Current expert consensus statements generally suggest cardiovascular risk assessment, including atrial fibrillation (AF) screening, on detection of covert brain infarctions (CBIs). However, evidence to guide management of CBI remains limited. In the absence of randomised clinical trials specifically targeting CBI populations, observational studies comparing individuals with and without CBI can provide insights into the prevalence and burden of cardiovascular risk factors.

We aimed to compare the burden of atherosclerosis and cardiovascular risk factors in participants with CBI to those without, and to explore the yield of AF screening in individuals with CBI.

A prospective population-based birth cohort study including men and women born in 1950 and resident in Akershus County, Norway.

The two hospitals serving the population of Akershus county, Norway.

Participants included in the Akershus Cardiac Examination (ACE) 1950 study who also underwent a subsequent MRI examination were eligible for this study.

Cardiovascular risk assessment was performed at study inclusion (2012–2015). Carotid ultrasound was used to quantify atherosclerosis through a carotid plaque score, and CHA₂DS₂-VA and Systematic COronary Risk Evaluation 2 (SCORE2) scores were calculated to estimate cardiovascular risk. Brain MRI was performed in a randomly selected, blood pressure-stratified subset of participants (2016–2024). CBI was defined as focal lesions consistent with ischaemia in the absence of clinical stroke. Participants with CBI were offered 72-hour ambulatory ECG monitoring for AF detection.

MRI was performed in 414 of 3706 (11%) participants in the ACE 1950 Study. The mean age at the time of the MRI examination was 70.2±2.3 years, and 165 (41%) were women. CBI was identified in 54 participants (13%), of whom 45 (83%) completed 72-hour ambulatory ECG monitoring. There were no differences in mean carotid plaque score, SCORE2 or CHA₂DS₂-VA score between participants with CBI compared with those with normal MRI findings. AF was detected in one (2%) participant with CBI.

In this community-based cohort of individuals in late midlife, individuals with CBI did not have an increased cardiovascular risk compared with those without, as indicated by SCORE2, CHA₂DS₂-VA score, age-appropriate carotid plaque burden and a low prevalence of AF.

URL: https://www.clinicaltrials.gov. Unique identifier: NCT01555411.

Stakeholder involvement in research processes is widely recommended to enhance the relevance, quality and uptake of research findings. However, existing studies highlight persistent challenges in engaging family caregivers in co-design research. This gap may result in research outcomes that fail to reflect family caregivers’ needs and preferences, contradicting the core purpose of co-design. Therefore, the aim of this systematic review is to synthesise the available evidence on family caregivers’ experiences of involvement in co-design research and to generate evidence-based strategies to support effective engagement.

This systematic review will be conducted using a meta-aggregative approach, following the Joanna Briggs Institute’s (JBI’s) Manual for Evidence Synthesis. Systematic searches will be conducted in PubMed, CINAHL, Scopus, Web of Science and PsycINFO, with no date restrictions. Preliminary searches were performed in EMBASE between September and October 2025. Qualitative primary studies that explore family caregivers’ experiences of involvement in co-design research will be included. Study selection and quality appraisal will be performed independently by two researchers using predefined protocols, disagreements will be resolved through discussion with a third reviewer. After calibration, a single reviewer will extract the data using a customised data extraction template with the dataset distributed among the authors. The first author will then review all extractions. Data will be analysed following JBI’s meta-aggregative method, and results will be presented in narrative summaries, tables and diagrams. The findings will inform strategies for stakeholder involvement in future co-design research. Family caregivers and co-design researchers will be involved in reviewing and revising generated recommendations to enhance their relevance and practical utility.

This protocol does not involve human participants. The findings of this review will be submitted for publication in a peer-reviewed journal and presented at relevant scientific conferences and meetings.

CRD420251229190.

The prognostic value of left atrial (LA) strain in patients with heart failure with reduced ejection fraction (HFrEF) has not been fully elucidated. Therefore, this study investigated the prognostic value of LA strain in HFrEF patients in relation to all-cause mortality.

A total of 822 echocardiograms from HFrEF patients admitted to a heart failure clinic were analysed offline. To calculate left atrial reservoir strain (LA RS) and left atrial contractile strain (LA CS), LA two-dimensional speckle tracking was performed in the 4-chamber, 2-chamber and 3-chamber view. The end-point was all-cause mortality. The association between LA strain parameters and outcome was examined using Cox regression.

The median follow-up time was 40 months and follow-up was 100% complete. During follow-up, a total of 137 patients (16.7%) died of all causes. In a final multivariable model adjusted for clinical and echocardiographic parameters including global longitudinal strain, LA RS and LA CS were significantly associated with all-cause death during follow-up (LA RS, HR 0.96, 95% CI 0.92 to 0.99, p=0.014, pr. 1% increase) (LA CS, HR 0.95, 95% CI 0.92 to 0.98, p=0.002, pr. 1% increase).

When added to the final multivariable model, both LA RS and LA CS contributed with incremental prognostic value as determined by C-statistic (LA RS: C-stat difference 0.007, 95% CI 0.000 to 0.020, p=0.050) (LA CS: C-stat difference 0.009, 95% CI 0.000 to 0.023, p=0.030).

In HFrEF patients, LA RS and LA CS were associated with all-cause mortality and contributed incremental prognostic value in addition to established prognostic measures.

Cannabis-based medicine may alleviate breathlessness. This study will investigate whether dronabinol, a synthetic form of ⁹-tetrahydrocannabinol (⁹-THC), reduces breathlessness in patients with severe and very severe chronic obstructive pulmonary disease (sCOPD) compared to placebo.

This single-centre, randomised, double-blinded, placebo-controlled, crossover trial will enrol 30 patients with sCOPD and persistent breathlessness despite optimal treatment. Patients will be recruited from a pulmonary outpatient clinic in Denmark over 24 months. Eligible patients (aged ≥18 years) will receive either dronabinol or placebo for 4 weeks, followed by a 2-week washout, before crossing over to the other treatment for 4 weeks. Exclusion criteria include ongoing infection, substance abuse and significant comorbidities. Primary outcome is breathing discomfort or unpleasantness measured using the 0–10 Numerical Rating Scale. Secondary outcomes include lung function (forced expiratory volume in one second), hair cortisol concentrations, functional tests, plasma THC blood concentrations and questionnaires assessing breathlessness, activity, quality of life, anxiety and depression. Continuous monitoring of vital signs, activity and sleep will be performed using a Garmin Venu 3 smartwatch. Data will be entered into electronic case report forms and monitored by the Good Clinical Practice (GCP) unit in Odense.

This will be the largest randomised, double-blinded, crossover trial to investigate dronabinol in patients with COPD and will provide new knowledge on the efficacy and safety.

Written informed consents will be obtained from study patients. The study has been approved by the Danish Medicines Agency (case number: 2023010659) and the medical research ethics committees (case number: 2301456). It is registered in the European Union Clinical Trials Registry (2024-513593-22-00) and ClinicalTrials.gov (NCT06473701). The trial follows the Declaration of Helsinki II and International Council for Harmonisation-GCP guidelines. Findings will be disseminated in peer-reviewed publications.

The European Union Clinical Trials Registry (2024-513593-22-00) and ClinicalTrials.gov (NCT06473701).

Glucocorticoid therapy is prescribed for a variety of inflammatory conditions and is associated with severe adverse effects. A glucocorticoid withdrawal syndrome (GWS) may occur after prolonged glucocorticoid treatment—with or without biochemical glucocorticoid-induced adrenal insufficiency (GIAI). Previously, GWS was not considered an entity, probably due to the overlap between symptoms of GWS and GIAI. The Addison’s disease-specific quality of life questionnaire (AddiQoL-30) is a validated tool for quantifying symptoms of adrenal insufficiency resembling GWS. In the present study, we test the hypothesis that patients with a low AddiQoL-30 score and/or low cortisol response to a short Synacthen test (SST), after cessation of prednisolone treatment, may benefit from low-dose hydrocortisone therapy without increasing the risk of metabolic and cardiovascular disease during prolonged cortisol exposure.

REPLACE is a multi-centre, double-blinded, placebo-controlled randomised controlled trial in patients with polymyalgia rheumatica or giant cell arteritis after cessation of prednisolone treatment. Criteria for randomisation are an AddiQoL-30 score ≤85 and/or plasma cortisol response to SST, 30-min p-cortisol >100 and 85; and (2) patients with a SST-stimulated cortisol ≤100 nmol/L.

The study is conducted in accordance with the Declaration of Helsinki, registered at the Clinical Trials Information System (CTIS: 2024-513822-53-00) and Clinicaltrials.gov (NCT05193396), and publications will be in accordance with the recommendations of the International Committee of Medical Journal Editors. The trial is monitored by local independent Good Clinical Practice units and overseen by the Danish Data Protection Agency (journal no. 21/27119), the Regional Committees on Health Research Ethics for Southern Denmark (project ID: S-20210076), the Danish Patient Safety Authority and the Danish Medicines Agency.

NCT05193396.

Across medicine, new therapies are shifting treatment from clinic to home settings. At-home subcutaneous immunoglobulin treatment for immunodeficiency is an example of one such therapy. In this qualitative interview study, we investigated experiences of patients living an everyday life with subcutaneous immunoglobulin at-home treatment.

24 Danish patients participated in semistructured interviews. Six patients were interviewed in individual home-visit interviews, while the remaining 18 participated in one of six subsequent group interviews using an online video format. Participants represented three patient groups: patients with primary immunodeficiency, patients with secondary immunodeficiency, and patients with chronic inflammatory demyelinating polyneuropathy or multifocal motor neuropathy.

According to the interviewed patients, at-home treatment provided a high degree of flexibility and freedom in everyday life. When transitioning to at-home treatment, a sense of security had been achieved through individualised training and access to healthcare professionals. Some patients experienced uncertainty or insecurity during the initial period of administering treatment at home; however, this typically receded over time. For the patients, at-home treatment had become embedded in everyday life either through incorporation into existing everyday routines or through the development of new routines. The time-related and place-related flexibility of the at-home treatment had benefits for several arenas of everyday life: work, family, and leisure. Patients associated at-home treatment with a sense of freedom, which they ascribed both to independence from the hospital and to not being confronted with medical conditions and other patients in the hospital setting. A small minority of the patients viewed the reduced contact with healthcare professionals as a disadvantage, describing feelings of being alone and responsible for their treatment.

Patients who had established at-home treatment routines in their everyday lives found the benefits of at-home treatment to outweigh the challenges.

Clinical trials have produced inconclusive results regarding the optimal glucose range for a patient with sepsis in the intensive care unit (ICU) receiving insulin treatment.

To investigate the optimal glucose range in patients with sepsis in the ICU independent of confounding covariates.

Targeted trial emulation of glucose ranges using causal inference targeted maximum likelihood estimation and longitudinal mixed-effects models combined with survival models.

Single-centre, academic referral hospital in Boston, Massachusetts, USA.

Adults fulfilling sepsis 3 criteria with at least three glucose readings and insulin treatment from the Medical Information Mart for Intensive Care (MIMIC)-IV database (2008–2019).

Five predefined glucose distributions with means at 100, 130, 160 (baseline), 190 and 220 mg/dL mimicking current guidelines’ recommendations (140–180 mg/dL).

The primary outcome was in-hospital mortality. Modified counterfactual treatment-policy risks across distinct time-weighted glucose ranges were estimated.

Of 73 181 eligible patients, 8002 patients with a median age of 66 years (41% women, 67% white ethnicity, 57% diabetes) were included. There was a U-shaped curve between glucose range and mortality in patients without diabetes, but overall, this association was not significant (mean glucose at 100 mg/dL with 21% mortality and mean glucose at 220 mg/dL with 26% mortality, p-for-trend 0.26). Mortality was lowest at 17%, with mean glucose between 130 and 160 mg/dL. Hypoglycaemic events (

Our data suggest a U-shaped association of glucose and mortality with an optimal average glucose between 160 and 190 mg/dL. These results confirm current guideline recommendations. Together with recent results from randomised controlled trials, intensivists should aim for a liberal glucose range in most patients.

To examine the self-reported adherence of ambulance nurses to acute chest pain guidelines and analyse how demographic and professional characteristics influence this adherence.

Cross-sectional study.

Regional ambulance service in southern Sweden (18 ambulance stations).

Ambulance nurses (registered and specialist nurses). Of the 397 ambulance nurses invited, 261 responded (65.7%) in 2023.

Descriptive statistics; independent-samples t-tests and ² tests for group comparisons; Pearson correlation; and stepwise linear regression to identify predictors of adherence.

Primary: adherence to the prehospital acute chest pain guideline, measured with the 5-item Self-Reported Adherence scale (5–25). Secondary: medication-specific adherence; guideline-access sources.

A cross-sectional study involving 261 ambulance nurses from 18 ambulance stations in southern Sweden. Adherence to acute chest pain guidelines was assessed using a validated instrument. Data collected in autumn 2023 were analysed using descriptive and inferential statistics, including stepwise linear regression analysis.

The study revealed an average self-reported adherence score of 19.2 out of 25 for acute chest pain guidelines. Mobile applications were the most commonly used source for accessing acute chest pain guidelines, while ambulance managers were the least used. Notably, older and more experienced ambulance nurses reported higher adherence scores. Additionally, a positive attitude towards the guidelines was correlated with higher adherence. Prioritisation of guidelines and age were predictors of adherence. In contrast, other demographic variables, such as sex and specialist nursing education, were not found to be associated with adherence.

The study indicates that self-reported adherence to acute chest pain guidelines among ambulance nurses is influenced by how highly they prioritise these guidelines and by their attitudes towards them, as well as their age and professional experience. Enhancing educational programmes and digital resources, particularly for younger and less experienced nurses, may improve adherence and patient outcomes in prehospital settings.

To explore differences in health-related benefit status over 3 years, focusing on patterns of sick leave, work assessment allowance and disability benefits, between people who underwent rehabilitation and a matched control group.

Prospective longitudinal multicentre cohort study using registry data over three consecutive years.

Secondary specialist rehabilitation services at 17 institutions across Norway.

Patients (n=2710), 42% with rheumatic and musculoskeletal diseases, aged 18–65 years referred for multidisciplinary rehabilitation at one of the participating institutions. They were propensity score matched with 37 760 controls from the national sick leave registry, based on sociodemographic factors and health-related benefit status.

Multidisciplinary rehabilitation programmes, commonly lasting 3 weeks (range: 1 week to 6 months), tailored to individual needs.

Days on health-related benefits (sick leave, work assessment allowance (WAA) and disability benefits) were quantified as lost workdays per month. Differences between groups were analysed using Generalised Estimating Equations across three consecutive years: the year before rehabilitation, the rehabilitation year and the year after rehabilitation.

The rehabilitation group had more days on health-related benefits per month than controls throughout the observation period. During the rehabilitation year, they had on average 1.7 more days on sick leave (95 % CI 1.3 to 1.9), 2.3 more WAA days (95% CI 1.9 to 2.7) and 0.2 more days on disability benefits (95% CI 0.1 to 0.3). In the year after rehabilitation, they had 0.6 fewer days on sick leave (95% CI –0.8 to –0.3), but 3.7 more days on WAA (95% CI 3.1 to 4.2) and 0.6 more days on disability benefits (95% CI 0.4 to 0.8). Patterns were similar for the subgroup with rheumatic and musculoskeletal diseases.

People undergoing rehabilitation had more days on health-related benefits and a greater increase in long-term benefits, even after matching, indicating a higher disease and support burden than controls. Tailoring interventions and health-related benefits is an essential aspect of rehabilitation for people with complex work participation needs. Future research should include longer observation periods to explore long-term outcomes of rehabilitation.

NCT03764982

The predictive value of carotid-femoral pulse wave velocity (cfPWV) for cardiovascular (CV) events in individuals with blood pressure (BP) 120–159/80–99 mm Hg, where more accurate risk stratification has the greatest clinical effect, is unknown. This study aims to determine whether cfPWV improves the prediction of CV events beyond traditional risk factors in individuals with moderate BP.

A systematic review and meta-analysis.

PubMed and EMBASE were searched through April 2023.

We included prospective, population-based cohort studies with ≥1 year follow-up that directly measured cfPWV as an index of arterial stiffness and reported incident CV disease (CVD), atherosclerotic CVD (ASCVD), coronary heart disease, stroke or all-cause mortality outcomes.

Individual participant data from 11 cohorts (n=15 987) were harmonised and analysed using two-stage random-effects meta-analysis. Incremental predictive and clinical utility analyses compared 10-year risk models with and without cfPWV.

There were 1279 first atherosclerotic CV events over a median follow-up of 9.9 years. A 1-SD increase in log_e(cfPWV) was associated with a 1.21-fold (95% CI 1.08 to 1.36) increase in risk of ASCVD. Adding cfPWV to traditional risk factors improved ASCVD prediction: change in discrimination (C-index): 0.0048 (95% CI 0.0002 to 0.0094), p=0.041. In hypothetical populations of 100 000 individuals with moderate BP, cfPWV-guided treatment could reduce event rates by 2.7% and 3.1% under European and US guidelines, respectively.

Adding cfPWV to traditional CV risk factors may improve the prediction and classification of first CV events in individuals with moderate BP. Additional screening with cfPWV could enhance risk stratification for antihypertensive treatment initiations.

Cardiovascular disease (CVD) risk remains high but unevenly distributed in patients with type 2 diabetes mellitus (T2DM). Current risk stratification strategies are far from optimal, leading to both undertreatment and overtreatment of patients. The STENO INTEN-CT trial aims to evaluate a strategy of improved CVD risk management by using cardiac CT (coronary artery calcification (CAC)) for stratification and tailoring of multifactorial cardiovascular treatment based on CAC score. We hypothesise that (1) intensified medical treatment will lower CVD event rates in high-risk patients (CAC≥100), and (2) less intensive multifactorial treatment is safe in very low-risk patients (CAC=0).

The Steno INTEN-CT trial is an investigator-initiated, pragmatic, open-label, event-driven randomised controlled trial including patients with T2DM without known CVD. All participants (expected n=7300) will be invited for a non-contrast coronary CT scan. After the scan, participants will be randomised to either standard treatment (blinded for CAC results) or CAC-based treatment. Participants in CAC-based treatment and their general practitioner (GP) will receive information on CAC and a recommendation of multifactorial treatment. High-risk participants in the interventional arm will be invited for one or more initial study visits to intensify treatment with a combination of sodium glucose co-transporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, high-dose lipid-lowering, antihypertensive and antithrombotic treatment. Very low-risk patients in the interventional arm will be recommended less intensive treatment targets. After initial study-related activities, all participants will continue to be taken care of by their GP guided by specific treatment recommendations. The primary outcome in the primary hierarchical analysis (the rate of the combined CVD endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalisation for heart failure) will be monitored through national health registries. The trial is event-driven, but a median follow-up of 5 years is expected. Key secondary outcomes include patient-reported outcomes, quality-adjusted life years and healthcare costs.

The protocol V.1.9 is approved by the Research Ethics Committee and the Danish Medicines Agency and the Danish Data Protection Agency. The results of the study—positive, negative or neutral—will be published in peer-reviewed journals and through www.clinicaltrials.org.

NCT05700877.

Our primary objectives were (1) to develop and validate an administrative data algorithm for the identification of hand trauma cases using clinical diagnoses documented in medical records as the reference standard and (2) to estimate the incidence of hand trauma in a universal public healthcare system from 1993 to 2023 using a population-based research cohort constructed using a validated case identification algorithm.

A population-based retrospective validation study.

Ontario, Canada, from 2022 to 2023 (validation) and from 1993 to 2023 (estimation).

Our reference standard was the known hand trauma status of 301 patients (N=147 with hand trauma) who presented to an urban tertiary-care hand trauma centre in Toronto, Ontario.

(1) The sensitivity, specificity, positive and negative predictive values of the optimal algorithm to identify hand trauma using provincial health administrative data and (2) age-standardised and sex-standardised incidence rates of hand trauma among men and women, by age, and by area of patient residence.

The optimal algorithm had a sensitivity of 73.8% (95% CI 66.6% to 81.0%), specificity of 80.1% (95% CI 73.8% to 86.5%), positive predictive value of 78.1% (95% CI 71.2% to 85.0%) and negative predictive value of 76.1% (95% CI 69.5% to 82.7%). Over the study period, the age-standardised and sex-standardised incidence of hand trauma increased from 384 to 530 per 100 000. The greatest increase was observed in males and individuals aged 0–19 and 80+, with higher incidence rates in Southern compared with Northern Ontario.

Our algorithm enabled identification of hand trauma cases using health administrative data suitable for population-level surveillance and health services research, revealing a rising burden of hand trauma from 1993 to 2023. These findings can support improved surveillance, resource allocation and care delivery for this public health problem.

An abnormal composition of gut bacteria along with alterations in microbial metabolites and reduced gut barrier integrity has been associated with the pathogenesis of chronic autoimmune and inflammatory rheumatic diseases (AIRDs). The aim of the systematic review, for which this protocol is presented, is to evaluate the clinical benefits and potential harms of therapies targeting the intestinal microbiota and/or gut barrier function in AIRDs to inform clinical practice and future research.

This protocol used the reporting guidelines from the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol. We will search Embase (Ovid), Medline (Ovid) and the Cochrane Library (Central) for reports of randomised controlled trials of patients diagnosed with an AIRD. Eligible interventions are therapies targeting the intestinal microbiota and/or gut barrier function including probiotics, synbiotics, faecal microbiota transplantation, live biotherapeutic products and antibiotics with the intent to modify disease activity in AIRDs. The primary outcome of the evidence synthesis will be based on the primary endpoint of each trial. Secondary efficacy outcomes will be evaluated and selected from the existing core domain sets of the individual diseases and include the following domains: disease control, patient global assessment, physician global assessment, health-related quality of life, fatigue, pain and inflammation. Harms will include the total number of withdrawals, withdrawals due to adverse events, number of patients with serious adverse events, disease flares and deaths. A meta-analysis will be performed for each outcome domain separately. Depending on the type of outcome, the quantitative synthesis will encompass both ORs and standardised mean differences with corresponding 95% CIs.

No ethics approval will be needed for this systematic review. We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to disseminate the study results through a peer-reviewed publication.

CRD42025644244.