultrasound, shortness-of-breath, diagnostic effectiveness

Andreas Clipet-Jensen, Hans Fjeldsøe-Nielsen, Peter Roy Kirkegaard Department of Anesthesiology and Intensive Care Medicine, Zealand University Hospital, Nykøbing, DenmarkCorrespondence: Andreas Clipet-Jensen, Email andreas.clipet-jensen.01@regionh.dk; a.clipet.jensen@gmail.comAbstract: Although peripheral nerve blocks are deemed very safe, a significant number of patients for whom this anesthetic technique may be particularly appealing to apply may present with preexisting peripheral neuropathies, putting them at risk for further nerve damage. We present a case with a 74-year-old male with several risk factors for peripheral neuropathy who developed a foot drop following a popliteal sciatic nerve block with ropivacaine. We suggest that the vasoconstrictive properties of ropivacaine may have contributed to a preexisting neuronal ischemia, thus further damaging an already compromised nerve.Keywords: peripheral nerve block, peripheral neuropathy, vasoconstriction, local anesthetics

Severe brain damage is common among premature infants, and the gut microbiota has been implicated in its pathology. Although the order of colonizing bacteria is well described, the mechanisms underlying aberrant assembly of the gut microbiota remain elusive. Here, we employed long-read nanopore sequencing to assess abundances of microbial species and their functional genomic potential in stool samples from a cohort of 30 extremely premature infants. We identify several key microbial traits significantly associated with severe brain damage, such as the genomic potential for nitrate respiration and iron scavenging. Members of the Enterobacteriaceae were prevalent across the cohort and displayed a versatile metabolic potential, including pathogenic and nonpathogenic traits. Predominance of Enterobacter hormaechei and Klebsiella pneumoniae were associated with an overall loss of genomic functional redundancy as well as poor neurophysiological outcome. These findings reveal microbial traits that may be involved in exacerbating brain injury in extremely premature infants and provide suitable targets for therapeutic interventions.

Abstract Background More knowledge is needed on the risk of developing chronic obstructive pulmonary disease (COPD) associated with housing conditions and indoor environment based on cohort studies with a long follow-up time. Objective To examine the association between housing conditions and indoor environment and the risk of developing COPD. Methods In this cohort study, we followed 11,590 individuals aged ≥ 30 years free of COPD at baseline. Information on incident COPD and housing conditions and indoor environment was obtained from the Danish national registers and the Danish Health and Morbidity Survey year 2000. Poisson regression of incidence rates (IRs) were used to estimate incidence rate ratios (IRRs) of COPD. Results The overall IR of COPD was 8.6 per 1,000 person-years. Individuals living outside the biggest cities vs. living in the biggest cities (≥ 50,000) had a lower risk of COPD (200-4,999; IRR 0.77 (95% CI 0.65-0.90). Individuals living in semi-detached houses had a higher risk compared to individuals living in detached houses (IRR 1.29 (95% CI 1.07-1.55)). Likewise, individuals living in rented homes had a higher risk (IRR 1.47 (95% CI 1.27-1.70)) compared to individuals living in owned homes. The IR of COPD was 17% higher among individuals living in dwellings build > 1982 compared with individuals living in older dwellings (

Abstract Background Traumatic brain injury (TBI) is a potential high-risk condition, but appropriate care pathways, including prehospital triage and primary referral to a specialised neurosurgical centre, can improve neurological outcome and survival. The care pathway starts with layman triage, wherein the patient or bystander decides whether to contact a general practitioner (GP) or emergency services (1-1-2 call) as an entryway into the health care system. The GP or 112-health care professional then decides on the level of urgency and dispatches emergency medical services (EMS) when needed. Finally, a decision is made regarding referral of the TBI patient to a specialised neurotrauma centre or a local hospital. Recent studies have shown that injuries are generally more severe in patients entering the health care system through EMS (112-calls) than through GPs; however, no information exists on whether mortality and morbidity outcomes differ depending on the referral choice. The aim of this study was to examine triage pathways, including the method of entry into the health care system, as well as patient characteristics and place of primary referral, to determine the associated 30-day and 1-year mortality rates in TBI patients with confirmed intracranial lesions. Methods This retrospective observational population-based follow-up study was conducted in the Central Denmark Region from 1 February 2017 to 31 January 2019. We included all adult patients who contacted hospitals and were ascribed a predefined TBI ICD-10 diagnosis code in the Danish National Patient Register. The obtained TBI cohort was merged with prehospital data from the Prehospital Emergency Medical Services, Central Denmark Region, and vital status from the Danish Civil Registration System. Binary logistic regression analysis of mortality was conducted. In all patients with TBI (including concussions), the primary outcome was primary referral to a specialised centre based on mode of entry (‘GP/HCP’, ‘112-call’ or ‘Unreferred’) into the health care system. In the subgroup of patients with confirmed intracranial lesions, the secondary outcomes were the relative risk of death at day 30 and 1 year based on the place of primary referral. Results Of 5,257 first TBI hospital contacts of adult patients included in the cohort, 1,430 (27.2%) entered the health care system via 1-1-2 emergency medical calls. TBI patients triaged by 112-calls were more likely to receive the highest level of emergency response (15.6% vs. 50.3%; p

Abstract Purpose To report a case of Purpureocillium lilacinum endophthalmitis. Methods The case of a fungal endophthalmitis caused by Purpureocillium lilacinum documented in an immunocompetent patient with no apparent trigger. Results A 64-year-old male with a two-month history of panuveitis in his left eye was referred to our hospital. Initially misdiagnosed as sympathetic ophthalmia due to a previous surgery on his right eye 4 months before the onset of the left ocular picture, the patient received corticosteroid treatment, leading to a rapid deterioration of the left eye condition. An urgent exploratory vitrectomy was performed to identify the underlying cause, revealing endophthalmitis. Microbiological investigation yielded Purpureocillium lilacinum as the causative agent. Despite intensive treatment, including intravitreal antibiotics and antifungals, along with another surgical intervention, clinical evolution remained unfavourable, ultimately leading to the evisceration of the affected eye. Conclusions Purpureocillium lilacinum poses a rare yet sever threat as a causative agent of fungal endophthalmitis. Managing such cases is challenging due to the delayed identification, fungus’s resistance to common antifungals, and its association with prior corticosteroid misuse in most patients. This case underscores the crucial importance of heightened clinical suspicion, early diagnosis, and the exploration of alternative treatment strategies in addressing Purpureocillium lilacinum endophthalmitis. The challenges posed by this rare fungal pathogen emphasize the need for a multidisciplinary approach and continued research to improve outcomes in these complex cases.

Abstract Background Cancer is a major global health concern. Unfortunately, Indigenous populations such as Greenlanders living in Denmark, face significant disparities in cancer risk, incidence, diagnosis, care quality, and outcomes. In Denmark, vulnerable Greenlanders face challenges accessing cancer screening. The aim of this study was to explore their perceptions of cancer, barriers to participation in cancer screening, and potential for developing a tailored intervention. Methods This qualitative study was based on participant observations and qualitative interviews. The sample comprised 46 participants from four distinct drop-in centres. Of these, 28 were vulnerable Greenlanders (19 women and 9 men), 9 were staff members (6 women and 3 men), and 6 were relatives (4 women and 2 men). The data were analysed through inductive content analysis. Results Vulnerable Greenlanders in Denmark believed they were responsible for their own health and were generally satisfied with the healthcare system. However, they found it challenging to manage their own health and many depended on support from others. Fear of cancer and death shaped their attitudes towards screening. Conclusion For vulnerable Greenlanders in Denmark participation in cancer screening programmes was positively viewed for most but could be challenging. Different intervention ideas raised by the vulnerable Greenlanders, relatives and staff members could guide the development of strategies to increase participation rates.

Abstract Background HIV remains a leading cause of death for adolescents and young people aged 10–24 years. HIV prevention requires multisectoral approaches that target adolescents and young people, addressing HIV risk pathways (e.g., transactional sex, gender-based violence, and school attendance) through bundled interventions that combine economic strengthening, health capabilities, and gender equality education. However, best practices are unknown because evidence on multisectoral programming targeted to adolescents and combining these components has not been systematically reviewed. Methods We conducted a systematic review to summarize the evidence on bundled interventions combining health and economic strengthening components for adolescents and young people and their effects on HIV/STI incidence and risk factors. We included studies from Africa published between 2005 and 2023, combining at least one economic strengthening and one health component, directed toward adolescents and young people aged 10–24 years. Included studies measured programmatic impacts on primary outcomes: HIV and STI incidence/prevalence; and mediators as secondary outcomes: sexual behaviours, sexual and reproductive health, school attendance, health-seeking behaviours, and violence. We conducted key word searches in PubMed, EMBASE, and Web of Science, imported titles/abstracts from the initial search, and reviewed them using the inclusion criteria. Full texts of selected articles were reviewed and information was extracted for analysis. Findings from the full texts identified were summarized. Results We reviewed 58 studies, including 43 quantitative studies and 15 qualitative studies, evaluating 26 unique interventions. A majority of studies reviewed were conducted in Eastern and Southern Africa. Interventions reviewed showed a greater number of significant results in improving economic outcomes; mental health and psychosocial outcomes; sexual and reproductive health knowledge and services utilization; and HIV prevention knowledge and testing. They showed fewer significant results in improving outcomes related to HIV incidence/prevalence; sexual risk behaviours; gender-based violence; gender attitudes; education; STI incidence, prevalence and testing; and sexual debut. Conclusions Our review demonstrated the potential for bundled, multisectoral interventions for preventing HIV and facilitating safe transitions to adulthood. Findings have implications for designing HIV sensitive programmes on a larger scale, including how interventions may need to address multiple strata of the social ecological model to achieve success in the prevention of HIV and related pathways.

Endometriosis and polycystic ovary syndrome (PCOS) are common gynecological disorders that constitute a significant burden of disease in women of fertile age. The disorders share a link to female reproduction and infertility; however, divergent effects on menstrual cycle, related hormones, and body composition have been proposed. Disorders of the thyroid gland including abnormal thyroid dysfunction (hyperthyroidism or hypothyroidism) and/or markers of thyroid autoimmunity similarly show a female predominance and onset in younger age groups. We reviewed the literature on the association between endometriosis, PCOS, and thyroid disease up until July 1, 2023, and identified 8 original studies on endometriosis and thyroid disease and 30 original studies on PCOS and thyroid disease. The studies were observational and heterogeneous regarding the design, sample size, and definitions of exposure and outcome; however, a tendency was seen toward an association between hyperthyroidism and endometriosis. Especially an association between endometriosis and slightly elevated levels of thyroid-stimulating hormone receptor antibodies has been found and corroborated in studies from different populations. On the other hand, the literature review turned a focus toward an association between hypothyroidism and PCOS, however, with uncertainties as to whether the association is caused by hypothyroidism per se and/or the thyroid autoantibodies (thyroid peroxidase and thyroglobulin antibodies). More evidence is needed to substantiate an association between endometriosis, PCOS, and thyroid disease, and to differentiate between the role of thyroid function and thyroid autoimmunity. Furthermore, studies are warranted to extend knowledge on the different disease characteristics and underlying mechanisms.

Bacterial endophytes dwelling in medicinal plants represent an as yet underexplored source of bioactive natural products with the potential to be developed into drugs against various human diseases. For the first time, several Streptomyces spp. were isolated from the rare and endangered traditional medicinal plant Leontopodium nivale ssp. alpinum, also known as Edelweiss. In the search for novel natural products, nine endophytic Streptomyces spp. from Edelweiss were investigated via genome sequencing and analysis, followed by fermentation in different media and investigation of secondary metabolomes. A total of 214 secondary metabolite biosynthetic gene clusters (BGCs), of which 35 are presumably unique, were identified by the bioinformatics tool antiSMASH in the genomes of these isolates. LC-MS analyses of the secondary metabolomes of these isolates revealed their potential to produce both known and presumably novel secondary metabolites, whereby most of the identified molecules could be linked to their cognate BGCs. This work sets the stage for further investigation of endophytic streptomycetes from Edelweiss aimed at the discovery and characterization of novel bioactive natural products.

Objectives The aim of this study was to map and compare stakeholders’ perceptions of barriers towards cervical cancer screening for vulnerable women in seven European countries.Design In Collaborative User Boards, stakeholders were invited to participate to identify barriers towards participation in cervical cancer screening.Setting The study is nested in the European Union-funded project CBIG-SCREEN which aims to tackle inequity in cervical cancer screening for vulnerable women (www.cbig-screen.eu). Data collection took place in Bulgaria, Denmark, Estonia, France, Italy, Portugal and Romania.Participants Participants represented micro-level stakeholders covering representatives of users, that is, vulnerable women, meso-level stakeholders covering healthcare professionals and social workers, and macro-level stakeholders covering programme managers and decision-makers.Methods Across the seven countries, 25 meetings in Collaborative User Boards with a duration of 2 hours took place between October 2021 and June 2022. The meetings were video recorded or audio recorded, transcribed and translated into English for a qualitative framework analysis.Results 120 participants took part in the Collaborative User Boards. Context-specific barriers were related to different healthcare systems and characteristics of vulnerable populations. In Romania and Bulgaria, the lack of a continuous screening effort and lack of ways to identify eligible women were identified as barriers for all women rather than being specific for women in vulnerable situations. The participants in Denmark, Estonia, France, Italy and Portugal identified providers’ lack of cultural and social sensitivity towards vulnerable women as barriers. In all countries, vulnerable women’s fear, shame and lack of priority to preventive healthcare were identified as psychological barriers.Conclusion The study provides an overview of stakeholders’ perceived barriers towards vulnerable women’s cervical cancer screening participation in seven European countries. The organisation of healthcare systems and the maturity of screening programmes differ between countries, while vulnerable women’s psychological barriers had several similarities.

Introduction The increasing elderly population has led to a growing demand for healthcare services. A hospital at home treatment model offers an alternative to standard hospital admission, with the potential to reduce readmission and healthcare consumption while improving patients’ quality of life. However, there is little evidence regarding hospital at home treatment in a Danish setting. This article describes the protocol for a randomised controlled trial (RCT) comparing standard hospital admission to hospital at home treatment. The main aim of the intervention is to reduce 30-day acute readmission after discharge and improve the quality of life of elderly acute patients.Methods and analysis A total of 849 elderly acute patients will be randomised in a 1:2 ratio to either the control or intervention group in the trial. The control group will receive standard hospital treatment in a hospital emergency department while the intervention group will receive treatment at home. The primary outcomes of the trial are the rate of 30-day acute readmission and quality of life, assessed using the European Quality of Life-5 Dimensions-5-Level instrument. Primary analyses are based on the intention-to-treat principle. Secondary outcomes are basic functional mobility, resource use in healthcare, primary and secondary healthcare cost, incremental cost-effectiveness ratio, and the mortality rate 3 months after discharge.Ethics and dissemination The RCT was approved by the Ethical Committee, Central Denmark Region (no. 1-10-72-67-20). Results will be presented at relevant national and international meetings and conferences and will be published in international peer-reviewed journals. Furthermore, we plan to communicate the results to relevant stakeholders in the Danish healthcare system.Trial registration number NCT05360914.

Previous studies have found a high degree of assortative mating for educational attainment (r = .56). However, this can be confounded by cohort effects or country effects, where certain nations may have more pronounced assortative mating than others. In addition, method variance regarding how educational attainment is measured may also result in heterogeneity of effect sizes. Effect sizes were gathered from various datasets and from academic literature, resulting in a large collection of effect sizes (k = 1498, n = 9,159,098), spanning 84 different countries. Assortative mating for educational attainment was stronger than what previous literature suggested (r = .66, [.64, .68]), largely due to the fact that assortative mating for educational attainment is stronger when latent methods are used. The strongest predictors of assortative mating for education between countries were individualism (r = −.61, p

Background Excess opioid prescribing after surgery can lead to prolonged opioid use and diversion. We interviewed surgeons who were part of a three-group cluster-randomised controlled trial aimed at reducing prescribed opioid quantities after surgery via two versions of a monthly emailed behavioural ‘nudge’ (messages encouraging but not mandating compliance with social norms and clinical guidelines around prescribing) at the end of the implementation year in order to understand surgeons’ reasoning for changing or continuing their prescribing behaviour as a result of the intervention and the context for their rationale.Methods The study took place at a large healthcare system in northern California with surgeons from three surgical specialties—orthopaedics, obstetrics/gynaecology and general surgery. Following the intervention period, we conducted semistructured interviews with 36 surgeons who had participated in the trial, ensuring representation across trial arm, specialty and changes in prescribing quantities over the year. Interviews focused on reactions to the nudges, impacts of the nudges on prescribing behaviours and other factors impacting prescribing. Three study team members coded and analysed the transcribed interviews.Results Nudges were equally effective in reducing postsurgical opioid prescribing across surgical specialties and between intervention arms. Surgeons were generally receptive to the nudge intervention, noting that it reduced the size of their discharge opioid prescriptions by improving their awareness and intentionality around prescribing. Most were unaware that clinical guidelines around opioid prescribing existed. Some had reservations regarding the accuracy and context of information provided in the nudges, the prescription quantities encouraged by the nudges and feelings of being watched or admonished. A few described discussing the nudges with colleagues. Respondents emphasised that the prescribing behaviours are informed by individual clinical experience and patient-related and procedure-related factors.Conclusions Surgeons were open to learning about their prescribing behaviour through comparisons to guidelines or peer behaviour and incorporating this feedback as one of several factors that guide discharge opioid prescribing. Increasing awareness of clinical guidelines around opioid prescribing is important for curbing postsurgical opioid overprescribing.Trial registration number NCT05070338.

Abstract Alpha-synuclein (α-syn) aggregation and immune activation represent hallmark pathological events in Parkinson’s disease (PD). The PD-associated immune response encompasses both brain and peripheral immune cells, although little is known about the immune proteins relevant for such a response. We propose that the upregulation of CD163 observed in blood monocytes and in the responsive microglia in PD patients is a protective mechanism in the disease. To investigate this, we used the PD model based on intrastriatal injections of murine α-syn pre-formed fibrils in CD163 knockout (KO) mice and wild-type littermates. CD163KO females revealed an impaired and differential early immune response to α-syn pathology as revealed by immunohistochemical and transcriptomic analysis. After 6 months, CD163KO females showed an exacerbated immune response and α-syn pathology, which ultimately led to dopaminergic neurodegeneration of greater magnitude. These findings support a sex-dimorphic neuroprotective role for CD163 during α-syn-induced neurodegeneration.

The N400 is an ERP component sensitive to semantic violations. Here, we probed if infants’ detection of a mismatch is subject to an altercentric bias: a bias by another person’s perspective. We hid the object in a box at the time of labelling, so its representation had to be maintained. Exp.1 established that 14-month-olds detect when an occluded object is labelled incorrectly (t(27)=2.12, p=0.043). Exp.2 included a perspective mismatch, and labelling was always incongruent for the infant, but in 50% congruent for the other. We found a reduced N400 for the congruent-for-other trials (t(33)=-2.19, p=.036), indicating an altercentric influence on infants’ semantic mismatch detection. Exp.3 probes whether infants detect any incongruence from their perspective when the labelling is always consistent for the other. Preliminary analyses (n=22 out of 34 pre-registered) show no effect of congruency from infants’ perspective, suggesting that congruency for the other may override infants’ own mismatch detection.

VIM-type-producing Gram-negative bacteria (GNB) infections are difficult to treat. This is a retrospective single-center study of 34 patients who received cefiderocol for the treatment of VIM-type-producing GNB infections, including 25 Pseudomonas spp., 7 Enterobacterales, and 5 Achromobacter sp. Primary outcomes were clinical failure (defined as death, lack of clinical improvement, or a switch to another drug) at day 14 and 30-day all-cause mortality. The median age was 59 years (IQR 53.7–73.4), and the median Charlson comorbidity index was 3.5 (IQR 2–5). The main infections were respiratory tract infections (n = 9, 27%) and skin and soft tissue infections (n = 9, 27%). Eight patients exhibited bacteremia. In 9/17 patients with a drainable focus, drainage was performed. The median cefiderocol treatment duration was 13 days (IQR 8–24). Five patients (15%) experienced clinical failure on day 14, and the thirty-day mortality rate was 9/34 (27%); two cases occurred because of an uncontrolled infection source, and one was due to a new infection caused by the same bacteria. The other six deaths were unrelated to the index infection. Five patients experienced microbiological recurrence within three months. Susceptibility testing revealed the development of cefiderocol resistance in 1/7 cases with persistent or recurrent positive cultures. Cefiderocol, even in monotherapy, could be considered for the treatment of VIM-type-producing GNB infections.

Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12-month, prospective, randomised, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2-18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5-domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5-domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of -1.40 (95% confidence interval: -2.76, -0.03; P = .046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of -2.06 in favour of arimoclomol (P = .006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment-related serious adverse events (n = 2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated.

Martin Gude,1 Hans Kirkegaard,1,2 Rolf Blauenfeldt,3 Anne Behrndtz,3 Jeppe Mainz,3 Ingunn Riddervold,4 Claus Z Simonsen,2,3 Niels Hjort,2,3 Søren P Johnsen,5 Grethe Andersen,2,3 Jan Brink Valentin5 1Department of Research and Development, Prehospital Emergency Medical Services, Central Denmark Region; and Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3Danish Stroke Center, Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; 4Norwegian Air Ambulance Foundation, Oslo, Norway; 5Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, DenmarkCorrespondence: Martin Gude, Prehospital Emergency Medical Services, Central Denmark Region and Aarhus University Hospital, Aarhus, Denmark, Email gude@dadlnet.dkObjective: To examine the agreement between emergency medical service (EMS) providers, neurology residents and neurology consultants, using the Cincinnati Prehospital Stroke Scale (CPSS) and the Prehospital Acute Stroke Severity Scale (PASS).Methods: Patients with stroke, transient ischemic attack (TIA) and stroke mimic were included upon primary stroke admission or during rehabilitation. Patients were included from June 2018 to September 2019. Video recordings were made of patients being assessed with CPSS and PASS. The recordings were later presented to the healthcare professionals. To determine relative and absolute interrater reliability in terms of inter-rater agreement (IRA), we used generalisability theory. Group-level agreement was determined against a gold standard and presented as an area under the curve (AUC). The gold standard was a consensus agreement between two neurology consultants.Results: A total of 120 patient recordings were assessed by 30 EMS providers, two neurology residents and two neurology consultants. Using the CPSS and the PASS, a total of 1,800 assessments were completed by EMS providers, 240 by neurology residents and 240 by neurology consultants. The overall relative and absolute IRA for all items combined from the CPSS and PASS score was 0.84 (95% CI 0.80; 0.87) and 0.81 (95% CI 0.77; 0.85), respectively. Using the CPSS, the agreement on a group-level resulted in AUCs of 0.83 (95% CI 0.78; 0.88) for the EMS providers and 0.86 (95% CI 0.82; 0.90) for the neurology residents when compared with the gold standard. Using the PASS, the AUC was 0.82 (95% CI 0.77; 0.87) for the EMS providers and 0.88 (95% CI 0.84; 0.93) for the neurology residents.Conclusion: The high relative and absolute inter-rater agreement underpins a high robustness/generalisability of the two scales. A high agreement exists across individual raters and different groups of healthcare professionals supporting widespread applicability of the stroke scales.Plain Language Summary: Early stroke identification is pivotal to enable faster treatment. To aid this identification, many symptom-based stroke scales have been constructed for both stroke screening and severity assessment. In the prehospital environment, several scales have been evaluated on performance, but only few studies have evaluated the agreement between the ambulance personnel (emergency medical service (EMS) providers) and stroke physicians when interpreting the assessed symptoms in the scales. It is of great importance to know how EMS providers interpret symptoms seen in connection with the use of the scales to focus the continuous training of the EMS providers but also to aid the decision on which scale to implement in ambulances. From previous studies, we know that complex stroke scales are used to a considerably lesser extent than more simple scales, which could be caused by difficulties interpreting specific symptoms. In this study, a variety of methods was applied to determine the inter-rater agreement for two simple stroke scales using dichotomously evaluated symptoms. High inter-rater agreement between EMS providers and Stroke Neurologists exists both between individual raters and between raters grouped according to their profession and seniority. Previous studies have also found high inter-rater agreement for simple stroke scales but lesser agreement for more advanced scales. In conclusion, simple stroke scales seem to produce the highest agreement.Keywords: observer variation, prehospital emergency care, emergency medical service provider, neurologists, stroke

Abstract Background Cognitive impairment is common following out-of-hospital cardiac arrest (OHCA), but the nature of the impairment is poorly understood. Our objective was to describe cognitive impairment in OHCA survivors, with the hypothesis that OHCA survivors would perform significantly worse on neuropsychological tests of cognition than controls with acute myocardial infarction (MI). Another aim was to investigate the relationship between cognitive performance and the associated factors of emotional problems, fatigue, insomnia, and cardiovascular risk factors following OHCA. Methods This was a prospective case–control sub-study of The Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. Eight of 61 TTM2-sites in Sweden, Denmark, and the United Kingdom included adults with OHCA of presumed cardiac or unknown cause. A matched non-arrest control group with acute MI was recruited. At approximately 7 months post-event, we administered an extensive neuropsychological test battery and questionnaires on anxiety, depression, fatigue, and insomnia, and collected information on the cardiovascular risk factors hypertension and diabetes. Results Of 184 eligible OHCA survivors, 108 were included, with 92 MI controls enrolled. Amongst OHCA survivors, 29% performed z-score ≤ − 1 (at least borderline–mild impairment) in ≥ 2 cognitive domains, 14% performed z-score ≤ − 2 (major impairment) in ≥ 1 cognitive domain while 54% performed without impairment in any domain. Impairment was most pronounced in episodic memory, executive functions, and processing speed. OHCA survivors performed significantly worse than MI controls in episodic memory (mean difference, MD = − 0.37, 95% confidence intervals [− 0.61, − 0.12]), verbal (MD = − 0.34 [− 0.62, − 0.07]), and visual/constructive functions (MD = − 0.26 [− 0.47, − 0.04]) on linear regressions adjusted for educational attainment and sex. When additionally adjusting for anxiety, depression, fatigue, insomnia, hypertension, and diabetes, executive functions (MD = − 0.44 [− 0.82, − 0.06]) were also worse following OHCA. Diabetes, symptoms of anxiety, depression, and fatigue were significantly associated with worse cognitive performance. Conclusions In our study population, cognitive impairment was generally mild following OHCA. OHCA survivors performed worse than MI controls in 3 of 6 domains. These results support current guidelines that a post-OHCA follow-up service should screen for cognitive impairment, emotional problems, and fatigue. Trial registration ClinicalTrials.gov, NCT03543371. Registered 1 June 2018.

Abstract Aim To explore and gain knowledge of the experiences and needs among patients with amyotrophic lateral sclerosis (ALS) of their decision‐making processes whether to choose invasive home mechanical ventilation or not. Design A qualitative study. Methods A phenomenological‐hermeneutic approach influenced by Ricoeur's interpretation theory was used. Seven patients with ALS were interviewed. The Consolidated Criteria for Reporting Qualitative Research checklist was used for reporting. Results Three themes were evident in patients' accounts of the decision‐making process: (1) being taken care of directly after receiving the diagnosis, (2) living in uncertainty about what the future would bring and (3) doubt causing patients with ALS to change their minds. Patients with ALS were burdened with everyday life challenging decision‐making processes about future treatment and doubt caused patients to change their minds about their future treatment. It is necessary to support patients in their decision‐making processes using shared decision‐making. Patient or Public Contribution No Patient or Public Contribution.

Abstract Computer-aided analysis of biological microscopy data has seen a massive improvement with the utilization of general-purpose deep learning techniques. Yet, in microscopy studies of multi-organism systems, the problem of collision and overlap remains challenging. This is particularly true for systems composed of slender bodies such as swimming nematodes, swimming spermatozoa, or the beating of eukaryotic or prokaryotic flagella. Here, we develop a end-to-end deep learning approach to extract precise shape trajectories of generally motile and overlapping slender bodies. Our method works in low resolution settings where feature keypoints are hard to define and detect. Detection is fast and we demonstrate the ability to track thousands of overlapping organisms simultaneously. While our approach is agnostic to area of application, we present it in the setting of and exemplify its usability on dense experiments of swimming Caenorhabditis elegans. The model training is achieved purely on synthetic data, utilizing a physics-based model for nematode motility, and we demonstrate the model’s ability to generalize from simulations to experimental videos.