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Background: Increasing severity of chronic obstructive pulmonary disease (COPD) is associated with increasing risk of poor outcomes. Using health registry data, we aimed to assess the association between treatment intensity levels (TIL), as a proxy for underlying COPD severity, and long-term outcomes., Methods: Using Danish nationwide registries, we identified patients diagnosed with COPD during 2001-2016, who were alive at index date of 1 January 2017. We stratified patients into exclusive TILs from least to most severe: no use, short term therapy, mono-, dual-, triple therapy, oral corticosteroid (OCS), and long-term oxygen treatment (LTOT). Survival analyses were used to assess 5-year outcomes by TIL., Results: We identified 53,803 patients with COPD in the study period (median age: 72 years [inter quartile range, 64-80], 48 % male). The three most severe TILs were associated with a significant incremental increase in all-cause mortality with an adjusted hazard ratio (aHR) for triple therapy, OCS and LTOT of 1.44 (95 % CI: 1.38-1.51), 1.67 (95 % CI: 1.59-1.75), and 2.91 (95 % CI: 2.76-3.07) compared with those receiving no therapy as reference. The same pattern was evident for the composite outcome of 5-year mortality or COPD-related hospitalization with an aHR for triple therapy, OCS and LTOT of 2.30 (95 % CI: 2.22-2.38), 2.85 (95 % CI: 2.74-2.96), and 4.00 (95 % CI: 3.81-4.20), respectively., Conclusion: Increasing TILs were associated with increasing five-year mortality and risk of COPD-related hospitalization. TILs may be used as a proxy for underlying COPD severity in epidemiological studies., 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 Elsevier Ltd. All rights reserved.)

Objectives . The prevalence of patients with prior stroke is increasing globally. Accordingly, there is a need for up-to-date evidence of patient-related prognostic factors for stroke recurrence, post stroke myocardial infarction (MI) and death based on long-term follow-up of stroke survivors. For this purpose, the RIALTO study was established in 2004. Design. A prospective cohort study in which patients diagnosed with ischemic stroke (IS) or transient ischemic attack (TIA) in three Copenhagen hospitals were included. Data were collected from medical records and by structured interview. Data on first stroke recurrence, first MI and all-cause death were extracted from the Danish National Patient Registry and the Danish Civil Registration System. Results . We included 1215 patients discharged after IS or TIA who were followed up by register data from April 2004 to end of 2018 giving a median follow-up of 3.5-6.9 years depending on the outcome. At the end of follow-up 406 (33%) patients had been admitted with a recurrent stroke, 100 (8%) had a MI and 822 (68%) had died. Long-term prognostic predictors included body mass index, diabetes, antihypertensive and lipid lowering treatment, smoking, a sedentary lifestyle as well as poor self-rated health and psychosocial problems. Conclusions . Long-term risk of recurrent stroke and MI remain high in patients discharged with IS or TIA despite substantial improvements in tertiary preventive care in recent decades. Continued attention to the patient risk profile among patients surviving the early phase of stroke, including comorbidities, lifestyle, and psychosocial challenges, is warranted.

Purpose: To describe phenotypic, genotypic, and histopathological features of inherited retinal dystrophies associated with the CRX gene (CRX-RDs)., Design: Retrospective multicenter cohort study including histopathology., Subjects: Thirty-nine patients from 31 families with pathogenic variants in the CRX gene., Methods: Clinical data of 152 visits were collected from medical records. The median follow-up time was 9.1 years (interquartile range (IQR), 3.3-15.3 years; range, 0.0-48.8 years). Histopathologic examination of the eye of a 17-year-old patient with advanced early-onset CRX-RD was performed., Main Outcome Measures: Visual acuity, retinal imaging, electroretinography, genotype-phenotype correlation, and histopathological examination were evaluated., Results: The age at onset ranged from birth to the eighth decade of life. Median visual acuity was 1.00 logarithm of the minimum angle of resolution (logMAR) (IQR, 0.69-1.48 logMAR; range, 0.06-3.00 logMAR) at a mean age of 52.0 ± 19.9 years (range, 4.6-81.9 years). Sufficient imaging was available for 36 out of 39 patients (92.3%), and all showed degeneration of at least the macula. Of these 36 patients, 22 (61.1%) had only macular dystrophy. Another 10 patients (27.8%) had additional degeneration beyond the vascular arcades, and 4 patients (11.1%) panretinal degeneration. Two patients (5.1%) had Leber congenital amaurosis. In total, 21 different disease-associated heterozygous CRX variants were identified (10 frameshift, 7 missense, 2 deletion, 1 nonsense, 1 deletion-insertion variants). Missense variants in the CRX homeodomain and 2 variants deleting all functional domains, thus causing haploinsufficiency, generally tended to cause milder late-onset phenotypes. Histopathologic examination of the eye of a 17-year-old patient with advanced early-onset retinal dystrophy due to a heterozygous deletion of exons 3 and 4 of the CRX gene revealed loss of laminar integrity and widespread photoreceptor degeneration especially in the central retina, with extensive loss of photoreceptor nuclei and outer segments., Conclusions: This study illustrates the large clinical and genetic heterogenic spectrum of CRX-RDs, ranging from Leber congenital amaurosis to mild late-onset maculopathy resembling occult macular dystrophy. Haploinsufficiency and missense variants tended to be associated with milder phenotypes. Patients showed degeneration predominantly affecting the central retina on imaging. The histopathological findings also mirror these clinical findings and features similar to previously reported animal models of CRX-RDs., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. All rights reserved.)

Purpose: To date, there is no standard treatment regimen for carbonic anhydrase inhibitors (CAIs) in X-linked retinoschisis (XLRS) patients. This retrospective study aims to evaluate the efficacy of CAIs on visual acuity and cystoid fluid collections (CFC) in XRLS patients in Dutch and Belgian tertiary referral centers., Design: Retrospective cohort study., Participants: Forty-two patients with XLRS., Methods: In total, 42 patients were enrolled. To be included, patients had to have previous treatment with an oral CAI (acetazolamide), a topical CAI (brinzolamide/dorzolamide), or a combination of an oral and a topical CAI for at least 4 consecutive weeks. We evaluated the effect of the CAI on best-corrected visual acuity (BCVA) and central foveal thickness (CFT) on OCT., Main Outcome Measures: Central foveal thickness and BCVA., Results: The median age at the baseline visit of the patients in this cohort study was 14.7 (range, 43.6) years, with a median (interquartile range [IQR]) follow-up period of 4.0 (2.2-5.2) years. During the follow-up period, 25 patients were treated once with an oral CAI (60%), 24 patients were treated once with a topical CAI (57%), and 11 patients were treated once with a combination of both topical and oral CAI (26%). We observed a significant reduction of CFT for oral CAI by 14.37 μm per 100 mg per day (P < 0.001; 95% confidence interval [CI], -19.62 to -9.10 μm) and for topical CAI by 7.52 μm per drop per day (P = 0.017; 95% CI, -13.67 to -1.32 μm). The visual acuity changed significantly while on treatment with oral CAI by -0.0059 logMAR per 100 mg (P = 0.008; 95% CI, -0.010 to -0.0013 logMAR). Seven patients (17%) had side effects leading to treatment discontinuation., Conclusions: Our data indicate that treatment with (oral) CAI may be beneficial for short-term management of CFC in patients with XLRS. Despite a significant reduction in CFT, the change in visual acuity was modest and not of clinical significance. Nonetheless, the anatomic improvement of the central retina in these patients may be of value to create an optimal retinal condition for future potential treatment options such as gene therapy., Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare patients with and without a history of mental illness on process and outcome measures in relation to prehospital and emergency surgical care for patients with perforated ulcer., Methods: A nationwide registry-based cohort study of patients undergoing emergency surgery for perforated ulcer. We used data from the Danish Prehospital Database 2016-2017 and the Danish Emergency Surgery Registry 2004-2018 combined with data from other Danish databases. Patients were categorized according to severity of mental health history., Results: We identified 4.767 patients undergoing emergency surgery for perforated ulcer. Among patients calling the EMS with no history of mental illness, 51% were identified with abdominal pain when calling the EMS compared to 31% and 25% among patients with a history of moderate and major mental illness, respectively. Median time from hospital arrival to surgery was 6.0 h (IQR: 3.6;10.7). Adjusting for age, sex and comorbidity, patients with a history of major mental illness underwent surgery 46 min (95% CI: 4;88) later compared to patients with no history of mental illness. Median number of days-alive-and-out-of-hospital at 90-day follow-up was 67 days (IQR: 0;83). Adjusting for age, sex and comorbidity, patients with a history of major mental illness had 9 days (95% CI: 4;14) less alive and out-of-hospital at 90-day follow-up., Conclusion: One-third of the population had a history of mental illness or vulnerability. Patients with a history of major mental illness were less likely to be identified with abdominal pain if calling the EMS prior to arrival. They had longer delays from hospital arrival to surgery and higher mortality., (© 2024. The Author(s).)

Background: Subarachnoid haemorrhage (SAH) and intraventricular haemorrhage (IVH) are associated with poor patient outcomes. Intraventricular fibrinolysis is effective in clearing IVH and improving patient survival and neurological outcome. By similar rationale, cisternal irrigation has been proposed as a potential method to accelerate haematoma clearance in SAH. We aimed to provide a comprehensive review and meta-analysis evaluating the effect of intraventricular and cisternal irrigation on clinical outcomes in patients with SAH and IVH., Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed preparing this systematic review and study selection was performed by multiple investigators. We extracted ORs from the individual studies and aggregated these using a random effects model. The quality of evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluations assessment and ROBINS-I or RoB-2., Results: 24 articles were included. In SAH, we found that cisternal irrigation with fibrinolytic agents was associated with reduced mortality (OR: 0.68, 95% CI 0.46 to 1.00), higher probability of favourable functional outcome (OR: 1.80, 95% CI 1.30 to 2.51), and reduced risks of DCI (OR: 0.28, 95% CI 0.18 to 0.42) and cerebral vasospasm (OR: 0.28, 95% CI 0.18 to 0.42), compared with conventional therapy. Cisternal irrigation with vasodilatory agents was associated with lower mortality (OR: 0.32, 95% CI 0.13 to 0.79) and reduced risk of cerebral vasospasm (OR: 0.37, 95% CI 0.17 to 0.79). The evidence for irrigation therapy of IVH was sparse and insufficient to show any significant effect., Conclusion: In this study, we found that cisternal irrigation could improve the prognosis in patients with SAH compared with conventional therapy. There is no evidence to support cisternal irrigation treatment of IVH., Competing Interests: Competing interests: ARK reports grants from IRRAS AB to Aarhus University Hospital to support the ACTIVE study and personal fees from IRRAS AB for a presentation at a scientific symposium describing his experiences with the IRRAflow technology during the conduct of the study; grants from IRRAS AB to Aarhus University Hos-pital to support the development of a neuromonitoring technology related to IRRAflow outside the submitted work; in addition, ARK has a patent for a neuromonitoring technology pending with relation to the IRRAflow technology. The remaining authors have no conflicts of interest to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Remote ischemic conditioning (RIC) is a simple and noninvasive procedure that has proved to be safe and feasible in numerous smaller clinical trials. Mixed results have been found in recent large randomized controlled trials. This is a post hoc subgroup analysis of the RESIST trial (Remote Ischemic Conditioning in Patients With Acute Stroke), investigating the effect of RIC in different acute ischemic stroke etiologies, and whether an effect was modified by treatment adherence., Methods: Eligible patients were adults (aged ≥18 years), independent in activities of daily living, who had prehospital stroke symptoms with a duration of less than 4 hours. They were randomized to RIC or sham. The RIC treatment protocol consisted of 5 cycles with 5 minutes of cuff inflation alternating with 5 minutes with a deflated cuff. Acceptable treatment adherence was defined as when at least 80% of planned RIC cycles were received. The analysis was performed using the entire range (shift analysis) of the modified Rankin Scale (ordinal logistic regression)., Results: A total of 698 had acute ischemic stroke, 253 (36%) were women, and the median (interquartile range) age was 73 (63-80) years. Median (interquartile range) overall adherence to RIC/sham was 91% (68%-100%). In patients with a stroke due to cerebral small vessel disease, who were adherent to treatment, RIC was associated with improved functional outcome, and the odds ratio for a shift to a lower score on the modified Rankin Scale was 2.54 (1.03-6.25); P =0.042. The association remained significant after adjusting for potential confounders. No significant associations were found with other stroke etiologies, and the overall test for interaction was not statistically significant (χ 2 , 4.33, P =0.23)., Conclusions: In patients with acute ischemic stroke due to cerebral small vessel disease, who maintained good treatment adherence, RIC was associated with improved functional outcomes at 90 days. These results should only serve as a hypothesis-generating for future trials., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481777., Competing Interests: Disclosures Dr Blauenfeldt received lecture fees from Bayer, Pfizer, and Novo Nordisk, unrelated to the submitted work. Dr Hess was supported by a research grant from the National Institutes of Health. Dr Simonsen was supported by research grants from the Health Research Foundation of the Central Denmark Region. The other authors report no conflicts.

Background: Atrial fibrillation (AF) is the most common sustained arrhythmia and results in a high risk of stroke. The number of immigrants is increasing globally, but little is known about potential differences in AF care across migrant populations., Aim: To investigate if initiation of oral anticoagulation therapy (OAC) differs for patients with incident AF in relation to country of origin., Methods: A nationwide register-based study covering 1999-2017. AF was defined as a first-time diagnosis of AF and a high risk of stroke. Stroke risk was defined according to guidelines from the European Society of Cardiology (ESC). Poisson regression adjusted for sex, age, socioeconomic position and comorbidity was made to compute incidence rate ratios (IRR) for initiation of OAC., Results: The AF population included 254 586 individuals of Danish origin, 6673 of Western origin and 3757 of non-Western origin. Overall, OAC was initiated within -30/+90 days relative to the AF diagnosis in 50.3% of individuals of Danish origin initiated OAC, 49.6% of Western origin and 44.5% of non-Western origin. Immigrants from non-Western countries had significantly lower adjusted IRR of initiating OAC according to all ESC guidelines compared with patients of Danish origin. The adjusted IRRs ranged from 0.73 (95% CI: 0.66 to 0.80) following the launch of the 2010 ESC guideline to 0.89 (95% CI: 0.82 to 0.97) following the launch of the 2001 ESC guideline., Conclusion: Patients with AF with a high risk of stroke of non-Western origin have persistently experienced a lower chance of initiating OAC compared with patients of Danish origin during the last decades., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Accurate estimation of ambulance transport time from the scene of incident to arrival at the emergency department (ED) is important for effective resource management and emergency care system planning. Further, differences in transport times between different urgency levels highlight the benefits of ambulance transports with highest urgency level in a setting where ambulances are allowed to not follow standard traffic rules. The objective of the study is to compare ambulance urgency level on the differences in estimates of ambulance transport times generated by Google Maps and the observed transport times in a prehospital setting where emergency vehicles have their own traffic laws. The study was designed as a natural experiment and register study. Ambulance transports dispatched with different levels of urgency (Level A and B) were included in the Central Denmark Region (a mixed urban and rural area) from March 10 to June 11, 2021. Ambulance transports for highest urgency level were compared to lowest urgency level with Google Maps estimated transport times as reference. We analyzed 1981 highest urgency level and 8.958 lowest urgency level ambulance transports. Google Maps significantly overestimated the duration of transports operating at highest level of urgency (Level A) by 1.9 min/10 km (95% CI 1.8; 2.0) in average and 4.8 min/10 km (95% CI 3.9; 5.6) for the first driven 10 km. Contrary, Google Maps significantly underestimated the duration of transports operating at lowest level of urgency (Level B) by -1.8 min/10 km (95% CI -2.1; -1.5) in average and -4.4 min/10 km (95% CI -5.4; -3.5) for the first driven 10 km. Google Maps systematically overestimates transport times of ambulance transports driven with Level A, the highest level of urgency in a setting where ambulances are allowed to not follow standard traffic rules. The results highlight the benefit of using urgency Level A and provide valuable information for emergency care management., (© 2023. The Author(s).)

Background: Patient-reported outcome measures (PROMs) are valuable and necessary tools for establishing and maintaining patient-centred healthcare. The PRO-Psychiatry initiative was primarily initiated to support the patient's voice in treatment decision-making and secondarily to monitor patient-perceived quality of care. The result of the initiative is a patient-reported instrument developed in collaboration between patients and clinicians. We aimed to validate the PROM developed for measuring self-perceived health among psychiatric patients in North Denmark Region, in terms of internal consistency, criterion validity and responsiveness., Method: Patients in contact with a psychiatric hospital in the North Denmark Region from September 2018 to March 2021 were included in the study. The PROM constitutes a scale of 17 items covering various aspects of self-perceived health including well-being (7 items), lack of well-being (5 items) and social functioning (5 items), where the former domain entails the WHO-5 Well-Being Index. The potential range of the total scale score is 0-85. We applied McDonald's omega, average inter-item correlation (AIIC) and differential item functioning (DIF). In addition, we used mixed effects analyses to estimate temporal correlations. The instrument was compared with self-rated overall mental and psychiatric health., Results: The patient population consisted of 1132 unique patients and a total of 2476 responses corresponding to one response per patient pathway. McDonald's omega was found to be 0.92 (95% CI 0.92 to 0.93), while the AIIC was found to be 0.42 (95% CI 0.39 to 0.44). For DIF, the largest systematic variation resulted in a maximum difference of 2.3 points on the total score when adjusting for the latent trait and was found when comparing initial measurements with follow-up measurements. The correlation between the total score and the outcomes regarding overall physical and mental health was 0.52 (95% CI 0.48 to 0.56) and 0.74 (95% CI 0.72 to 0.76). Similar correlations were found for the corresponding changes over time., Conclusion: The scale showed high consistency and little systematic variation between the comparison groups. The concurrent correlations and analyses of responsiveness coincided with the prespecified hypotheses. Overall, we deem the Danish PRO-Psychiatry instrument to possess suitable psychometric properties for measuring self-perceived health among a psychiatric population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: A high concentration of inspired supplemental oxygen may possibly cause hypercapnia and acidosis and increase mortality in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Even so, patients with AECOPD are being treated with high oxygen flow rates when receiving inhalation drugs in the prehospital setting. A cluster-randomised controlled trial found that reduced oxygen delivery by titrated treatment reduced mortality-a result supported by observational studies-but the results have never been reproduced. In the STOP-COPD trial, we investigate the effect of titrated oxygen delivery compared with usual care consisting of high flow oxygen delivery in patients with AECOPD in the prehospital setting., Methods: In this randomised controlled trial, patients will be blinded to allocation. Patients with suspected AECOPD (n = 1888) attended by the emergency medical service (EMS) and aged > 40 years will be allocated randomly to either standard treatment or titrated oxygen, targeting a blood oxygen saturation of 88-92% during inhalation therapy. The trial will be conducted in the Central Denmark Region and include all ambulance units. The power to detect a 3% 30-day mortality risk difference is 80%. The trial is approved as an emergency trial. Hence, EMS providers will include patients without prior consent., Discussion: The results will provide evidence on whether titrated oxygen delivery outperforms standard high flow oxygen when used to nebulise inhaled bronchodilators in AECOPD treatment. The trial is designed to ensure unselected inclusion of patients with AECOPD needing nebulised bronchodilators-a group of patients that receives high oxygen fractions when treated in the prehospital setting where the only compressed gas is generally pure oxygen. Conducting this trial, we aim to improve treatment for people with AECOPD while reducing their 30-day mortality., Trial Registration: European Union Clinical Trials (EUCT) number: 2022-502003-30-00 (authorised 06/12/2022), ClinicalTrials.gov number: NCT05703919 (released 02/02/2023), Universal trial number: U1111-1278-2162., (© 2024. The Author(s).)

Within the last decade, a wide variety of protocols have emerged for the generation of retinal organoids. A subset of studies have compared protocols based on stem cell source, the physical features of the microenvironment, and both internal and external signals, all features that influence embryoid body and retinal organoid formation. Most of these comparisons have focused on the effect of signaling pathways on retinal organoid development. In this study, our aim is to understand whether starting cell conditions, specifically those involved in embryoid body formation, affect the development of retinal organoids in terms of differentiation capacity and reproducibility. To investigate this, we used the popular 3D floating culture method to generate retinal organoids from stem cells. This method starts with either small clumps of stem cells generated from larger clones (clumps protocol, CP) or with an aggregation of single cells (single cells protocol, SCP). Using histological analysis and gene-expression comparison, we found a retention of the pluripotency capacity on embryoid bodies generated through the SCP compared to the CP. Nonetheless, these early developmental differences seem not to impact the final retinal organoid formation, suggesting a potential compensatory mechanism during the neurosphere stage. This study not only facilitates an in-depth exploration of embryoid body development but also provides valuable insights for the selection of the most suitable protocol in order to study retinal development and to model inherited retinal disorders in vitro.

Background: Atrial fibrillation and flutter (AF) is the most common sustained arrhythmia with an increasing prevalence in Western countries. However, little is known about AF among immigrants compared to non-immigrants., Aim: To examine the incidence of hospital-diagnosed AF according to country of origin., Method: Immigrants were defined as individuals born outside Denmark by parents born outside Denmark. AF was defined as first-time diagnosis of AF. All individuals were followed from the age of 45 years from 1998 to 2017. The analyses were adjusted for sex, age, comorbidity, contact with the general practitioner and socioeconomic variables. Adjustment was conducted using standardised morbidity ratio weights, standardised to the Danish population in a marginal structural model., Results: The study population consisted of 3,489,730 Danish individuals free of AF and 108,914 immigrants free of AF who had emigrated from the 10 most represented countries. A total of 323,005 individuals of Danish origin had an incident hospital diagnosis of AF, among the immigrants 7,300 developed AF. Adjusted hazard rate ratios (HRRs) of AF for immigrants from Iran (0.48 [95%CI:0.35;0.64]), Turkey (0.74 [95%CI:0.67;0.82]) and Bosnia-Herzegovina (0.42 [95%CI:0.22;0.79]) were low compared with Danish individuals. Immigrants from Sweden, Germany and Norway had an adjusted HRR of 1.13 [95%CI:1.03;1.23], 1.12 [95%CI:1.05;1.18] and 1.11 [95%CI:1.03;1.21], respectively (Danish individuals as reference)., Conclusions: Substantial variation in the incidence of hospital-diagnosed AF according to country of origin was observed. The results may reflect true biological differences but could also reflect barriers to AF diagnosis for immigrants. Further efforts are warranted to determine the underlying mechanisms., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: LF was supported by the Health Research Foundation of Central Denmark Region and is a consultant for BMS/Pfizer and AstraZeneca.

Introduction: Dementia after stroke is common and is a great concern for patients and their caregivers. The objective was to investigate if intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) was associated with lower risk of dementia after stroke., Patients and Methods: When IVT was introduced in Denmark, not all eligible patients were treated due to restricted access. We conducted a nationwide register-based cohort study of all patients with AIS in Denmark from 2004 to 2011. IVT-treated patients were propensity score-matched with comparable non-treated patients. Cox proportional hazards regression was used to estimate the hazard ratio (HR) for all-cause and vascular dementia 2, 5, and 10 years after stroke., Results: Of the 5919 patients eligible for the study, 2305 IVT-treated patients were propensity score-matched with 2305 non-treated patients. Mean (SD) age was 66.6 (13.3) and 61.2% were male. Rate of all-cause dementia was lower for the IVT-treated 2 years (8.4/1000 person years (PY) vs 13.6/1000 PY, HR 0.63 (0.40-0.99)) and 5 years after stroke (7.3/1000 PY vs 11.4/1000 PY, HR 0.65 (0.46-0.91)). 10 years after stroke, the rates of all-cause dementia remained in favor of IVT (8.0/1000 PY vs 9.8/1000 PY, HR 0.83 (0.64-1.07)). IVT-treated had lower rates of vascular dementia 2 years (2.4/1000 PY vs 7.4/1000 PY, HR 0.33 (0.15-0.71)), 5 years (2.3/1000 PY vs 6.2/1000 PY, HR 0.38 (0.23-0.65)), and 10 years after stroke (3.0/1000 PY vs 5.4/1000 PY, HR 0.56 (0.38-0.81))., Conclusion: IVT treatment was associated with lower long-term risk of both vascular and all-cause dementia after AIS., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: The complete mesocolic excision competency assessment tool (CMECAT) is a novel tool designed to assess technical skills in minimally invasive complete mesocolic excision (CME) surgery. The aim of this study was to assess construct validity and reliability of CMECAT in a clinical context., Method: Colorectal surgeons were asked to submit video recorded laparoscopic CME resections for independent assessment of their technical abilities. The videos were grouped by surgeons' training level, and four established CME experts were recruited as CMECAT assessors. Extended reliability analysis (G-theory) was applied to describe assessor agreement., Results: A total of 19 videos and 72 assessments were included in the analysis. Overall, technical skills assessed by CMECAT improved with increased training level: the experts scored significantly better than the untrained surgeons (3.3 vs. 2.5 points; p < 0.01). On right-sided resections, significantly higher scores were reported with increased training level for all categories and sections, while for left-sided resections, the variance across groups was smaller and significantly higher scores were only reported for oncological safety describing items. Overall, assessor agreement was high (G-coefficient: 0.81)., Conclusion: This study confirms that CMECAT can be applied to video recorded CME cases for technical skill assessment. Further, it can reliably assess technical performance in right sided CME surgery, where construct validity has now been established. More videos are required to evaluate its validity on left colonic CME. In the future, we hope CMECAT can improve feedback during CME training, serve as a tool in certification processes and contribute to distinguishing CME from conventional surgery in future research., (© 2023 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Purpose: To investigate the histology of Bruch's membrane (BM) calcification in pseudoxanthoma elasticum (PXE) and correlate this to clinical retinal imaging., Design: Experimental study with clinicopathological correlation., Subjects and Controls: Six postmortem eyes from 4 PXE patients and 1 comparison eye from an anonymous donor without PXE. One of the eyes had a multimodal clinical image set for comparison., Methods: Calcification was labeled with OsteSense 680RD, a fluorescent dye specific for hydroxyapatite, and visualized with confocal microscopy. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy (SEM-EDX) and time-of-flight secondary ion mass spectrometry (TOF-SIMs) were used to analyze the elemental and ionic composition of different anatomical locations. Findings on cadaver tissues were compared with clinical imaging of 1 PXE patient., Main Outcome Measures: The characteristics and topographical distribution of hydroxyapatite in BM in eyes with PXE were compared with the clinical manifestations of the disease., Results: Analyses of whole-mount and sectioned PXE eyes revealed an extensive, confluent OsteoSense labeling in the central and midperipheral BM, transitioning to a speckled labeling in the midperiphery. These areas corresponded to hyperreflective and isoreflective zones on clinical imaging. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy and TOF-SIMs analyses identified these calcifications as hydroxyapatite in BM of PXE eyes. The confluent fluorescent appearance originates from heavily calcified fibrous structures of both the collagen and the elastic layers of BM. Calcification was also detected in an aged comparison eye, but this was markedly different from PXE eyes and presented as small snowflake-like deposits in the posterior pole., Conclusions: Pseudoxanthoma elasticum eyes show extensive hydroxyapatite deposition in the inner and outer collagenous and elastic BM layers in the macula with a gradual change toward the midperiphery, which seems to correlate with the clinical phenotype. The snowflake-like calcification in BM of an aged comparison eye differed markedly from the extensive calcification in PXE., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Crown Copyright © 2023 Published by Elsevier Inc. on behalf of the American Academy of Ophthalmology.)

Importance: Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke., Objective: To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke., Design, Setting, and Participants: This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023)., Intervention: The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants., Main Outcomes and Measures: The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke., Results: Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group., Conclusions and Relevance: RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke., Trial Registration: ClinicalTrials.gov Identifier: NCT03481777.

Objective: 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., Competing Interests: Dr Rolf Blauenfeldt reports speaker fees from Novo Nordisk and Bayer, outside the submitted work. Prof. Dr Claus Z. Simonsen reports grants from Novo Nordisk Foundation and Health Research Foundation of Central Denmark Region, during the conduct of the study. The authors report no other conflicts of interest in this work., (© 2023 Gude et al.)

Objectives: To examine costs of care from a healthcare sector perspective within 1 year before death in patients with non-cancer diseases and patients with cancer., Methods: This nationwide registry-based study identified all Danish citizens dying from major non-cancer diseases or cancer in 2010-2016. Applying the cost-of-illness method, we included costs of somatic hospitals, including hospital-based specialist palliative care, primary care, prescription medicine and hospice expressed in 2022 euros. Costs of patients with non-cancer diseases and cancer were compared using regression analyses adjusting for sex, age, comorbidity, residential region, marital/cohabitation status and income level., Results: Within 1 year before death, mean total healthcare costs were €27,185 [95% confidence interval (CI) €26,970-27,401] per patient with non-cancer disease (n = 109,723) and €51,348 (95% CI €51,098-51,597) per patient with cancer (n = 108,889). The adjusted relative total healthcare costs, i.e. the ratio of the mean costs, of patients with non-cancer diseases was 0.64 (95% CI 0.63-0.66) at 12 months before death and 0.91 (95% CI 0.90-0.92) within 30 days before death compared with patients with cancer. Mean costs of hospital-based specialist palliative care and hospice in the year leading up to death were €17 (95% CI €13-20) and €90 (95% CI €77-102) per patient with non-cancer disease but €1552 (95% CI €1506-1598) and €3411 (95% CI €3342-3480) per patient with cancer., Conclusions: Within 1 year before death, total healthcare costs, mainly driven by hospital costs, were substantially lower for patients with non-cancer diseases compared with patients with cancer. Moreover, the costs of hospital-based specialist palliative care and hospice were minimal for patients with non-cancer diseases., (© 2023. The Author(s).)

Multinomial logistic regression (MLR) is often used to model the association between a nominal outcome variable and one or more covariates. The results of MLR are interpreted as relative risk ratios (RRR) and warrant a more coherent interpretation than ordinary logistic regression. Some authors compare the results of MLR to ordinal logistic regression (OLR), irrespective of the fact that these estimate different quantities. We aim to investigate the time trends in the use and misuse of MLR in studies including stroke patients, specifically the extent to which (1) the results are denoted as anything other than RRR, (2) comparisons are made of results with results of OLR and (3) results have been interpreted coherently. Secondarily, we examine the use of model validation techniques in studies with predictive aims. We searched EMBASE and PubMed for articles using MLR on populations of stroke patients. Identified studies were screened, and information pertaining to our aims was extracted. A total of 285 articles were identified through a systematic literature search, and 68 of these were included in the review. Of these, 60 articles (88%) did not denote exponentiated coefficients of MLR as relative risk ratios but rather some other measure. Additionally, 63 articles (93%) interpreted the results of MLR in a non-coherent manner. Two articles attempted to compare MLR results with those of OLR. Nine studies attempted to use MLR for predictive means, and three used relevant validation techniques. From these findings, it is clear that the interpretation of MLR is often suboptimal., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: Severe chronic obstructive pulmonary disease (COPD) has been associated with futile outcome after transcatheter aortic valve replacement (TAVR). Data on outcomes according to COPD severity are warranted to aid identification of patients who may not benefit from TAVR. We aimed to examine the association between risk of COPD exacerbation and 1-year mortality after TAVR., Methods: Using Danish nationwide registries we identified patients undergoing first-time TAVR during 2008-2021 by COPD status. COPD severity levels were defined as low or high risk of acute exacerbation of COPD (AE-COPD) and treatment intensity levels (none or short-term, mono/dual, triple therapy, or home oxygen). Kaplan-Meier functions and adjusted Cox regression models were used to assess 1-year mortality comparing COPD severity groups with patients without COPD., Results: We identified 7,047 patients with TAVR of whom 644 had a history of COPD (low risk of AE-COPD: 439, high risk of AE-COPD: 205). The median age of the TAVR cohort was 81.4 years (IQR: 76.8-85.1) and 55.8% were males. One-year mortality for TAVR patients without COPD was 8.5% (95% CI: 7.8-9.2) and 15.4% (95% CI: 12.5-18.2) for those with COPD (adjusted HR: 1.63 [95% CI: 1.28-2.07]). Patients with low or high risk of AE-COPD had 1-year mortality of 13.1% (95% CI: 9.8-16.3) and 20.2% (95% CI: 14.6-25.8) corresponding to adjusted HRs of 1.31 (95% CI: 0.97-1.78) and 2.44 (95% CI: 1.70-3.50) compared with patients without COPD. Patients with high risk of AE-COPD and no/short term therapy or use of home oxygen represented the subgroups of patients with the highest 1-year mortality (31.6% [95% CI: 14.5-48.7] and 30.9% [95% CI: 10.3-51.6])., Conclusion: Among patients undergoing TAVR, increasing risk of exacerbation with COPD was associated with increasing 1-year mortality compared with non-COPD patients. Patients with a high risk of exacerbation with COPD not using any guideline recommended COPD medication and those using home oxygen had the highest 1-year mortality., Competing Interests: Disclosures Dr. Lauridsen has nothing to declare. Mr. Valentin has nothing to declare. Dr. Strange has nothing to declare. Dr. Jacobsen reports personal fees from AstraZeneca outside the submitted work. Dr. Møller Weinreich reports personal fees from Astra Zeneca, Chiesi, Novartis, Boehringer Ingelheim, Pfizer, GSK, and Orion pharma outside the submitted work. Dr. Johnsen reports personal fees from BMS and Pfizer, outside the submitted work. Dr. Køber reports personal fees from Novartis, BMS, and AstraZeneca, outside the submitted work. Dr. Fosbøl reports a grant from Novo Nordisk, outside the submitted work., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: This retrospective cohort study aimed to examine the positive predictive value (PPV) of pediatric stroke diagnoses in the Danish National Registry of Patients (DNRP) and the impact of different stroke definitions on the PPV., Methods: We included children registered with a stroke or stroke-related diagnosis in the DNRP between January 2017 through December 2020. Two assessors reviewed medical records and validated cases according to the American Heart and American Stroke Association (AHA/ASA) stroke definition. The level of interrater agreement was examined using kappa statistics. Validation by the AHA/ASA definition was compared with validation according to the definition in the International Classification of Disease 11th version (ICD-11) and the World Health Organization's definition., Results: Stroke was confirmed in 120 of 309 included children, yielding an overall PPV of 0.39 (95% CI: 0.33-0.45). PPV varied across stroke subtypes from 0.83 (95% CI: 0.71-0.92) for ischemic stroke (AIS), 0.57 (95% CI: 0.37-0.76) for unspecified stroke, 0.42 (95% CI: 0.33-0.52) for intracerebral hemorrhage (ICH) to 0.31 (95% CI: 0.55-0.98) and 0.07 (95% CI: 0.01-0.22) for cerebral venous thrombosis and subarachnoid hemorrhage (SAH), respectively. Most non-confirmed ICH and SAH diagnoses were in children with traumatic intracranial hemorrhages (36 and 66% respectively). Among 70 confirmed AIS cases, 25 (36%) were identified in non-AIS code groups. PPV varied significantly across stroke definitions with the highest for the AHA/ASA definition (PPV = 0.39, 95% CI: 0.34-0.45) and the lowest for the WHO definition (PPV = 0.29, 95% CI: 0.24-0.34). Correspondingly, the incidence of pediatric AIS per 100.000 person-years changed from 1.5 for the AHA/ASA definition to 1.2 for ICD-11 and 1.0 for the WHO-definition. The overall interrater agreement was considered excellent (κ=0.85)., Conclusion: After validation, stroke was confirmed in only half of the children registered in the DNRP with a stroke-specific diagnosis. Non-validated administrative data should be used with caution in pediatric stroke research. Pediatric stroke incidence rates may vary markedly depending on which stroke definition is used., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 Bindslev et al.)

Objective: To examine hospital-based specialist palliative care (SPC) utilisation among patients with gynaecological cancer, including temporal trends, predictors and associations with high-intensity end-of-life care., Methods: We conducted a nationwide registry-based study for all patients dying from gynaecological cancer in Denmark during 2010-2016. We estimated the proportions of patients receiving SPC by year of death and used regression analyses to examine predictors of SPC utilisation. Use of high-intensity end-of-life care according to SPC utilisation was compared by regression analyses adjusting for type of gynaecological cancer, year of death, age, comorbidities, residential region, marital/cohabitation status, income level and migrant status., Results: Among 4502 patients dying from gynaecological cancer, the proportion of patients receiving SPC increased from 24.2% in 2010 to 50.7% in 2016. Young age, three or more comorbidities, residence outside the Capital Region and being immigrant/descendant were associated with increased SPC utilisation, whereas income, cancer type and stage were not. SPC was associated with lower high-intensity end-of-life care utilisation. Particularly, when compared with patients not receiving SPC, patients who accessed SPC >30 days before death had 88% lower risk of intensive care unit admissions within 30 days before death (adjusted relative risk: 0.12 (95% CI: 0.06; 0.24)) and 96% lower risk of surgery within 14 days before death (adjusted relative risk: 0.04 (95% CI: 0.01; 0.31))., Conclusions: Among patients dying from gynaecological cancer, SPC utilisation increased over time and age, comorbidities, residential region and migrant status were associated with access to SPC. Furthermore, SPC was associated with lower use of high-intensity end-of-life care., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: In complex and high-risk aortic root disease, the porcine Freestyle stentless bioprosthesis (Medtronic Inc, Minneapolis, Minn) is an important surgical treatment option. We aimed to determine prevalence and clinical effect of structural and functional abnormalities after full-root Freestyle implantation., Methods: Our cross-sectional 2-center study combined with clinical follow-up included 253 patients with full-root Freestyle bioprostheses implanted from 1999 to 2017. Patients underwent transthoracic echocardiography (TTE) and contrast-enhanced, electrocardiogram-gated 4-dimensional cardiac computed tomography (4DCT) at median age 70 (interquartile range, 62-75) years. After 4DCT, clinical follow-up continued throughout 2018. Median follow-up was 3.3 years before 4DCT and 1.4 years after., Results: We identified abnormalities in 46% of patients, including pseudoaneurysms (n = 32; 13%), moderate or severe coronary ostial stenosis (n = 54; 21%), and moderate-severe leaflet thickening or reduced leaflet motion (n = 51; 20%). TTE only identified 1 patient with pseudoaneurysm. After 4DCT, the unadjusted hazard ratio for surgical reintervention among patients with abnormal 4DCT was 4.2 (95% confidence interval, 1.2-15.3), in all, 10% required a reintervention. 4DCT abnormalities were associated with a statistically nonsignificant increased risk of death, stroke, or myocardial infarction (hazard ratio obtained using Cox proportional hazards regression analysis, 2.4; 95% confidence interval, 0.7-7.6). In all, 4.0% died, 3.6% had a myocardial infarction, and 2.0% had a stroke., Conclusions: Structural and functional abnormalities of the aortic root are frequent after Freestyle implantation and TTE appears to be insufficient for follow-up. Abnormalities might be associated with increased risk of reintervention and potentially adverse clinical outcomes. Longer follow-up and larger study populations are needed to further clarify the clinical implications of abnormalities identified with 4DCT., (Copyright © 2021 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: In a publicly financed healthcare system we aimed to study the development in socioeconomic disparity in ischemic stroke outcomes over time. In addition, we study whether the healthcare system affects these outcomes through the quality of early stroke care when adjustments are made for various patient characteristics incl. comorbidity and stroke severity., Patients and Methods: Using nationwide, detailed individual-level register-data we analysed how income-related and education-related inequality in 30-day mortality and 30-day readmission risk developed between 2003 and 2018. In addition, focusing on income-related inequality, we applied mediation analyses to estimate the mediating role of quality of acute stroke care on 30-day mortality and 30-day readmission., Results: A total of 97,779 individual ischemic stroke patients were registered in Denmark with a first ever stroke in the study period. Three-point-seven percent died within 30 days of their index-admission and 11.5% were readmitted within 30 days of discharge. The income-related inequality in mortality remained virtually unchanged over time from an RR of 0.53 (95% CI: 0.38; 0.74) in 2003-06 to RR 0.69 (95% CI: 0.53; 0.89)) in 2015-18 when high income was compared to low income (Family income-time interaction: RR 1.00 (95% CI: 0.98-1.03)). A similar but less uniform trend was found for the education-related inequality in mortality (Education-time interaction: RR 1.00 (95% CI: 0.97-1.04)). The income-related disparity in 30-day readmission was smaller than in 30-day mortality and it diminished over time from 0.70 (95% CI: 0.58; 0.83) to 0.97 (95% CI: 0.87; 1.10). The mediation analysis showed no systematic mediating effect of quality of care on neither mortality nor readmission. However, it cannot be ruled out that residual confounding may have washed out some mediating effects., Discussion and Conclusion: The socioeconomic inequality in stroke mortality and re-admission risk has yet to be eliminated. Additional studies from different settings are warranted in order to clarify the impact of socioeconomic inequality of quality of acute stroke care., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© European Stroke Organisation 2022.)

Background: Insomnia in depression is common and difficult to resolve. Unresolved depression-related sleep disturbances increase risk of relapse at high costs for individuals and society. Trials have suggested music for insomnia in various populations, but there is little research on the effectiveness of music for depression-related insomnia., Methods: We examined the efficacy of a music intervention on insomnia, depression symptoms and quality of life in adults with depression-related insomnia. A two-armed randomized controlled trial was conducted, including depression outpatients with insomnia ( n  = 112) in a 1:1 ratio to music intervention and waitlist control group. The intervention group listened to music at bedtime for 4 weeks. Participants received treatment as usual during 8 weeks with assessments at baseline, at 4 and 8 weeks. The primary outcome measure was Pittsburgh Sleep Quality Index (PSQI), secondary outcomes comprised Actigraphy, the Hamilton Depression Rating Scale (HAMD-17) and World Health Organisation well-being questionnaires (WHO-5, WHOQOL-BREF)., Results: The music intervention group experienced significant improvements in sleep quality and well-being at 4 weeks according to global PSQI scores (effect size = -2.1, 95%CI -3.3; -0.9) and WHO-5 scores (effect size 8.4, 95%CI 2.7;14.0). At 8 weeks, i.e. 4 weeks after termination of the music intervention, the improvement in global PSQI scores had decreased (effect size = -0.1, 95%CI -1.3; 1.1). Actigraphy sleep assessments showed no changes and there was no detection of change in depression symptoms., Conclusions: Music intervention is suggested as a safe and moderately effective sleep aid in depression-related insomnia. Trial registration: Clinicaltrials.gov. ID NCT03676491.

A significant number of individuals with a rare disorder such as Usher syndrome (USH) and (non-)syndromic autosomal recessive retinitis pigmentosa (arRP) remain genetically unexplained. Therefore, we assessed subjects suspected of USH2A -associated disease and no or mono-allelic USH2A variants using whole genome sequencing (WGS) followed by an improved pipeline for variant interpretation to provide a conclusive diagnosis. One hundred subjects were screened using WGS to identify causative variants in USH2A or other USH/arRP-associated genes. In addition to the existing variant interpretation pipeline, a particular focus was put on assessing splice-affecting properties of variants, both in silico and in vitro . Also structural variants were extensively addressed. For variants resulting in pseudoexon inclusion, we designed and evaluated antisense oligonucleotides (AONs) using minigene splice assays and patient-derived photoreceptor precursor cells. Biallelic variants were identified in 49 of 100 subjects, including novel splice-affecting variants and structural variants, in USH2A or arRP/USH-associated genes. Thirteen variants were shown to affect USH2A pre-mRNA splicing, including four deep-intronic USH2A variants resulting in pseudoexon inclusion, which could be corrected upon AON treatment. We have shown that WGS, combined with a thorough variant interpretation pipeline focused on assessing pre-mRNA splicing defects and structural variants, is a powerful method to provide subjects with a rare genetic condition, a (likely) conclusive genetic diagnosis. This is essential for the development of future personalized treatments and for patients to be eligible for such treatments., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Aim: To (1) develop an assessment tool for laparoscopic complete mesocolic excision (LCME) and (2) report evidence of its content validity., Method: Assessment statements were revealed through (1) semi-structured expert interviews and (2) consensus by the Delphi method, both involving an expert panel of five LCME surgeons. All experts were interviewed and then asked to rate LCME describing statements from 1 (strongly disagree) to 5 (strongly agree). Responses were returned anonymously to the panel until consensus was reached. Statements were directly included as content in the assessment tool if ≥60% of the experts responded "agree" or "strongly agree" (ratings 4 and 5), with the remaining responses being "neither agree nor disagree" (rating 3). Interclass correlation coefficient (ICC) was calculated for expert agreement evaluation. All included statements were subsequently reformulated as tool items and approved by the experts., Results: Four Delphi rounds were performed to reach consensus. Disagreement was reported for statements describing instrument handling around pancreas; visualisation of landmarks before inferior mesenteric artery ligation; lymphadenectomy around the inferior mesenteric artery, and division of the terminal ileum and transverse colon. ICC in the last Delphi-round was 0.84. The final tool content included 73 statements, converted to 48 right- and 40 left-sided items for LCME assessment., Conclusion: A procedure-specific, video-based tool, named complete mesocolic excision competency assessment tool (CMECAT), has been developed for LCME skill assessment. In the future, we hope it can facilitate assessment of LCME surgeons, resulting in improved patient outcome after colon cancer surgery., (© 2022 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Objectives: Accurate prediction of heart failure (HF) patients at high risk of atrial fibrillation (AF) represents a potentially valuable tool to inform shared decision making. No validated prediction model for AF in HF is currently available. The objective was to develop clinical prediction models for 1-year risk of AF., Methods: Using the Danish Heart Failure Registry, we conducted a nationwide registry-based cohort study of all incident HF patients diagnosed from 2008 to 2018 and without history of AF. Administrative data sources provided the predictors. We used a cause-specific Cox regression model framework to predict 1-year risk of AF. Internal validity was examined using temporal validation., Results: The population included 27 947 HF patients (mean age 69 years; 34% female). Clinical experts preselected sex, age at HF, NewYork Heart Association (NYHA) class, hypertension, diabetes mellitus, chronic kidney disease, obstructive sleep apnoea, chronic obstructive pulmonary disease and myocardial infarction. Among patients aged 70 years at HF, the predicted 1-year risk was 9.3% (95% CI 7.1% to 11.8%) for males and 6.4% (95% CI 4.9% to 8.3%) for females given all risk factors and NYHA III/IV, and 7.5% (95% CI 6.7% to 8.4%) and 5.1% (95% CI 4.5% to 5.8%), respectively, given absence of risk factors and NYHA class I. The area under the curve was 65.7% (95% CI 63.9% to 67.5%) and Brier score 7.0% (95% CI 5.2% to 8.9%)., Conclusion: We developed a prediction model for the 1-year risk of AF. Application of the model in routine clinical settings is necessary to determine the possibility of predicting AF risk among patients with HF more accurately and if so, to quantify the clinical effects of implementing the model in practice., Competing Interests: Competing interests: GYHL: Consultant and speaker for BMS/Pfizer, Boehringer Ingelheim and Daiichi-Sankyo. No fees are received personally. SPJ: Consultant and speaker for BMS/Pfizer. Research grants from BMS/Pfizer and Novo Nordisk. LF: Supported by a grant from Health Research Fund of Central Denmark Region. Consultant for BMS and Pfizer., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: We aimed to determine the treatment delay for ischemic stroke patients in Denmark., Methods: A nationwide register-based study on acute ischemic stroke patients admitted through emergency medical services. Treatment delay comprised patient, prehospital, and in-hospital delay. Analyses were stratified according to length of prehospital delay (<3 vs. ≥3 h)., Results: A total of 5,356 ischemic stroke episodes were included. The median onset-to-door time was 187 min, and 2,405 (43%) arrived at the stroke unit within 3 h. Overall, the median patient delay was 115 min. For early arrival (n = 2,280), patient delay was 27 min compared to 437 min for late arrivals (n = 2,448). Median prehospital delay varied by 9 min between early- and late-arriving patients. Approximately 48% of the early-arriving patients compared to 9% of the late-arriving patients received i.v. thrombolysis. For thrombectomy, the numbers were 10% and 3%, respectively. This corresponded to an unadjusted relative risk (RR) of 0.18 (95% CI: 0.16-0.21) and adjusted (age, sex, cohabitation status, and stroke severity) RR of 0.20 (95% CI: 0.18-0.23) for i.v. thrombolysis when comparing patients arriving later than 3 h with patients arriving earlier. For thrombectomy, the unadjusted and adjusted RRs were 0.30 (95% CI: 0.23-0.39) and 0.40 (95% CI: 0.31-0.52), respectively., Conclusions: Patient delay remains the most important barrier for use of reperfusion therapy among acute ischemic stroke patients calling 1-1-2, whereas system delay seems independent of patient delay., (© 2022 S. Karger AG, Basel.)

Objective: Endocervical sampling in women with suspected cervical neoplasia can be performed by either endocervical brush or endocervical curettage. This study aimed to estimate the diagnostic accuracy, discomfort, and number of inadequate samples with either test., Data Sources: Four bibliographic databases were searched on June 9, 2022, with no date or language restrictions., Study Eligibility Criteria: We included all diagnostic studies and randomized clinical trials that compared the endocervical brush with endocervical curettage in women with an indication for colposcopy., Methods: The review protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021222406). Two authors independently screened studies, extracted data, performed the risk-of-bias assessment (Quality Assessment of Diagnostic Accuracy Studies-2), and rated the certainty of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. A meta-analysis of diagnostic test accuracy was performed using a bivariate random-effects model., Results: We included 7 studies: 4 diagnostic cohort studies and 3 randomized clinical trials. The reference standard was conization or hysterectomy. Risk of bias and concern about applicability were high for some of the studies in patient selection and flow and timing. Overall pooled sensitivity was 81% (95% confidence interval, 48-95; 799 women; 7 studies; low quality of evidence) for endocervical brush and 70% (95% confidence interval, 42-89; 761 women; 7 studies; low quality of evidence) for endocervical curettage. Overall pooled specificity was 73% (95% confidence interval, 36-93; 799 women; 7 studies; low quality of evidence) for endocervical brush and 81% (95% confidence interval, 56-94; 761 women; 7 studies; low quality of evidence) for endocervical curettage. The risk ratio for inadequate samples with endocervical curettage compared with endocervical brush was 2.53 (95% confidence interval, 0.58-11.0; P=.215; low-certainty evidence). Two studies reported on patient discomfort; one found less discomfort in the endocervical brush group, and the other found no difference., Conclusion: No difference was found between endocervical brush and endocervical curettage in diagnostic accuracy, inadequate sampling rate, and adverse effects based on low-quality of evidence. Variation in the characteristics of women and the resulting diagnostic pathways make the external validity limited., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The increasing global migration has made migrants' health a pertinent topic. This article aimed to examine whether migrants were less likely than Danish-born residents to receive guideline recommended care when hospitalized for major depressive disorder (MDD) and potential differences in clinical outcomes, including all-cause mortality, suicidal behavior, and readmissions during 1-year follow-up after first-time admission., Methods: A national cohort study was performed, including all adult MDD inpatients at mental care units in the period 2011-2017. Migrants and two migrant subgroups (non-Western and Western) were compared with Danish-born patients. Quality of care was examined using multivariable Poisson and linear regression models. Clinical outcomes were examined using Cox proportional hazards regression analysis., Results: Migrant-status was associated with a non-significantly lower chance of receiving high-quality care (relative risk [RR] = 0.93, confidence interval [CI] 0.86:1.01) and lower readmission rates for depression (hazard rate ratio [HR] = 0.93, CI 0.86:1.01), and significantly higher all-cause mortality (HR = 1.55, CI 1.19:2.01) and lower all-cause readmission rate (HR = 0.88, CI 0.83:0.94). No clear association was found regarding suicidal behavior. While associations were comparable for migrant subgroups regarding readmission, the associations with low quality of care and of all-cause mortality appeared strongest among Western migrants., Conclusions: Among inpatients with MDD in a universal tax-financed healthcare system, being a migrant was associated with a potential lower quality of in-hospital care and worse clinical outcomes. These results warrant further investigation to clarify the underlying explanation for these inequalities and to develop and test interventions to ensure better quality of care and clinical outcomes for migrant patients.

Background: Persons with bipolar disorder (BD) have a higher cardiovascular mortality compared to the general population, partially explained by the increased burden of cardiovascular risk factors. Research regarding outcomes following acute coronary syndrome (ACS) in this population remains scarce., Design: This Danish register-based study included patients diagnosed with BD and ACS in the period between January 1st, 1995, to December 31st, 2013. Study participants were matched 1:2 to patients without BD on sex, date of birth, time of ACS diagnosis and comorbidities. The primary outcome of interest was major adverse cardiovascular events (MACE) a composite of all-cause mortality, reinfarction or stroke. MACE and its individual components were compared between patients with and without BD., Results: 796 patients with BD were compared to 1592 patients without BD, both groups had a mean age of first ACS of 66.5 years. MACE was 38% increased (HR 1.38 95% CI 1.25-1.54), all-cause mortality was 71% increased (HR 1.71 95% CI 1.52-1.92), stroke was 94% increased (HR 1.94 95% CI 1.56-2.41) and reinfarction rates were 17% lower (HR 0.83 95% CI 0.69-1.00) in the BD population compared to the population without BD. We also found higher prevalences of heart failure (9.1% vs. 6.5%), valve disease (5.3% vs. 3.5%), anemia (8.7% vs. 5.8%), chronic obstructive pulmonary disease (13.4% vs. 9.3%) and stroke (11.8% vs. 7.8%) in the population with BD at baseline, all p-values <0.05., Conclusion: Bipolar disorder was associated with a higher risk of composite MACE, all-cause mortality, and stroke, after ACS compared to patients without BD., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: This propensity-score matched study investigated clinical outcomes associated with left atrial appendage occlusion (LAAO) versus direct oral anticoagulation (DOAC) in patients with AF and prior ischemic stroke., Methods: AF patients enrolled in the Amulet Observational Study with a history of ischemic stroke and successful LAAO (n = 299) were compared with a propensity-score matched cohort of incident AF patients with prior ischemic stroke and treated by DOAC (n = 301). The control cohort was identified through the Danish National Patient Registries. Propensity score matching was based on covariates of the CHA 2 DS 2 -VASc and HAS-BLED scores, with a 1:2 ratio and using Greedy 5:1 digit matching with replacement. The analysis included 2-years follow-up, with a primary composite outcome of ischemic stroke, major bleeding (BARC ≥ 3) or all-cause mortality., Results: Mean (SD) CHA 2 DS 2 -VASc scores were 5.26 (1.42) and 5.40 (1.31) and HAS-BLED scores were 3.95 (0.91) and 4.03 (0.96), for the LAAO and DOAC group, respectively. Total number of primary composite outcome events were 61 (12.4 events/100 patient-years) and 117 (26.9 events/100 patient-years) in the LAAO and DOAC group, respectively. Risk of the primary composite outcome was significantly lower in the LAAO group, hazard rate ratio [HR] 0.48 (95% CI: 0.35-0.65). Ischemic stroke risk was comparable, HR 0.71 (95% CI: 0.34-1.45), while risk of major bleeding, HR 0.41 (95% CI: 0.25-0.67), and all-cause mortality, HR 0.48 (95% CI: 0.32-0.71), were significantly lower with LAAO. Cardiovascular mortality did not differ statistically between the LAAO and DOAC group, HR 0.75 (95% CI: 0.39-1.42). Results were consistent across sensitivity analyses., Conclusion: This study indicated significantly lower risk of the composite outcome of stroke, major bleeding and all-cause mortality with LAAO therapy compared to DOAC, in patients with AF and prior stroke. The stroke prevention effectiveness appeared similar, with a significantly lower risk of major bleeding events with LAAO. The suggested clinical benefit of LAAO over DOAC require confirmation in the ongoing randomized OCCLUSION-AF trial., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To describe the spectrum of Leber congenital amaurosis (LCA) and cone-rod dystrophy (CORD) associated with the GUCY2D gene and to identify potential end points and optimal patient selection for future therapeutic trials., Design: International, multicenter, retrospective cohort study., Subjects: Eighty-two patients with GUCY2D-associated LCA or CORD from 54 families., Methods: Medical records were reviewed for medical history, best-corrected visual acuity (BCVA), ophthalmoscopy, visual fields, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain OCT [SD-OCT], fundus autofluorescence)., Main Outcomes Measures: Age of onset, evolution of BCVA, genotype-phenotype correlations, anatomic characteristics on funduscopy, and multimodal imaging., Results: Fourteen patients with autosomal recessive LCA and 68 with autosomal dominant CORD were included. The median follow-up times were 5.2 years (interquartile range [IQR] 2.6-8.8 years) for LCA and 7.2 years (IQR 2.2-14.2 years) for CORD. Generally, LCA presented in the first year of life. The BCVA in patients with LCA ranged from no light perception to 1.00 logarithm of the minimum angle of resolution (logMAR) and remained relatively stable during follow-up. Imaging for LCA was limited but showed little to no structural degeneration. In patients with CORD, progressive vision loss started around the second decade of life. The BCVA declined annually by 0.022 logMAR (P < 0.001) with no difference between patients with the c.2513G>A and the c.2512C>T GUCY2D variants (P = 0.798). At the age of 40 years, the probability of being blind or severely visually impaired was 32%. The integrity of the ellipsoid zone (EZ) and that of the external limiting membrane (ELM) on SD-OCT correlated significantly with BCVA (Spearman ρ = 0.744, P = 0.001, and ρ = 0.712, P < 0.001, respectively) in those with CORD., Conclusions: Leber congenital amaurosis associated with GUCY2D caused severe congenital visual impairment with relatively intact macular anatomy on funduscopy and available imaging, suggesting long preservation of photoreceptors. Despite large variability, GUCY2D-associated CORD generally presented during adolescence, with a progressive loss of vision, and culminated in severe visual impairment during mid-to-late adulthood. The integrity of the ELM and EZ may be suitable structural end points for therapeutic studies of GUCY2D-associated CORD., (Copyright © 2022 American Academy of Ophthalmology. All rights reserved.)

Background: Endovascular therapy (EVT) is standard of care for stroke caused by large vessel occlusion. Whether EVT should be performed under general anesthesia (GA) or conscious sedation (CS) is controversial. While a meta-analysis of randomized trials showed better outcome for EVT under GA, observational studies suggested the opposite. A proposed advantage of GA is better reperfusion achieved via more successful handling of the immobile patient. The aim of this study was to investigate if the good outcome seen in patients treated under GA was mediated by better reperfusion., Methods: The meta-analysis included 368 individual patients from three randomized controlled trials, of whom 185 patients were randomized to CS. A mediator analysis was performed to examine if the better outcome in the GA arm was driven by higher reperfusion rate., Results: The total effect showed a risk difference (RD) of 0.15 (95% CI 0.04 to 0.25), associating GA with a beneficial outcome. The direct effect of GA constituted a large portion, with an RD of 0.12 (95% CI 0.01 to 0.22), while only a small portion was mediated through the degree of reperfusion, with an RD of 0.03 (95% CI 0.02 to 0.04)., Conclusion: The better outcome after EVT in the GA arm was mainly a direct effect-that is, an effect that was not explained by better reperfusion. We also found a better outcome in the GA arm when reperfusion was not achieved. Whether this is an effect of the stable condition and blood pressure under GA or a neuroprotective effect will need to be investigated in future research., Competing Interests: Competing interests: MR and CZS are supported by research grants from Health Research Foundation of Central Denmark Region. CZS is also supported by a research grant from the Novo Nordisk Foundation. JB reports speaker honoraria and travel support from Medtronic and Pfizer and participation in a PCORI award for the SETPOINT2 trial, all unrelated to the study., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The objective was to examine potential socioeconomic inequities in guideline recommended quality of care as well as several clinical outcomes among first-time inpatients with major depressive disorder (MDD) in a tax-financed universal health care system., Patients and Methods: A nationwide cohort study was performed based on individual-level record linkage of public registers in Denmark. The study included all adult incident inpatients with MDD at Danish psychiatric hospitals in the period 2011-2017 (n=10,949). Socioeconomic position was assessed according to the level of education and income. Outcomes included quality of depression care for inpatients as reflected by the fulfillment of guideline recommended quality of care measures as well as clinical outcomes in terms of all-cause mortality, suicidal behavior, readmission for depression and all-cause readmission., Results: Patients with low-level education or low-level income were statistically significantly less likely to receive high quality of in-hospital care, defined as fulfillment of at least 70% of relevant performance measures (adjusted relative risk (RR) 0.92 and 0.87, respectively). In addition, the same patients had a higher all-cause mortality (adjusted RR 1.22 and 1.41, respectively). Patients with low education or middle income were associated with a higher risk of suicidal behavior (adjusted RR 1.28 and 1.19, respectively). While no differences were found in the risk of all-cause readmission, low-level education and income was associated with a lower risk of readmission due to MDD (adjusted RR 0.91 and 0.87, respectively)., Conclusion: Inequities in quality of care and clinical outcomes were observed among MDD inpatients in a tax-financed universal health care system, indicating that lack of access to care and insurance is not the only explanation for inequity in health., Competing Interests: None of the authors have any conflicts of interest to disclose., (© 2022 Knudsen et al.)

Background: Quality indicators are used to quantify the quality of care. A large number of quality indicators makes assessment of overall quality difficult, time consuming and impractical. There is consequently an increasing interest for composite measures based on a combination of multiple indicators., Objective: To examine the use of different approaches to construct composite measures of quality of care and to assess the use of methodological considerations and justifications., Methods: We conducted a literature search on PubMed and EMBASE databases (latest update 1 December 2020). For each publication, we extracted information on the weighting and aggregation methodology that had been used to construct composite indicator(s)., Results: A total of 2711 publications were identified of which 145 were included after a screening process. Opportunity scoring with equal weights was the most used approach (86/145, 59%) followed by all-or-none scoring (48/145, 33%). Other approaches regarding aggregation or weighting of individual indicators were used in 32 publications (22%). The rationale for selecting a specific type of composite measure was reported in 36 publications (25%), whereas 22 papers (15%) addressed limitations regarding the composite measure., Conclusion: Opportunity scoring and all-or-none scoring are the most frequently used approaches when constructing composite measures of quality of care. The attention towards the rationale and limitations of the composite measures appears low., Discussion: Considering the widespread use and the potential implications for decision-making of composite measures, a high level of transparency regarding the construction process of the composite and the functionality of the measures is crucial., Competing Interests: The authors have declared that no competing interests exist.